Proefschrift steggerda by Nicole Nijhuis

Alcohol septal ablation for hypertrophic cardiomyopathy

Robbert Steggerda

Alcohol septal ablation for obstructive hypertrophic cardiomyopathy

Thesis

Robbert Steggerda

ISBN 978-94-6233-175-4 Cover: The illustration shows a bottle filled with limoncello produced by my father in law, Alberto Gracchi from Framura - Italy. The label on the bottle describes the original content of 95% alcohol used for the production of the limoncello. Printed by Gildeprint, Enschede – the Netherlands No Financial support for publication and printing of this thesis © 2015 R. C. Steggerda All rights are reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without the permission of the author.

Alcohol septal ablation for obstructive hypertrophic cardiomyopathy

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op maandag 1 februari 2015 om 16.15 uur door

Robbert Cees Steggerda geboren op 2 juni 1974 te Utrecht

Promotor Prof. dr. M.P. van den Berg Copromotores Dr. K. Damman Dr. J.M. ten Berg Beoordelingscommissie Prof. dr. T. Ebels Prof dr. M.J. de Boer Prof. dr. D.E. Atsma

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Contents Chapter 1 General introduction and objectives of the thesis.

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Chapter 2 Myocardial disease: The patient with hypertrophic cardiomyopathy. ten Berg J, Steggerda RC, Siebelink HM. Heart 2010;96:1764-1772.

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Chapter 3.1 p.45 Optimal gradient reduction after alcohol septal ablation: a case report with anatomical and practical determinants. Steggerda RC Balt JC, ten Berg JM Neth Heart J 2011;19;301-303. Chapter 3.2 p.53 Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Special interest for the septal coronary anatomy. Steggerda RC, Balt JC, Damman K, van den Berg MP, ten Berg JM Neth Heart J 2013;21:504-509. Chapter 4 p.71 Basal infarct location but not larger infarct size is associated with a successful outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. A Cardiovascular Magnetic Resonance imaging study. Steggerda RC, Geluk CA, Brouwer W, van Rossum AC, ten Berg JM, van den Berg MP. Int Journal of Cardiovasc Imaging 2015;31;831-839. Chapter 5 p.95 Effect of alcohol dosage on long-term outcomes after alcohol septal ablation in patients with hypertrophic cardiomyopathy Liebregts M, Vriesendorp PA, Steggerda RC, Schinkel AFL, Balt JC, ten Cate FJ, Michels M, ten Berg JM. Submitted Chapter 6.1 p.113 Outcome after alcohol septal ablation and surgical myectomy in hypertrophic obstructive cardiomyopathy. Special focus on periprocedural complications and long-term cardiovascular morbidity Steggerda RC, Damman K, Balt JC, Liebregts M, ten Berg JM, van den Berg MP. JACC Cardiovasc Interv 2014;7:1227-1234. Chapter 6.2 Myectomy versus alcohol septal ablation: experience remains key: editorial Geske JB, Gersh BJ JACC Cardiovasc Interv 2014;7:1235-1236.

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Chapter 7.1 p.139 Long-term effects of medical and invasive treatment on sudden cardiac death in obstructive hypertrophic cardiomyopathy. Vriesendorp PA, Liebregts M, Steggerda RC, Schinkel AFL, Willems R, ten Cate FJ, van Cleemput J, ten Berg JM, Michels M. JACC Heart Fail 2014;2:630-636. Chapter 7.2 p.159 Revisiting arrhythmia risk after alcohol septal ablation: is the pendulum swinging back?: editorial Maron BJ, Nishimura RA. JACC Heart Fail 2014;2:637-640 Chapter 8 p.169 Long-term outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy in the young and the elderly. Liebregts M, Steggerda RC, Vriesendorp PA, van Velzen H, Schinkel AFL, Willems R, van Cleemput J, van den Berg MP, Michels M, ten Berg JM. Submitted Chapter 9 p.187 Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: Results from the Euro-ASA registry Veselka J, Kvistholm Jensen M, Liebregts M, Januska J, Krejci J, Bartel T, Dabrowski M, Riis Hansen P, Almaas VM, Seggewiss H, Horstkotte D, Tomasov P, Adlova R, Bundgaard H, Steggerda RC, ten Berg J, Faber L. Submitted. Chapter 10 Discussion

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Chapter 11 Summary

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ABBREVIATIONS AMVL ASA CMR HCM ICD LAD LBBB LVOT MCE PM SAM SCD RBBB TEE VT

anterior mitral valve leaflet alcohol septal ablation cardiac magnetic resonance imaging hypertrophic cardiomyopathy internal cardioverter defibrillator left anterior descending artery left bundle branch block left ventricular outflow tract myocardial contrast echocardiography pacemaker systolic anterior motion sudden cardiac death right bundle branch block transesophageal echocardiography ventricular tachycardia

Chapter 1

General introduction

Objectives of the thesis

Chapter 1

Obstructive hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is characterised by hypertrophy of the left ventricle (LV) in the absence of abnormal loading conditions (pressure overload). It is a genetic disease caused by mutations in genes encoding components of the sarcomere. It is the most common form of cardiomyopathy with a prevalence of 1:500 in the European population (1,2), a figure that is fairly constant worldwide. On the one hand, it is generally a relatively benign disease associated with a good life expectancy, with an overall mortality rate averaging 1%/year (35). On the other hand, HCM can be associated with symptoms of heart failure and atrial fibrillation, and selected patient groups have a higher mortality rate averaging 5%/year (3,6). Around a third of all patients with HCM do not have obstruction of the left ventricular outflow tract (LVOT). However, these patients may have symptoms of heart failure due to diastolic dysfunction (seen in 10-20% of this group) or, less commonly, due to end-stage heart failure with systolic dysfunction (3%) (4-8). Around two thirds of patients with HCM do have obstruction of flow in the LVOT, which can also cause symptoms of heart failure and is a predictor of cardiovascular death (9). The obstruction of flow is due to a thickened septum and to systolic anterior motion (SAM) of the mitral valve leaflet. This causes obstruction and a dynamic gradient over the LVOT with a characteristic dagger-shaped Doppler flow pattern (10). Invasive treatment of this particular group of HCM patients with LVOT obstruction was investigated in the present thesis. Obstruction of flow in patients with hypertrophic cardiomyopathy A pressure gradient measured in the LVOT in the absence of a clear anatomic site of obstruction was first recognised in the late 1950s and was attributed to massive left ventricular hypertrophy (11-13). A long debate followed on whether these gradients were actually caused by obstruction or not. The hypothesis put forward by Criley, the main opponent in this debate, was that rapid ejection itself causes the pressure gradients and subsequent SAM of the anterior mitral valve leaflet. The increased ejection fraction and ventricular emptying that is seen in patients with a dynamic gradient was – according to Criley – very different to that seen in aortic stenosis, where ventricular emptying is hindered and reduced. This increased ejection fraction, rapid ejection and consequent gradient should therefore not be seen as a cause of symptoms of heart failure but as a mere consequence of the diseased hypertrophic myocardium itself. Thus, according to Criley’s hypothesis, reducing the gradient using myectomy is not a correct form of treatment, and research should instead focus on the investigation and treatment of the underlying causes of the diseased hypertrophic 10

General Introduction

myocardium. According to Criley’s hypothesis, symptoms of heart failure were merely due to diastolic dysfunction, and the positive effect of beta blockers on symptom improvement were due to improved relaxation and diastolic filling of the left ventricle and not to gradient reduction (14-15). This discussion continued until the mid-1980s (16-17). However, the positive outcomes of surgical myectomy – which alleviated symptoms and abolished the gradient – together with data from results of echocardiography studies led to the belief that obstruction of flow in hypertrophic cardiomyopathy does by itself lead to symptoms of heart failure. According to current guidelines, the first line of treatment for patients with a symptomatic obstructive hypertrophic cardiomyopathy is medical treatment (18). Indeed, the negative chronotropic and inotropic effects of beta blockers, disopyramide or calcium antagonists have the potential to improve symptoms and reduce outflow tract obstruction. When medical treatment fails to reduce symptoms and outflow tract obstruction, invasive septum reduction therapy is indicated (18). Development of and improvements to surgical myectomy The first surgical myectomy procedures were performed in the 1960s and published by Morrow et al (19). Subsequent results that were presented in the 1980s showed improvement of symptoms in 70% and abolition of the gradient in 98% of the patients, though with a periprocedural mortality rate of 6.6-8.0% (20,21). Patients undergoing surgical myectomy were operated on during cardiopulmonary bypass under mild hypothermia (30°C). A vertical incision in the aorta was made towards the noncoronary sinus. The left coronary artery was continuously perfused through a cannula supplying oxygenated blood from the arterial return line of the heart-lung machine. The surgeon was thus able to palpate the protruding ventricular mass obstructing the outflow tract via the aortic valve. This palpable mass was then resected using two parallel incisions and a part of the muscle between these lines was then removed. Afterwards, the channel thus obtained was palpated by the surgeon for evaluation of the procedure and for removal of any particulate matter. The aortotomy was closed while the patient’s temperature was restored to normal (19,22). Many changes to this procedure have since been introduced, such as improvement of cardiopulmonary bypass, cardioplegia, a more extended resection of the protruding ventricular mass, and the use of periprocedural transesophegal echocardiography (TEE) for the evaluation of the procedure (23). Other improvements are the extended myectomy and the combination with mitral valvular plasty when necessary (24).

Chapter 1

Development of and improvements to the alcohol septal ablation procedure The concept and development of the alcohol septal ablation procedure was based firstly on the finding of a gradient reduction during temporary balloon occlusion of the first septal branch, and secondly on the idea that injection of alcohol in the first septal branch could cause a scar in the basal septum with a permanent reduction of the gradient. The basal part of the septum would become thinner due to the scar and thus the outflow tract would widen, thereby abolishing both SAM and the obstructive gradient. The extensive experience that had been gained with transcoronary injection of ethanol for treatment of cardiac arrhythmia made the practical development of ASA possible. The first descriptions of ASA were published by Gietzen et al in 1994 (25-27). The procedure was initially performed by cannulating the first septal branch with a guidewire. A balloon was placed in the first septal branch and then inflated in order to induce temporary ischaemia (Figures 1A and 1B).

General Introduction

Figure 1. Coronary angiograns and pressure recordings obtained during alcohol septal ablation. A: Coronary angiogram of the left coronary artery, with the white arrow indicating the first septal branch. B: The same view of the left coronary artery after cannulation and inflation of an over-the-wire balloon in the first septal branch (indicated by the white arrow). Contrast is injected to evaluate complete closure of the septal branch by the balloon. C: Pressure recordings in the left ventricle and aorta before balloon occlusion, showing a gradient of 65 mmHg. D: After balloon occlusion the pressure drops and the gradient disappears.

Chapter 1

Simultaneous pressure recording using a catheter in the left ventricle and the aorta was used to observe a reduction of at least 30% of the gradient (Figure 1C and D). In cases where the gradient did not drop, the next septal branch would be cannulated and pressure recordings repeated. When a pressure drop was found, the balloon was left inflated and 96% ethanol (average volume 4-6 ml) would be injected in order to induce a sustained reduction of the gradient. The potential risk of ventricular rhythm disturbances was recognised from the inception of the ASA procedure. An extensive study was published in 1999 by Gietzen et al. that included electrophysiological testing and a pathoanatomical study (28). Early reports of periprocedural mortality after ASA that came from this study were 4% in 62 patients, and permanent pacemaker implantation was necessary in 38% of all patients. However, electrophysiological induction of sustained ventricular tachycardia (VT) occurred only in 2.6% of patients after the ASA procedure. This was much lower than the 20-34% of patients reported to have inducible sustained VT seen after myocardial infarction (29). This gave good hope that the incidence of VT after ASA would be much lower than the incidence of VT seen after myocardial infarction. The pathology results of the deceased patients also showed that the histological pattern of the alcohol-induced scar was different to the histopathology of scarred tissue after myocardial infarction. “A well-defined area of circular necrosis around the occluded septal branch with small protrusions, characterised by a homogeneous necrosis with contracted fibres encircled by a sharply demarcated scar” was thus seen in deceased ASA patients (29). This was thought to be the reason why patients who have undergone ASA are much less susceptible to the induction of VT. The ASA procedure was improved after the introduction of myocardial contrast echocardiography (MCE) for determining the correct site of myocardial infarction, leading to a reduction in complications and an increase in success rate (30). Other improvements to the technique were the use of decreasing amounts of alcohol over time and slower injection of alcohol instead of a bolus (31,32). Since then, many studies have been published that have shown improved results both in the short and long term.

General Introduction

Objectives of the current thesis Since the introduction of ASA as an alternative to surgical myectomy, the question has arisen regarding which treatment option is the preferred treatment. Does ASA yield the same results as myectomy in terms of gradient reduction, symptomatic improvement, risk of complications and long-term results? In the current thesis, ASA was therefore investigated in depth and compared with myectomy. Chapter 2 describes the aetiology, pathophysiology, genetics, and clinical course and management of hypertrophic cardiomyopathy. Chapter 3.1 describes how septal coronary anatomy can limit the interventional cardiologist to perform a successful procedure. In Chapter 3.2 the characteristics of septal coronary anatomy and its relation to residual gradients after the infarction is investigated. In Chapter 4, the relationship between the size and location of the septal infarction after ASA is investigated using cardiac magnetic resonance imaging (CMR). In Chapter 5, the effect of a larger-sized infarction and larger amounts of alcohol on outcome and increased risk of ventricular arrhythmia after ASA are investigated. The ASA procedure is considered by some as being less safe than surgical myectomy. Chapter 6 therefore focuses on periprocedural complications and long-term outcome in a single-centre study. Survival, cardiac death, symptomatic improvement and gradients are also investigated in Chapter 7, which describes a multi-centre study that compared myectomy and ASA. American guidelines state that ASA is mainly an option for the elderly. This notion is addressed in Chapter 8, which compares periprocedural complications and long-term outcome between younger and older age groups. Using data from the European database for ASA – which contains data from ten European centres – Chapter 9 further investigates complications and survival, including the effect of residual obstruction on survival. Finally, the data are discussed (Chapter 10) and summarised (Chapter 11). In particular, the practical implications in terms of the technical aspects of the procedure and the potential impact on the current guidelines are discussed.

Chapter 1

Reference list: 1. Richard P, Charron P, Carrier L et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003; 107: 2227-32 2.Elliott PM, Gimeno B jr, Mahon NG et al. Relation between severity of left ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. 3.Maron BJ, Maron MS. Hypertrophic cardiomyoptahy. Lancet 2013; 381: 242-255. 4.Maron BJ, Casey SA, Hauser RG, Aeppli DM. Clinical course of hypertrophic cardiomyopathy with survival to advanced age. J Am Coll Cardiol 2003; 42:882-88. 5.Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy: clinical spectrum and treatment. Circulation 1995; 92:1680-92. 6.Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol 2000; 36:2212-18. 6. Olivotto I1, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, Udelson JE, Cecchi F, Maron BJ. Gender realted differences in the clinical presentation and outcome of hypertrophic cardiomyoapthy. J Am Coll Cardiol 2005; 46:480-87. 7.Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic of hypertrophic cardiomyopathy. N Engl J Med 1997;336:775-85. 8.Harris KM, Spirito P, Maron MS et al. Prevalence , clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006; 114:216-225. 9. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003 Jan 23;348(4):295-303. 10. ten Berg J, Robbert C Steggerda RC, Siebelink HMJ. Myocardial disease: the patient with hypertrophic cardiomyopathy. Heart 2010; 96: 1764-1772. 11.Brock RC. Functional obstruction of the left ventricle (aquired aortic subvalvular stenosis). Guys Hosp Rep 1957; 106: 221. 12.Teare D. Asymmetrical hypertrophy of the heart in young adults. R Heart J 1958; 20: 1-8. 13.Morrow AG, Braunwald E. Functional aortic stenosis. A malformation characterized by resistance to left ventricular outflow tract obstruction. Circulation 1959; 20: 181-9. 14.Criley JM, Kenneth BL, White RI, Ross RS. Pressure gradient without stenosis. a new concept of “ Hypertrophic subaortic stenosis”. Circulation 1965; 32: 881-887. 16

General Introduction

15.Criley JM, Siegel RJ. Has ‘obstruction’ hindered our understanding of hypertrophic cardiomyopathy? 1985; 72(6): 1148-1154. 16.Murgo JP, Alter BR, Dorethy JF, Altobelli SA, McGranahan GM Jr. Dynamics of left ventricular ejection in obstructive and non-obstructive hypertrophic cardiomyopathy. J Clin Invest 1980; 66: 1369-1382. 17.Jenni R, Ruffmann K, Vieli A, Anliker M, Krayenbuchl HP. Dynamics of aortic flow in hypertrophic cardiomyopathy. Eur Heart J 1985; 6: 391-398. 18.Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. European Heart J 2014; 35: 2733-2779. 19.Morrow AG, Lambrew CT, Braunwald E. Idiopathic hypertrophic subaortic stenosis II. Operative treatment and the results of pre- and postoperative hemodynamic evaluations. Circulation 1964; 29:supl4:120. 20.Maron BJ, Epstein SE, Morrow AG. Symptomatic status and prognosis of patients after operation for hypertrophic obstructive cardiomyopathy: efficacy of ventricular septal myotomy and myectomy. European Heart J 1983; supplF: 175-180. 21.Bircks W, Schulte HD. Surgical treatment of hypertrophic obstructive cardiomyopathy with special reference to complications and to atypical hypertrophic obstructive cardiomyopathy. Eur Heart J 1983; supplF: 187-190. 22.Morrow AG, Fogarty TJ, Hannah III H, Braunwald E. Operative treatment in idiopathic hypertrophic subaortic stenosis. Circulation 1968; 38:589-596. 23.Schoendube FA, Klues HG, Reith S, Flachskampf FA, Hanrath P, Messmer BJ. Long-term Clinical and echocardiographic follow-up after surgical correction of hypertrophic obstructive cardiomyopathy with extended myectomy and reconstruction of the subvalvular mitral apparatus. Circulation 1995; 95: 122-127. 24.Swistel DG, Balaram SK. Surgical myectomy for hypertrophic cardiomyopathy in the 21st century, the evloution of the “RPR” repair: resection, plication and release. Progress in cardiovascular disease 2012; 54: 498-502. 25.Gietzen F, Leuner Ch, Gerenkamp T, Kuhn H. Relief of obstruction in hypertrophic cardiomyopathy by transient occlusion of the first septal branch of the left coronary artery. Eur Heart J 1994; 15:125 26. Kuhn H, Gietzen F, Leuner Ch, Gerenkamp T. Induction of subaortic septal ischemia to reduce obstruction in hypertrophic obstructive cardiomyopathy. Studies to develop a new cathter-based concept of tretmant. Eur Heart J 1997; 18: 846-851.

Chapter 1

27.Kay GN, Epstein AE, Bubien RS et al. Intracoronary ethanol ablation for the treatment of recurrent sustained ventricular tachycardia. J Am Coll Cardiol 1992; 19: 159-168. 28.Gietzen FH, Leuner CJ, Raute-Kreinsen U, Dellman A, Hegselmann J, Strunk-Mueller C, Kuhn HJ. Acute and long-term results after transcoronary ablation of septal hypertrophy (TASH). catheter interventional treatment for hypertrophic obstructive cardiomyopathy. Eur. Heart J 1999; 20: 1342-1354. 29.Denniss AR, Richard DA, Cody DV et al. Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction. Circulation 1986; 74:731-745. 30.Faber L, Seggewiss H, Welge D, Fassbender D, Schmidt HK, Gleichmann U, Horstkotte D. Echo-guided percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: 7 years of experience. Eur J Echocardiography 2004; 5: 347-355. 31. Veselka J, Tomašov P, Zemánek D. Long-term effects of varying alcohol dosing in percutaneous septal ablation for obstructive hypertrophic cardiomyopathy: A randomised study with a follow-up up to 11 years. Can J Cardiology 2011; 27: 763-767. 32. Su Min Chang, MD, Sherif F. Nagueh, MD, William H. Spencer, III, MD, Nasser M. Lakkis, MD. Complete Heart Block: Determinants and Clinical Impact in Patients With Hypertrophic Obstructive Cardiomyopathy Undergoing Nonsurgical Septal Reduction Therapy J Am Coll Cardiol 2003;42: 296–300.

Chapter 2

Myocardial disease: The patient with hypertrophic cardiomyopathy.

Jurriën ten Berg, Robbert C Steggerda, Hans-Marc J Siebelink

Heart 2010; 96: 1764-1772

Chapter 2

Hypertrophic cardiomyopathy (HCM) is characterised by idiopathic hypertrophy of the left ventricle (LV), sometimes accompanied by hypertrophy of the right ventricle. HCM is estimated to occur in 1:500 subjects in the general population (1). The disease is inherited as an autosomal dominant trait, but about 50% of the patients do not have relatives with HCM, suggesting sporadic mutations, unidentified genes or more complex patterns of heredity. The presentation of the disease is diverse with on the one hand asymptomatic subjects diagnosed through family screening or routine clinical examination, and on the other hand severely symptomatic subjects with impaired LV systolic function. Patients may also present with sudden cardiac death (SCD). The distribution of hypertrophy is also variable; the most common pattern is asymmetrical septal hypertrophy, but other LV morphologies are seen including concentric hypertrophy, apical hypertrophy, and hypertrophy of the LV free wall. About one quarter of patients have obstruction of the left ventricular outflow tract (LVOT); less commonly, dynamic obstruction may occur in the mid LV cavity or at the right ventricular (RV) outflow tract (2,3).

Microscopy, macroscopy, and pathophysiology Microscopy demonstrates a variety of abnormalities, including myocyte hypertrophy, myocardial fibre disarray (myocytes are not in parallel but lay chaotically intersected), interstitial and perivascular fibrosis, and intimal and medial hypertrophy in intramural arteries leading to narrowing of the microcirculation. These abnormalities are thought to contribute to LV diastolic dysfunction by impairing relaxation and reducing compliance as well as to scarring of the myocardium. Fibrosis and scarring may predispose to ventricular and atrial arrhythmias. Elevated left atrial and LV end diastolic pressures lead to reduced stroke volume, reduced cardiac output, and pulmonary congestion. The cardiomyopathic abnormalities are not confined to the (mostly septal) hypertrophic ventricular segments, and can be demonstrated in non-hypertrophied myocardium. Many patients show diffuse hypertrophy of the LV; in about one third the hypertrophy is localised to one part (septal (figure 1), lateral or apical (figure 2)) of the LV wall. In addition to hypertrophy, patients with HCM can have anteroapical displacement of (bifid) anterolateral papillary muscles, larger mitral leaflets and slack chordae that, when combined with septal hypertrophy, can lead to systolic anterior movement (SAM) (figure 3) and thus LVOT obstruction and often mitral insufficiency. SAM is caused by an intriguing phenomenon in which the septal hypertrophy 20

Myocardial disease: The patient with hypertrophic cardiomyopathy

redirects the blood flow more laterally and posteriorly which drags the larger and more anterior positioned mitral valve into the LVOT (figure 4) (4). In hypertrophic obstructive cardiomyopathy (HOCM), during systole the orifice narrows while the flow accelerates. This leads to a characteristic continuous wave Doppler tracing (figure 5) which can be discriminated from the tracing of an stenotic aortic valve where the orifice is relatively fixed (figure 6). If the posterior leaflet of the mitral valve is too short or restricted to provide sufficient coaptation to the anterior mitral leaflet during SAM (figure 7), an eccentric posteriorly directed mitral regurgitation develops (figure 8). LVOT obstruction causes further reduction of stroke volumes. Mitral regurgitation directed centrally or anteriorly should raise the suspicion of an intrinsic mitral valve abnormality. Mitral regurgitation may lead to high pulmonary venous pressures. It is important to note that the gradient in the LVOT is highly variable depending on volume load (increased gradient with volume depletion due to diuretics), afterload (increased gradient with afterload reduction due to, for example, angiotensin converting enzyme (ACE) inhibitors) and LV contractility (increased gradient due to exercise or positive inotropic drugs, eg, β-agonists). The gradient may change after food or alcohol intake or even spontaneously. Less frequently mid ventricular hypertrophy occurs leading to mid ventricular obstruction and apical akinesia. In some elderly patients the anterior displacement of the mitral valve leading to SAM is caused by a calcified thickened mitral valve annulus (5). A very rare variant is a papillary muscle inserting directly into the anterior mitral leaflet and obstructing the LVOT during systole (6).

Figure 1 Septal hypertrophy (arrow) demonstrated on four chamber MRI (A) and on four chamber two dimensional (2D) echocardiography (B).

Chapter 2

Figure 2 Apical hypertrophy (arrow) demonstrated with four chamber MRI (A) and with four chamber 2D echocardiography (B and C). Note that on standard echocardiography (B) apical hypertrophy was not detected, but with contrast echocardiography (C) the apical hypertrophy was clearly diagnosed.

Figure 3 Systolic anterior movement (SAM; arrow) of the anterior mitral valve leaflet in a patient with hypertrophic obstructive cardiomyopathy demonstrated with 2D echocardiography in parasternal long axis view.

Myocardial disease: The patient with hypertrophic cardiomyopathy

Figure 4 In hypertrophic obstructive cardiomyopathy (HOCM) the papillary muscle is often situated more anteriorly, the chordae are slack, and the anterior leaflet is enlarged with redundant tissue at the coaptation point. The flow is directed posterolaterally due to the septal hypertrophy and drags the enlarged mitral valve into the outflow tract. If the posterior leaflet of the mitral valve is restricted a posteriorly directed mitral regurgitation develops. (A) Normal; (B) HOCM: 1, normal flow direction; 2, septal hypertrophy; 3, posterolaterally directed flow; 4, anteriorly displaced papillary muscle; 5, slack chordae; 6, larger anterior mitral leaflet; 7, restricted posterior mitral leaflet.

Chapter 2

Figure 5 CW Doppler tracing of outflow obstruction in hypertrophic obstructive cardiomyopathy.

Myocardial disease: The patient with hypertrophic cardiomyopathy

Figure 6 CW Doppler tracing of aortic stenosis.

Figure 7 Short posterior mitral valve leaflet (arrow) and systolic anterior movement (SAM) (arrowhead) on 2D transoesophageal echocardiography (A). The combination of short posterior mitral valve leaflet and SAM leads to eccentric mitral valve regurgitation (arrow) and to dynamic left ventricular outflow tract obstruction indicated by flow turbulence (arrowhead) (B).

Chapter 2

Figure 8 Eccentric posteriorly directed mitral insufficiency demonstrated on parasternal long axis 2D echo image.

Genetics H(O)CM is inherited as an autosomal dominant trait caused by a mutation in genes which encode mostly for the sarcomere. The majority of mutations occur in the genes β-myosin heavy chain, myosin binding protein C, and cardiac troponin T, while a small minority occurs in at least seven other genes. At least 150 different mutations have thus far been identified, reflecting the genetic heterogeneity of this disease. Genotyping is the ultimate method to establish the diagnosis in H(O)CM and can be useful in excluding risk of disease development in relatives who do not currently have LV hypertrophy. Genotyping is, to date, not able to predict sudden cardiac death (‘malignant genes’). Nevertheless, recent data suggest that patients with a positive H(O)CM genetic test have a greater chance of disease progression and chance to develop symptoms than those H(O)CM patients with a negative genetic test (7). Genotyping is, however, time consuming and expensive and is currently mainly used for selected patients and for conducting research (8). 26

Myocardial disease: The patient with hypertrophic cardiomyopathy

Symptoms and diagnosis Many patients with H(O)CM are asymptomatic and are referred because of a positive family history or an abnormal ECG. In some patients a murmur is heard—for example, during sports examination. Symptomatic patients present with dyspnoea, angina, dizziness or syncope. Dyspnoea is caused by high pulmonary venous pressure due to diastolic dysfunction, ischaemia and/or mitral regurgitation. Angina usually occurs during exercise and is due to a mismatch between reduced oxygen supply through narrowed intramural arteries and a high oxygen demand associated with the hypertrophied (and often obstructed) LV myocardium. Dizziness and syncope can be due to arrhythmias or low cardiac output due to diastolic dysfunction, LVOT obstruction or inappropriate peripheral vasodilation. In many patients the physical examination is normal. In the minority of patients a murmur can be heard at the left lower sternum border that does not radiate to the carotids. As the gradient can be absent during rest, provocable manoeuvres (the Valsalva manoeuvre, post-extrasystolic potentiation, exercise) have to be performed during the examination which at the same time can also unmask mitral regurgitation. An ECG is helpful to establish the diagnosis, but it is abnormal only in about 80% of the patients. Diagnosis is usually made by two dimensional echocardiography demonstrating hypertrophy (wall thickness ≥13 mm in the anterior septum or ≥15 mm in the posterior septum of free wall) and normal LV dimensions. Cardiac magnetic resonance (CMR) imaging may be indicated where echocardiographic views are limited, when there is an unusual distribution of hypertrophy, or to detect milder magnitudes of hypertrophy (9). In addition CMR with delayed gadolinium enhancement imaging will detect myocardial scarring in about two thirds of HCM patients, a finding considered helpful in differentiating HCM from other causes of left ventricular hypertrophy (LVH) (figure 9). The presence of myocardial scarring may prove prognostically important.

Chapter 2

Figure 9 Using gadolinium delayed enhanced MRI, myocardial fibrosis (arrow) is shown as a white area localised in the severe hypertrophic septum (31 mm) in the short axis view. Angiography in patients with HOCM can demonstrate the profile of the septal bulge on the LV cavity in right oblique angulation (figure 10), septal bridging (figure 11) and the SAM in the LVOT in left superior oblique angulation (figure 12). Invasive assessment of the gradient can best be done with a simultaneous measurement of the pressure in the LV cavity and the aorta. When there is no gradient at rest, provocable manoeuvres (the Valsalva manoeuvre (figure 13) or post-extrasystolic potentiation (figure 14)) can be performed.

Myocardial disease: The patient with hypertrophic cardiomyopathy

Figure 10 Angiogram of the left ventricle in the right oblique view. 1, small end-systolic left ventricular cavity; 2, septal bulge impinging on left ventricular cavity; 3, severe eccentric mitral regurgitation.

Chapter 2

Figure 11 Bridging of septal branch. Angiographic image.

Myocardial disease: The patient with hypertrophic cardiomyopathy

Figure 12 Angiogram of the left ventricle in the left oblique view. 1, eccentric mitral regurgitation; 2, silhouette of anterior mitral leaflet during systolic anterior movement in the outflow tract of the left ventricle.

Chapter 2

Figure 13 Pressure tracing simultaneously in the left ventricular cavity and the aorta. The gradient increases during the Valsalva manoeuvre.

Myocardial disease: The patient with hypertrophic cardiomyopathy

Figure 14 Pressure tracing simultaneously in the left ventricular cavity and the aorta. The gradient increases post ventricular extrasystole.

Clinical course In the majority of patients, mostly asymptomatic or mildly symptomatic, H(O)CM has a favourable course with an annual mortality of about 1%. Many H(O)CM patients are diagnosed at older age, consistent with the view that the disease is benign in many individuals. As LVOT obstruction is prevalent in these elderly patients it shows that even

Chapter 2

gradients are well tolerated for many years. In adolescence it is advised to repeat ECG and echocardiography every year as H(O)CM frequently develops during puberty. Hypertrophy developing after the end of adolescence is rare, but a normal ECG and echocardiogram do not exclude H(O)CM. In adults, repeated evaluation every 5 years is therefore recommended. Preadolescent children should be evaluated if they are symptomatic, participate in competitive sports or if SCD occurs in the family (3). Most of the symptomatic patients present with exertional dyspnoea, frequently accompanied by fatigue, angina, and dizziness. Characteristic in these symptomatic patients is that deterioration is slow; severity of symptoms can differ by day, and very often are interrupted by periods of fewer symptoms. A minority of patients presents with severe symptoms (New York Heart Association (NYHA) functional class III and IV) and signs of heart failure such as oedema. The prognosis of these symptomatic patients is worse with an annual mortality of over 5% (1-3).

Atrial fibrillation Atrial fibrillation occurs in about a quarter of patients with H(O)CM. It is related to LV dysfunction and the associated enlargement of the left atrium. Although atrial fibrillation does not lead to symptoms in a minority of H(O)CM patients, in others it results in severe symptoms as the loss of the atrial kick is essential in patients with a non-compliant LV. At the onset, atrial fibrillation can even lead to acute haemodynamic deterioration, especially in those patients with obstruction in the LV outflow tract (10). The most effective antiarrhythmic drugs seem to be amiodarone and disopyramide and all patients should receive warfarin unless contraindicated. Recently, catheter or surgically based electrical isolation of the pulmonary veins has become an option. Sudden cardiac death Many deaths, in symptomatic but also in asymptomatic H(O)CM patients, are sudden and in all patients a careful risk assessment for SCD has to be made. Although the annual mortality in H(O)CM is quite low with an estimated incidence of 1% per year, selected patients treated with an implantable cardioverter defibrillator (ICD) receive appropriate shocks in up to 10% per year, demonstrating the appropriateness of ICD implantation in these high risk patients (11). Risk factors for SCD are estimated to occur in about 15% of patients with H(O)CM and 34

Myocardial disease: The patient with hypertrophic cardiomyopathy

the risk of SCD varies between individual patients and within patients as they age. SCD occurs more often in younger patients, but does take place in the elderly. A higher risk for SCD is present in those patients with one or more of the following: prior cardiac arrest, first degree family member with H(O)CM related SCD, multiple syncopes especially when occurring during or immediately after exercise, non-sustained ventricular tachycardia especially when occurring under age 30, inadequate rise (<20 mm Hg) in blood pressure during exercise especially in patients aged 20–50 years, resting LVOT obstruction >30 mm Hg, and LVH with a maximal wall thickness ≥30 mm (2, 3, 12, 13). The treatment of choice for patients at higher risk for SCD is the ICD. The implantation is essential in those patients who have suffered a cardiac arrest and in those who have more than one risk factor for SCD. In selected patients, only one risk factor (family history of SCD) may warrant implantation of an ICD. About half of the SCD cases occur during strenuous exercise and competitive sports should therefore be avoided. There is no evidence that medical treatment (β-blockers, amiodarone) reduces the risk of SCD and prevention should therefore not rely on medical treatment alone (3). Predictors for sudden cardiac death • Prior cardiac arrest • Sustained ventricular tachycardia • First degree family member with H(O)CM related SCD • Multiple syncopes, especially when occurring during or immediately after exercise • Non-sustained ventricular tachycardia, especially when occurring under the age of 30 years • Inadequate rise (<20 mmHg) in blood pressure during exercise, especially in patients aged 20–50 years • Resting left ventricular outflow tract obstruction >30 mmHg

Drug treatment In symptomatic patients with non-obstructive HCM, symptoms are due to diastolic dysfunction and ischaemia. None of the currently used drugs (β-blockers, verapamil) has been shown to improve compliance of the LV. Verapamil may even worsen the diastolic function

Chapter 2

of the LV. In addition, both drugs can cause chronotropic incompetence, which may hinder an increase in cardiac output during exercise; in patients with diastolic dysfunction and a fixed stroke volume, cardiac output relies on increasing the heart rate more than in normal hearts. These drugs can therefore lead to reduced exercise capacity. The principal positive effect of these drugs is in reducing ischaemia. Thus in non-obstructive HCM, negative inotropic drugs should be administered with great care and these patients should be followed regularly to evaluate symptoms. Measurements of exercise capacity before and after administering drugs can be useful. In patients with HOCM, β-blockers and verapamil effectively reduce symptoms and exercise induced LVOT gradients. There is, however, not much effect on LVOT gradients at rest. β-blockers are most often used, but when a patient does not respond favourably, verapamil can be efficacious. On the other hand, verapamil can be deleterious in patients with high LVOT gradients and should therefore be used with care in these patients (14). Disopyramide is an alternative in patients with LVOT gradients, (usually combined with βblockers to counteract its anticholinergic effects on atrioventricular conduction). Due to its negative inotropic effect and possibly an increase in systemic vascular resistance, it lowers the LVOT gradient and reduces symptoms. Because of its antiarrhythmic properties it seems to be the treatment of choice in HOCM patients with atrial fibrillation. Although symptomatic improvement and increased exercise capacity are crucial in the evaluation of drug treatment, LV pulsed echo Doppler tracings before and after treatment can be used to corroborate its effect (14).

Invasive treatment in HOCM Patients who remain symptomatic despite optimal medical treatment, and in whom a gradient ≥50 mmHg is present at rest or with physiologic (exercise) provocation, are candidates for two treatment options. First, septal myectomy according to the technique developed by Morrow in which, after aortic cross-clamping and aortotomy, a small bar of myocardium is excised from the proximal septum and sometimes combined with a mid septal excision and/or mobilisation of papillary muscles. In the 1980s, high operative mortality rates of >5% were reported. However, over the last 10–15 years myectomy has been performed with low mortality rates of 1–2%, and reports from the major centres performing septal myectomy show virtually no operative deaths in the most recent consecutive series (eg, involving up to >250 cases per institution). Complications such as total atrioventricular block needing 36

Myocardial disease: The patient with hypertrophic cardiomyopathy

permanent pacing (in approximately 3% of the patients) and ventricular septal defect needing direct closure (in <1% of the patients) rarely occur. In non-randomised studies, myectomy is very effective in alleviating symptoms in a large majority (>90%) of patients, concurrent with diminishing or abolishing LVOT gradients (residual gradient usually <20 mmHg) and mitral regurgitation (15). Long term follow-up shows sustained reduction in symptoms, LVOT gradients as well as hypertrophy of the free wall of the LV. Survival after myectomy is suggested to be better than in medically treated patients with HOCM. In some patients an extended myectomy down towards the apex (4–5cm) to avoid persistent SAM due to unaltered posterolateral flow around the remaining mid septal hypertrophy is needed (16). In addition, large (bifid) anteriorly displaced papillary muscles can be dissected from the anterior wall to free the LVOT from papillary muscle, chordae, and the mitral leaflet (16). Because some HOCM patients may not be ideal surgical candidates, either because of concomitant medical disorders, advanced age, prior cardiac surgery or patient choice, an alternative treatment, alcohol septal ablation (ASA), was introduced by Sigwart that might replace surgical myectomy in these patients. In ASA, after placement of a temporary pacemaker lead in the right ventricle, ethanol (1–3ml) is injected through an inflated over-thewire angioplasty balloon directly into a septal perforator branch of the left anterior descending coronary artery (figures 15 and 16). The correct septal branch, usually the first septal branch showing systolic compression or ‘milking’, is selected with the use of contrast echocardiography, which can demonstrate the targeted septal segment that makes contact with the anterior mitral leaflet of the mitral valve during SAM. This causes a controlled myocardial infarction, leading to necrosis followed by shrinkage, which results in an enlargement of the narrowed LVOT. Several studies have shown that ASA can substantially reduce the basal outflow gradient and decreases symptoms (17). In non-randomised studies, operative mortality is similar to that achieved with myectomy, while myectomy has been shown to be slightly more effective in alleviating the LVOT gradient. Symptomatic improvement (>80% of the patients) over time seems to be comparable with myectomy, but more patients need a second intervention after ASA. However, one has to keep in mind that the patients treated with ASA are more often older and have more comorbidities than those undergoing myectomy. Also after ASA, reduction of hypertrophy of the free wall of the LV has been demonstrated. Complications occur more frequently with ASA than with myectomy.17 Atrioventricular block occurs in about 5–10% of the patients while its incidence has decreased with the use of contrast echocardiography, enabling more localised and smaller septal infarctions. Incidentally, coronary dissection, leakage of alcohol causing remote

Chapter 2

myocardial infarction, and perforation of the right ventricle by the temporary pacemaker can occur. Also sustained ventricular tachycardia occurring during or shortly after ASA has been reported.

Figure 15 Angiogram of left coronary artery before alcohol septal ablation. 1, first septal branch.

Myocardial disease: The patient with hypertrophic cardiomyopathy

Figure 16 Angiogram of left coronary artery after alcohol septal ablation. 1, occluded septal branch. In younger patients myectomy is preferred for several reasons. First, ASA might induce an electrical substrate which may lead to lethal ventricular tachyarrhythmias over time, although recent data suggest a low incidence (18). Second, myectomy has proven to convey sustained symptomatic improvement as well as an excellent long term prognosis over a considerable time frame, while ASA has a relative short follow-up. Myectomy is also the treatment of choice in patients with extensive septal hypertrophy, intrinsic mitral valve abnormalities (prolapse in about 3% of the patients), aortic stenosis or multivessel obstructive coronary disease. Dual chamber pacing has been advocated in the past but is presently not a treatment option. Table 1 lists the pros and cons of alcohol septal ablation versus septal myectomy.

Chapter 2

Table 1: Alcohol septal ablation versus Morrow septal myectomy: the pros and cons Alcohol septal ablation

Morrow septal myectomy

Operative mortality

<1%

Need for permanent pacemaker

5–10%

<5%

Procedural complications

Coronary dissection, alcohol leakage to left anterior descending coronary artery, perforation of the right ventricle with temporary pacemaker

Long term followup

Available ±10 years

Tamponade, ventricular septal defect Available >40 years

Recovery

Days

Weeks–months

Skills needed

Easy to perform

Expert surgeon needed

Present

Absent

20–30 mmHg

<20 mmHg

Intramyocardial scar Gradient after intervention

Management of H(O)CM So how should we treat patients with H(O)CM who are referred to our practice? In all H(O)CM patients the risk of SCD should be evaluated. Therefore all patients have to undergo echocardiography and sometimes MRI assessment of the wall thickness, Holter monitoring (check for non-sustained ventricular tachycardia, especially in the young), and an exercise test (assessment of blood pressure response). In addition, an extensive family history has to be taken. In patients with a higher risk for SCD an ICD is placed. In asymptomatic patients with H(O)CM and absent risk factors for SCD no treatment is needed. It has to be remembered that a gradient in the LVOT in an asymptomatic patient does not warrant therapy. In symptomatic HOCM patients, β-blockers, and if the patient does not respond properly verapamil or disopyramide, are indicated. In HOCM patients who remain symptomatic despite optimal medical treatment, surgery is indicated. To obtain an optimal result in addition to Morrow resection, MRI guided surgery of the anomalous papillary muscles by an experienced surgeon seems to be essential. In HOCM patients with contraindications for surgery, percutaneous

Myocardial disease: The patient with hypertrophic cardiomyopathy

alcohol ablation is a good alternative. In symptomatic non-obstructive HCM the only option is to treat the symptoms of heart failure with ACE inhibitors, β-blockers and diuretics. Atrial fibrillation has to be treated aggressively with amiodarone or disopyramide and if needed pulmonary vein ablation. All H(O)CM patients with atrial fibrillation have to be treated with warfarin.

Chapter 2

Reference list 1. Maron BJ, Olivotto I, Spirito P, et al. Epidemiology of hypertrophic cardiomyopathyrelated death: revisited in a large non-referral-based patient population. Circulation 2000;102:858–64. 2. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287:1308–20. 3. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology foundation task force on clinical expert consensus documents and the European Society of Cardiology committee for practice guidelines. J Am Coll Cardiol 2003;42:1687–713. 4. Sherrid MV, Gunsburg DZ, Moldenhauer S, et al. Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2000;36:1344–54. 5. Maron BJ, Harding AM, Spirito P, et al. Systolic anterior motion of the posterior mitral leaflet: a previously unrecognized cause of dynamic subaortic obstruction in patients with hypertrophic cardiomyopathy. Circulation 1983;68:282–93. 6. Klues HG, Roberts WC, Maron BJ. Anomalous insertion of papillary muscle directly into anterior mitral leaflet in hypertrophic cardiomyopathy. Significance in producing left ventricular outflow obstruction. Circulation 1991;84:1188–97. 7. Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 2008;83:63. 8. Mogensen J, Bahl A, McKenna WJ. Hypertrophic cardiomyopathy – the clinical challenge of managing a hereditary heart condition. Eur Heart J 2003;24:496–8. 9. Olivotto I, Maron MS, Autore C, et al. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol 2008;52:567–8. 10. Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104:2517–24. 11. Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405–12 12. Monserrat L, Elliott PM, Gimeno JR, et al. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol 2003;42:873–9. 42

Myocardial disease: The patient with hypertrophic cardiomyopathy

13. Ciampi Q, Betocchi S, Lombardi R, et al. Hemodynamic determinants of exercise-induced abnormal blood pressure response in hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:278–84. 14. Sherrid M. Pathophysiology and treatment of hypertrophic cardiomyopathy. Prog Cardiovasc Dis 2006;49:123–51. 15. Heric B, Lytle BW, Miller DP, et al. Surgical management of hypertrophic obstructive cardiomyopathy. Early and late results. J Thorac Cardiovasc Surg 1995;110:195–206. 16. Schoendube FA, Klues HG, Reith S, et al. Long-term clinical and echocardiographic follow-up after surgical correction of hypertrophic obstructive cardiomyopathy with extended myectomy and reconstruction of the subvalvular mitral apparatus. Circulation 1995;92(Suppl):II122–7. 17. Qin JX, Shiota T, Lever HM, et al. Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery. J Am Coll Cardiol 2001;38:1994–2000. 18. Cuoco FA, Spencer WH 3rd., Fernandes VL, et al. Implantable cardioverter-defibrillator therapy for primary prevention of sudden death after alcohol septal ablation of hypertrophic cardiomyopathy. J Am Coll Cardiol 2008;52;1718–23.

Chapter 3.1

Optimal gradient reduction after alcohol septal ablation: a case report with anatomical and practical determinants

R. C. Steggerda, J. C. Balt, J. M. ten Berg

Netherlands Heart Journal 2011; 19: 301-303.

Chapter 3.1

Summary We present a case report of alcohol septal ablation (ASA) in a patient with a symptomatic hypertrophic obstructive cardiomyopathy. The first septal branch (S1) was small and difficult to cannulate. Myocardial contrast echocardiography was used in the second septal branch (S2) that seemed an appropriate target. However, after ablation of S2 the gradient remained. Subsequently after significant effort and probatory balloon inflation, ablation of S1 resulted in complete gradient reduction. This case report illustrates how coronary anatomy and related infarct location play an important role in the success of ASA. Introduction Recent meta-analyses have shown good long-term survival of patients with hypertrophic obstructive cardiomyopathy (HOCM) after alcohol septal ablation (ASA) comparable to surgical myectomy. However, gradient reduction after ASA was slightly less favourable [1,2] and in a single center study a higher rate of aborted sudden cardiac death was found [3]. The following case report illustrates the importance of coronary anatomy and infarct location that determine outcome after ASA. Case report: A 53-year old male patient was referred to undergo alcohol septal ablation (ASA) for symptoms due to hypertrophic obstructive cardiomyopathy despite medical therapy. His echocardiogram revealed a septal wall thickness of 18 mm, severe systolic anterior motion of the mitral valve and a severe posterolaterally directed mitral valve regurgitation. The gradient in the left ventricular outflow tract was 54 mm Hg at rest and 100 mm Hg after valsalva manoeuvres. Coronary angiography revealed 2 septal branches of which the first was very small and could not be cannulated. Subsequently the second branch (S2) was cannulated (figure 1) and myocardial contrast echocardiography (MCE) was used to delineate the perfused area across the septal contact area of the mitral valve. However, during probatory inflation of the balloon the invasively measured gradient was only reduced from 60 mm Hg to 50 mm Hg (figure 2A and 2B). Also after injection of 2 ml of alcohol, the gradient remained elevated at 50 mm Hg. Therefore, after perseverance, the smaller and more proximal septal branch was successfully cannulated. After probatory inflation of the balloon the gradient resolved completely and this septal branch was ablated as well (figure 2C). The second ablation resulted in complete resolution of the outflow tract gradient (figure 2D), but was offset by necessity for pacemaker 46

Optimal gradient reduction: case report

implantation due to total AV block. An MRI was performed three days after the procedure and revealed an infarction of the entire basal part of the septum (see figure 3). At three months follow-up the echocardiogram revealed a gradient in the outflow tract of only 10 mmHg and the patient no longer experienced shortness of breath. Figure 1 Coronary angiogram before ASA. Arrows indicate a proximal and more distal septal branch (S1 and S2).

Chapter 3.1

Figure 2. Simultaneous pressure recordings of the pressures in the aorta and left ventricle. The difference between these two reflects the left ventricular outflow tract gradient. A=measurement at baseline. B=measurement during balloon inflation of S2, just before the first ablation. C=measurement during balloon inflation of S1, just before the second ablation. D=measurement after the ablation of both septal branches.

Optimal gradient reduction: case report

Figure 3. MRI of the heart, three chamber view. The white arrow indicates a basal infarction (dark, not perfused area).

Discussion Patients with HOCM can exhibit severely reduced exercise tolerance. A prevalvular obstruction is caused by a thickened protruding septum and systolic anterior motion of the mitral valve (SAM). Gradient reduction can be achieved by surgical removal of a part of the thickened septum or by ASA. With ASA, alcohol is selectively infused in an appropriate septal branch. This causes infarction and thinning of the septum. First probatory balloon inflation and later myocardial contrast echocardiography (MCE) were introduced for guidance and selection of the appropriate branch for ASA. Probatory balloon inflation in a septal branch leads to temporary ischemia and reduction of the obstructive gradient but has a limited predictive value [4]. MCE delineates the septal perfusion area which should include the SAM induced mitral valve septal contact area. After the introduction of MCE, outcome improved and complications were reduced [4,5]. Despite these techniques, gradient reduction after ASA remains slightly less compared to surgical myectomy [1,2]. This may be important since higher outflow gradients after ASA are associated with a less favourable long-term

Chapter 3.1

haemodynamic outcome [6]. Additionally, even though meta-analyses have shown comparable long-term outcome between ASA and myectomy, in a recently published single center study, a higher rate of aborted sudden cardiac death was found after ASA compared to myectomy and therefore myectomy was advised as the preferred treatment [3]. In this case report MCE revealed S2 (see figure 1) as the appropriate target and this septal branch was therefore ablated. The sustained gradient after ablation of S2 was probably due to the fact that the basal part of the septum was still perfused by the more proximal branch S1. After ablation of S1 in addition to S2 an infarction was caused of the entire basal septum which can be seen on the MRI performed three days after the procedure (see figure 3). For complete gradient resolution it was necessary to include the perfusion of the basal part of the septum that apparently still formed an obstruction and SAM in the outflow tract. At three months follow-up, the patient was free from symptoms and gradient in the outflow tract on echocardiogram was completely reduced to a provoked gradient of 10 mmHg. Complete gradient reduction was however offset by necessity for pacemaker implantation due to total AV block. We conclude that coronary anatomy, infarct location, infarct size and technical difficulty for cannulation of the appropriate septal branch can be important determinants for a successful outcome after ASA. With the increasing rate of use of ASA compared to myectomy, future research is necessary to predict outcome after ASA in order to determine which patients are suitable for ASA.

Optimal gradient reduction: case report

Reference list 1. Mahboob A, Hisham D and Nasser ML. Hypertrophic obstructive cardiomyopathy-alcohol septal ablation vs. myectomy: a meta-analysis. European Heart Journal. 2009;30(9):10801087. 2. Agarwal S, Tuczu EM, Desay MY et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010; 55(8):823-34. 3. ten Cate FJ, Soliman Ol, Michels M, et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail. 2010; 3(3):362-369. 4. Faber L, Ziemssen P, Seggewiss H. Targeting percutaneous transluminal septal abalation for

hypertrophic

obstructive

cardiomyopathy

intraprocedural

echocardiographic

monitoring. J Am Soc Echocardiogr. 2000;13:1074-9. 5. Faber L, Seggewiss H, and Gleichmann U. Percutaneous Transluminal Septal Myocardial Ablation in Hypertrophic Obstructive Cardiomyopathy: Results With Respect to Intraprocedural Myocardial Contrast Echocardiography. Circulation. 1998;98:2415-2421. 6. Faber L, Welge D, Fassbender D et al. One-year follow-up of percutaneous septal ablation for symptomatic hypertrophic cardiomyopathy in 312 patients: predictors of hemodynamic and clinical response. Clin Res Cardiol. 2007; 96(12):851-5.

Chapter 3.2

Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Special interest for the septal coronary anatomy. Robbert C. Steggerda, Jippe C. Balt, Kevin Damman, Maarten P. van den Berg, Jurriën M. ten Berg

Netherlands Heart Journal 2013 21(11):504-9.

Chapter 3.2

Abstract Background: Alcohol septal ablation (ASA) provides symptomatic relief in most but not all patients with hypertrophic obstructive cardiomyopathy (HOCM). Therefore we investigated predictors of outcome after ASA. Methods: Clinical, echocardiographic, angiographic and procedural characteristics were analyzed in 113 consecutive patients. Successful ASA was defined as NYHA ≤ 2 with improvement of at least 1 class combined with a resting gradient < 30 mm Hg and provoked gradient < 50 mm Hg at 4 months follow-up. Results: In 37 patients ASA was not successful. In multivariate analysis, baseline gradient (OR 1.06 (1.01-1.11) per 5 mmHg, p = 0.024) and distance to the ablated septal branch (OR 1.09 (1.03 – 1.16) per mm, p = 0.004) were predictors of unsuccessful outcome. The combined presence of a non-ablated septal branch and a distance ≥ 19 mm to the ablated branch was a predictor of unsuccessful outcome (OR 5.88 (2.06 – 16.7), p < 0.001). Conclusions Baseline gradient and a greater distance from the origo of the left anterior descending artery to the ablated septal branch combined with a non-ablated proximal septal branch are associated with an unsuccessful outcome after ASA. Keywords: hypertrophic obstructive cardiomyopathy, left ventricular outflow tract, alcohol septal ablation, outcome, septal anatomy

Predictors of outcome after ASA: septal anatomy

Introduction In patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM), percutaneous alcohol septal ablation (ASA) is an accepted alternative to surgical septal myectomy (“myectomy”) [1,2,3]. Although no randomized controlled trials have been performed, observational meta-analyses for ASA versus myectomy show excellent long-term survival rates for both procedures [4-7]. However, reduction of the gradient in the left ventricular outflow tract (LVOT) appears to be slightly less for patients who undergo ASA [4], repeat interventions are performed more often after ASA [8] and in a single center study cardiac death occurred more often after ASA compared to myectomy [9]. With myectomy, the basal part of the septum, responsible for the obstruction of the LVOT, is usually resected completely. In contrast, after ASA the most basal part of the septum may in some cases be spared causing residual obstruction [10]. In this study we studied the predictors of outcome after ASA with special interest for the septal coronary anatomy.

Chapter 3.2

Methods Patients We studied patients who were treated for HOCM at the St. Antonius hospital in Nieuwegein, the Netherlands. For patients to be selected for septum reduction (either ASA or myectomy) they had to have severe symptoms (New York Heart Association functional class ≥ 3) despite trial of optimal medical therapy in combination with a resting gradient in the left ventricular outflow tract (LVOT) ≥ 30 mm Hg and/or a provocable gradient ≥ 50 mm Hg. All patients were required to have left ventricular asymmetrical septal hypertrophy, with a minimal septum diameter ≥ 15 mm. Patients with concomitant (sub)valvular disease or other conditions that warranted surgery were accepted to undergo surgical myectomy. Patients who were eligible for both options were informed about the known risks and benefits of both ASA and surgical myectomy and were offered the choice between these procedures. Routine clinical and echocardiographic assessments were performed in all patients. We performed a retrospective analysis of all the clinical data along with analysis of the echocardiographic images and coronary angiograms. Civil registries were used to determine survival on January 2011. The study conformed to principles defined in the Helsinki Declaration. Definitions Successful symptomatic relief was defined as a New York Heart Association (NYHA) functional class ≤ 2 with a lowering of at least one NYHA at follow-up. The combination of both successful symptomatic relief with a resting gradient < 30 mm Hg and a provoked gradient < 50 mm Hg during echocardiographic assessment at 4 months follow-up was used as a strict definition for successful outcome.

Alcohol septal ablation ASA was performed as described in detail previously [11]. In short, with the aid of a flexible coronary guide wire, a coronary balloon was placed in the most proximal septal branch. Myocardial contrast echocardiography was used for further guidance. Only when the region of contrast in the septum was satisfactory and adjacent to the area of septal contact of the anterior mitral valve leaflet, 0.5 to 3 ml of concentrated ethanol was slowly injected through the inflated balloon catheter. The balloon was left inflated for 10 minutes to prevent retrograde spill of ethanol. Invasive gradients in the LVOT were measured continuously during the procedure using a 6 French pigtail catheter inserted in the left ventricle. For testing 56

Predictors of outcome after ASA: septal anatomy

of a provocable gradient, the Valsalva maneuver and extrasystolic beats were used. When the gradient in the LVOT remained ≥ 30 mm Hg after the first ablation (either at rest or after provocation), the procedure was repeated in a second septal branch. During the procedure, all patients received a temporary transvenous pacemaker. If an AV block remained more than 48 hours after the procedure, a definitive pacemaker was implanted. Echocardiography All echocardiograms were performed with Hewlett-Packard sonos 5500 and Philips IE33 ultrasound imaging systems and were stored as digital images in a database. Philips’ Excelera software program was used for all measurements, which were performed by a single observer (RCS) who was blinded for the purpose of the study. Measurement of the peak LVOT gradient both at rest and after provocation using the Valsava maneuver was obtained in the apical 3 or 5 chamber view. The degree of mitral insufficiency (MI) was graded from 0 to 4 (grade 0 = no MI, grade 1 = mild, grades 2 and 3 = moderate, grade 4 = severe) [12]. The degree of systolic anterior motion (SAM) was graded from 0 to 4 (grade 0 = no SAM, grade 1 = SAM with distance from septum to AMVL >10 mm, grade 2 = SAM with distance from septum to AMVL <10 mm, grade 3 = AMVL makes brief septal contact, grade 4 = septal contact > 30% during systole) [13]. The minimal LVOT diameter was measured as the narrowest part in the LVOT between the septum and the basis of the anterior mitral valve leaflet (AMVL) during systole. At 4 months follow-up after ASA baseline measurements were repeated and in addition, in the parasternal long axis view septal thinning due to the infarction was evaluated at end-diastole. When septal thinning was found from the beginning of the septum the infarction was considered to be without sparing of the basal septum. Otherwise, the infarction was considered to have spared the basal septum. Akinesia of the basal septum was rated as either present or absent. Coronary angiography Coronary angiography was usually performed shortly before the procedure. For the purpose of the present study, the coronary angiograms of all patients were retrospectively analyzed for the presence of non-ablated proximal septal branches. All branches that clearly perfused the septum and were proximal to the first ablated septal branch were considered non-ablated septal branches. Furthermore, using Philips suite QCA with the catheter diameter for calibration, we measured the distance from the origo of the LAD to the origo of the ablated

Chapter 3.2

septal branch. We also measured the diameters of the origo of both the non-ablated proximal septal branch and the ablated septal branches.

Statistical analysis Data are given as the mean and standard deviation when normally distributed, as the median with interquartile range for skewed distributions, and as frequencies and percentages for categorical variables. The Student’s t-test was used for continuous variables and the chisquare test was used to compare categorical variables. Pearson’s test was used for calculating correlations. Logistic regression was carried out to identify univariate predictors of unsuccessful outcome. Stepwise backward logistic regression analysis was carried out in a multivariate analysis. Variables were considered in the multivariate models when a P-value of < 0.1 was obtained in the univariate analysis. In secondary analysis, interaction analysis was carried out to establish significant interactions between the variables of septal coronary anatomy and unsuccessful outcome. All reported probability values are two-tailed, a P-value < 0.05 was considered statistically significant and a P-value < 0.1 was considered significant for interaction analysis. Statistical analyses were performed using STATA, College Station, Texas, version 10.0.

Predictors of outcome after ASA: septal anatomy

Results A dataset of 113 patients that underwent ASA in our institution from January 2000 to December 2009 was completed. At 4 months follow-up a successful symptomatic result was found in 90% of all patients. The total group showed reduction of the echocardiographic gradient both at rest and after provocation from respectively 50 mmHg ± 43 and 113 mmHg ± 61 before the procedure to 22 mmHg ± 26 and 38 mmHg ± 40, measured 4 months after ASA (p<0.001). According to the definition of the present study, ASA was successful in 76 patients (successful group) and unsuccessful in 37 patients (unsuccessful group). The baseline characteristics of the patients in the two groups did not differ significantly (Table 1). At 4 months post-procedure, NYHA functional class had improved, resulting in a post-procedural NYHA functional class of 1.0 ± 0.6 in the successful group versus 1.9 ± 1.0 in the unsuccessful group (p < 0.001). In terms of periprocedural complications ventricular fibrillation occurred once and was treated with defibrillation, tamponade occurred once and was treated with pericardiocentesis and dissection in the LAD occurred once and was treated with a stent implantation. A definitive pacemaker was inserted in five patients. During a follow-up of 5.3 ± 2.5 years there were 4 deaths (3 non-cardiac, 1 cardiac), amounting an annual all cause mortality of 0.7%.

Chapter 3.2

Table 1. Baseline Characteristics Outcome after ASA Variables

Successful (n=76)

Unsuccessful (n=37)

P-value

Age (years)

56 ± 17

57 ± 14

0.93

Male sex (% (n))

55 (41)

44 (17)

0.32

NYHA functional class

2.9 ± 0.4

2.8 ± 0.7

0.78

Angina functional class

1.9 ± 0.4

2.0 ± 0.4

0.33

Syncope (% (n))

23 (17)

18 (7)

0.71

β-blocker or Ca-blocker (% (n))

83 (63)

78 (29)

0.52

5 (4)

0 (0)

0.36

Max CK (U/L)

1294 ± 461

1431 ± 793

0.34

Max CK Mb (U/L)

201 ± 124

167 ± 59

0.051

Hospital stay, days

5.6 ± 4

6.3 ± 5

0.49

Non-ablated branch present (% (n))

26 (19)

50 (19)

0.01

Distance to ablated branch (mm)

16 ± 7

20 ± 8

0.006

Diameter ablated branch (mm)

1.7 ± 0.4

1.6 ± 0.5

0.25

Diameter non-ablated branch (mm )

1.0 ± 0.3

1.1 ± 0.4

0.32

Amount of alcohol (mL)

2.4 ± 0.7

2.3 ± 0.5

0.55

Number of ablated branches

1.2 ± 0.4

0.99

Invasive gradient pre ASA (mmHg)

83 ± 32

95 ± 35

0.08

Previous pacemaker (% (n))

Angiographic findings

Data are presented as mean ± standard deviation or as percentage (number). Abbreviations: ASA: alcohol septal ablation, CCS: Canadian Cardiovascular Society, CK: creatine kinase,: New York Heart Association.

Predictors of outcome after ASA: septal anatomy

Echocardiographic findings Echocardiographic findings at baseline and at 4 months follow-up comparing both groups are shown in Table 2. Before ASA, the resting gradient in the LVOT was higher in the unsuccessful group than in the successful group, but the other characteristics were comparable. Inherent to the definition of successful outcome, after ASA the LVOT gradient in the unsuccessful group was higher than in the successful group. Furthermore, in the unsuccessful group, infarctions with sparing of the basal septum were more common than in the successful group. Of note, infarctions without sparing of the basal septum were associated with a larger minimal LVOT (20 ± 4 vs 15 ± 4, p < 0.001) and a lower grade of SAM (0.7 ± 0.6 vs 2.0 ± 1.1, p < 0.001) compared to infarctions with sparing.

Chapter 3.2

Table 2. Echocardiographic findings at baseline and 4 months follow up Variables Baseline

Outcome after ASA Successful

Unsuccessful

P value

(n=76)

(n=37)

Septal thickness (mm)

22 ± 5

0.95

Posterior wall thickness (mm)

15 ± 3

16 ± 3

0.71

Enddiastolic volume (mL)

77 ± 25

74 ± 26

0.63

Endsystolic volume (mL)

18 ± 11

16 ± 7

0.20

Ejection fraction (%)

76 ± ?

78 ± ?

0.41

LVOT min (mm)

14 ± 5

13 ± 5

0.66

Degree of MI

1.5 ± 1.0

1.7 ± 1.1

0.50

Degree of SAM

2.9 ± 0.6

3.0 ± 0.6

0.14

Resting gradient (mmHg)

43 ± 40

63 ± 46

0.026

Provoked gradient (mmHg)

107 ± 53

126 ± 67

0.15

Septal thickness (mm)

20 ± 4

0.43

Posterior wall thickness (mm)

14 ± 3

0.62

Enddiastolic volume (mL)

81 ± 27

74 ± 24

0.14

Endsystolic volume (mL)

23 ± 15

18 ± 9

0.053

Ejection fraction (%)

74 ± 10

77 ± 10

0.16

LVOT min (mm)

19 ± 4

15 ± 5

<0.001

LVOT min, increase

5.6 ± 4

1.7 ±3

<0.001

Degree of MI

0.5 ± 0.7

1.0 ± 1.0

0.020

Degree of SAM

1.0 ± 0.9

2.2 ± 1.1

<0.001

Akinetic basal septum (% (n))

72 (55)

19 (7)

<0.001

Without sparing basal septum (% (n))

58 (45)

17 (6)

<0.001

Resting gradient (mmHg)

12 ± 7

41 ± 38

<0.001

Provoked gradient (mmHg)

17 ± 10

91 ± 53

<0.001

Decrease provoked gradient (mmHg)

91 ± 53

35 ± 60

<0.001

At 4 month follow-up

Data are presented as mean ± standard deviation or as percentage (number). Abbreviations: LVOT: left ventricular outflow tract, MI: Mitral insufficiency, SAM: systolic anterior motion.

Predictors of outcome after ASA: septal anatomy

Angiographic findings The angiographic findings are shown in Table 1. In the unsuccessful group, there were more patients with a non-ablated proximal septal branch and the distance from the origo of the LAD to the ablated branch was greater. In both groups the diameter of the first ablated branch was larger than the diameter of the non-ablated proximal septal branch (p < 0.01 for both groups). Predictors of unsuccessful outcome Of all the clinical and echocardiographic characteristics at baseline, only baseline resting gradient at echocardiography predicted outcome. Of the angiographic characteristics both the presence of a non-ablated proximal septal branch and the distance to the ablated septal branch were predictors of outcome (Table 3). After multivariate analysis, only the distance to the ablated branch and baseline resting gradient were found to be predictive for outcome after ASA (Table 3). Secondary analysis revealed a significant interaction between the distance to the ablated branch and the presence of a nonablated proximal septal branch when the distance was dichotomized based on the 19 mm optimal cut off point (using highest sensitivity and specificity) (P-value for interaction 0.025). The presence of a non-ablated proximal septal branch and a distance ≥ 19 mm to the ablated branch predicted an unsuccessful outcome (OR 5.88 (2.06 – 16.74), P < 0.001), Table 4) Of note, in this subgroup of patients (n = 27/113, 24%), sparing of the basal septum was more common (55% versus 15%, p < 0.001) compared to the other patients.

Chapter 3.2

Table 3 Univariate and multivariate predictors of unsuccessful outcome Variable

Univariate

Multivariate

OR (95% CI)

P-value

Age

1.00 (0.97 – 1.03)

0.87

Sex (males)

1.50 (0.68 – 3.32)

0.32

1.06 (1.01 – 1.11)

Baseline resting gradient (per 5 mmHg) Distance to ablated branch (per mm) Non-ablated branch present

OR (95% CI)

P-value

0.024

1.06 (1.01 – 1.11)

0.024

1.08 (1.03 – 1.55)

0.005

1.09 (1.03 – 1.16)

0.004

2.85 (1.24 – 6.53)

0.013

Abbreviations: OR: Odds Ratio

Predictors of outcome after ASA: septal anatomy

Table 4 Multivariate predictors of successful outcome taking into account the interaction between the distance to the ablated branch and the presence of a nonablated branch Variable

Baseline resting gradient (per

Univariate

Multivariate

OR (95% CI)

P-value

OR (95% CI)

P-value

1.06 (1.01 – 1.11)

0.024

1.05 (1.00 – 1.10)

0.061

5 mmHg) Distance vs non-ablated branch Distance < 19 mm, non-

1.00

0.99 (0.30 – 3.21)

0.98

1.14 (0.33 – 3.88)

0.83

0.32 (0.36 – 2.70)

0.29

0.40 (0.05 – 3.52)

0.41

5.36 (1.97 – 14.57)

0.001

5.88 (2.06 – 16.74)

0.001

ablated branch not present Distance ≥ 19 mm, non-

1.00

ablated branch not present Distance < 19 mm, nonablated branch present Distance ≥ 19 mm, nonablated branch present

Abbreviations: OR: Odds Ratio, Distance: the measured distance from the origo of the LAD to the origo of the ablated septal branch

Chapter 3.2

Discussion Symptomatic relief was found in 90% of patients, comparable to previous results [1,14], but success of ASA in terms of reduction of the gradient was somewhat less common. We found that a greater distance from the origo of the LAD to the ablated septal branch, especially in the presence of a non-ablated proximal septal branch, was associated with an unsuccessful outcome 4 months after ASA, independent of the severity of the baseline resting gradient. In terms of safety; mortality rate was low. Complication rates in our study were low including the number of pacemaker implantations, probably due to the low amounts of alcohol we used based on careful assessment with myocardial contrast echocardiography. Unfavorable coronary anatomy As previously demonstrated using cardiac MRI, patients exhibit a more variable location of septal thinning after ASA compared to surgical myectomy [10]. The access to the perfusion bed of the most basal part of the septum may for the interventional cardiologist be limited or difficult due to the variablility of the septal anatomy [15,16,17]. Even though ASA was performed only after contrast was seen in the region of interest using myocardial contrast echocardiography, we also found a considerable variation of the location of the infarction in our study. Moreover, an unfavourable anatomy (combined presence of a non-ablated proximal septal branch and a distance ≥ 19 mm to the ablated branch) was associated with an unsuccessful outcome. In these patients more frequent sparing of the most basal septum was found accompanied by a smaller minimal LVOT diameter and a higher grade of SAM. This may explain a lower success rate of ASA in patients with an unfavourable anatomy. For these patients, surgical myectomy might thus be a preferred method instead of ASA. The effect of an unfavourable anatomy on long-term survival and clinical outcome warrants further study. Limitations This was a retrospective single centre study. Measurements were performed on the available angiographic images but we cannot rule out that more targeted imaging might have yielded more anatomically correct values. We used a strict definition for success consisting of a combined symptomatic result with the same hemodynamic criteria for invasive treatment mentioned in current guidelines [18], however there is no clear consensus for definition of success after ablation. The choice of the endpoint at 4 months was a practical one, simply based on the first contact at the outpatient clinic. It cannot be excluded that further

Predictors of outcome after ASA: septal anatomy

improvements in symptomatic status and LVOT gradients occurred beyond 4 months after ASA. Conclusions Baseline gradient and the combined presence of a non-ablated proximal of septal branch with a greater distance to the ablated septal branch was found to be associated with an unsuccessful outcome after ASA. In practical terms this implies that ASA should probably not be performed when septal anatomy is unfavourable.

Acknowledgments: We thank Jackie Senior for editing the manuscript.

Chapter 3.2

Reference List 1. Fifer MA, Sigwart U. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation. Eur Heart J. 2011;32:1059-1064. 2. Maron BJ, Maron MS, Wigle ED, et al. The 50-year history, controversy and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: From idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009;54:191-200. 3. ten Berg J, Steggerda RC, Siebelink HM. Myocardial disease: The patient with hypertrophic cardiomyopathy. Heart. 2010;96:1764-1772. 4. Alam M, Dokainish H, Lakkis NM. Hypertrophic obstructive cardiomyopathy-alcohol septal ablation vs myectomy: a meta-analysis. Eur Heart J. 2009;30:1080-1087. 5. Leonardi RA, Kransdorf EP, Simel DL, et al. Meta-analysis of septal reduction therapies for obstructive hypertrophic cardiomyopathy. Comparative rates of overall mortality and sudden cardiac death after treatment. Circ Cardiovasc Interv. 2010;3:1-7. 6. Agarwal S, Tuzcu EM, Desai MY, et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010;55:823-834. 7. Ball W, Ivanov J, Rakowski H, et al. Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol. 2011;58:2313-2321. 8. Alam M, Dokainish H, Lakkis N. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a systematic review of published studies. J Interv Cardiol. 2006;19:319-327. 9. ten Cate FJ, Soliman Ol, Michels M, et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail 2010;3(3):362-9.

Predictors of outcome after ASA: septal anatomy

10. Valeti US, Nishimura RA, Holmes DR, et al. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2007;49:350-357. 11. Van der Lee C, Scholzel B, ten Berg JM, et al. Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation. Am J Cardiol. 2008;101:1315-1320. 12. Destefano FR. Determination of mitral regurgitation severity. In: Armstrong WF, Ryan T, eds. Feigenbaum’s Echocardiography, 7th edition, Philadelphia, Lippincott Williams and Wilkins. 2009:320-325. 13. Pollick C, Rakowski H, Wigle ED. Muscular subaortic stenosis: the quantative relationship between systolic aortic motion and pressure gradient. Circulation. 1984;69:43-49. 14. Sorajja P, Binder J, Nishimura RA, et al. Predictors of an optimal clinical outcome with alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Catheter Cardiovasc Interv. 2013;81:E58-E67. 15. Nagueh SF, Groves BM, Schwartz L, et al. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2011;58:2322-2328. 16. Singh M, Edwards WD, Holmes DR, et al. Anatomy of the first septal perforating artery: a study with implications for ablation therapy for hypertrophic cardiomyopathy. Mayo Clin Proc. 2001:76;799-802. 17. Brinkjikji W, Harris SR, Froemming AT, et al. Descriptive anatomy of the dominant septal perforators using dual source coronary CT angiography. Clin Anat. 2010;23:70-78. 18. Steggerda RC, Balt JC, ten Berg JM. Optimal gradient reduction after alcohol septal ablation: a case report with anatomical and practical determinants. Neth Heart J. 2011;19(6):301-303. 19. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2011;58:e212-e260.

Chapter 4

Basal Infarct Location but not Larger Infarct Size is associated with a Successful Outcome after Alcohol Septal Ablation in Patients with Hypertrophic Obstructive Cardiomyopathy. A Cardiovascular Magnetic Resonance Imaging Study.

Robbert C. Steggerda, MD, Christiane A. Geluk, MD, PhD, Wessel Brouwer, MD, Albert C. van Rossum, MD, PhD, Jurriën M. ten Berg, MD, PhD, Maarten P. van den Berg, MD, PhD

Int Journal Cardiovasc Imaging, 2015

Chapter 4

Abstract: Purpose: Alcohol septal ablation (ASA) is successful in most but not in all patients with obstructive hypertrophic cardiomyopathy (HCM). We therefore sought to investigate the relation between infarct location versus infarct size with outcome after ASA in patients with obstructive HCM. Methods: Baseline characteristics, procedural characteristics, and Cardiovascular Magnetic Resonance findings at baseline and 4-6 month follow-up after ASA were analysed in 47 patients with obstructive HCM in a single-center retrospective study. Infarct size was determined using late gadolinium enhancement (LGE). Infarct location was divided into “basal infarction” and “distal infarction” based on an optimal cut-of value of the distance from the basal septum to the beginning of the infarction. A “successful” outcome was defined as 80% reduction of the invasive gradient with a post-procedural gradient of < 10 mmHg. Results: Basal infarctions (n=31) compared to distal infarctions (n=16) were associated with successful outcome (100% vs. 38%, P<0.001). Larger infarct size (n=20) compared to smaller infarct size (n=27) was not associated with successful outcome (75% vs. 82%, P=0.72). A more distal location of the infarction, was the only predictor of a less successful outcome (Odds Ratio 0.76, 95% Confidence interval: 0.54-0.98), P=0.03)). Basal versus distal infarctions were also associated with a lower provoked gradient at late (2.6 ± 2.2 years) follow-up (11 (6-20) mmHg vs 27 (12-94) mmHg, P =0.01). Conclusion: Basal infarctions were associated with a successful outcome after ASA. A larger infarct size was not associated with a better outcome. Key-words: alcohol septal ablation, CMR, infarct location, outcome

Basal infarct location and successful outcome after ASA: A CMR study

Introduction Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterised by hypertrophy of the left ventricle (LV). About 70% of the patients with HCM have obstruction of the left ventricular outflow tract (LVOT), referred to as obstructive HCM [1]. Patients with severe symptoms despite pharmacologic treatment can undergo invasive treatment to reduce the obstruction. Both alcohol septal ablation (ASA) and surgical myectomy can reduce the gradient by widening the outflow tract and improve symptoms, and after both treatments long-term survival rates are good [2-7]. However, relief of the obstruction is not always complete and a reintervention may be necessary after ASA in about 9% [3)] This may be important since necessity for reinterventions after ASA were found to be associated with a higher mortality rate [8]. We therefore sought to investigate predictors of outcome after ASA with special interest for the location and size of the infarction induced by ASA. The location of the infarction produced by ASA is variable and the most basal part of the septum may in some cases be spared leading to incomplete relief of obstruction [9]. Regarding infarct size, whereas a smaller infarct size measured by CK value may predispose to residual obstruction [10], a larger infarct size may predispose to ventricular arrhythmia [11,12]. In addition, large infarction does not necessarily imply that the basal part of the septum is targeted. We hypothesized that basal infarct location rather than large infarct size per se, is associated with a successful outcome.

Chapter 4

Methods We studied patients with obstructive HCM that underwent cardiovascular magnetic resonance (CMR) imaging before and 4 months after ASA, performed between January 2000 and December 2013 in a retrospective study. All patients were treated at a single centre, St. Antonius Hospital in Nieuwegein, the Netherlands. For patients to be selected for septum reduction (either ASA or surgical myectomy) they had to have severe symptoms despite trial of optimal medical therapy in combination with a resting gradient in the LVOT ≥ 30 mmHg or a provocable gradient ≥ 50 mm Hg. All patients were required to have left ventricular hypertrophy with a minimal septum diameter ≥15 mm evaluated with echocardiography. Patients with concomitant (sub)valvular disease or other conditions that warranted surgery were advised to undergo surgical myectomy. Patients who were eligible for both ASA and surgical myectomy were informed about the known risks and benefits of both procedures and were offered the choice between them. CMR was considered a routine exam but was at the discretion of the attending physician and patient. CMR was routinely performed 4 to 6 months after the procedure. Due to incompatibility with CMR, patients with an implanted pacemaker, ICD or implantable loop recorder did not undergo CMR imaging. The clinical and periprocedural data of all patients who undergo ASA in our institution are routinely entered into a database. A previously used definition of success by Sorajja et al, i.e.reduction of 80% of the gradient combined with a post-procedural gradient of <10 mmHg measured invasively during the procedure, was used as the definition of “successful outcome” in the present study (4). The remaining cases were considered to have an “unsuccessful outcome”. The study conformed to the principles defined in the Helsinki Declaration. Local review board approval was obtained.

Basal infarct location and successful outcome after ASA: A CMR study

Alcohol septal ablation and coronary angiogram. ASA was performed as described in detail previously [13]. In short, with the aid of a flexible coronary guide wire, a coronary balloon was placed in the most proximal septal perforator branch. Myocardial contrast echocardiography was used for further guidance. Only when the region of contrast in the septum was judged satisfactory and adjacent to the area of septal contact of the anterior mitral valve leaflet, 0.5 to 3 ml of concentrated ethanol was slowly injected through the inflated balloon catheter. The balloon was left inflated for 10 minutes to prevent retrograde spill of ethanol. Invasive gradients in the LVOT were measured continuously during the procedure using a 6 French pigtail catheter inserted in the left ventricle. For testing of a provocable gradient, the Valsalva maneuver and extrasystolic beats were used. When the gradient in the LVOT remained ≥ 30 mm Hg after the first ablation (either at rest or after provocation), the procedure was repeated in one or two more septal branches. During the procedure, all patients received a temporary transvenous pacemaker. If an AV block remained more than 48 hours after the procedure, a definitive pacemaker was implanted. Coronary angiography was usually performed shortly before the procedure. For the purpose of the present study, the coronary angiograms were retrospectively analysed. Using Philips suite QCA-analysis software package, with the catheter diameter for calibration and line distance measurement, we measured the distance from the origin of the LAD to the origin of the ablated septal branch. Pre-ASA CMR and CMR at mid-term (4-6 months) follow-up. CMR studies were performed on a 1.5-Tesla whole body scanner (Magnetom Sonata, Siemens, Erlangen Germany) at the VU medical centre Amsterdam, the Netherlands from 2000-2003 and from 2003-2013 on a 1.5–Tesla whole body scanner (Achieva scan, Philips medical system, Best, The Netherlands) in St. Antonius hospital Nieuwegein, the Netherlands. After standard survey scans, Cine Steady State Free Precession images were used for cine images. Data sets with full coverage of the left ventricle were obtained on short axis slides and on long axis slides of the three and four-chamber views. From 2000-2003, image parameters were (slice thickness 5 mm, slice gap 5 mm, repetition time 3 ms, echo time 1.5 ms and a typical in-plane resolution of 1.3 by 1.6 mm. From 2003-2013 image parameters were: slice thickness 8 mm, gap thickness 0 mm, repetition time 4 ms, echo time 2 ms and in plane resolution of 1.6 mm by 1.6 mm. Cine images were used to determine end diastolic volume (EDV), end systolic volume (ESV) and left ventricular (LV) mass during diastole. For LV mass, papillary muscles were included. LVOT diameter was measured in the three

Chapter 4

chamber view for a maximum diameter during end-diastole and a minimal diameter during end-systole. Septal thickness at follow-up was measured outside the area of thinning due to the septal infarction. Systolic anterior motion (SAM) of the anterior mitral valve leaflet (AMVL) was graded from 0 to 4 (grade 0= no SAM, grade 1 = SAM with distance to AMVL more than 10 mm, grade 2 = SAM with distance to AMVL less than 10 mm, grade 3 = AMVL makes brief contact with the septum and grade 4 = septal contact more than 30% during systole) [14, 15]. Late Gadolinium Enhanced (LGE) images were obtained 10-15 minutes after injection of 0.2 mmol/Kg gadolinium-DPTA. A single breath hold, inversion recovery turbo Fast Low Angle Shot (FLASH) sequence was used. Short axis images and long axis (four and three chamber) images were available for analysis. Cine CMR and LGE images were analysed off-line, using MASS (Medis medical imaging systems, Leiden, the Netherlands) at the VU University Medical Center in Amsterdam by an observer (WB) blinded for all other data. Infarct location was identified by the thinning and akinetic wall motion on the three chamber cine images of the follow-up CMR that was not present on the pre-ASA CMR. The distances were measured from the basal septum to both the beginning and to the end of the thinned myocardium. Infarct location was divided into “basal infarction” (Figure 1A,B,C) and “distal infarction” (Figure 1D,E,F) by the optimal cut-off value of the distance to the beginning of the infarction. The distance to the middle of the infarction was calculated from the beginning and the end of the infarct location. Also on the LGE images the same distances were measured. Infarctions were also divided in right sided, left sided and transmural septal infarctions as defined previously using LGE images [16].

Basal infarct location and successful outcome after ASA: A CMR study

Figure 1: CMR imaging in a patient with a successful outcome (A, B, C) and in a patient with an unsuccessful outcome after ASA (D, E, F). All images were obtained during systole.

A: Septal hypertrophy before ASA, with SAM (white arrow). B basal infarction after ASA, SAM is no longer present. C: basal infarction after ASA: after injection of gadolinium contrast, late enhancement due to the infarction is seen from the beginning of the basal septum (black arrow). D: Septal hypertrophy before ASA, with SAM (white arrow). E: distal infarction with sparing of the basal septum after ASA, SAM is still present (white arrow). F: distal infarction, after injection of gadolinium contrast, late enhancement is now seen more distally with sparing of the basal septum (black arrow). Within the white late enhancement area a black area is seen due to no-reflow as part of the infarction.

Using LGE imaging, volume of enhancement was quantified using semi-automatic MASS software on the short axis slides. Enhancement was defined as a signal intensity exceeding 2 standard deviations (SD) above the mean signal intensity of a region of interest drawn in remote myocardium without LGE of the same slice. Epicardial and endocardial borders were delineated manually. After application of the 2 SD threshold, manual corrections were performed excluding any LGE outside the region of the septal infarction from the quantification of the volume of enhancement due to the infarction. Central dark areas within the infarcted region due to no-reflow were considered as a part of the infarction and were included in the volume of late enhancement using manual corrections [9]. Infarct size was

Chapter 4

thus estimated in grams. Infarct size was divided in ‘small infarction’ and ‘large infarction’ (divided by the optimal cut-off value). Relative infarct size was calculated by dividing infarct size by total LV mass. Echocardiogram: baseline, mid-term (4 months) and late follow-up Echocardiograms were performed with a Hewlett Packard and Philips IE33 ultrasound imaging system. Parasternal and apical images were obtained with standard and with colour flow images to reveal any mitral valve insufficiency and presence of turbulent flow in the outflow tract. Both at baseline and at follow-up, measurement of peak outflow tract gradient both at rest and after provocation (valsalva manoeuvres) was obtained in the apical three or five chamber view. Colour Doppler imaging was used to avoid a mixed signal of the mitral insufficiency and the flow in the LVOT. The last available report of an echocardiogram was used for determination of the gradient at late follow-up.

Basal infarct location and successful outcome after ASA: A CMR study

Statistics Variables were described using mean ± SD if distributed normally or median and interquartile range otherwise. Categorical variables were described using frequency counts and percentages. Comparative analyses were performed by using the Student t test, the MannWhitney or the Fisher exact test, where appropriate. Investigation for a prognostic cut-off value was based on receiver operator curves (ROC) analysis, choosing the highest sensitivity and specificity for successful outcome. A cut-off value of distance to the thinned infarction in mm was determined for the division between basal and distal infarct location. And a cut-off value of infarct size in grams was determined, for the division between small and large infarctions. Univariate and multivariate logistic regression analysis was applied to examine whether infarct size in grams and distance to infarct location in mm were associated with successful outcome. Covariates of interest were baseline echocardiographic gradient (resting and provoked), baseline septal diameter and baseline minimal LVOT diameter. The covariates were stepwise included in a multivariate logistic regression model if the univariate association reached statistical significance. P < 0.05 was considered statistically significant. The covariates were tested for collineairity using the variance inflation factor, no colineairity was observed. Calculations were performed using the statistical package SPSS (SPSS, Chicago, USA).

Chapter 4

Results The CMR images before and after ASA were available in 47 patients that underwent ASA from January 2000 until December 2013 in St Antonius hospital, Nieuwegein and these patients were followed for 2.6 ± 2.2 years. In this time period 48 patients with an implanted pacemaker, ICD or implantable loop recorder did not undergo CMR imaging. A coronary angiogram was available for evaluation in 44/47 (94%) of patients. The entire group showed a reduction of the echocardiographic resting gradient and provoked gradient from 27 (18-60) mmHg and 88 (67-139) mmHg before ASA to 12 (8-28) mmHg and 20 (10-58) mmHg after ASA (P < 0.001, P < 0.001). NYHA class improved from 2.9 ± 0.4 before to 1.2 ± 0.8 after ASA (P < 0.001). According to the definition used in this study, 37 (79%) patients had a successful outcome (“successful group”), whereas ASA was not successful in 10 (21%) patients (“unsuccessful group”). The successful group showed a reduction of the echocardiographic resting gradient and provoked gradient from 24 (17-39) mmHg and 86 (67120) mmHg before ASA to 12 (8-23) mmHg and 12 (9-36) mmHg after ASA (P = 0.003, P < 0.001). The unsuccessful group showed a reduction of the echocardiographic resting gradient and provoked gradient from 68 (23-137) mmHg and 130 (68-168) mmHg before ASA to 17 (9-37) mmHg and 49 (19-88) mmHg after ASA (P = 0.049, P = 0.013). Baseline clinical and procedural characteristics were similar in the 2 groups (Table 1). Forty-two patients (89%) were in NYHA class 3-4 before ASA. The other 5 (11%) patients were accepted for ASA due to intolerance for medication combined with unacceptable symptoms. Major complications such as ventricular tachycardia/ventricular fibrillation, tamponade or ventricular septal rupture did not occur.

Basal infarct location and successful outcome after ASA: A CMR study

Table 1: Baseline clinical, procedural and CMR characteristics Variables

Successful group (n=37)

Unsuccessful group (n=10)

P-value

Age, years

61 ± 12

60 ± 13

0.69

Male sex, n (%)

18 (49%)

5 (50%)

0.99

NYHA, functional class

2.9 ± 0.4

2.9 ± 0.3

0.88

Beta-blocker/Ca-antagonist, n (%)

29 (78%)

8 (80%)

0.99

Gradient rest, mmHg

24 (16-40)

68 (23-137)

0.06

Gradient provoked, mmHg

86 (67-119)

130 (68-168)

0.34

100 (70-100)

100 (80-120)

0.35

Alcohol, ml

2.3 ± 0.6

2.3 ± 0.5

0.96

Ablated branches, average nr.

1.2 ± 0.4

1.3 ± 0.7

0.40

1225 ± 479

1429 ± 574

0.26

178 ± 71

196 ± 74

0.47

Septal thickness, mm

20 ± 3

22 ± 6

0.07

Posterior wall thickness, mm

12 ± 3

13 ± 3

0.40

LV mass, grams

165 ± 70

161 ± 56

0.86

EDV, ml

164 ± 41

157 ± 30

0.62

ESV, ml

54 ± 20

60 ± 20

0.50

LVOT min, mm

13 ± 3

11 ± 4

0.06

LVOT max, mm

23 ± 5

22 ± 2

0.42

EF (%)

67± 7

62 ± 9

0.09

3.4 ± 0.7

3.5 ± 0.5

0.59

Transthoracic echocardiography

Procedural characteristics Gradient invasive, mmHg

Max CK, U/L Max CK Mb, U/L Pre ASA CMR

SAM, grade

Chapter 4

Data are presented as mean ± standard deviation, median with interquartile range or as number (percentage). Abbreviations: ASA: alcohol septal ablation, CK: creatine kinase, EDV: end diastolic volume, ESV: end systolic volume, EF: ejection fraction, LVOT min: minimal diameter during systole of the left ventricular outflow tract, LVOT max: maximum diameter of the left ventricular outflow tract during diastole, NYHA: New York Heart Association, SAM: systolic anterior motion.

Pre ASA CMR and CMR at mid-term (4-6 months) follow-up All pre-ASA CMR characteristics were comparable in the successful vs. the unsuccessful group (Table 1). At follow-up CMR grade of SAM was smaller in the successful group compared to the unsuccessful group and minimal LVOT diameter was larger (Table 2). Infarct location: Basal infarctions (distance to beginning infarction < 8.9mm) were present in 31 patients and distal infarctions (distance > 8.9 mm) in 16 patients. Basal infarctions were more often successful compared to distal infarctions (100% vs 38%, P<0.001) (Figure 2). Basal infarctions compared to distal infarctions were associated with a larger minimal LVOT diameter and a lower grade of SAM. Also at 4 months and at late follow-up (2.6 ± 2.2 years), echocardiographic gradients remained lower in patients with a basal infarction compared to a distal infarction (Table 3). An association was found between infarction location and the distance from the origin of the LAD to the origin of the ablated septal branch, a longer distance being associated with distal infarction (Table 3). Infarct size: The optimal cut-off value was 15.9 gram for the division between small and large infarct size. Large infarction size (both absolute and relative to total LV mass) was not associated with a more successful outcome (Table 2, Figure 2). Moreover, large infarctions (n=20) compared to small infarctions (n=27) did not show any difference in minimal LVOT diameter (15 ± 5 mm vs 16 ± 4 mm, P = 0.27) or grade of SAM (1.8 ± 1.2 vs 1.5 ± 1.1, P = 0.40) at follow-up. Larger compared to smaller infarctions were associated with larger baseline septal diameters (22 ± 4 mm vs 19 ± 2 mm, P=0.002) and not with the use of larger amounts of alcohol (2.4 ± 0.67ml vs 2.3 ± 0.6 ml, P=0.64).

Basal infarct location and successful outcome after ASA: A CMR study

Table 2: CMR at follow-up Variables

Successful

Unsuccessful

group

(n=37)

(n=10)

Septal thickness , mm

17 ± 4

19 ± 3

0.12

Posterior wall thickness, mm

11 ± 2

13 ± 2

0.05

LV mass, grams

146 ± 64

148 ± 52

0.92

EDV, ml

152 ± 27

155 ± 39

0.76

ESV, ml

55 ± 19

60 ± 20

0.48

LVOT min, mm

16 ± 4

13 ± 5

0.02

LVOT max, mm

22 ± 2

0.34

EF (%)

65 ± 9

62 ± 6

0.35

1.4 ± 1.0

2.4 ± 1.1

0.01

Basal infarction, n (%)

31 (84%)

0 (0%)

<0.001

Distal infarction, n (%)

6 (16%)

10 (100%)

<0.001

Distance to middle thinned infarct, mm

13 ± 5

20 ± 6

<0.001

Distance to middle LE infarct, mm

14 ± 5

21 ± 7

<0.001

32 (86%)

7 (70%)

0.34

Only Right sided infarction, n (%)

2 (5%)

2 (20)

0.19

Only Left sided infarction, n (%)

3 (8%)

1 (10%)

0.99

Relative infarct size (% of total LV mass)

12 ± 7

15 ± 6

0.18

Infarct size, grams

15 ± 6

23 ± 12

0.003

Small infarction, n (%)

22 (59%)

5 (50%)

0.72

Large infarction, n (%)

15 (41%)

5 (50%)

0.72

SAM grade

P-value

Infarct location

Transmural infarction

Chapter 4

Data are presented as mean ± standard deviation, median with interquartile range or as number (percentage). Abbreviations: ASA: alcohol septal ablation, EDV: end diastolic volume, ESV: end systolic volume, EF: ejection fraction, LV: left ventricular, LVOT max: maximum diameter of the left ventricular outflow tract during diastole, LVOT min: minimal diameter during systole of the left ventricular outflow tract, SAM: systolic anterior motion.

Figure 2: Percentage of successful outcome according to location (basal versus distal) and size of the infarction (small versus large).

Basal infarct location and successful outcome after ASA: A CMR study

Table 3: Basal versus distal infarction Variables

Basal Infarction (n=31)

Distal infarction (n=16)

P-value

31 (100%)

6 (38%)

<0.001

15 ± 6

22 ± 7

0.003

1.2 ± 0.5

1.1 ± 0.3

0.420

Distance to beginning thinned infarction, mm

2±3

13 ± 3

<0.001

Distance to middle thinned infarction, mm

12 ± 4

21 ± 4

<0.001

Distance to end thinned infarction, mm

22 ± 6

29 ± 5

0.003

Distance to beginning LE infarction, mm

1±3

13 ± 4

<0.001

Distance to middle LE infarction, mm

13 ± 3

21 ± 5

<0.001

Distance to end LE infarction, mm

23 ± 6

29 ± 7

0.003

LVOT min, mm

17 ± 4

13 ± 4

<0.001

SAM, grade

1.1 ± 1.0

2.4 ± 1.0

<0.001

Transmural infarction, n (%)

29 (94%)

10 (63%)

0.013

15 ± 9

18 ± 8

0.263

ECHO rest, mmHg

12 (7-22)

17 (10-32)

0.161

ECHO valsalva, mmHg

12 (8-34)

32 (13-81)

0.025

9 (5-16)

15 (9-32(

0.009

Successful outcome, n (%) Coronary anatomy Distance to ablated branch, mm Ablated branches, average nr. MRI mid term (4-6 months)

Infarct size, grams Gradient mid term (4 months)

Gradient late term (2.6 years)* ECHO rest, mmHg

ECHO valsalva, mmHg 11 (6-20) 27 (12-94) Data are presented as mean ± standard deviation, median with interquartile range or as

0.011

number (percentage). Gradient late term*: In 4/47 the gradient of the last available report was at 4 months follow-up. Abbreviations: ASA: alcohol septal ablation, CK: creatine kinase,

Chapter 4

EDV: end diastolic volume, ESV: end systolic volume, EF: ejection fraction, LVOT max: maximum diameter of the left ventricular outflow tract during diastole, LVOT min: minimal diameter during systole of the left ventricular outflow tract, NYHA: New York Heart Association, SAM: systolic anterior motion.

Basal infarct location and successful outcome after ASA: A CMR study

Outcome after ASA, univariate and multivariate analysis Univariate predictors of a successful outcome were the baseline resting echocardiographic gradient (Odds ratio (OR) 0.98 per mmHg (95% confidence interval (CI) (0.96-1.00), P = 0.021), infarct location (distance to the infarction) (OR 0.80 per mm(95% CI 0.69-0.94), P = 0.006), and infarct size (OR 0.89 per gram(95% CI 0.81-0.98), P = 0.016). The other covariates of interest were not associated with a successful outcome in univariate analysis. Both after manual stepwise inclusion of the significant univariate and after manual inclusion of all significant univariate variables, only a more distal infarct location was associated with a less successful outcome (O R 0.76 per mm (95% CI 0.54-0.98, P = 0.03) See Table 4. Table 4: Univariate and multivariate logistic regression analysis for predictors of successful outcome. Univariate

Multivariate

Parameter

OR (95% CI)

P-value

OR (95% CI)

P-value

Baseline Septal diameter (mm)

0.85 (0.71-1.02) 0.089

Baseline LVOT min (mm)

1.26 (0.98-1.62) 0.073

Baseline gradient rest (mmHg)

0.98 (0.96-1.00) 0.021

0.98 (0.95-1.01)

0.15

Baseline gradient provoked (mmHg)

0.99 (0.98-1.02) 0.35

Distance to beginning infarct (mm)

0.80 (0.69-0.94) 0.006

0.76 (0.54-0.98)

0.03

Infarct Size (gram)

0.89 (0.81-0.98) 0.016

0.92 (0.82-1.04)

0.21

Data are presented using Odds ratio (OR) with the 95% confidence interval (95% CI). Abbreviation: Baseline gradient: The gradient measured before ASA using echocardiography. LVOT min: minimal diameter during systole of the left ventricular outflow tract.

Chapter 4

Discussion In the present CMR study we found that basal infarction is associated with a successful outcome after ASA despite a smaller infarct size. Infarctions that spared the most basal part of the septum were less often associated with a successful outcome. We also found that infarct size does not predict outcome after ASA (Figure 2). Variations in infarct location after ASA were described in a CMR study as compared to a more consistent resection of the basal septum in patients that underwent myectomy [9]. In our study we also found considerable variation in infarct location (Table 2). In previous CMR studies by van Dockum et al. right sided ASA-induced scar was related to higher postprocedural gradients and less reduction of remote LV mass [16,17]. In a CMR study by Yuan et al. infarct location and size after ASA was investigated and no relation was found with the gradient at follow-up. Infarct location again was reported as a left sided, a right sided or a transmural infarction, while basal versus distal infarct location were not investigated [18]. In the present study right sided infarctions were uncommon compared to the study of van Dockum et al. We did however also observe a relation between infarct location and outcome, basal infarctions being associated with successful outcome as opposed to distal infarctions. Also at mid-term and late follow-up the echocardiographic gradient was lower. These distal infarctions were found to be characterised by a narrower LVOT due to sparing of the basal septum, explaining a less successful outcome compared to the basal infarctions (Table 3). In addition, we clearly showed that infarct size per se does not matter; larger infarcts were not associated with better outcome. Putting it differently, a relatively small infarction is apparently sufficient provided it is placed well, i.e. in very basal septum. Although these findings would appear rather obvious, to our knowledge our study is the first to combine data on location and size of the infarct induced by ASA, and to show that infarct location is a decisive factor determining outcome after ASA. Still six patients had a successful outcome despite a distal infarction. None of the investigated characteristics i.e. baseline characteristics, infarct size or any investigated CMR characteristics listed in tables 1, 2 could explain this finding. One of the factors that was not systematically investigated that might explain these findings is an altered/reduced contraction and/or fibrosis of the basal septum prior to ASA. In addition, others factors such as changes in left ventricular geometry and contraction pattern due to the septal infarction may also play a considerable role in the reduction of the gradient after ASA. In fact, in a small study biventricular pacing, inducing a different contraction pattern of the left ventricle, was found to reduce outflow tract obstruction [19].

Basal infarct location and successful outcome after ASA: A CMR study

Sudden cardiac death, appropriate ICD shocks due to ventricular arrhythmia have been observed after ASA, possibly due to the use of relatively large amounts of alcohol [11]. Smaller compared to larger amounts of alcohol were found associated with a smaller infarct size after ASA, but with equal gradient reduction and without an excess of ventricular arrhythmia [12]. In order to reduce the risk for ventricular arrhythmia it therefore seems sensible to keep the size of infarctions after ASA as small as possible. Though a relation between infarct size and amount of alcohol was not found in the present study, our results do support this approach since larger infarctions did not lead to a better outcome in terms of relief of symptoms and gradient. One of the reasons why larger infarctions may not lead to a better outcome is that a small well placed basal infarction can already lead to sufficient widening of the LVOT and a larger infarction therefore cannot give any further improvement. Still it is possible that infarctions smaller in size than the infarctions seen in the present study may not be able to give a successful outcome. The association of sparing of the basal septum with outcome after ASA in this study provides a possible explanation for the previously found higher gradients after ASA as compared to surgical myectomy. [3,5,6]. Myocardial contrast echocardiography (MCE) can be used to determine the perfusion area of the cannulated septal branch. However, it can be challenging to obtain optimal images and it is conceivable that this causes a suboptimal result of ASA. Septal coronary anatomy has previously been found associated with outcome after ASA [20]. Although not the primary goal of the present study an association was indeed found between septal anatomy and location of the infarction, a longer distance being associated with distal infarction (Table 3). The operator remains dependent on septal coronary anatomy and when the perfusion bed of the basal part of the septum cannot be reached, the basal part will remain intact and the infarction is inflicted more distally. This can explain why infarct location remains variable after ASA causing gradients to remain higher in some patients after ASA. Taken together, it appears that the operator should evaluate MCE and septal anatomy and try to target the septal branch that will induce a small basal infarction. Limitations: The small sample size of the study group is a limitation. We used a strict definition of success, previously defined by Sorajja et al (4). There is, however, no clear consensus for definition of success after ablation in the literature. Another potential limitation is the fact that this was a retrospective observational center study and patients have not been randomized between ASA and surgical myectomy. Measurements were semi-automatic of nature and

Chapter 4

were performed by a single observer which may have caused bias, though the observer was blinded for all other data. Both cine images and LGE images were used with a quantitative measurement for the location of the infarction and yielded similar results. With late enhancement thin non-transmural protrusions of the ASA induced infarction are seen that may not cause thinning of the septum and can therefore overestimate the actual thinned and scarred area of infarction. As the thinning of the myocardium is important for the enlargement of the LVOT the assessment of cine images for thinned myocardium was used for the division of basal versus distal infarction. In theory infarct size may have been overestimated due to presence of LGE prior to ASA in the exact same location, however fibrosis directly outside the infarct location was not included in the analysis therefore limiting influence on the infarct size. Finally, patients with a pacemaker or ICD were excluded and not all eligible patients underwent CMR imaging leading to possible selection bias. Conclusion: An infarct location without sparing of the most basal part of the septum was associated with successful outcome after ASA for obstructive HCM. Residual obstruction after ASA can be explained by infarct location (i.e. distal infarction) but not by smaller infarct size. Acknowledgments: none No conflict of interest No funding resources

Basal infarct location and successful outcome after ASA: A CMR study

Reference List 1. Maron BJ, Maron MS (2013). Hypertrophic cardiomyopathy. Lancet 381(9862):242-255. doi: 10.1016/S0140-6736(12)60397-3 2. Ball W, Ivanov J, Rakowski H, Wigle ED, Linghorne M, Ralph-Edwards A, Woo A (2011). Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol 58:2313-2321. doi: 10.1016/j.jacc.2011.08.040 3. Alam M, Dokainish H, Lakkis NM (2009). Hypertrophic obstructive cardiomyopathyalcohol septal ablation vs myectomy: a meta-analysis. Eur Heart J 30:1080-1087. doi: 10.1093/eurheartj/ehp016 4. Sorajja P, Ommen SR, Homes Jr. DR, Dearani JA, Rihal CS, Gersh BJ, Lennon RJ, Nishimura RA (2012). Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 126:2374-2380. doi: 10.1161/CIRCULATIONAHA.111.076257 5. Leonardi RA, Kransdorf EP, Simel DL, Wang A (2010). Meta-analysis of septal reduction therapies for obstructive hypertrophic cardiomyopathy. Comparative rates of overall mortality and sudden cardiac death after treatment. Circ Cardiovasc Interv 3:1-7. doi: 10.1161/CIRCINTERVENTIONS.109.916676 6. Agarwal S, Tuzcu EM, Desai MY, Smedira N, Lever Hm, Lytle BW, Kapadia SR (2010). Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol 55:823-834. doi: 10.1016/j.jacc.2009.09.047 7. Jensen MK, Prinz C, Horsthotte D, van Beure F, Bitter T, Faber L, Bundgaard H (2013). Alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy: low incidence of sudden cardiac death and reduced risk profile. Heart 99(14): 1012-1017 doi: 10.1136/heartjnl-2012-303339 8. Nagueh SF, Groves BM, Schwartz L, Smith KM, Wang A, Bach RG, Nielsen C, Leya F, Maldonado YM, Spencer WH 3rd (2011). Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy. A multicenter North American registry. J Am Coll Cardiol 58:2322-2328. doi: 10.1016/j.jacc.2011.06.073 9. Valeti US, Nishimura RA, Holmes DR, Araoz PA, Glockner JF, Breen JF, Ommen SR, Gersh BJ, Tajik AJ, Rihal CS, Schaff HV, Maron BJ (2007). Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 49:350-357. doi:10.1016/j.jacc.2006.08.055

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10. Chang SM, Lakkis NM, Franklin J, Spencer WH 3rd, Nagueh SF (2004). Predictors of outcome after alcohol septal ablation therapy in patients with hypertrophic obstructive cardiomyopathy. Circulation 109:824-827. doi: 10.1161/01.CIR.0000117089.99918.5A 11. ten Cate FJ, Soliman OII, Michels M, Theuns DA, de Jong PL, Geleijnse ML, Serruys PW (2010). Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy. A word of caution. Circ Heart Fail 3:362-369. doi: 10.1161/CIRCHEARTFAILURE.109.862359 12. Veselka J, Procházková S, Duchonová R, Bomovolá-Homovolá I, Pálenícková J, Tesar D, Cervinka P, Honek T (2004). Alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Lower alcohol dose reduces size of infarction and has comparable hemodynamic and clinical outcome. Cath Cardiovasc Interv 63(2):231-235. DOI: 10.1002/ccd.20176 13. Van der Lee C, Scholzel B, ten Berg JM, Geleijnse ML, Idzerda HH, van Domburg RT, Vletter WB, Serruys PW, ten Cate FJ (2008). Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation. Am J Cardiol 101:1315-1320. doi: 10.1016/j.amjcard.2008.01.003 14. Guarise A, Faccioli N, Foti G, Da Pozzo S, Meneghetti P, Morana G (2011). Role of echocardiography and cardiac MRI in depicting morphological and functional imaging findings useful for diagnosing hypertrophic cardiomyopathy. Radiol med 116:197-210. doi: 10.1007/s11547 15. Pollick C, Rakowski H, Wigle ED (1984). Muscular subaortic stenosis: the quantative relationship between systolic anterior motion and pressure gradient. Circulation 69:43-49. doi: 10.1161/01.CIR.66.5.1087 16. van Dockum WG, ten Cate FJ, ten Berg JM, Beek AM, Twisk JW, Vos J, Hofman MB, Visser CA, van Rossum AC (2004). Myocardial infarction after percutaneus transluminal septal ablation in hypertrophic obstructive cardiomyopathy: evaluation by contrast-enhanced magnetic resonance imaging. J Am Coll Cardiol 43:27-24. DOI: 10.1016/j.jacc.2003.08.031 17. van Dockum WG, Beek AM, ten Cate FJ, ten Berg JM, Bondarenko O, Götte MJ, Twisk JW, Hofman MB, Visser CA, van Rossum AC (2005). Early onset and progression of left ventricular remodeling after alcohol septal ablation in hypertrophic obstructive cardiomyopathy. Circulation 111:2503-2508. doi: 10.1161/01.CIR.0000165084.28065.01 18. Yuan J, Qiao S, Zhang Y, You S, Duan F, Hu F, Yang W (2010). Follow-up by cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy who underwent

Basal infarct location and successful outcome after ASA: A CMR study

percutaneous ventricular septal ablation. Am J Cardiol 106:1487-1491. doi: 10.1016/j.amjcard.2010.07.017 19. Berruezo A, Vatasescu R, Mont L, Sitges M, Perez D, Papishvilli G, Vidal B, Francino A, Fernández-Armenta J, Silva E, Bijnens B, González-Juanatey JR, Brugada J (2011). Biventricular pacing in hypertrophic obstructive cardiomyopathy: A pilot study. Heart Rhythm ;8:221-227. doi: 10.1016/j.hrthm.2010.10.010 20. Steggerda RC, Balt JC, Damman K, van den Berg MP, ten Berg JM (2013). Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Special interest for the septal coronary anatomy. Neth Heart J 21(11): 504509. doi: 10.1007/s12471-013-0453-4 21. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Failure Society of America; Heart Rhythm Society; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons (2011). 2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.. Circulation 124(24):e783-831. doi: 10.1161/CIR.0b013e318223e2bd

Chapter 5

Effect of Alcohol Dosage on Long-Term Outcomes after Alcohol Septal Ablation in Patients with Hypertrophic Cardiomyopathy

Max Liebregts, M.D., Pieter A Vriesendorp, M.D., Robbert C Steggerda, M.D., Arend FL Schinkel, M.D., Ph.D., Jippe C Balt, M.D., Ph.D., Folkert J ten Cate, M.D., Ph.D., Michelle Michels, M.D., Ph.D., Jurriën M ten Berg, M.D., Ph.D.

Submitted

Chapter 5

Abstract Background: Alcohol septal ablation (ASA) can be performed to reduce left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy (HCM). However, the effect of alcohol dosage on long-term outcome is unknown. The aim of this study is to assess the longterm effects of alcohol dosage on mortality and adverse arrhythmic events (AAE). Methods and Results: This retrospective cohort study includes 296 HCM patients who underwent ASA (age 60 ± 22 years, 58% male) because of symptomatic LVOT obstruction. 29 patients (9.8%) were excluded because the alcohol dosage could not be retrieved. Primary endpoints were all-cause mortality and AAE. During 6.3 ± 3.7 years of follow-up all-cause mortality and AAE rates were similar in patients who received ≤2.0 mL (n= 142) and >2.0 mL (n= 121) alcohol during ASA. Age was the only independent predictor of mortality (HR 1.1 95% CI 1.0-1.1, p< 0.001). Predictors of AAE were maximum CK-MB >240 U/L (HR 3.3 95% CI 1.5-7.2, p= 0.003), and sudden cardiac death survivor (HR 5.9 95% CI 1.7-20.3, p= 0.004). There was a mild to moderate correlation between CK-MB levels and amount of alcohol (Spearman’s ρ 0.39, p< 0.001), cross-sectional area of the target septal branch ostium/ostia (Spearman’s ρ 0.19, p= 0.003), and maximum ventricular wall thickness (Spearman’s ρ 0.17, p= 0.006). Conclusion: Alcohol dosage appears not to have a long-term effect on mortality or AAE. A larger infarct size created by ASA increases the risk of AAE, and extensive monitoring of these patients is advised. Keywords: hypertrophic cardiomyopathy; alcohol septal ablation; septal reduction therapy

Alcohol dosage and outcome after ASA

Introduction Hypertrophic cardiomyopathy (HCM) is an inheritable myocardial disease present in one in 500 of the general population (1). HCM is characterized by left ventricular hypertrophy and is often associated with (provocable) left ventricular outflow tract (LVOT) obstruction (2). Symptoms such as dyspnea (on exertion), syncope and angina due to LVOT obstruction can be alleviated by the use of β-‐receptor antagonists, verapamil or disopyramide. If patients remain severely symptomatic despite optimal medical therapy, septal reduction therapy should be considered, either by surgical myectomy or alcohol septal ablation (ASA) (3-‐6). ASA was introduced as a percutaneous alternative to surgical myectomy, and has shown to be effective in reducing LVOT obstruction and associated symptoms (7-‐9). In the nearly 20 years since its introduction, ASA has become a valuable alternative in the management of HCM patients, and important developments (e.g. the use of intramyocardial ultrasound contrast agents) have improved the safety and efficacy of the technique (8-‐10). Concerns about ASA remain however, especially about the possible arrhythmogenic effect of the ablation scar in patients already at an increased risk of life-‐threatening arrhythmias (11). The effect of the dosage of intracoronary alcohol in this context remains controversial, and long-term results are scarce (12-15). The aim of this study is to evaluate the long-term effects of alcohol dosage in ASA on mortality and adverse arrhythmic events (AAE). Methods Study design and patient population A two-center, observational cohort design was used. The study population consisted of 296 consecutive HCM patients who underwent ASA in the St. Antonius Hospital Nieuwegein, Nieuwegein, the Netherlands (n = 209), and the Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands (n = 87). All patients met the criteria for invasive treatment: (i) ventricular septal thickness ≥ 15 mm, (ii) (provocable) LVOT gradient ≥ 50 mmHg, and (iii) persistent New York Heart Association (NYHA) class III/IV dyspnea or Canadian Cardiovascular Society class III/IV angina despite optimal medical therapy (3-5). The choice of ASA instead of surgical myectomy was based on patient profile (age, comorbidities, etc.) and patient preference. Patients were divided in 2 groups, based on the amount alcohol received: a high dose alcohol group (> 2.0 mL) and a low dose alcohol group (≤ 2.0 mL). A 2.0 mL cut-off was chosen because this was the mean amount of intracoronary alcohol used in

Chapter 5

the entire cohort (range 0.75-8 mL), and because this was in line with previous studies (1213). Patients where the alcohol dosage could not be retrieved were excluded. The study conforms to the principles of the Helsinki Declaration. The patients gave informed consent prior to the procedure, and local institutional review board approval was obtained. The procedure ASA was performed as described previously (16-17). After placement of a temporary right ventricular pacing lead, a double lumen pigtail catheter was advanced in the left ventricle allowing for simultaneous pressure recordings in de left ventricle and ascending aorta. Coronary angiography was then performed and after visual assessment of the septal perforator branches of the left anterior descending artery the first or second septal perforator was wired with a 0.014” coronary guidewire introduced into an over-the-wire (OTW) balloon. After removal of the coronary guidewire, 2 mL of echo contrast agent (Sonovue, Bracco Diagnostics, Milan, Italy) was selectively injected into the septal perforator through the inner lumen of the OTW balloon to allow for echocardiographic identification of the basal left ventricular septum as appropriate anatomical target. If the area of perfusion on the septum was not the area of contact by systolic anterior motion of the anterior leaflet of the mitral valve, another septal perforator was cannulated. Subsequent dosages of 0.5 mL of absolute alcohol were injected slowly over 1-15 minutes in the septal perforator under continuous echocardiographic guidance. If significant LVOT gradient would remain afterwards, additional septal perforators could be treated. Once success was achieved, the balloon was deflated, and coronary angiography was repeated to confirm the occlusion of the septal branch and patency of the left anterior descending coronary artery. The temporary pacemaker lead was kept in place for at least 24 hours. All patients were monitored for at least 24 hours at the intensive coronary care unit afterwards. Follow-up and endpoints Follow-up started at the time of ASA, and the first procedures were performed in 1999. At baseline all patients were evaluated for the following characteristics: age, sex, NYHA class, maximum left ventricular wall thickness (LVWT), maximum (provocable) LVOT gradient, left ventricular function, atrial fibrillation, coronary artery disease, medication used, conventional risk factors for sudden cardiac death (SCD) (3-5), amount of intracoronary alcohol used during the procedure and the cross-sectional area of the ostium/ostia of the target septal perforator(s). The primary endpoints of this study were all-cause mortality and AAE during follow-up. AAE consisted of: SCD, resuscitated cardiac arrests due to ventricular fibrillation or 98

Alcohol dosage and outcome after ASA

tachycardia, and appropriate implantable cardioverter-defibrillator (ICD). Secondary endpoints were periprocedural (< 30 days) AAE and mortality, LVOT gradient reduction, maximum CK-MB, temporary atrioventricular (AV) block, permanent pacemaker implantation, re-intervention (ASA or myectomy) and HCM-related death (death due to heart failure, stroke or SCD). Mortality and adverse events were retrieved from hospital patient records at the center where follow-up occurred, from civil service population registers, and from information provided by patients themselves and/or their general practitioners. All ICD shocks were evaluated by an experienced electrophysiologist, unaware and independent of the study purpose and endpoints. If no events occurred during follow-up, the administrative censoring date was set at November 1st, 2012. Statistical Analysis SPSS version 20 (IBM, Armonk, NY, USA) and Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) were used for all statistical analyses. Categorical variables were summarized as percentages. Normally distributed continuous data are expressed as mean ± standard deviation and non-normally distributed data are expressed as median ± interquartile range. To compare continuous variables Student t test or MannWhitney U-test were used, and to compare categorical variables the χ2-test was used. To identify clinical predictors of all-cause mortality and AAE univariable and multivariable Cox regression analysis was used. Variables were selected for multivariable analysis if univariable p-value was < 0.10 and were expressed as hazard ratio (HR) with 95% confidence interval. The final number of variables was restricted according to the number of endpoint events to avoid overfitting the multivariable model. For correlation analysis, spearman’s ρ was calculated in case of a non-linear relationship between the variables, or if the variables were non-normally distributed. A p-value ≤ 0.05 was considered statistically significant. Results Clinical characteristics In the cohort of 296 patients, 29 (9.8%) were excluded because no alcohol dosage could be retrieved. Of these 29 patients (age 60 ± 22, 44% male), 1 experienced periprocedural ventricular fibrillation and 3 patients died (none in the first 30 days). The cause of death was SCD in 1 patient, and non-cardiac in the others. The baseline characteristics of the remaining 267 patients (age 61 ± 14, 58% male) are found in Table 1. Patients in the low dose group (n = 143) were older (63 ± 24 years) than those

Chapter 5

from the high dose group (n = 124, age 58 ± 22 years, p = 0.005). Conversely, fewer patients from the low dose group were in NYHA class III/IV (76% vs. 85%, p = 0.05) or had systolic dysfunction on echocardiography (2% vs. 9%, p = 0.03). Procedural outcomes Over time a reduction of the mean amount of alcohol used for ASA was seen (Figure 2, p < 0.001). This was irrespective of the pre and post-procedural LVOT gradient (Figure 3). The infarct size after a high amount of alcohol was greater than after a low dose (maximum CKMB levels 213 ± 137 U/L vs. 152 ± 91 U/L, p < 0.001), which resulted in a slightly greater reduction in LVOT gradient (95% vs. 86%, p < 0.001). The NYHA class post-procedure was similar in both groups though (p = 0.08), and more re-intervention (ASA or myectomy) was necessary in patients who received a high dose compared with the low alcohol group (15% vs. 6%, p = 0.01) (Table 3). The maximum CK-MB level was correlated with amount of alcohol (Spearman’s ρ 0.39, p < 0.001), cross-sectional area of the target septal branch ostium (Spearman’s ρ 0.19, p = 0.003), and maximum LVWT (Spearman’s ρ 0.17, p = 0.006). Temporary periprocedural AV block was present in 78 patients (29%). This resulted in permanent pacemaker implantation in 14 patients (10%) of the low alcohol group and 9 patients (7%) of the high alcohol group (p = 0.5). Within the first 30 days of follow-up 4 patients died, of which 3 received a high amount of alcohol (p = 0.3). AAE occurred in 10 patients, of which 6 received a high amount of alcohol (p = 0.3) (Table 2). Long-term outcomes Of the 267 patients, follow-up was completed in 263 patients (99%) with a median follow-up duration of 6.3 ± 3.7 years. The four patients lost to follow-up had moved abroad and could not be reached. During follow-up there was a total of 38 deaths in the entire cohort (Table 3): 13 (34%) were HCM-related, 22 (58%) patients died of certified non-cardiac causes, and no cause of death could be identified in 3 (8%). Kaplan-Meier estimates of survival are shown in Figure 1. All-cause mortality was similar in patients who received ≤ 2.0 mL and patients who received > 2.0 mL intracoronary alcohol during ASA (p = 0.2). The same applied for HCM-related mortality (p = 0.2). The 5- and 10year survival for patients receiving a low amount of alcohol was 94% and 89%, respectively. Which was similar to the 91% and 85% for patients receiving a high amount of alcohol (p = 0.5 and p = 0.8, respectively). The only independent predictor of all-cause mortality was age (HR 1.1 95% CI 1.0-1.1, p < 0.001). A persisting high post-procedural LVOT gradient (≥ 50 mmHg) showed a trend towards increased mortality (p = 0.06) (Table 4). 100

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AAE during follow-up were also similar in the two groups: 7 events (5%) occurred in the low dose group and 9 events (7%) in the high dose group (Table 3, p = 0.4). This translates in an annual event rate of 0.91% after ASA with < 2.0 mL alcohol and 0.99% after ASA with > 2.0 mL alcohol. Multivariable analysis identified the following independent predictors of AAE: maximum CK-MB > 240 U/L (HR 3.3 95% CI 1.5-7.2, p = 0.003), and SCD survivor (HR 5.9 95% CI 1.7-20.3, p = 0.004) (Table 4). Discussion The most important result of this study was that long-term mortality and AAE rates after ASA were not increased if a higher dose of alcohol was used. Also, periprocedural AAE and mortality, AV-blocks and pacemaker implantations were similar in both high dose alcohol and low dose alcohol groups. ASA and alcohol dosage ASA was introduced in 1995 as an alternative to surgical myectomy (7). Initially, relatively high doses of alcohol were used (3-6 mL). Over time clinical experience combined with better strategies to identify the target septal branches (e.g. the use of intramyocardial ultrasound contrast agents) led to the use of lower doses of alcohol during ASA (8-10). The subsequent “learning curve” of the centers participating in this study is shown in Figure 2. The first study to investigate the correlation between amount of intracoronary alcohol and the outcome of ASA was conducted by Kuhn et al. (12). This retrospective study comprises two series: 329 patients treated in a dose finding strategy with decreasing amounts of alcohol until 2001, and 315 patients of the “low alcohol dose era” treated until 2005. Patients treated with high amounts of alcohol (> 2.0 mL) had a higher mortality rate than those treated with less alcohol. The mean follow-up of this cohort is no more than 2.1 years though. Also, the patients treated with a high dose of alcohol were by definition the first patients to undergo ASA at this center. Veselka et al. (13) conducted a prospective study with 76 patients who were randomized into two equal groups, and subsequently treated with ≤ 2.0 mL and > 2.0 mL intracoronary alcohol. They found no differences in post-procedural complications between both groups and after a median follow up of 7 years all-cause mortality was equal. Though these findings are in line with this study, the small size of the study doesn’t allow for a reliable survival analysis and the study may not be powered enough to detect this difference.

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In the study by ten Cate et al. (11), which included a subset of the patients included in this study, ASA was associated with an increased risk for SCD. The study was criticized for the use of high amounts of alcohol (3.5 ± 1.5 mL) in its ASA patients. In their analysis no effect of alcohol dosage was observed however. ASA and infarct size We found that higher CK-MB levels after ASA predicted AAE during follow-up (HR 3.3 95% CI 1.5-7.2, p = 0.003). Although no direct effect of alcohol on AAE was observed, a higher dose of intracoronary alcohol was associated with higher CK-MB levels. This is in line with previous studies (18-20). In addition to amount of alcohol, caliber of the target septal perforator(s) and LVWT also showed a positive correlation with CK-MB levels. The infarct size and concomitant risk of AAE may therefore be the resultant of a combination of these variables. Since the separate correlations are mild to moderate at best however, the infarct size for an individual patient can still be hard to predict. On the contrary, finding high CK-MB levels post-procedure could warrant extended monitoring or preventive ICD implantation, especially in the presence of other risk factors for SCD. A low dose of intracoronary alcohol in ASA can be as effective as a high dose. Veselka et al. (14) showed that the use of a very low dose of alcohol (mean 1.0 +/- 0.1 mL) is as effective in reducing the LVOT gradient as using a mean dose of 2.5 +/- 0.8 mL. Boekstegers et al. (15) came to the same conclusion after treating 50 patients with a mean amount of 1.9 +/- 0.7 mL intracoronary alcohol. These findings are in line with our study. Despite a slightly lower gradient at follow-up in the high dose alcohol group, this did not lead to a difference in NYHA class at follow-up, nor to a lower rate of re-do procedures. In fact, re-interventions were even more common in the high dose group compared with the low dose group (15% vs. 6%, p = 0.01). This circumstantial evidence suggests that the smallest effective infarct size should be pursued. This may be achieved by using a low dose of alcohol, more distally in the target septal perforator(s). Study limitations This study has several limitations. Data collection was limited to variables that were routinely collected. The study was performed in 2 referral centers for the care of HCM, and selection and referral bias can be present. The cause of death could not be determined in 3 of the 38

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deaths (8%) that occurred. In addition there was a large group (10%) in which no dose of alcohol could be retrieved, but events in this group were low (1 case of SCD). It was not possible to correct for individual or local alterations of percutaneous technique. However, all procedures were performed by experienced interventional cardiologists, plus this implies that our findings are more generalizable than those of single-center investigations. The cut-off value of 2.0 mL of alcohol was arbitrarily chosen because this was the median alcohol dose in this ASA cohort and previous studies have used this cutoff value, facilitating comparison to these studies. Choosing a cut-off value of 3.0 mL however, didn’t result in a significant difference in long-term mortality and AAE either. Conclusion Alcohol dosage appears not to have a long-term effect on mortality or AAE. A larger infarct size created by ASA increases the risk of AAE, and extensive monitoring of these patients is advised. Disclosures None

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Figure 1. Kaplan Meier graphs showing 10-year survival in 263 patients after alcohol septal ablation.

P = 0.8

Figure 2. The learning-curve effect, showing systematic reduction of the mean amount of alcohol injected during the procedure over time.

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Figure 3. Pre-procedure LVOT gradient (red) and post-procedure LVOT gradient (black) over time.

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Table 1. Baseline characteristics of 267 alcohol septal ablation patients.

n = Age, median ± IQR, years Female NYHA III/IV Maximum LVWT, median ± IQR, mm LVOT gradient, median ± IQR, mmHg Systolic dysfunction (EF < 50%) Coronary artery disease Atrial fibrillation Medication β-‐receptor antagonist Calcium-‐channel blocker Risk factors Sudden cardiac death survivor

Low alcohol group (≤ 2.0 mL) 143 63 ± 24 63 (44) 108 (76) 20 ± 5

High alcohol group (> 2.0 mL)

124 58 ± 22 50 (40) 105 (85) 20 ± 6

P 0.005 0.5 0.05 0.1

90 ± 86

100 ± 42

0.8

3 (2) 34 (24) 37 (26)

11 (9) 23 (19) 24 (19)

0.03 0.3 0.2

92 (64) 54 (38) 4 (3)

87 (70) 41 (33) 3 (2)

0.3 0.4 1.0

≥ 2 conventional risk factors for 13 (9) 14 (11) 0.4 SCD Procedure Volume of alcohol injected, 2 ± 0 3 ± 1.5 < 0.001 median ± IQR, mL Ostium area, median ± IQR, mm² 1.8 ± 1.4 2.3 ± 1.4 < 0.001 Data represented as n (percentage) unless stated otherwise. EF: ejection fraction, IQR: interquartile range, LVOT: left ventricular outflow tract, LVWT: left ventricular wall thickness, NYHA: New York Heart Association, SCD: sudden cardiac death.

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Table 2. Periprocedural (< 30 days) outcomes after alcohol septal ablation in 267 patients.

Low alcohol group High alcohol (≤ 2.0 mL) group (> 2.0 mL) n = 143 124 P Maximal CK-‐MB levels, median ± IQR, 152 ± 91 213 ± 137 < U/L 0.001 Atrioventricular block 46 (32) 32 (26) 0.2 Pacemaker implantation 14 (10) 9 (7) 0.5 Periprocedural mortality 0.3 Total mortality 1 (1) 3 (2) Sudden cardiac death 1 (1) 2 (2) 0.5 Cardiac tamponade -‐ 1 (1) -‐ Periprocedural adverse arrhythmic events Total adverse events 4 (3) 6 (5) 0.3 Sudden cardiac death 1 (1) 2 (2) 0.5 Sustained ventricular tachycardia 2 (1) -‐ -‐ Resuscitated cardiac arrest 1 (1) 4 (3) 0.2 Data are represented as n (percentage) unless stated otherwise. IQR: interquartile range.

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Table 3. Long-term outcomes after alcohol septal ablation in 263 patients.

Low alcohol group (≤ 2.0 mL) 142 4.9 ± 6.1

High alcohol group (> 2.0 mL)

n = 121 P Years of follow-‐up, median ± 7.6 ± 4.1 < 0.001 IQR Residual LVOT gradient > 3 11 ± 18 6 ± 20 < 0.001 months post-‐procedure, median ± IQR, mmHg Reduction in LVOT gradient 86 ± 25 95 ± 21 < 0.001 > 3 months post-‐procedure, median ± IQR, % NYHA class III/IV > 3 8 (6) 15 (12) 0.08 months post-‐procedure Redo septal reduction 8 (6) 18 (15) 0.01 therapy Mortality Total mortality 17 (12) 21 (17) 0.2 1. HCM-related death 5 (4) 8 (7) 0.2 Non-cardiac 11 (8) 11 (9) 0.7 Unknown 1 (1) 2 (2) 0.5 5-‐year survival, % 94 91 0.5 10-‐year survival, % 89 85 0.8 Adverse arrhythmic events (> 30 days post-‐procedure) Total adverse events 7 (5) 9 (7) 0.4 Sudden cardiac death 2 (1) 3 (2) 0.5 Resuscitated cardiac arrest 2 (1) 1 (1) 1.0 Appropriate ICD shocks 2 (1) 4 (3) 1.0 Annual events, %/year 0.91 0.99 0.4 Data are represented as n (percentage), unless stated otherwise. HCM: hypertrophic cardiomyopathy, ICD: internal cardioverter defibrillator, IQR: interquartile range, LVOT: left ventricular outflow tract, NYHA: New York Heart Association.

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Table 4. Analysis of clinical variables associated with all-cause mortality and adverse arrhythmic events in 263 patients after ASA. Univariable Multivariable HR CI 95% P HR CI 95% P Mortality (n = 38) Age 1.06 1.03-‐1.09 < 0.001 1.07 1.04-‐1.10 < 0.001 Female 2.2 1.12-‐4.13 0.02 1.2 0.56-‐2.64 0.6 High dose alcohol (> 2.0 mL) 1.0 0.53-‐1.93 1.0 Post-‐procedure NYHA III/IV 1.7 0.64-‐4.38 0.3 Post-‐procedure LVOT gradient > 50 mmHg 2.8 1.09-‐7.35 0.03 2.6 0.97-‐6.78 0.06 Coronary artery disease 2.2 1.15-‐4.30 0.02 1.6 0.78-‐3.30 0.2 Adverse arrhythmic events (n = 26) Age 0.99 0.97-‐1.02 0.6 Female 0.8 0.40-‐1.93 0.7 High alcohol dose (> 2.0 mL) 1.3 0.63-‐2.99 0.4 CK-‐MB > 240 U/L 4.5 2.02-‐10.1 < 0.001 3.3 1.51-‐7.16 0.003 Ostium area > 2 mm² 1.9 0.90-‐4.10 0.09 1.7 0.77-‐3.79 0.2 Atrial fibrillation 1.2 0.51-‐2.90 0.7 Coronary artery disease 0.8 0.33-‐2.35 0.8 Sudden cardiac death survivor 6.8 2.02-‐22.9 0.002 5.9 1.74-‐20.3 0.004 ≥ 2 conventional risk factors for 1.66-‐8.83 SCD 3.8 0.002 2.2 0.66-‐7.05 0.2 Backwards multivariable Cox regression analysis was used. CI: confidence interval, HR: hazards ratio, LVOT: left ventricular outflow tract, NYHA: New York Heart Association, SCD: sudden cardiac death.

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Reference list: 1.Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary artery risk development in (young) adults. Circulation. 1995;92:785-789. 2.Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114:2232-2239. 3.Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH 3rd, Spirito P, Ten Cate FJ, Wigle ED; Task Force on Clinical Expert Consensus Documents. American College of Cardiology; Committee for Practice Guidelines. European Society of Cardiology. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol. 2003;42:1687-1713. 4.Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124:2761-2796. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri 5.S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European society of cardiology (ESC) [published online ahead of print August 29 2014]. Eur Heart J. 2014. doi: 10.1093/eurheartj/ehu284. 6.ten Berg JM, Steggerda RC, Siebelink HM. Myocardial disease: the patient with hypertrophic cardiomyopathy. Heart. 2010;96:1764-1772. 7.Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet. 1995;346:211-214.

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8.Fifer MA, Sigwart U. Controversies in cardiovascular medicine. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation. Eur Heart J. 2011;32:1059-1064. 9.Rigopoulos AG, Seggewiss H. A decade of percutaneous septal ablation in hypertrophic cardiomyopathy. Circ J. 2011;75:28-37. 10.Faber L, Seggewiss H, Welge D, Fassbender D, Schmidt HK, Gleichmann U, Horstkotte D. Echo-guided percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: 7 years of experience. Eur J Echocardiogr. 2004;5:347-355. 11.ten Cate FJ, Soliman OI, Michels M, Theuns DA, de Jong PL, Geleijnse ML, Serruys PW. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail. 2010;3:362-369. 12.Kuhn H, Lawrenz T, Lieder F, Leuner C, Strunk-Mueller C, Obergassel L, Bartelsmeier M, Stellbrink C. Survival after transcoronary ablation of septal hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience. Clin Res Cardiol. 2008;97:234-243. 13.Veselka J, Tomašov P, Zemánek D. Long-term effects of varying alcohol dosing in percutaneous septal ablation for obstructive hypertrophic cardiomyopathy: a randomized study with a follow up to 11 years. Can J of Cardiol. 2011;27:763-767. 14.Veselka J, Zemánek D, Tomasov P, Duchonová R, Linhartová K. Alcohol septal ablation for obstructive hypertrophic cardiomyopathy: ultra-low dose of alcohol (1 ml) is still effective. Heart vessels. 2009;24:27-31. 15.Boekstegers P, Steinbigler P, Molnar A, Schwaiblmair M, Becker A, Knez A, Haberl R, Steinbeck G. Pressure guided nonsurgical myocardial reduction induced by small septal infarctions in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2001;38:846-853. van der Lee C, ten Cate FJ, Geleijnse ML, Kofflard MJ, Pedone C, van Herwerden LA, 16.Biagini E, Vletter WB, Serruys PW. Percutaneous versus surgical treatment for patients with hypertrophic obstructive cardiomyopathy and enlarged anterior mitral valve leaflets. Circulation. 2005;112:482-488. 17.van der Lee C, Scholzel B, ten Berg JM, Geleijnse ML, Idzerda HH, van Domburg RT, Vletter WB, Serruys PW, ten Cate FJ. Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation. Am J Cardiol. 2008;101:1315-1320. 18.Li ZQ, Cheng TO, Liu L, Jin YZ, Zhang M, Guan RM, Yuan L, Hu J, Zhang WW. Experimental study of relationship between intracoronary alcohol injection and the size of the resultant myocardial infarction. Int J Cardiol. 2003;91:93-96.

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19.van Dockum WG, ten Cate FJ, ten Berg JM, Beek AM, Twisk JW, Vos J, Hofman MB, Visser CA, van Rossum AC. Myocardial infarction after percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: evaluation by contrastenhanced magnetic resonance imaging. J Am Coll Cardiol. 2004;43:27-34. 20.Veselka J, Procházková S, Duchonová R, Bolomová-Homolová I, Pálenícková J, Tesar D, Cervinka P, Honek T. Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy: Lower Alcohol Dose Reduces Size of Infarction and Has Comparable Hemodynamic and Clinical Outcome. Catheter Cardiovasc Interv. 2004;63:231-235.

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Outcome after Alcohol Septal Ablation and Surgical Myectomy in Hypertrophic Obstructive Cardiomyopathy. Special focus on periprocedural complications and long-term cardiovascular morbidity.

Robbert C. Steggerda MD, Kevin Damman MD, PhD, Jippe C. Balt MD, PhD, Max Liebregts MD3, Jurriën M. ten Berg MD, PhD, Maarten P. van den Berg MD, PhD

JACC cardiovasc Interv. 2014; 7(11): 1227-1234

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Abstract: Objective To compare alcohol septal ablation (ASA) and surgical myectomy for periprocedural complications and long-term clinical outcome in patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM). Background Debate remains whether ASA is equally effective and safe compared to myectomy. Methods All procedures performed between 1981 and 2010 were evaluated for periprocedural complications and long term clinical outcome. The primary endpoint was allcause mortality, secondary endpoints consisted of annual cardiac mortality, NYHA class, rehospitalisation for heart failure, re-intervention, cerebrovascular accident (CVA) and myocardial infarction. Results 161 patients after ASA and 102 patients after myectomy were compared during a maximum follow-up period of 11 years. The peri-procedural (30-day) complication frequency after ASA was lower compared to myectomy(14% vs 27%, p = 0.006), and duration of inhospital stay was shorter (5 (4–6) vs 9 (6–12), p < 0.001). After ASA provoked gradients were higher compared to myectomy (19 (10-42 vs 10 (7-13), p<0.001). After multivariate analysis, age (per 5 years) (OR 1.34 (1.08-1.65), P = 0.007) was the only independent predictor for all cause mortality. Annual cardiac mortality after ASA and myectomy was comparable (0.7% vs 1.4% p=0.15). During follow up no significant differences were found in symptomatic status, rehospitalisation for heart failure, re-intervention, CVA or myocardial infarction between both groups. Conclusions Survival and clinical outcome were good and comparable after ASA and Myectomy. More periprocedural complications and longer duration of hospital stay after myectomy were offset by higher gradients after ASA. Keywords: hypertrophic obstructive cardiomyopathy, myectomy, long-term outcome, alcohol septal ablation

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Condensed Abstract: Complications and outcome after alcohol septal ablation (ASA) and myectomy for symptomatic hypertrophic obstructive cardiomyopathy were retrospectively analyzed. Longterm mortality during a maximum follow-up of 11 years was comparable. After multivariate analysis the only predictor for all-cause mortality was age (per 5 years) (HR 1.34 (1.08-1.65), P = 0.007), but not type of procedure (ASA vs myectomy). Also symptomatic relief and clinical outcome on the long-term were comparable. After ASA, periprocedural complications were however less common and duration of hospital stay was shorter though gradients at late follow-up were higher compared to myectomy.

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Abbreviations list: ASA: alcohol septal ablation HOCM: hypertrophic obstructive cardiomyopathy LVOT: left ventricular outflow tract SAM: systolic anterior motion AMVL: anterior mitral valve leaflet VT: ventricular tachycardia VF: ventricular fibrillation SCD: sudden cardiac death

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Introduction Obstruction of flow in the left ventricular outflow tract (LVOT) is found in about 70% of patients with hypertrophic cardiomyopathy, referred to as hypertrophic obstructive cardiomyopathy (HOCM)(1). Though medical treatment can provide relief of symptoms, a sizeable subset of patients with HOCM remains symptomatic and in these subjects invasive treatment, i.e. septum reduction, is an established treatment option (2,3). Both alcohol septal ablation (ASA) and surgical myectomy have proven to be effective methods for relief of symptoms (4,5,6). In recent studies ASA is associated with excellent survival, comparable to survival in an age and sex matched population (7,8). Since ASA is also a less invasive treatment than myectomy, it may thus be a preferred treatment. On the other hand previous studies have also reported a higher need for pacemaker implantation and a higher rate of reinterventions after ASA as compared to myectomy (3,4), and in one single center study a warning was given that ASA may in fact increase cardiac mortality (9). We report our experience in a comprehensive study of both procedures including periprocedural complications, survival, cardiac survival, long-term symptomatic status and clinical outcome.

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Methods Study design and patient population. All patients that underwent either ASA or a surgical myectomy at the St.Antonius Hospital, Nieuwegein, The Netherlands, between January 1981 and January 2010 were included. ASA was carried out from January 2000 onwards. For patients to be selected for septum reduction (either ASA or myectomy) they had to have severe symptoms (New York Heart Association functional class ≥ 3) despite optimal medical therapy, in combination with a resting gradient in the LVOT ≥ 30 mm Hg and/or a provocable gradient ≥ 50 mm Hg. Patients with concomitant (sub)valvular disease, coronary artery disease or other conditions that warranted surgery underwent myectomy. Patients who were eligible for both options were informed about the known risks and benefits of both ASA and surgical myectomy and were offered the choice between these procedures. We performed a retrospective analysis of all baseline characteristics and periprocedural complications. Long-term survival and clinical outcome were investigated using a questionnaire and hospital records. The study conformed to principles defined in the Helsinki Declaration. Local institutional review board approval was obtained. Procedure. ASA was performed as described in detail previously (10). In short, with the aid of a flexible coronary guide wire, a coronary balloon was placed in the most proximal septal perforator branch. Myocardial contrast echocardiography was used for further guidance. Only when the region of contrast in the septum was judged satisfactory and adjacent to the area of septal contact of the anterior mitral valve leaflet, 0.5 to 3 ml of concentrated ethanol was slowly injected through the inflated balloon catheter. The balloon was left inflated for 10 minutes to prevent retrograde spill of ethanol. Invasive gradients in the LVOT were measured continuously during the procedure using a 6 French pigtail catheter inserted in the left ventricle. For testing of a provocable gradient, the Valsalva maneuver and extrasystolic beats were used. When the gradient in the LVOT remained ≥ 30 mm Hg after the first ablation (either at rest or after provocation), the procedure was repeated in one or two more accessible septal branches. During the procedure, all patients received a temporary transvenous pacemaker. If an AV block remained more than 48 hours after the procedure, a definitive pacemaker was implanted. Myectomy was performed as described previously (11). Peri-operative transesophageal echocardiography and visual inspection by the surgeon was performed in order to determine

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the extension of the myectomy and any (sub)valvular abnormalities. When necessary, surgery was combined with coronary artery bypass grafting (CABG). Follow-up. The degree of LVOT obstruction prior to intervention was measured using transthoracic echocardiography. Determination of the gradient directly after surgical myectomy was performed intra-operatively using transesophageal echocardiography. The gradient post ASA was determined invasively immediately after the procedure. For follow-up the last available report of an echocardiogram was used for determination of left ventricular ejection fraction and the gradient in the LVOT. A questionnaire was sent to all patients still alive in December 2010. In this questionnaire patients were asked about their symptomatic status; NYHA status (1-4 out of 4), chest pain and syncope. Clinical events (re-admittance for heart failure, a repeat intervention with ASA or surgical myectomy and appropriate ICD shocks) were captured any time after the procedure using hospital records and questionnaires. Telephonic inquiry was used to complete data when necessary. Civil registries were used to determine if patients were still alive. The cause of death was obtained from hospital and general practitioner records. Study endpoints. The primary endpoint was all-cause mortality and was determined during a maximal followup period of 11 years after both procedures. Secondary endpoints consisted of annual cardiac death rate, NYHA class at late follow-up, rehospitalisation due to heart failure, reintervention, cerebrovascular accident (CVA) and myocardial infarction and were determined during the entire follow-up period (average 9.1 (3.3-13.5) years after myectomy and 5.1 (2.97.5) years after ASA). Cardiac death consisted of death due to heart failure and due to sudden cardiac death. In order to prevent underestimation of cardiac death, deaths of unknown cause were also considered as cardiac death. Patients with an ICD were investigated for appropriate ICD shocks. Complications were considered periprocedural when occurring during the intervention or in the first 30 days after the intervention. Statistical analysis. Data are given as mean with standard deviation when normally distributed, as median and interquartile range for skewed distributions, and as frequencies and percentages for categorical variables. Student’s t-test (two-paired) and Mann-Whitney U test were used to compare variables between groups, where appropriate. Fisher’s-Exact test was used for comparison of categorical variables. Cox proportional hazard analysis was carried out for the first occurrence of all cause mortality. All baseline variables listed in table 1 were considered

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in the multivariate models when a P-value of < 0.1 was obtained in univariate analysis. In a second analysis, type of treatment (myectomy or ASA) was forced into the multivariate model to evaluate the multivariate effect on outcome. Due to the difference in follow-up duration, cardiac mortality and clinical events were compared on an annual basis. All cause mortality was also compared during a maximal follow-up duration of 11 years after both procedures. All reported probability values are two-tailed, and a P-value < 0.05 was considered statistically significant. Statistical analyses were performed using STATA, College Station, Texas, version 11.0.

Results 161 patients underwent ASA and 102 patients underwent myectomy. Baseline characteristics of the 2 treatment groups are shown in Table 1. Angina pectoris and coronary artery disease were more common in patients who underwent myectomy. Also revascularisation by combining CABG with myectomy was more common than revascularisation by combining PCI with ASA. Septal and posterior wall diameter were slightly larger in the ASA patients. Other baseline characteristics were comparable.

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Table 1 Baseline characteristics

Parameter

Myectomy

ASA

P value

(N = 102)

(N = 161)

Age (yrs)

56 ± 16

59 ± 14

0.09

Sex (% male)

46% (47)

53% (85)

0.31

NYHA class (I/II/III or IV, %)

5/19/76

1/19/80

0.12

Angina (CCS)

2.3 ± 0.6

2.0 ± 0.5

0.002

Syncope

20% (20)

18% (29)

0.74

LVH > 30 mm

5.9% (6)

5.6% (9)

0.999

VT on Holter

1% (1)

6% (10)

0.17

β -blocker or Ca-blocker (%)

88% (90)

80% (129)

0.16

Previous CVA

2.0% (2)

1.2% (2)

0.999

Previous AF

21% (21)

15% (24)

0.67

Coronary artery disease

17% (17)

5% (8)

0.004

ICD

2.9% (3)

2.5% (4)

0.999

Appropriate shock

1.0% (1)

0.6% (1)

0.999

Pacemaker

1.0% (1)

4.3% (7)

0.16

Family history of SCD

11% (11)

9% (14)

0.66

Family history of HCM

23% (23)

19% (31)

0.53

Septal thickness (mm)

20 (17-24)

21 (19-24)

0.03

Posterior wall thickness (mm)

14 ± 3

15 ± 4

0.01

Degree of MI

2.0 ± 1.1

1.6 ± 1.0

0.38

Gradient baseline (mmHg)

50 (25-75)

32 (18-75)

0.088

Gradient after Provocation (mmHg)

95 (70-120)

101 (69-150)

0.31

Myectomy + CABG

18% (18)

ASA + PCI

2.5% (4)

Medical history (%)

Echocardiogram

Additional Intervention

Data are presented as mean ± standard deviation, median and interquartile range for skewed distributions or as percentage (number). Abbreviations: ASA: alcohol septal ablation, AF: atrial fibrillation, CABG: coronary artery bypass graft, CCS: Canadian Cardiovascular

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Society, CVA: cerebrovascular accident, HCM: hypertrophic cardiomyopathy, ICD internal cardioverter defibrillator, LVH: Left ventricular hypertrophy, MI: myocardial infarction, NYHA:New York Heart Association, PCI: percutaneous coronary intervention, SCD: sudden cardiac death, VT: ventricular tachycardia. Periprocedural complications. Periprocedural severe complications (death, CVA and VT/VF) after ASA and myectomy were not significantly different (Table 2). One patient in the ASA group died due to spill of alcohol and a second patient died due to tamponade caused by a pacemaker lead perforation. Two patients died after myectomy due to refractory cardiogenic shock. In the first patient no cause of the cardiogenic shock was identified, in the second patient the cause was right ventricular infarction. Two other patients who underwent myectomy had a disabling CVA. A rethoracotomy was necessary in 11 patients; in seven patients because of excessive bleeding, two patients underwent an additional myectomy because of a significant residual gradient, one patient had an aneurysm of the aortic sinus needing repair and in one patient a ventricular septal rupture occurred which was repaired with a patch. After ASA a closure of a ventricular septal rupture was also performed but at a later stage and this was combined with a myectomy. All re-thoracotomies were performed successfully and were not associated with a worse long-term outcome. Other periprocedural complications were comparable between ASA and myectomy (Table 2) Total peri-procedural complication frequency was lower in the ASA group compared to the myectomy group (14% (22/161) vs 28% (29/102), P = 0.004). When comparing ASA and myectomy in the same time period of 2000-2010, 77% (161/209) of patients underwent ASA. In this time period ASA patients also had a lower periprocedural complication frequency than the myectomy patients (14% (22/161) vs 38 % (18/48), P < 0.001). Patients after ASA also had a lower complication frequency compared to patients after myectomy without CABG (14% (22/161) vs 29% (24/84), P = 0.006). Complication frequency of patients undergoing surgical myectomy with CABG was comparable to patients undergoing myectomy without CABG (28% (5/18) vs 29% (24/84), P = 1.0).

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Table 2 Periprocedural complications (30 days) Myectomy

ASA

P Value

(N = 102)

(N = 161)

Periprocedural death

2.0% (2)

1.2% (2)

0.56

Ventricular fibrillation/sustained VT

2.5% (4)

0.16

CVA

2% (2)

0.15

Dissection LAD

0.6% (1)

1.0

Pneumothorax

2% (2)

0.6% (1)

0.56

Mediastinitis

2% (2)

0.15

Pacemaker infection

1.2% (2)

0.52

Pacemaker implantation

9% (9)

7% (11)

0.64

Tamponade

8.8% (9)

1.2% (2)

0.004

Urgent re-thoracotomy

11.4% (11)

< 0.001

All complications (1 per patient)

28% (29)

14% (22)

0.004

Duration in-hospital stay (days)

9 (6–12)

5 (4–6)

<0.001

Data are presented as a percentage (number) and as median with interquartile range for skewed distributions. Abbreviations: CVA: cerebrovascular accident, LAD: Left anterior descending artery, VT ventricular tachycardia.

Survival and appropriate ICD shocks. Follow-up was completed in 99% (261/263) of the study population. Two patients were lost to follow-up due to a foreign address. During the maximal follow-up duration of 11 years allcause mortality after ASA and myectomy was comparable (Table 3 and Figure 1), and after multivariate analysis only age at baseline was an independent predictor (Table 4). After type of procedure was forced into a second multivariate analysis, ASA versus myectomy was also not associated with death (hazard ratio1.20 (0.49 – 2.94), P = 0.69). The median follow-up duration was 9.1 (3.3-13.5) years after myectomy and 5.1 (2.9-7.5) years after ASA. After myectomy, two deaths were due to heart failure, two patients had sudden cardiac death and in nine patients the cause of death was unknown. After ASA three deaths were due to heart failure and in three patients the cause of death could not be determined. Even when the unknown deaths were considered to be cardiac deaths, the annual occurrence of cardiac death after ASA and myectomy was comparable (table 3).In total seven ICDs were implanted

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before the procedure (myectomy n=3, ASA n=4), and a total of six ICDs were implanted after the procedure (myectomy n=1, ASA n=5)(Table 1,2). No appropriate ICD shocks were observed during the entire follow-up period in any of the ICD carriers.

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Table 3: Clinical outcome Myectomy

ASA

(N = 102)

(N = 159)

Follow-up duration (years)

9.1 (3.3-13.5)

5.1 (2.9-7.5)

< 0.0001

All cause death, annual

2.2% (21)

1.5% (13)

0.25

Cardiac death, annual

1.4% (13)

0.7% (6)

0.15

Non-cardiac death, annual

0.8% (8)

0.8% (7)

0.91

NYHA class (I/II/III or IV, %)

52/30/18

53/31/16

0.89

Angina status (CCS)

0.5 ± 0.9

0.7 ± 1.0

0.14

Syncope

2.0% (2)

8.2% (13)

0.053

0.6% (6)

0.3% (3)

0.40

Myocardial infarction, annual

0.2% (2)

0.1% (1)

0.66

CVA, annual

0.5% (5)

0.3% (3)

0.57

ICD-implantation

1% (1)

3% (5)

0.41

Appropriate ICD shock

(0)

Re intervention

1% (1)

6.3% (10)

0.055

(Re-)ASA

3.8 % (6)

0.08

(Re-)myectomie

1% (1)

2.5% (4)

0.65

12 (8-20)

10 (0-20)

< 0.001

Gradient baseline (mmHg)

9 (4-10)

10 (7-19)

0.003

Gradient after provocation(mmHg)

10 (7-13)

19 (10-42)

< 0.001

Ejection fraction %

61 ± 11

63 ± 8

0.26

Re-hospitalization for heart failure, annual

Post-procedural gradient (mmHg)

P Value

Echocardiogram (late follow-up)

Data are presented as mean ± standard deviation, median and interquartile range for skewed distributions or as an annual percentage (total numbers during total follow-up period). Abbreviations: AF: atrial fibrillation, ASA: alcohol septal ablation, CCS: Canadian Cardiovascular Society, CVA: cerebrovascular accident , ICD: Internal cardioverter defibrillator,NYHA: New York Heart Association.

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Figure 1. Survival after ASA versus Myectomy.

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Outcome after ASA and myectomy: periprocedural complications

Table 4: Univariate

Multivariate

Parameter

HR (95% CI)

P-value

HR (95% CI)

P-value

Baseline Septal diameter (mm)

0.85 (0.71-1.02)

0.089

Baseline LVOT min (mm)

1.26 (0.98-1.62)

0.073

Baseline gradient (mmHg)

0.98 (0.96-1.00)

0.021

0.98 (0.95-1.01)

0.146

Distance to begin infarct (mm)

0.80 (0.69-0.94)

0.006

0.76 (0.54-0.98)

0.034

Infarct Size (gram)

0.89 (0.81-0.98)

0.016

0.92 (0.82-1.04)

0.205

Data are presented using hazard ratio (HR) with the 95% confidence interval (95% CI). Abbreviation: LVOT: Left ventricular outflow tract Treatment effect. Questionnaires for symptomatic status were completed in 96% (220/229) of patients still alive at follow-up. No differences were found between myectomy and ASA patients for symptomatic status, re-hospitalisation for heart failure, CVA and myocardial infarction at follow-up (Table 3). Echocardiograms at late follow-up were retrieved in 92% (241/263) of patients with an average interval after the procedure of 3.9 ± 4.7 years. Baseline and provoked gradients in the LVOT at late follow-up were higher for patients after ASA (Table 3). A total of 10 re-interventions because of both a significant residual/recurrent gradient and symptoms were performed after ASA; six by means of ASA and four with surgical myectomy, whereas one second procedure (i.e. ASA) was performed in the myectomy group (6.3% vs. 1.0%, p=0.055)(Table 3).

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Discussion The main finding of the study is that long-term survival in our single center study was comparable after ASA and myectomy In addition we found that long-term symptomatic improvement after both procedures was comparable as well as the occurrence of cardiac death, CVA, myocardial infarction and rehospitalisation for heart failure. However, ASA was associated with a lower frequency of peri-procedural complications and a shorter duration of in-hospital stay compared to myectomy. Periprocedural complications. Severe periprocedural complications (death, CVA and VT/VF) were comparable between both treatments (Table 2) and largely comparable to previous studies (7, 12, 13). Regarding the need for pacemaker implantation the results after myectomy and ASA were also comparable, which is somewhat at variance with data reported in the literature, including in meta analyses, generally showing a higher need for pacemaker implantation after ASA (4,5). Importantly, in these meta-analyses age at baseline was higher for ASA, which may have confounded the relation between ASA patients and the need for pacemaker implantation, whereas in the present study age at baseline was comparable for ASA and myectomy. Another explanation for the comparable rate of pacemaker implantation in the present study may be the periprocedural use of myocardial contrast echocardiography or the judicious use of alcohol in the present study (14,15). The total frequency of peri-procedural complications in the present study was however lower for patients undergoing ASA compared to myectomy and this has not been reported previously. Also after correction for the time period and after exclusion of myectomy combined with CABG the frequency of complications remained lower after ASA. The difference in complication frequency was mainly due to a need for re-thoracotomy after myectomy (because of bleeding, tamponade, repair of an aneurysm of the aortic sinus and the need for a second myectomy). These complications and the longer stay in hospital after myectomy do reflect the more invasive nature of myectomy. Nevertheless, all periprocedual complications were treated successfully and were not associated with a worse long-term outcome.

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Outcome after ASA and myectomy: periprocedural complications

Long term outcome. One of the feared long-term complications after ASA is the possible predisposition for ventricular arrhythmia after the induction of a septal infarction (1). In one single center study, a higher rate of ICD shocks and sudden cardiac death was found after ASA compared to myectomy (9). In the present study, other recent studies and a meta-analysis the occurrence of sudden cardiac death and appropriate ICD shocks was comparable and uncommon both after ASA and myectomy (4-8). However, it should be stressed that post-septal reduction HCM patients with a high risk for SCD (irrespective of the procedure) should nonetheless be considered for ICD implantation (16). Regarding the treatment effect, long-term symptomatic results determined with a questionnaire were comparable with a sustained benefit after both interventions at long-term follow-up, which is comparable with a previous single center study (7). We also did not find any difference in cardiovascular events during long-term follow-up. A trend was seen for more syncope after ASA but this did not reach statistical significance. Post-procedural gradients after ASA and myectomy were measured under different circumstances using different techniques (invasive vs transesophageal echocardiography) and therefore cannot be compared. At long-term follow-up echocardiographic gradients were slightly higher for ASA patients compared to myectomy in the present study. The number of re-interventions after ASA in the present study was low (6%) compared to 8-9% in previous studies (7,17). In the myectomy group only one re-intervention was performed (1%). In two patients the myectomy-procedure was immediately repeated after evaluation with intra-operative transesophageal echocardiography requiring a second pump run. They were counted as complications and not as a re-intervention. Strengths and weaknesses. Like all previous studies comparing ASA and myectomy, this study was a non-randomized observational study. However, with the exception of concomitant coronary artery disease and a slight difference in the degree of LVH all clinical characteristics in the two treatment groups were comparable. In particular average age was comparable in the two groups, which suggests that selection bias did not play a major role. The low prevalence of VT on Holter in myectomy patients was possibly related to missing Holter reports in these patients. Another potential weakness is the fact that myectomy was performed during a longer time period than ASA. ASA patients were therefore treated in a more modern era which could have influenced our results. However, after statistical correction, these factors did not translate in a difference

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in survival between both treatment groups. Also the difference in periprocedural complications frequency between ASA and myectomy remained after correction for the same time period. A strength of the study is the long follow-up and the completeness of the data. An extensive search of all hospital records and operation reports was performed and completed for complications in all patients. Questionnaires and when necessary telephonic consulting were used to obtain a more objective result of symptomatic status of the patient at late-term follow-up. Finally, unlike many other studies, a strength of the study is the fact that both periprocedural complications and long-term outcome were analyzed in a single study.

Conclusion and implications. This study adds to the increasing body of evidence (4-8) that long term survival, clinical outcome in terms of symptomatic status, risk of heart failure and arrhythmic events after ASA is good and comparable to myectomy. Due to the comprehensiveness of the present study, besides advantages also some disadvantages of a more invasive surgical versus a percutaneous procedure have become clear. After ASA periprocedural complication frequency was lower and duration of in-hospital stay was shorter, reflecting its less invasive nature compared to myectomy. On the other hand gradients after myectomy are lower at late follow-up which could favour myectomy. Furthermore some conditions warrant a surgical approach such as coronary septal anatomy unsuitable for ASA (18), (sub)valvular abnormalities or multivessel coronary artery disease. Taken together, patients should be evaluated on an individual basis in a multidisciplinary team of cardiologists and surgeons. When both procedures are feasible, after providing adequate information, preference of the patient should be part of the equation to determine what is the best treatment option.

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Reference List: 1. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013;381(9862):242-55. 2. Nagueh SF, Groves MG, Schwartz L et al. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy. A multicenter North American Registry. J Am Coll Cardiol 2011;58:2322-8. 3. Ball W, Ivanov J, Rakowski H et al. Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol 2011;58:2313-2321. 4. Alam M, Dokainish H, Lakkis NM. Hypertrophic obstructive cardiomyopathy-alcohol septal ablation vs myectomy: a meta-analysis. Eur Heart J 2009;30:1080-1087. 5. Leonardi RA, Kransdorf EP, Simel DL et al. Meta-analysis of septal reduction therapies for obstructive hypertrophic cardiomyopathy. Comparative rates of overall mortality and sudden cardiac death after treatment. Circ Cardiovasc Interv. 2010;3:97-104. 6. Agarwal S, Tuzcu EM, Desai MY et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010;55:823-834. 7. Sorajja P, Ommen SR, Holmes Jr. DR, et al. Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2012 126(20):2374-80. 8. Jensen MK, Prinz C, Horstkotte D et al. Alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy: low incidence of sudden cardiac death and reduced risk profile. Heart 2013; 99:1012-1017. 9. ten Cate FJ, Soliman Ol, Michels M, et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail 2010;3(3):362-9. 10. Van der Lee C, Scholzel B, ten Berg JM et al. Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation. Am J Cardiol 2008;101:1315-1320. 11. Morrow AG, Roberts WC, Ross J Jr et al. Obstruction to left ventricular outflow. Current concepts of management and operative treatment. Ann Intern Med 1968;69:1255-1286. 12. Fifer MA, Sigwart U. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation Controversies in cardiovascular medicine. Eur Heart J 2011;32:1059-1064. 13. Ommen SR, Maron BJ, Olivotto I et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005 46(3):470-476.

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14. Monakier D, Woo A, Puri T et al. Usefulness of myocardial contrast echocardiographic quantification of risk area for predicting postprocedural complications in patients undergoing septal ethanol ablation for obstructive hypertrophic cardiomyopathy. Am J Cardiol 2004; 94:1515-1522. 15. Veselka J, Duchoňová R, Páleníčkova J et al. Impact of ethanol dosing on the long-term outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. A singlecenter, prospective, and randomized study. Circ J 2006; 70:1550-1552. 16. Rothman RD, Safiia MA, Lowry PA et al. Risk stratification for sudden cardiac death after septal myectomy. J Card Cas 2011; 3:e65-67. 17. Alam M, Dokainish H, Lakkis N. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a systematic review of published studies. J Interv Cardiol 2006; 19:319-27. 18. Steggerda RC, Balt JC, Damman K, van den Berg MP, Ten Berg JM. Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Neth Heart J 2013; 21(11): 504-9.

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editorial Myectomy Versus Alcohol Septal Ablation : Experience Remains Key∗

Jeffrey B. Geske MD, Bernard J. Gersh MD

JACC: Cardiovascular Interventions, Volume 7, Issue 11, November 2014

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Chapter 6.2

In this issue of JACC: Cardiovascular Interventions, Steggerda et al. (1) present a singlecenter experience comparing alcohol septal ablation (ASA) and septal myectomy for the treatment of symptomatic patients with hypertrophic obstructive cardiomyopathy. They present results of 102 myectomy and 161 ASA patients studied over a mean of 9.1 and 5.1 years, respectively. They note higher periprocedural complication rates with myectomy, driven primarily by a high rate of repeat thoracotomy (most commonly for hemothorax and residual gradient). There were no differences between the procedures in annual mortality (including sudden cardiac death), symptomatic status, or, somewhat surprisingly, permanent pacemaker implantation. Myectomy is a well-established, effective surgical technique with decades of experience in its use (2). Since its introduction in 1995 (3), use of ASA has increased precipitously given a percutaneous approach, such that there are estimates of >5,000 procedures performed over the course of less than a decade, more than the number of septal myectomies performed in the past half century (4). Olivotto et al. (5) previously outlined the impracticality of a theoretical randomized, controlled trial comparing ASA and myectomy, which would necessitate screening of 34,000 patients for enrollment and randomization of 600 patients in each arm. Therefore, existing published data comparing the 2 techniques is limited to registries and meta-analyses. There remains substantial controversy regarding choice of procedure (4 and 6). Current American College of Cardiology Foundation/American Heart Association guidelines recommend septal myectomy at experienced centers as the first consideration for septal reduction therapy (Class IIa, Level of Evidence: B) and ASA as an alternative in selected patients with contraindication to myectomy or who favor ASA over myectomy following informed discussion (Class IIb, Level of Evidence: B) (6). The present study highlights the paramount importance of procedural experience. Myectomy was performed at a rate of 3.5 operations/year (102/29 years), whereas ASA was pursued at a rate >16 procedures/year (161/10 years). Put in this context, the post-myectomy perioperative mortality rate of 2%, the high rate of perioperative complications (28%) including permanent pacemaker implantation in 9%, and lengthy post-myectomy hospital stay (mean 9 days) may indeed relate to operative experience as opposed to inherent procedural limitations. Current guidelines stress the need for extensive procedural experience for both myectomy and ASA, defined as >20 procedures per individual operator or a program with >50 procedures, mortality rates <1%, complication rates <3%, and documented success at symptom relief (7). 134

Editorial: periprocedural complications after ASA and Myectomy

In contrast to the current series, we performed 232 myectomies at our institution in 2013 alone. We previously reported our operative results, with a myectomy mortality rate <1%, a pacemaker implantation rate of 2.4%, and hospital length of stay a median of 6 days, comparable to the ASA experience reported here (8). Similar results have been reported at the Cleveland Clinic (9) and other high-volume myectomy centers (10). Although the anatomic site of septal myectomy frequently results in postoperative left bundle branch block (11), in the absence of preexisting right bundle branch block, it is difficult to explain the high rate of permanent pacemaker implantation in the present study. Subjectively assessed symptomatic status post-procedurally was similar between the myectomy and ASA groups, consistent with known meta-analysis data (12), although interestingly objective quantification of cardiopulmonary exercise capacity has shown more improvement with myectomy compared with ASA in previous evaluation (13). Whether this relates to less long-term gradient reduction with ASA (a finding again demonstrated herein) is unknown. Arrhythmogenic risk post-ablation remains an area of uncertainty. On the basis of MRI (14) and necropsy studies (15), it is clear that ASA is associated with scarring not seen in myectomy. As the authors appropriately cite, there have been reports of higher rates of implantable cardiac defibrillator discharge after ASA (16). In the current evaluation, increased arrhythmogenesis was not seen, a finding echoed in other recent studies (17). However, given the differences in follow-up duration, further longitudinal assessment is warranted. Where do we go from here? Myectomy has a proven track record of success, yet it is clear that the percutaneous appeal of ASA remains attractive to both physicians and patients. In experienced centers of excellence, ASA may be a reasonable alternative to myectomy in selected patients. A comparison of age- and sex-matched patients undergoing ASA and myectomy at our center revealed no significant difference in survival free of death or need for additional septal reduction therapy; however, there was greater symptom relief in young patients with myectomy and more pacemaker implantation with ASA (18). Assessment of procedural success and risk must be individualized on the basis of both the patient and institutional experience. The present investigation has significant potential for skewing of results on the basis of the discrepant rates of myectomy and ASA. A thorough investigation of

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Chapter 6.2

adverse procedural outcomes and septal reduction therapy comparative effectiveness remains of immense clinical value, a point emphasized in the guidelines (7). However, it remains clear that procedural success is closely linked to institutional experience, and septal reduction therapies should be limited to referral centers of excellence.

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Reference List: 1. R.C. Steggerda, K. Damman, J.C. Balt, M. Liebregts, J.M. ten Berg, M.P. van den Berg. Periprocedural complications and long-term outcome after alcohol septal ablation versus surgical myectomy in hypertrophic obstructive cardiomyopathy: a single-center experience. J Am Coll Cardiol Intv, 7 (2014), pp. 1227–1234 2.A.G. Morrow, E.C. Brockenbrough. Surgical treatment of idiopathic hypertrophic subaortic stenosis: technic and hemodynamic results of subaortic ventriculomyotomy. Ann Surg, 154 (1961), pp. 181–189 3.U. Sigwart. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet, 346 (1995), pp. 211–214 4.B.J. Maron. Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation, 116 (2007), pp. 196–206 discussion 206 5.I. Olivotto, S.R. Ommen, M.S. Maron, F. Cecchi, B.J. Maron. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Will there ever be a randomized trial? J Am Coll Cardiol, 50 (2007), pp. 831–834 6.M.A. Fifer. Controversies in cardiovascular medicine. Most fully informed patients choose septal ablation over septal myectomy. Circulation, 116 (2007), pp. 207–216 discussion 216. 7.B.J. Gersh, B.J. Maron, R.O. Bonow, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 58 (2011), pp. 2703–2738. 8.H.V. Schaff, J.A. Dearani, S.R. Ommen, P. Sorajja, R.A. Nishimura. Expanding the indications for septal myectomy in patients with hypertrophic cardiomyopathy: results of operation in patients with latent obstruction. J Thorac Cardiovasc Surg, 143 (2012), pp. 303– 309. 9.N.G. Smedira, B.W. Lytle, H.M. Lever, et al. Current effectiveness and risks of isolated septal myectomy for hypertrophic obstructive cardiomyopathy. Ann Thorac Surg, 85 (2008), pp. 127–133. 10.R.E. Ross, M.V. Sherrid, M.M. Casey, D.G. Swistel, S.K. Balaram. Does surgical relief of obstruction improve prognosis for hypertrophic cardiomyopathy? Prog Cardiovasc Dis, 54 (2012), pp. 529–534. 11.D.R. Talreja, R.A. Nishimura, W.D. Edwards, et al. Alcohol septal ablation versus surgical

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septal myectomy: comparison of effects on atrioventricular conduction tissue. J Am Coll Cardiol, 44 (2004), pp. 2329–2332. 12. S. Agarwal, E.M. Tuzcu, M.Y. Desai, et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol, 55 (2010), pp. 823–834. 13.S. Firoozi, P.M. Elliott, S. Sharma, et al. Septal myotomy-myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy. A comparison of clinical, haemodynamic and exercise outcomes. Eur Heart J, 23 (2002), pp. 1617–1624. 14.U.S. Valeti, R.A. Nishimura, D.R. Holmes, et al. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol, 49 (2007), pp. 350–357. 15.U. Raute-Kreinsen. Morphology of necrosis and repair after transcoronary ethanol ablation of septal hypertrophy. Pathol Res Pract, 199 (2003), pp. 121–127. 16.F.J. ten Cate, O.I. Soliman, M. Michels, et al.Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail, 3 (2010), pp. 362–369. 17.R.A. Leonardi, E.P. Kransdorf, D.L. Simel, A. Wang. Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment. Circ Cardiovasc Interv, 3 (2010), pp. 97–104. 18.P. Sorajja, S.R. Ommen, D.R. Holmes Jr., et al. Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation, 126 (2012), pp. 2374–2380

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Chapter 7.1

Long-Term Outcomes After Medical and Invasive Treatment in Patients With Hypertrophic Cardiomyopathy

Pieter A. Vriesendorp, MD, Max Liebregts, MD, Robbert C. Steggerda, MD, Arend F.L. Schinkel, MD, PHD, Rik Willems, MD, PHD Folkert J. ten Cate, MD, PHD, Johan van Cleemput, MD, PHD, Jurriën M. ten Berg, MD, PHD, Michelle Michels, MD, PHD

JACC Heart Failure 2014; 2: 630-636.

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Abstract Objectives The aim of this study was to determine the long-term outcomes (all-cause mortality and sudden cardiac death [SCD]) after medical therapy, alcohol septal ablation (ASA), and myectomy in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Therapy-resistant obstructive HCM can be treated both surgically and percutaneously. But there is no consensus on the long-term effects of ASA, especially on SCD. Methods This study included 1,047 consecutive patients with HCM (mean age 52 ± 16 years, 61% men) from 3 tertiary referral centers. A total of 690 patients (66%) had left ventricular outflow tract gradients < 30 mmHg, of whom 124 (12%) were treated medically, 316 (30%) underwent ASA, and 250 (24%) underwent myectomy. Primary endpoints were all-cause mortality and SCD. Kaplan-Meier graphs and Cox regression models were used for statistical analyses. Results The mean follow-up period was 7.6 ± 5.3 years. Ten-year survival was similar in medically treated patients (84%), ASA patients (82%), myectomy patients (85%), and patients with nonobstructive HCM (85%) (log-rank p = 0.50). The annual rate of SCD was low after invasive therapy: 1.0%/year in the ASA group and 0.8%/year in the myectomy group. Multivariate analysis demonstrated that the risk for SCD was lower after myectomy compared with the ASA group (hazard ratio: 2.1; 95% confidence interval: 1.0 to 4.4; p 1⁄4 0.04) and the medical group (hazard ratio: 2.3; 95% confidence interval: 1.0 to 5.2; p = 0.04). Conclusions Patients with obstructive HCM who are treated at referral centers for HCM care have good survival and low SCD risk, similar to that of patients with nonobstructive HCM. The SCD risk of patients after myectomy was lower than after ASA or in the medical group.

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Hypertrophic cardiomyopathy (HCM) is the most prevalent inheritable myocardial disease, and (provocable) left ventricular outflow tract (LVOT) obstruction is present in the majority of patients with HCM (±70%) (1). Not only is LVOT obstruction associated with symptoms such as dyspnea on exertion, fatigue, chest pain, and syncope, but previous studies have also demonstrated that the presence of obstruction increases all-cause mortality and the occurrence of sudden cardiac death (SCD) in these patients (2,3), and it is included as a risk factor in the novel clinical risk prediction model presented by the HCM Outcomes Investigators (4). Therapy-resistant obstructive HCM can be treated both surgically and percutaneously, and in recent years there has been an intense and polarizing debate to define the best strategy (5–8). Surgical approaches have been used for more than 5 decades, and at experienced centers, relief of obstruction can be achieved with minimal perioperative morbidity and mortality (9– 11). However, myectomy is open-heart surgery with relatively long rehabilitation, so in 1995, alcohol septal ablation (ASA), a percutaneous alternative, was developed (12). This strategy was quickly adopted all over the world, and patients who underwent ASA quickly outnumbered those who underwent myectomy (5–8,12,13). In some European countries, ASA has fully replaced myectomy (7). Concerns about ASA remain, however, especially about the arrhythmogenic effect of the ablation scar in patients already at increased risk for lifethreatening arrhythmias (14–17). Although a randomized controlled trial does not seem feasible (18), and recent meta-analyses (19,20) evaluated only short-term SCD rate and survival, there is no consensus on the longterm outcomes of ASA (17,21–24). The aim of the present study was therefore to determine the long-term effects of medical treatment, ASA, and myectomy on all-cause mortality and SCD.

Methods Study design and population. An international multicenter, observational cohort design was used. The study conformed to the principles of the Declaration of Helsinki. All patients gave informed consent for the intervention, and local institutional review board approval was obtained. The study population consisted of 1,065 consecutive patients with HCM from University Hospital Leuven (Leuven, Belgium; n = 200), St. Antonius Hospital Nieuwegein (Nieuwegein, the Netherlands; n = 318), and Thoraxcenter, Erasmus Medical Center

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(Rotterdam, the Netherlands; n = 547). Each patient had an established diagnosis of HCM, based on unexplained left ventricular hypertrophy of ≥15 mm, assessed by echocardiography (25,26). Patients with HCM linked to Noonan’s syndrome, Fabry’s disease, mitochondrial disease, or congenital heart defects were excluded. The LVOT gradient was measured in all patients using continuous-wave Doppler echocardiography, at rest and after provocative maneuvers. Patients were considered to have obstructive HCM if the LVOT gradient was ≥ 30 mm Hg, at rest or after provocation. Invasive therapy was indicated if the peak LVOT gradient was ≥ 50 mm Hg, ventricular septal thickness was ≥ 15 mm, and there was persistent New York Heart Association (NYHA) functional class III or IV dyspnea or Canadian Cardio- vascular Society class III or IV angina despite optimal medical therapy (26). Patients without LVOT gradients ≥ 30 mmHg after provocation were considered to have nonobstructive HCM and used as a control group. Patients with obstructive HCM were classified in 3 groups on the basis of the clinical treatment strategy: a medically treated group, an ASA group, and a myectomy group. Surgical septal myectomy was performed throughout the study period and as described previously (27,28), and postoperative care was in accordance with local protocols. ASA was performed starting from 1999 as described previously (28,29). Afterward, all patients were monitored for at least 24 h in the intensive coronary care unit. Endpoints The primary endpoints of this study were all-cause mortality and SCD-related events. The SCD endpoint was a composite endpoint consisting of: 1) instantaneous and unexpected death within 1 h of witnessed collapse in patients who were previously in stable clinical condition, or nocturnal death with no antecedent history of worsening symptoms; 2) successful resuscitation after cardiac arrest; 3) appropriate implantable cardioverter-defibrillator (ICD) intervention for ventricular fibrillation or for fast ventricular tachycardia (>200 beats/min); and 4) unknown cause of death. Unknown death was included in the SCD endpoint to estimate the maximal occurrence of SCD in the population. We also evaluated periprocedural arrhythmic events and mortality, reinterventions, LVOT gradient reduction, and implantation of ICDs. Mortality and adverse events were retrieved from hospital patient records at the center at which follow- up occurred, from civil service population registers, and from information provided by patients themselves or their general practitioners. Cardiac transplantation was

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considered an HCM-related death, and patients were censored at the time of transplantation. All ICD interventions were evaluated by an experienced electrophysiologist.

Data collection and follow-up. Follow-up started at the time of intervention. In the medically treated cohort, follow-up started at the first outpatient clinic contact after January 1, 1990. At baseline, all patients were evaluated for the following characteristics: NYHA class, maximal left ventricular wall thickness, maximal (provocable) LVOT gradient, systolic and diastolic left ventricular function, and medications used. During follow-up, the established risk factors for SCD were evaluated (25,26). Other potential modifiers of SCD risk were also examined: atrial fibrillation and coronary artery disease. In patients treated with ASA, the dose of alcohol used was also collected. If no endpoints occurred during follow-up, the final censoring date was set at November 1, 2012. If alternative septal reduction therapy was necessary (e.g., ASA after myectomy or vice versa), follow-up was censored at the date of the second intervention, because of the difficulty attributing any later event to any intervention.

Statistical analysis SPSS version 20 (IBM, Armonk, New York) and Excel 2010 (Microsoft Corporation, Redmond, Washington) were used for all statistical analyses. Categorical variables are summarized as percentages. Normality was assessed using the Shapiro-Wilk test combined with visual inspection of histograms and Q-Q plots. Normally distributed continuous data are expressed as mean ± SD and non- normally distributed data as median (interquartile range [IQR]). To compare continuous variables, Student t tests, Mann-Whitney U tests, and oneway analysis of variance were used. When appropriate, post hoc comparisons were carried out using Bonferroni correction. To compare categorical variables, chi-square tests were used. To identify clinical predictors of SCD mortality, univariate and multivariate Cox regression analyses were used. Variables were selected for multivariate analysis if univariate p values were <0.10 and are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). The final number of variables was restricted according to the number of endpoint events to avoid overfitting the multivariate model. All tests were 2 sided, and p values <0.05 were considered statistically significant.

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Results Baseline characteristics Table 1 lists the baseline characteristics of all patients. Of the 1,065 patients (mean age 52 ± 16 years, 61% men) included in this study, 716 (67%) had obstructive HCM; in 269 (25%), LVOT obstruction was present only after provocation. Of these 716 patients, 142 (20%) were treated medically, 321 (45%) underwent ASA, and 253 (35%) underwent myectomy. Patients in the ASA group were older (58 ± 14 years) than those in the surgery group (52 ± 16 years, p < 0.001) and in the medical group (53 ± 15 years, p = 0.001). The majority of medically treated patients (n = 124 [87%]) reported no symptoms or mild (NYHA functional class I or II) symptoms at baseline, despite a mean LVOT gradient of 70 ± 32 mm Hg. The other 18 patients (13%) had indications for invasive treatment but were considered not eligible because of severe comorbidities (e.g., 1 patient had liver cirrhosis due to alcohol abuse and kidney failure) or patient refusal (several patients refused further invasive treatment, mostly because they were at old age and preferred no further interventions). In this group, mortality was high (8 deaths [44%]), and these patients were excluded from further analysis. The distribution of established risk factors for SCD, among the 3 intervention groups and controls, is shown in Table 1. Complete risk stratification was not available for all patients: blood pressure response during exercise testing was available in 645 patients (61%), and documented rhythm information was available in 656 patients (62%). Significantly more patients in the myectomy group (n = 44 [17%]) had ≥ 2 established risk factors for SCD than those in ASA group (n = 32 [10%]) (p 1⁄4 0.009).

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Table 1 Baseline Characteristics of 1065 Patients With HCM Medical

Variable

ASA group

group

Myectomy

Control (non-‐

group

obstructive) group

n= Age (yrs) Women NYHA class III or IV Atrial fibrillation Coronary artery disease Maximal LVWT (mm) LVOT gradient (mm Hg) Systolic dysfunction (EF <50%) Diastolic dysfunction Medications Beta-receptor antagonists Calcium-channel blockers Risk factors Survivor of SCD Sudden death in family history Abnormal BP response Maximal LVWT >30 mm Nonsustained VT Syncope 0 risk factors ≥2 risk factors

(n=142)

(n=321)

(n=253)

(n=349)

53 ± 15‡ 54 (38%)∗ 18 (13%) 21 (15%)† 4 (3%) 20 ± 5 70 ± 32‡ 17 (12%) 99 (70%)†

58 ± 14‡ 143 (45%)‡ 249 (78%)‡ 76 (24%) 18 (6%)† 21 ± 5‡ 102 ± 52‡ 18 (6%)‡ 130 (40%)‡

52 ± 16‡ 117 (46%)‡ 165 (65%)‡ 62 (25%) 25 (10%)† 21 ± 5‡ 92 ± 39‡ 18 (7%)‡ 105 (42%)†

46 ± 16 98 (28%) 40 (11%) 103 (30%) 12 (3%) 20 ± 5 9±6 63 (18%) 190 (54%)

83 (58%)∗ 47 (33%)‡

218 (68%)‡ 116 (36%)‡

167 (66%)‡ 90 (36%)‡

166 (48%) 49 (14%)

4 (3%)∗ 23 (16%) 9 (6%) 9 (6%) 22 (15%)† 10 (7%) 87 (61%)† 15 (11%)∗

7 (2%)‡ 24 (7%)‡ 31 (10%) 22 (7%) 41 (13%)‡ 52 (16%) 188 (59%)† 32 (10%)†

8 (3%)∗ 42 (17%) 37 (15%) 18 (7%) 37 (15%) 41 (16%) 136 (54%)∗ 44 (17%)

29 (8%) 81 (23%) 29 (8%) 19 (5%) 98 (28%) 45 (12%) 158 (45%) 66 (19%)

Values are mean ± SD or n (%). ASA = alcohol septal ablation; BP = blood pressure; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; LVOT = left ventricular outflow tract; LVWT = left ventricular wall thickness; NYHA = New York Heart Association; SCD = sudden cardiac death; VT = ventricular tachycardia. ∗p < 0.05, †p < 0.01, and ‡p < 0.001 compared with controls.

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Procedural data. Invasive therapy was performed in 574 patients with obstructive HCM. Periprocedural mortality was similar between ASA (n 1⁄4 5 [1.6%]) and myectomy (n 1⁄4 3 [1.2%]) (p 1⁄4 0.70). In the first 30 days post-procedure, ventricular arrhythmias occurred more frequently in the ASA group (n 1⁄4 11 [3.1%]) than in the myectomy group (n 1⁄4 1 [0.4%]) (p < 0.001). Cardiac resuscitation was necessary in 7 ASA patients (2.2%). Residual LVOT gradient was measured after 3 months and was reduced after both ASA and myectomy: from a median of 97 mm Hg (IQR: 66 to 130 mm Hg) to 10 mm Hg (IQR: 1 to 24 mm Hg) after ASA, and from a median of 90 mm Hg (IQR: 70 to 100 mm Hg) to 9 mm Hg (IQR: 0 to 16 mm Hg) after myectomy. In 31 ASA patients (9.7%), additional septal reduction therapy was necessary, and this was higher than after myectomy (n 1⁄4 6 [2.3%], p < 0.001) (Table 2).

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Table 2 Invasive Therapy in 574 patients with HCM Variable Center Leuven Nieuwegein Rotterdam Procedural details Volume of alcohol injected (ml) Residual LVOT gradient (mm Hg) Reduction in LVOT gradient (%) Redo septal reduction therapy Periprocedural arrhythmic event Total SCD Sustained VT Resuscitated cardiac arrest Periprocedural mortality Total SCD Heart failure death Cardiac tamponade

ASA

Myectomy

(n =321)

(n = 253)

18 (6%) 209 (65%) 94 (29%)

28 (11%) 109 (43%) 116 (46%)

2.0 (1.0)∗ 10 (24) 87 ± 30 31 (9.7%)

NA 9 (16)† 90 ± 19† 6 (2.3%)‡

11 (3.1%) 3 (0.9%) 1 (0.3%) 7 (2.2%)

1 (0.4%)‡ 1 (0.4%) 0 (0%) 0 (0%)

5 (1.6%) 3 (0.9%) 0 (0%) 2 (0.6%)

3 (1.2%) 1 (0.4%) 2 (0.8%) 0

Values are n (%) or mean ± SD. NA = not applicable; other abbreviations as in Table 1. ∗In 53 patients (16.5%), the dose of alcohol could not be retrieved. †p < 0.01. ‡p < 0.001.

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Mortality In 1,047 patients, mean follow-up duration was 7.5 ± 5.3 years (maximum 22.8 years). There were 156 deaths in the entire cohort (Table 3): 8 (5%) were procedure related, 80 (51%) were HCM related, 56 (36%) patients died of noncardiac causes, and causes of death were unknown in 12 (8%). Twelve patients underwent cardiac transplantation and were considered as HCM-related death. Kaplan-Meier estimates of survival are shown in Figure 1A. Five-year and 10-year survival was similar after ASA, myectomy, and medical treatment in patients in NYHA class I or II and those with nonobstructive HCM (Table 3). Independent predictors of all-cause mortality were age (HR: 1.05; 95% CI: 1.0 to 1.1; p < 0.001); systolic dysfunction, with ejection fraction <50% (HR: 1.8; 95% CI: 1.2 to 2.6; p = 0.005); and a trend toward diastolic dysfunction (HR: 1.4; 95% CI: 0.98 to 1.88; p = 0.07) (Table 4).

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Table 3 Mortality and SCD in 1047 Patients with HCM Variable

Medical

ASA

Myectomy

Treatment (n = 142)

Follow-up (yrs) Mortality Periprodecural death HCM-related death Noncardiac death Unknown death Total 5-yr survival 10-yr survival SCD SCD Resuscitated CA Appropriate ICD shock Unknown death Total Annual SCD rate, %/year ICD recipients

Control (Nonobstructive HCM)

(n = 316)

(n = 249)

(n = 349)

7.1 ± 4.8∗

6.3 ± 3.6†

7.9 ± 6.1

8.7 ± 5.7

— 11 (8.9%) 8 (6.5%) 0 (0%) 19 (15.3%) 89% 84%

5 (1.6%) 12 (3.7%)‡ 23 (7.2%)∗ 3 (0.9%) 38 (11.8%) 91% 82%

3 (1.2%) 21 (8.4%) 12 (4.8%) 6 (2.4%) 39 (15.6%) 92% 85%

36 (10.3%) 13 (3.7%) 3 (0.8%) 52 (14.9%) 95% 85%

5 (4.0%) 1 (0.8%) 5 (4.0%) 0 (0%) 11 (8.9%) 1.26 14 (11.3%)‡

6 (1.9%) 2 (0.6%)∗ 8 (2.5%) 3 (0.9%) 19 (6.0%) 0.96 41 (13.0%)†

6 (2.4%) 2 (0.8%) 1 (0.4%) 6 (2.4%) 15 (6.0%) 0.75 29 (11.6%)‡

9 (2.6%) 9 (2.6%) 12 (3.4%) 3 (0.8%) 31 (8.9%) 1.02 83 (23.8%)

Values are mean ± SD or n (%). CA = cardiac arrest; ICD = implantable cardioverter-defibrillator; other abbreviations as in Table 1. ∗p < 0.05. †p < 0.001 compared with controls. ‡p < 0.01.

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Table 4 Analysis of Clinical Variables Associated with SCD and All-cause Mortality in 1047 Patients With HCM Variable Mortality (n = 156) Age Female Atrial fibrillation Coronary artery disease Systolic dysfunction (EF <50%) Diastolic dysfunction Myectomy (reference) ASA Medical therapy (NYHA class I or II) SCD (n = 76) Age (yrs) Male LVWT Atrial fibrillation Coronary artery disease SCD survivor ≥2 established risk factors Myectomy (reference) ASA Medical therapy (NYHA class I or II)

Univariate HR CI 95%

Multivariate p Value

1.05 1.8 1.6 1.9 2.2 1.5 1.0 1.3 1.3

1.03–1.06 1.27–2.43 1.18–2.29 1.25–2.74 1.51–3.22 1.08–2.07

<0.001 0.001 0.003 0.002 <0.001 0.02 —

0.79–2.02 0.73–2.20

0.3 0.4

1.00 1.6 1.03 1.8 1.8 6.5 3.3 1.0 2.0 2.2

0.98–1.01 0.98–2.68 0.98–1.08 1.14–2.87 1.06–3.20 3.82–10.9 2.04–5.23

0.7 0.06 0.2 0.01 0.03 <0.001 <0.001 —

0.99–4.25 0.99–4.91

0.05 0.05

HR CI 95% 1.05 1.3 1.2 1.4 1.4 1.8 1.0 1.0 1.2

1.04–1.06 0.93–1.79 0.89–1.78 0.94–2.08 1.19–2.59 0.98–1.89

<0.001 0.1 0.2 0.1 0.005 0.07 —

0.65–1.61 0.68–2.13

0.9 0.5

1.6

0.97–2.73

0.06

1.7 1.7 6.0 2.7 1.0 2.1 2.3

1.06–2.75 0.98–3.04 3.43–10.7 1.65–4.44

0.03 0.06 <0.001 <0.001 —

1.02–4.39 1.03–5.19

0.04 0.04

Backward multivariate Cox regression analysis was used. CI = confidence interval; HR = hazard ratio; other abbreviations as in Table 1.

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p Value

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Figure 1 Survival in 1047 patients with HCM

Kaplan-Meier graphs of survival (A) and survival free of sudden cardiac death (B) in 1,047 patients with hypertrophic cardiomyopathy (HCM)

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SCD. The SCD endpoint occurred in 76 patients over 8,003 patient-years (0.9%/year). The annual SCD rate was 0.96%/year after ASA, 0.76%/year after myectomy, 1.26%/year in medically treated groups, and 1.02%/year in nonobstructive HCM patients (p = 0.40). Appropriate ICD shocks were more common after ASA (in 8 of 41 patients [20%]) than after myectomy (in 1 of 29 patients [3.4%]) (p = 0.03). Other characteristics of SCD are described in Table 3. Kaplan-Meier estimates of survival free from SCD are shown in Figure 1B. Multivariate analysis identified the following independent predictors of SCD: patients who survived ventricular fibrillation or sustained ventricular tachycardia (HR: 6.0; 95% CI: 3.4 to 10.6; p < 0.001), patients with >2 established risk factors (HR: 2.7; 95% CI: 1.6 to 4.4; p < 0.001), patients with atrial fibrillation (HR: 1.7; 95% CI: 1.1 to 2.8; p 1⁄4 0.03), and, when compared with myectomy, ASA (HR: 2.1; 95% CI: 1.0 to 4.4; p = 0.04) and medically treatment (HR: 2.3; 95% CI: 1.1 to 5.1; p 1⁄4 0.04) (Table 4). Discussion The purpose of this investigation was to compare the long-term effects of medical treatment, ASA, and myectomy on all-cause mortality and SCD in patients with obstructive HCM. There were 2 important results. First, the mortality rates in patients with prior ASA or myectomy and in medically treated patients in NYHA functional class I or II were similar to those in patients with nonobstructive HCM. Second, the long- term risk for SCD was low after both myectomy (0.8%/year) and ASA (1.0%/year), a small but significant difference (HR for SCD after ASA vs. myectomy: 2.1; p = 0.04). Low Mortality in patients with obstructive HCM The observed survival after both myectomy (10-year survival 85%) and ASA (10-year survival 82%) (p = 0.50) was similar to that in patients with nonobstructive HCM (85%) (p = 0.70 and p = 0.20, respectively). This demonstrates that the survival disadvantage associated with LVOT obstruction can be effectively annulled by appropriate invasive therapy and management at referral centers for HCM care (2). ASA was performed in carefully selected patients who were older and had more comorbidities (61% of the deaths were due to noncardiac causes), but despite this, the observed mortality after ASA was not significantly higher than in the other groups. The observed survival after invasive therapy in this study confirms other studies evaluating long-term outcomes for the individual approaches (21-24) The good survival of patients with obstructive HCM who remained in NYHA class I or II on

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optimal medical therapy (10-year survival 84%) could imply that earlier intervention in asymptomatic or mildly symptomatic patients with obstructive HCM is not indicated, despite the low procedural mortality and morbidity of both invasive therapies. Mortality, not surprisingly, was high (44%) in a limited group of patients (n = 18 [13%]) with indications for invasive treatment (NYHA class III or IV despite optimal medical therapy) but who were deemed to be ineligible because of severe comorbidities.

SCD After ASA Since the introduction of ASA, there have been concerns regarding the arrhythmogenic effect of the ablation scar in patients already at increased risk for life-threatening arrhythmias. Studies of short-term follow-up after ASA have described frequent episodes of sustained ventricular tachycardia and ventricular fibrillation (14, 15, 16 and 17). Our findings confirm this and show that although arrhythmic events were more frequent after ASA (3.1%) than after myectomy (0.4%) (p < 0.001), this had no effect on procedure-related mortality (1.6% vs. 1.2%, p = 0.70). The aim of this study was to assess the long-term effects of the different treatment modalities, especially because the long-term effect of ASA on SCD is unclear. Two meta-analyses showed that the risk for SCD was not higher in ASA patients than in patients who underwent myectomy. These studies did not focus on long-term outcomes: the mean follow-up period across the cohorts in a study by Agarwal et al. (19) was <3 years, and in a study by Leonardi et al. (20), there was a significant difference in follow-up duration between the ASA and myectomy cohorts, with median follow-up durations of 1,266 patientyears in the myectomy studies and 51 patient-years in the ASA studies. Other concerns, especially about the calculated SCD risk, have already been illustrated by Nishimura and Ommen (30). The risk for SCD after myectomy has generally been low (11), and the study by McLeod et al. (31) even suggests that myectomy could decrease the risk for SCD. Our study found that the annual SCD rate (excluding periprocedural events) in patients who underwent ASA was 1.0%/year, which was similar to that in patients with nonobstructive HCM and medically treated patients. A study by ten Cate et al. (17), which included a subset of the patients from the present study, reported a higher SCD rate than this study. The reason for this is 2-fold: 1) a separate endpoint for SCD (instead of a composite of cardiac mortality and SCD) was used, and 2) we excluded periprocedural events from the final analysis to focus on the long-term effects of ASA. Two recently published studies with long-term follow-up found that the risk for SCD was not high after ASA. Jensen et al. (23) examined 470 ASA

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patients, with a mean follow- up period of 8.4 years, and found an annual SCD rate of 0.5%/year. Sorajja et al. (24) examined 177 ASA patients and 177 age- and sex-matched myectomy patients, with a mean follow-up period of 5.7 years. They found annual SCD rates (including unknown death) of 1.3%/year after ASA and 1.1%/year after myectomy. The results of this study are in line with these findings, but the SCD risk after ASA is still higher than after myectomy (0.8%/year; HR for SCD after ASA vs. myectomy: 2.1; p = 0.04).

Patient selection and specialised care The present findings may have implications for the clinical management of patients with obstructive HCM who are considered for septal reduction therapy. Patients who underwent myectomy had a statistically significantly lower risk for SCD compared with patients who underwent ASA. This, combined with a lower need for additional septal reduction therapy and lower periprocedural arrhythmic events, favors surgical myectomy over ASA when an invasive strategy is chosen, for example, in younger and otherwise healthy patients. In older patients or patients with comorbidities and drug-refractory symptoms, and appropriate septal anatomy, the expected survival after ASA is excellent, and in these patients, ASA is a valuable therapy. Open-heart surgery can be avoided, and rehabilitation is much faster. We recommend that a multidisciplinary heart team (consisting of at least a cardiothoracic surgeon, an interventional cardiologist, and a cardiologist specializing in the care of patients with HCM) determines the optimal strategy for septal reduction. Also, in line with the 2003 European Society of Cardiology and American College of Car- diology (25) and 2011 American College of Cardiology Foundation and American Heart Association (26) guidelines, the procedure should be performed by experienced operators and confined to centers with substantial and specific experience with HCM care.

Study limitations This study had several limitations. The 3 centers are all tertiary referral centers for the diagnostic and therapeutic care of patients with HCM, and the patient population might not represent the general HCM population. This referral and selection bias could have influenced the results. Data collection was limited to variables that were routinely collected. Because rhythm documentation of the event was not available for all SCD cases, it was not 154

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possible to ascertain that all deaths were arrhythmic in nature. Neither was it possible to correct for individual or local alterations of surgical or percutaneous technique, but all procedures were performed by experienced interventional cardiologists or cardiothoracic surgeons. This implies that our findings are more generalizable than those of single-center investigations. Conclusions Patients with obstructive HCM who are treated at referral centers for HCM care have good survival and low SCD risk, similar to that of patients with nonobstructive HCM. The SCD risk in patients after myectomy was lower than that after ASA and in the medical group. Acknowledgements The authors thank D.A.M.J. Theuns, O.I.I. Soliman, R.T. van Domburg, H. Heid- buchel, P.L. de Jong, A.J. Hauer, and J.C. Balt and all treating physicians for providing additional data and assisting the authors in the realization of this study.

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Reference List 1. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation 2006;114:2232–9. 2. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295–303. 3. Elliott PM, Gimeno JR, Tome MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1933– 41. 4. O’Mahony C, Jichi F, Pavlou M, et al. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM Risk- SCD). Eur Heart J 2014;35:2010– 20. 5. Maron BJ. Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation 2007;116:196–206. 6. Fifer MA. Controversies in cardiovascular medicine. Most fully informed patients choose septal ablation over septal myectomy. Circulation 2007; 116:207–16. 7. Maron BJ, Yacoub M, Dearani JA. Controversies in cardiovascular medicine. Benefits of surgery in obstructive hypertrophic cardiomyopathy: bring septal myectomy back for European patients. Eur Heart J 2011;32:1055–8. 8. Fifer MA, Sigwart U. Controversies in cardiovascular medicine. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation. Eur Heart J 2011;32:1059–64. 9. Kirklin JW, Ellis FH Jr. Surgical relief of diffuse subvalvular aortic stenosis. Circulation 1961;24: 739–42. 10. Morrow AG, Reitz BA, Epstein SE, et al. Operative treatment in hypertrophic subaortic stenosis. Techniques, and the results of pre and postoperative assessments in 83 patients. Circu- lation 1975;52:88–102. 11.Ommen SR, Maron BJ, Olivotto I, et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;46:470–6. 12. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet 1995;346:211–4. 13. Rigopoulos AG, Seggewiss H. A decade of percutaneous septal ablation in hypertrophic cardiomyopathy. Circ J 2011;75:28–37.

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14. Boltwood CM Jr., Chien W, Ports T. Ventricular tachycardia complicating alcohol septal ablation. N Engl J Med 2004;351:1914–5. 15. Kuhn H, Lawrenz T, Lieder F, et al. Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience. Clin Res Cardiol 2008;97:234–43. 16. Sorajja P, Valeti U, Nishimura RA, et al. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2008; 118:131–9. 17. ten Cate FJ, Soliman OI, Michels M, et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail 2010;3: 362–9. 18. Olivotto I, Ommen SR, Maron MS, Cecchi F, Maron BJ. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Will there ever be a randomized trial? J Am Coll Cardiol 2007;50:831–4. 19. Agarwal S, Tuzcu EM, Desai MY, et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;55:823–34. 20. Leonardi RA, Kransdorf EP, Simel DL, Wang A. Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment. Circ Cardiovasc Interv 2010;3:97–104. 21. Ball W, Ivanov J, Rakowski H, et al. Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol 2011;58:2313–21. 22. Nagueh SF, Groves BM, Schwartz L, et al. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy. A multicenter North American registry. J Am Coll Cardiol 2011;58:2322–8. 23. Jensen MK, Prinz C, Horstkotte D, et al. Alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy: low incidence of sudden cardiac death and reduced risk profile. Heart 2013;99:1012–7. 24. Sorajja P, Ommen SR, Holmes DR, et al. Sur- vival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2012; 126:2374–80. 25. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy— a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Commit- tee for Practice Guidelines. European Heart Jour- nal 2003;24:1965–91.

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26. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Associa- tion Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:2703–38. 27. Maat LP, Slager CJ, van Herwerden LA, et al. Spark erosion myectomy in hypertrophic obstructive cardiomyopathy. Ann Thorac Surg 1994;58: 536–40. 28. van der Lee C, ten Cate FJ, Geleijnse ML, et al. Percutaneous versus surgical treatment for patients with hypertrophic obstructive cardiomyopathy and enlarged anterior mitral valve leaflets. Circulation 2005;112:482–8. 29. van der Lee C, Scholzel B, ten Berg JM, et al. Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation. Am J Cardiol 2008;101:1315–20. 30. Nishimura RA, Ommen SR. Septal reduction therapy for obstructive hypertrophic cardiomyopathy and sudden death: what statistics cannot tell you. Circ Cardiovasc Interv 2010;3: 91–3. 31. McLeod CJ, Ommen SR, Ackerman MJ, et al. Surgical septal myectomy decreases the risk for appropriate implantable cardioverter defibrillator discharge in obstructive hypertrophic cardiomyopathy. Eur Heart J 2007;28: 2583–8.

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Revisiting Arrhythmic Risk After Alcohol Septal Ablation Is the Pendulum Finally Swinging Back to Myectomy?*

Barry J. Maron, MD, Rick A. Nishimura, MD

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For the past 10 years, a debate has raged within the international cardiovascular medicine community regarding treatment options for severely symptomatic and drug-refractory patients with obstructive hypertrophic cardiomyopathy (HCM) (1–21). Surgical myectomy has been the gold-standard treatment for this relatively small HCM subset since the early 1960s, with proven efficacy in abolishing left ventricular (LV) outflow gradients and heart failure symptoms, enhancing quality of life associated with long-term survival equivalent to the general population, and recently with low operative mortality (<1%) when performed by highly experienced surgeons (1–6,20–22) (Figure 1). Catheter-based alcohol septal ablation entered the therapeutic arena for HCM about 10 years ago, also with the capability for reducing gradient and symptoms, and became widely available, performed by many interventional cardiologists trained in standard percutaneous coronary interventions (7–18). This introduction of alcohol ablation triggered a polarized and sometimes contentious debate focused on defining the most practical and effective strategy for severely symptomatic patients with obstructive HCM (1–22). Advocates for septal ablation have underscored the less invasive nature of the technique, the shorter recovery time, as well as its widespread availability. However, concern has been raised regarding the extensive use of alcohol ablation, given that it produces a sizable transmural myocardial infarction (on average 10% of LV mass and 30% of septum), potentially leading to increased arrhythmogenicity (23) (Figure 2). In addition, ablation is associated with an increased risk for complications such as heart block (requiring permanent pacing), generally less efficacious relief of gradient and symptoms, and the limited length of follow-up available for comparison with surgical myectomy. Proponents of each strategy have argued their respective positions, and an extensive literature of almost 500 published papers has emerged. Notably, international consensus panels of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology have weighed in on the debate by interrogating the assembled data, unanimously judging septal myectomy to be the primary treatment option for most patients with HCM (particularly the young) experiencing unrelenting symptoms due to marked LV outflow tract gradients at rest and/or with physiologic (exercise) provocation, despite maximal medical management (1–6,19,20,22,24). Alcohol septal ablation is regarded as a selective alternative to myectomy reserved for patients at unacceptable operative risk because of comorbidities, advanced age, or with strong aversion to surgery (1–3). Despite these recommendations, selection of patients for these management options has varied considerably in geographic terms. Surgical myectomy has been virtually abolished and 160

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replaced by alcohol ablation in much of Europe, including countries such as Germany and Switzerland, where myectomy programs had previously been robust. There is, however, recent evidence of a resurgence in surgery for obstructive HCM in Italy, United Kingdom, and the Netherlands (25). In the United States, alcohol septal ablation has been performed by interventional cardiologists at many institutions across the country, some of whom learn the technique from attending a conference. This is in contrast to septal myectomies performed primarily by the highly trained surgeons at HCM centers of excellence. The decision regarding which procedure a patient will undergo may depend more on the location, referral pattern, and current knowledge of the managing cardiologist rather than scientific evidence and shared decision-making. In the report by Vriesendorp et al. (26) in this issue of JACC: Heart Failure, investigators from 3 tertiary institutions have joined together to describe their experience with HCM in >1,000 patients, including 566 with either myectomy or ablation: Thoraxcenter in Rotterdam, St. Antonius Hospital Nieuwegein (also in the Netherlands), and University Hospital Leuven in Belgium. This ambitious analysis focuses on the sudden death risk associated with both septal reduction procedures. Because HCM is characteristically a low–event-rate disease, it is not surprising that the investigators observed that the sudden death rate was generally low in patients with either surgery or ablation, as well as in a medically treated group with nonobstructive HCM. However, most importantly, there are several novel observations in the Vriesendorp et al. (26) report regarding the arrhythmogenic potential of alcohol septal ablation compared to myectomy. First, on the basis of a multivariate analysis, there was a 2- fold increase in sudden death risk with alcohol ablation (hazard ratio: 2.1; 95% confidence interval: 1.0 to 4.4; p 1⁄4 0.04) over the duration of the study, which could have been much higher if the investigators had included early life-threatening periprocedural arrhythmic complications (i.e., 11:1 for ablation to myectomy). The sudden death rate per year associated with alcohol ablation was 25% greater than with myectomy (1.0% vs. 0.8%). In terms of individual patients, sudden death events were 80% more common with ablation (16 vs. 9 with myectomy), including appropriate implantable cardioverter-defibrillator shocks for ventricular tachycardia or ventricular fibrillation that were 8:1 more frequent post-ablation. Finally, myectomy patients had a greater number of independent risk markers for sudden cardiac death but paradoxically fewer events than in the septal ablation patients. Taken together, these observations support a level of arrhythmogenicity that is a direct consequence of the alcohol-induced transmural myocardial infarct. In addition, such a

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significant sustained occurrence of ventricular tachyarrhythmias after alcohol ablation in the Vriesendorp et al. (26) study is consistent with prior data from important centers at the Massachusetts General Hospital (15) and the Thoraxcenter (14,18), as well as in a study by Cuocco et al. (16) in which a large alcohol ablation population implanted with cardioverterdefibrillators is reported. In addition, a particularly low risk for sudden death and potentially lethal ventricular tachyarrhythmias has been reported after septal myectomy from the Mayo Clinic (21,27). Indeed, the arrhythmogenic risk associated with alcohol septal ablation has been an issue of concern since the inception of this procedure (28,29), repeatedly raised by many clinicians and HCM experts, as well as by guideline and consensus panels. The 250 patients with myectomy reported here from 3 institutions in the Netherlands and Belgium could reflect an emerging profile for this surgery in parts of Europe, although this is difficult to assess in precise terms because the investigators do not specify the period of time over which the procedures were performed. Nevertheless, myectomy was 2-fold more common in the Leuven group, and also constituted the majority of septal reduction procedures in Rotterdam. Indeed, in the United States, paradoxically, myectomy operations appear to have increased concomitant with the introduction of alcohol septal ablation (30) (Figure 1).

FIGURE 1 Number of Surgical Myectomies Versus Alcohol Ablation Procedures Performed at the Mayo Clinic (Rochester, Minnesota) by Year, After an Informed Discussion of Both Options and Shared Decision-Making

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Furthermore, myectomy versus alcohol ablation decisions must be made weighing the risk with alcohol ablation for permanent pacemakers (10% to 15%), therapeutic failures with multiple procedures (12%), ineffective results in patients with particularly substantial LV hypertrophy (in whom adequate septal thinning cannot be achieved), and the potential for post-procedural arrhythmic risk, particularly in younger patients, against the inconvenience and post-operative rehabilitation required after open-heart surgery (1–23). Also important, the heterogeneous and complex LV outflow tract morphology characteristic of obstructive HCM is often most amenable to the myectomy operation, for which the skilled and experienced surgeon has the distinct advantage of direct anatomic visualization, thereby increasing the likelihood of an optimal hemodynamic and symptomatic result (1–6,19–21,28–31). In contrast, alcohol ablation is a “blind” approach restricted by the size and distribution of the septal perforator artery and its fixed anatomic relationship to the target site of outflow obstruction (where the anterior mitral leaflet contacts the septum in systole) (1– 4,19,20,28,29,31). Therefore, there will be patients in whom the optimal hemodynamic benefit will not be obtained by alcohol ablation because of these anatomic considerations. Finally, Vriesendorp et al. (26) appropriately underscore the value of HCM subspecialty multidisciplinary teams at dedicated clinics and centers (e.g., with myectomy surgeons, interventional cardiologists, and cardiologists specialized in the care of patients with HCM) (32), creating an environment in which decisions between myectomy and alcohol ablation can be made effectively and in cooperation with fully informed patients (1,5,19). In conclusion, the Vriesendorp et al. (26) data revisit the important issue of arrhythmogenicity associated with alcohol septal ablation and offer support to the consensus and guideline recommendations from the United States (2003 and 2011) (2,3) and Europe (2003) (2) panels that septal myectomy should be considered the treatment of choice for most patients with HCM and severe drug-refractory heart failure symptoms attributable to LV outflow obstruction. Although the myectomy-versus-ablation pendulum may be swinging back toward septal myectomy, the controversy will undoubtedly continue, although perhaps now in a more balanced environment, permitting greater repenetration of surgical myectomy into contemporary care for patients with HCM. This would represent a much anticipated adjustment in the management armamentarium of HCM, in the best interests of this patient population.

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FIGURE 2 Post-Contrast CMR Images Show the Distinctly Different Morphologic Consequences of Alcohol Septal Ablation and Surgical Myectomy Alcohol ablation (left) produces a bright dense transmural scar (arrow), whereas intramyocardial scarring is absent after surgical myectomy and muscular resection (right). Adapted with permission from Valeti et al. (23). CMR 1⁄4 cardiovascular magnetic resonance; LV 1⁄4 left ventricular wall; VS 1⁄4 ventricular septum.

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Reference list: 1. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013;381:242–55. 2. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Prac- tice Guidelines Committee to Develop an Expert Consensus Document on Hypertrophic Cardiomy- opathy. J Am Coll Cardiol 2003;42:1687–713. 3. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guidelines for the diagnosis and treatment of hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124: 2761–96. 4. Maron BJ. Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation 2007;116:196–206. 5. Maron BJ, Rastegar H, Udelson JE, Dearani JA, Maron MS. Contemporary surgical management of hypertrophic cardiomyopathy, the need for more myectomy surgeons and disease-specific centers, and the Tufts initiative. Am J Cardiol 2013;112: 1512–5. 6. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy present and future with translation into contemporary cardiovascular medicine. J Am Coll Cardiol 2014;64:83–99. 7. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet 1995;346:211–4. 8. Sorajja P, Ommen SR, Holmes DR Jr., et al. Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2012;126:2374–80. 9.Sorajja P, Valeti U, Nishimura RA, et al. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2008; 118:131–9. 10. Qin JX, Shiota T, Lever HM, et al. Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery. J Am Coll Cardiol 2001;38:1994–2000. 11. Nagueh SF, Groves BM, Schwartz L, et al. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy. A multicenter North American registry. J Am Coll Cardiol 2011;58:2322–8.

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12. Agarwal S, Tuzcu EM, Desai MY, et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;55:823–34. 13. Kwon DH, Kapadia SR, Tuzcu EM, et al. Long- term outcomes in high-risk symptomatic patients with hypertrophic cardiomyopathy undergoing alcohol septal ablation. J Am Coll Cardiol Intv 2008;1:432–8. 14. ten Cate FJ, Soliman OI, Michels M, et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail 2010;3: 362–9. 15. Noseworthy PA, Rosenberg MA, Fifer MA, et al. Ventricular arrhythmia following alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Am Cardiol 2009;104:128–32. 16. Cuoco FA, Spencer WH III, Fernandes VL, et al. Implantable cardioverter-defibrillator therapy for primary prevention of sudden death after alcohol septal ablation of hypertrophic cardiomyopathy. J Am Coll Cardiol 2008;52:1718–23. 17. Ralph-Edwards A, Woo A, McCrindle BW, et al. Hypertrophic obstructive cardiomyopathy: comparison of outcomes after myectomy or alcohol ablation adjusted by propensity score. J Thorac Cardiovasc Surg 2005;129:351–8. 18. van der Lee C, ten Cate FJ, Geleijnse ML, et al. Percutaneous versus surgical treatmetn for patients with hypertrophic obstructive cardiomyopathy and enlarged anterior mitral valve leaflets. Circulation 2005;112:482–8. 19. Nishimura RA, Ommen SR. Septal reduction therapy for obstructive hypertrophic cardiomyopathy and sudden death: what statistics cannot tell you. Circ Cardiovasc Interv 2010;3:91–3. 20. Maron BJ, Dearani JA, Ommen SR, et al. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44: 2044–53. 21. Ommen SR, Maron BJ, Olivotto I, et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;46:470–6. 22. Maron BJ, Braunwald E. Evolution of hypertrophic cardiomyopathy to a contemporary treatable disease. Circulation 2012;126:1640–4. 23. Valeti US, Nishimura RA, Holmes DR, et al. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2007;49:350–7.

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24. Sherrid MV, Shetty A, Winson G, et al. Treat- ment of obstructive hypertrophic cardiomyopathy symptoms and gradient resistant to first-line therapy with b-blockade or verapamil. Circ Heart Fail 2013;6:694–702. 25. Maron BJ, Yacoub M, Dearani JA. Benefits of surgery for obstructive hypertrophic cardiomyopathy: bring septal myectomy back for European patients. Eur Heart J 2011;32:1055–8. 26. Vriesendorp PA, Liebregts M, Steggerda RC, et al. Long-term outcomes after medical and invasive treatment in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol HF 2014;2: 630–6. 27. McLeod CJ, Ommen SR, Ackerman MJ, et al. Surgical septal myectomy decreases the risk for appropriate implantable cardioverter defibrillator discharge in obstructive hypertrophic cardiomyopathy. Eur Heart J 2007;28:2583–8. 28. Maron BJ. Role of alcohol septal ablation in treatment of obstructive hypertrophic cardiomyopathy. Lancet 2000;355:425–6. 29. Spirito P, Maron BJ. Perspectives on the role of new treatment strategies in hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 1999;33:1071–5. 30. Maron BJ, Ommen SR, Dearani JA. Myths about surgical myectomy: rumor of its death have been greatly exaggerated. Am J Cardiol 2008;101:887–9. 31. Dearani JA, Ommen SR, Gersh BJ, Schaff HV, Danielson GK. Surgery insight: septal myectomy for obstructive hypertrophic cardiomyopathy—the Mayo Clinic experience. Nat Clin Pract Cardiovasc Med 2007;4:503–12. 32. Maron BJ. Hypertrophic cardiomyopathy centers. Am J Cardiol 2009;104:1158–9.

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Chapter 8 Long-term Outcome of Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy in the Young and the Elderly Max Liebregts, M.D.; Robbert C Steggerda, M.D.; Pieter A Vriesendorp, M.D.; Hannah van Velzen, M.D.; Arend FL Schinkel, M.D., Ph.D.; Rik Willems, M.D., Ph.D.; Johan van Cleemput, M.D., Ph.D.; Maarten P van den Berg, M.D., PhD.; Michelle Michels, M.D., Ph.D.; Jurriën M ten Berg, M.D., Ph.D. Submitted

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Abstract Objectives The aim of this study is to compare outcomes of alcohol septal ablation (ASA) in young and elderly patients with obstructive hypertrophic cardiomyopathy (HCM). Background: The ACCF/AHA guidelines reserve ASA for elderly patients and patients with serious comorbidities. Information on long-term age-specific outcomes after ASA is scarce. Methods: This cohort study included 217 HCM patients (54±12 years) who underwent ASA because of symptomatic left ventricular outflow tract (LVOT) obstruction. Patients were divided in a young (≤55 years) and elderly (>55 years) group, and matched by age in a 1:1 fashion to nonobstructive HCM patients. Results: Atrioventricular block following ASA was more common in elderly patients (43% vs. 21%, P=0.001), resulting in pacemaker implantation in 13% and 5%, respectively (P=0.06). Residual LVOT-gradient, post-procedural NYHA class, and necessity for additional septal reduction therapy was comparable between age groups. During a follow-up of 7.6 ± 4.6 years, 54 patients died. Five- and 10-year survival following ASA was 93% and 90% in patients ≤55 years, and 92% and 79% in patients >55 years, comparable to their control groups. The annual adverse arrhythmic event (AAE) rate following ASA was 0.7%/year in young patients, and 1.4%/year in elderly patients, comparable to their control groups. Conclusion: ASA is similarly effective for reduction of symptoms in young and elderly patients, however younger patients have a lower risk of procedure-related atrioventricular conduction disturbances. The long-term mortality rate and risk of AAE following ASA are low, both in young and elderly patients, and comparable to age-matched non-obstructive HCM patients. Keywords hypertrophic cardiomyopathy; alcohol septal ablation; septal reduction therapy

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Condensed abstract Alcohol septal ablation (ASA) is a valuable treatment option for patients with medical therapy resistant obstructive hypertrophic cardiomyopathy (HCM). The ACCF/AHA guidelines reserve ASA for elderly patients and patients with serious comorbidities. We found that ASA is similarly effective for reduction of symptoms in young and elderly patients, but younger patients have a lower risk of procedure-related atrioventricular conduction disturbances. The long-term mortality rate and risk of adverse arrhythmic events following ASA was low, both in young and elderly patients, and comparable to age-matched non-obstructive HCM patients. We propose that the indication for ASA can be broadened to younger patients.

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Abbreviation list AAE = adverse arrhythmic events ASA = alcohol septal ablation HCM = hypertrophic cardiomyopathy ICD = implantable cardioverter-defibrillator LVOT = left ventricular outflow tract LVWT = left ventricular wall thickness NYHA = New York Heart Association SCD = sudden cardiac death

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Introduction If patients with obstructive hypertrophic cardiomyopathy (HCM) remain severely symptomatic despite optimal medical therapy, septal reduction therapy should be considered. This can be done, either by surgical myectomy or alcohol septal ablation (ASA).(1,2) ASA was introduced as a percutaneous alternative to surgical myectomy, and has shown to be effective in reducing left ventricular outflow tract (LVOT) obstruction and associated symptoms in the 20 years since.(3-5) Concerns about ASA remain however, especially about the possible arrhythmogenic effect of the ablation scar in patients already at an increased risk of life-threatening arrhythmias.(6) The American College of Cardiology Foundation/American Heart Association guidelines on HCM state that ASA should be reserved for elderly patients and patients with serious comorbidities.(1) Little is known about the differences in outcome of the procedure between young and elderly patients. The aim of this study is to compare complication rates, symptom relief and long-term outcomes of ASA in young and elderly patients. Methods Study design and patient population A multicenter observational cohort design was used. The study population consisted of 217 consecutive HCM patients who underwent ASA in the St. Antonius Hospital Nieuwegein, Nieuwegein, the Netherlands (n = 147), or the Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands (n = 70). All patients met the criteria for invasive treatment: (i) ventricular septal thickness ≥15 mm, (ii) (provocable) LVOT gradient ≥50 mmHg, and (iii) persistent New York Heart Association (NYHA) class III/IV dyspnea or Canadian Cardiovascular Society class III/IV angina despite optimal medical therapy.(1,2) The choice of ASA instead of surgical myectomy was based on patient profile (age, comorbidities, etc.) and patient preference. ASA was performed as described previously.(7,8) All patients gave informed consent prior to the procedure. Local institutional review board approval was obtained. Patients were divided in a ≤55 year old group and a group >55 years of age. A 55 year cut-off was chosen because this was the median age of the study population (range 18-80 years). For the long-term outcomes two control groups were selected from a cohort of 349 non-obstructive HCM patients, also used as control group in a previous analysis.(9) Patients from this cohort were matched by age in a 1:1 fashion to patients who underwent ASA.

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Follow-up and endpoints Follow-up started at the time of ASA or, for the non-obstructive patients, at first outpatient clinic contact after January 1st, 1990. At baseline all patients were evaluated for the following characteristics: age, sex, NYHA class, maximum left ventricular wall thickness (LVWT), maximum (provocable) LVOT gradient, left ventricular function, coronary artery disease, atrial fibrillation, and conventional risk factors for sudden cardiac death (SCD).(1) The primary endpoints of this study were all-cause mortality and adverse arrhythmic events (AAE) during long-term follow-up (i.e., after 30 days post-procedure). AAE consisted of: SCD, resuscitated cardiac arrests due to ventricular fibrillation or tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) shock. Secondary endpoints were HCM-related death (death due to heart failure, stroke or SCD), peri-procedural (<30 days) AAE and mortality, new right bundle branch block, (temporary) atrioventricular block, permanent pacemaker implantation, ICD implantation, reduction in LVWT, LVOT gradient and NYHA class >3 months post-procedure, and re-intervention (ASA or myectomy). Mortality and adverse events were retrieved from hospital patient records at the center where follow-up occurred, from civil service population registers, and from information provided by patients themselves and/or their general practitioners. All ICD shocks were evaluated by an experienced electrophysiologist, unaware and independent of the study purpose and endpoints. If no events occurred during follow-up, the administrative censoring date was set at November 1st, 2012. Statistical Analysis SPSS version 20 (IBM, Armonk, NY, USA) and Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) were used for all statistical analyses. Categorical variables were summarized as percentages. Normally distributed continuous data are expressed as mean ± standard deviation and non-normally distributed data are expressed as median ± interquartile range. To compare continuous variables Student t test or Mann-Whitney U-test were used, and to compare categorical variables the χ2-test was used. Kaplan-Meier graphs were used to show survival rates. In all analyses, a P value of <0.05 was considered significant. Results Clinical characteristics The baseline characteristics of the 217 patients who underwent ASA and their age matched control groups are shown in Table 1. The mean age of the patients ≤55 years was 43 ± 8 174

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years, and the mean age of the patients >55 years was 64 ± 6 years. There were more nonobstructive patients with systolic dysfunction, as compared to patients who underwent ASA. A higher alcohol dose was used for ASA in patients ≤55 years, compared to patients >55 years (P = 0.013). Procedural outcomes Procedural outcomes of the patients who underwent ASA are shown in Table 2. Atrioventricular block following ASA was more common in patients >55 years compared to patients ≤55 years (43% vs. 21%, P = 0.001), resulting in permanent pacemaker implantation in 13% and 5%, respectively (P = 0.06). Other peri-procedural complications, including AAE and mortality, were similar in both groups. Residual LVWT, LVOT gradient and NYHA class >3 months post-procedure were comparable in both age groups, as was necessity for additional septal reduction therapy. Long-term outcomes During a mean follow-up of 7.6 ± 4.6 years there was a total of 20 deaths in the ASA cohorts, and 34 deaths in the control groups. Follow-up was complete in 98% of patients. The 5- and 10-year survival following ASA of patients ≤55 years was 93% and 90%, respectively, compared to 97% and 75% in the control group (P = 0.87; Figure 1, Table 3). The 5- and 10year survival following ASA of patients >55 years was 92% and 79%, respectively, compared to 89% and 80% in the control group (P = 0.51; Figure 2, Table 4). The annual AAE rate following ASA in patients ≤55 years was 0.7% per year, compared to 1% per year in the control group (P = 0.6) (Table 3). The annual AAE rate following ASA in patients >55 years was 1.4% per year, compared to 0.5% per year in their control group (P = 0.07) (Table 4).

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Discussion The most important result of this 7.6-year follow-up study is that long-term survival following ASA in young and elderly patients is comparable to survival in age matched non-obstructive HCM patients, and the same holds true for AAE rates. Furthermore, ASA is similarly effective for reduction of symptoms in young and elderly patients, although younger patients have a lower risk of procedure related atrioventricular conduction disturbances. Previous age specific ASA studies Currently, information on the long-term age-specific outcomes after ASA in patients with obstructive HCM is scarce. Two previous studies(10,11) have evaluated age specific outcomes of ASA patients during a follow-up period of respectively 1 and 5.1 years. Leonardi et al(10) compared the outcomes of 360 HCM patients undergoing ASA of 3 age categories (<45, 45-64, and >65 years). Likewise, they found that the reduction in LVOT gradient and NYHA class following ASA was similar independent of age, and that elderly patients more often required pacemaker implantation following the procedure. There were no control groups however, and not surprisingly the mortality rate after a follow-up of 1 year was highest in patients >65 years. Veselka et al(11) assessed the 5.1-year outcomes following ASA in 75 patients aged 42 ± 7 years, which is comparable to the mean age of our young patients. They found a survival free of all-cause mortality at 5- and 10 years of 94% each, in line with our findings. No comparisons with elderly patients were made however. Current guidelines The American College of Cardiology Foundation/American Heart Association guidelines on HCM of 2011 state that ASA should be reserved for elderly patients and patients with serious comorbidities, and gives a class III recommendation (level of evidence C) to ASA for younger patients if myectomy is a viable option.(1) This is probably in part because of the concern for an increased arrhythmogenic effect of the ablation scar in patients already at an increased risk of life-threatening arrhythmias.(6) Recent studies have shown however, that the long-term risk of SCD after ASA is low and comparable to patients who undergo myectomy.(9,12,13) This study showed an annual AAE rate following ASA of 0.7% per year in the young patients, which was similar to age-matched non-obstructive HCM patients, and half the rate of elderly patients. Another conceivable reason to choose myectomy instead of ASA in younger patients is the >2 times higher risk of atrioventricular block requiring pacemaker implantation following ASA.(13,14) This higher need for pacemaker implantation 176

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may at least partly be explained by the higher age of the patients undergoing ASA: the ASA patients from both meta-analyses were on average 9 years older than the myectomy patients. The present and previous studies have shown that atrioventricular conduction disturbances following ASA are mainly seen in elderly patients,(10,15) with a need for pacemaker implantation in only 5% of the young patients. This, despite the use of a higher amount of alcohol in the young patients. Large outcome studies following myectomy in HCM patients of similar age categories (mean age 37-47 years) showed incidences of atrioventricular block requiring pacemaker implantation of 1-6%.(16-19) Since the improvement in functional status following ASA in young and elderly patients is similarly good as well, we propose that the indication for ASA can be broadened to younger patients. In other words, younger age alone should not be a reason not to consider ASA. For children and adolescents however, little to no results are available following ASA, while there is substantial experience with myectomy.(20) We therefore recommend against ASA in this age group, until studies have proven the safety and efficacy of the procedure in these very young patients. Patient selection and specialized care In line with the 2011 American College of Cardiology(1) and the 2014 European Society of Cardiology(2) guidelines, we recommend that all patients considered for septal reduction therapy are assessed by a multidisciplinary heart team (consisting of at least one cardiothoracic surgeon, an interventional cardiologist, and a cardiologist specialized in the care of patients with HCM) to determine the optimal therapy, by taking into account not only age, but also factors like mitral valve anatomy, coronary anatomy, septal thickness, and comorbidities. When both procedures are possible, shared decision making between the informed patient and treating physician should also be part of the equation. Furthermore, septal reduction therapy should be performed by experienced operators and confined to centers with substantial and specific expertise in HCM care. Study limitations This study has several limitations. The study was performed in tertiary referral centers for the care of HCM, and the patient population might not represent the general HCM population. This referral and selection bias could have influenced the results. Data collection was limited to variables that were routinely collected. It was not possible to correct for individual or local alterations of percutaneous technique. However, all procedures were performed by experienced interventional cardiologists, plus this implies that our findings are more generalizable than those of single-center investigations.

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Conclusion ASA is similarly effective for reduction of symptoms in young and elderly patients, however younger patients have a lower risk of procedure related atrioventricular conduction disturbances. The long-term mortality rate and risk of AAE following ASA is low, both in young and elderly patients, and comparable to age matched non-obstructive HCM patients. We propose that the indication for ASA can be broadened to younger patients.

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Figure 1. Kaplan-Meier graph of all-cause survival in patients ≤55 years who underwent ASA vs. age-matched non-obstructive HCM patients.

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Figure 2. Kaplan-Meier graph of all-cause survival in patients >55 year who underwent ASA vs. age-matched non-obstructive HCM patients.

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Table 1. Baseline characteristics of 107 patients ≤55 years and 110 patients > 5 years undergoing ASA, and their age matched control groups. ASA ≤ 55 control ≤ years 55 years n =

ASA > 55 years

control > 55 years

107

110

43 ± 8

0.99

64 ± 6

0.98 <0.001

21 (20)

30 (28)

0.20

54 (49)

39 (36)

0.056 <0.001

NYHA III/IV

90 (84)

9 (8)

<0.001 84 (76)

18 (16) <0.001 0.21

Maximum LVWT, mm

20 ± 6

18 ± 5

<0.001 19 ± 4

18 ± 5

Maximum LVOT gradient, mmHg

65 ± 56

6 ± 5

<0.001 60 ± 63

7 ± 5

Systolic dysfunction (EF < 50%)

2 (2)

15 (14)

0.002

10 (9)

25 (23)

0.010 0.042

Coronary artery disease

8 (8)

12 (11)

0.48

37 (34)

18 (16)

0.005 <0.001

Atrial fibrillation

20 (19)

29 (27)

0.19

26 (24)

47 (43)

0.004 0.47

Sudden cardiac death survivor

4 (4)

8 (8)

0.38

2 (2)

11 (10)

0.022 0.44

≥ 2 conventional risk factors for SCD

16 (15)

1.0

9 (8)

22 (20)

0.020 0.18

-‐

2.0 ± 1.0

-‐

Age, years Female

Amount of alcohol, 3.0 ± 1.0 mL

0.17 0.001 <0.001 0.68

-‐

0.013

Values are mean ± SD, n (percentage), or median (interquartile range) for skewed distributions. ASA = alcohol septal ablation; EF = ejection fraction; LVOT = left ventricular outflow tract; LVWT = left ventricular wall thickness; NYHA = New York Heart Association; SCD = sudden cardiac death.

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Table 2. Procedural outcomes after alcohol septal ablation in 107 patients ≤55 years and 110 patients >55 years. ASA ≤ 55 years

ASA > 55 years

107

110

New right bundle branch block

42 (39)

39 (36)

0.66

(temporary) atrioventricular block

22 (21)

47 (43)

0.001

Permanent pacemaker implantation

5 (5)

14 (13)

0.063

15 (14)

11 (10)

0.48

Adverse arrhythmic events

8 (8)

8 (7)

1.0

Mortality

2 (2)

0 (0)

0.24

Residual LVWT > 3 months post-procedure, mm

14 ± 5

14 ± 4

0.45

Residual LVOT gradient > 3 months postprocedure, mmHg

12 ± 27

10 ± 27

0.99

Reduction in LVOT gradient > 3 months postprocedure, %

78 ± 60

76 ± 60

0.68

NYHA class III/IV > 3 months post-procedure

5 (5)

9 (9)

0.43

14 (13)

13 (12)

0.94

n= Peri-procedural(<30 days) complications

ICD implantation

Procedure efficacy

Redo septal reduction therapy

Values are n (percentage), or median (interquartile range). ASA = alcohol septal ablation; ICD = internal cardioverter defibrillator; LVOT = left ventricular outflow tract; LVWT = left ventricular wall thickness; NYHA = New York Heart Association.

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Table 3. Long-term outcomes after alcohol septal ablation in 107 patients ≤55 years compared to their age matched control group. ASA ≤ 55 years

control ≤ 55 years

107

7.2 ± 3.4

9.2 ± 5.6

5 (5)

15 (14)

0.036

- HCM-related death

3 (3)

11 (10)

0.055

- Non-cardiac

2 (2)

4 (4)

0.68

5-year survival, %

0.87

10-year survival, %

0.87

5 (5)

9 (8)

0.41

- Sudden cardiac death

2 (2)

4 (4)

0.68

- Resuscitated cardiac arrest

1 (1)

2 (2)

1.0

- Appropriate ICD shocks

2 (2)

3 (3)

1.0

0.7

1.0

0.58

n= Years of follow-up

Mortality (>30 days post-procedure) Total mortality

Adverse arrhythmic events (>30 days post-procedure) Total adverse events

Annual events, %/year

Values are median (interquartile range), or n (percentage), unless stated otherwise. ASA = alcohol septal ablation; HCM: hypertrophic cardiomyopathy, ICD: internal cardioverter defibrillator.

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Table 4. Long-term outcomes after alcohol septal ablation in 107 patients >55 years compared to their control group. ASA > 55 years

control > 55 years

110

6.5 ± 3.8

7.5 ± 4.8

15 (14)

19 (17)

0.58

4 (4)

10 (9)

0.17

11 (10)

8 (7)

0.63

5-year survival, %

0.51

10-year survival, %

0.51

10 (9)

4 (4)

0.17

- Sudden cardiac death

3 (3)

0 (0)

0.25

- Resuscitated cardiac arrest

2 (2)

1(1)

1.0

- Appropriate ICD shocks

5 (5)

3 (3)

0.72

1.4

0.5

0.070

n= Years of follow-up

Mortality(>30 days post-procedure) Total mortality - HCM-related death - Non-cardiac

Adverse arrhythmic events (>30 days post-procedure) Total adverse events

Annual events, %/year

Values are median (interquartile range), or n (percentage), unless stated otherwise. ASA = alcohol septal ablation; HCM: hypertrophic cardiomyopathy, ICD: internal cardioverter defibrillator.

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Reference list: 1.Gersh BJ, Maron BJ, Bonow RO et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:2761-96. 2.Elliott PM, Anastasakis A, Borger MA et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European society of cardiology (ESC). Eur Heart J 2014;35:2733-79. 3.Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet 1995;346:211-4. 4.Fifer MA, Sigwart U. Controversies in cardiovascular medicine. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation. Eur Heart J 2011;32:1059-64. Rigopoulos AG, Seggewiss H. A decade of percutaneous septal ablation in hypertrophic cardiomyopathy. Circ J 2011;75:28-37. 5. Rigopoulos AG, Seggewiss H. A decade of percutaneous septal ablation in hypertrophic cardiomyopathy. Circ J 2011;75:28-37. 6.ten Cate FJ, Soliman OI, Michels M et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail 2010;3:362-9. 7.van der Lee C, ten Cate FJ, Geleijnse ML et al. Percutaneous versus surgical treatment for patients with hypertrophic obstructive cardiomyopathy and enlarged anterior mitral valve leaflets. Circulation 2005;112:482-8. 8.van der Lee C, Scholzel B, ten Berg JM et al. Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation. Am J Cardiol 2008;101:1315-20. 9.Vriesendorp PA, Liebregts M, Steggerda RC et al. Long-term outcomes after medical and invasive treatment in patients with hypertrophic cardiomyopathy. JACC Heart Fail 2014;2:630-6. 10.Leonardi RA, Townsend JC, Patel CA et al. Alcohol septal ablation for obstructive hypertrophic cardiomyopathy: outcome in young, middle-aged, and elderly patients. Catheter Cardiovasc Interv 2013;82:838-45.

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11.Veselka J, Krejci J, Tomasov P et al. Survival of patients ≤50 years of age after alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Can J Cardiol 2014;30:634-8. 12.Sorajja P, Ommen SR, Holmes DR, Jr. et al. Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2012;126:2374-80. 13.Liebregts M, Vriesendorp PA, Mahmoodi BK, Schinkel AFL, Michels M, ten Berg JM. A Systematic Review and Meta-analysis of Long-term Outcomes After Septal Reduction Therapy in Patients with Hypertrophic Cardiomyopathy. [published online ahead of print]. JACC Heart Fail 2015. 14.Leonardi RA, Kransdorf EP, Simel DL, Wang A. Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment. Circ Cardiovasc Interv 2010;3: 97-104. 15.Lawrenz T, Lieder F, Bartelsmeier M et al. Predictors of complete heart block after transcoronary ablation of septal hypertrophy: Results of a prospective electrophysiological investigation in 172 patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2007;49:2356–63. 16.Desai MY, Bhonsale A, Smedira NG et al. Predictors of long-term outcomes in symptomatic hypertrophic obstructive cardiomyopathy patients undergoing surgical relief of left ventricular outflow tract obstruction. Circulation 2013;128:209-16. 17.Woo A, Williams WG, Choi R et al. Clinical and echocardiographic determinants of longterm survival after surgical myectomy in obstructive hypertrophic cardiomyopathy. Circulation 2005;111:2033-41. 18.Ommen SR, Maron BJ, Olivotto I et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;46:470-6. 19.Schonbeck MH, Brunner-La Rocca HP, Vogt PR et al. Long-term follow-up in hypertrophic obstructive cardiomyopathy after septal myectomy. Ann Thorac Surg 1998;65:1207-14. 20.Altarabsheh SE, Dearani JA, Burkhart HM et al. Outcome of septal myectomy for obstructive hypertrophic cardiomyopathy in children and young adults. Ann Thorac Surg 2013;95:663-9.

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Chapter 9 Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: Results from the Euro-ASA registry Josef Veselka MD, PhD, Morten Kvistholm Jensen MD, PhD, Max Liebregts, MD, Jaroslav Januska, MD, Jan Krejci, MD, PhD, Thomas Bartel, MD, Maciej Dabrowski, MD, PhD, Peter Riis Hansen, MD, DMSc, PhD, Vibeke Marie Almaas, MD, Hubert Seggewiss, MD, Dieter Horstkotte, MD, Pavol Tomasov, MD, Radka Adlova, MD, Henning Bundgaard, MD, DMSc, Robbert Steggerda, MD, Jurriën ten Berg, MD, PhD, Lothar Faber, MD. Submitted

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Abstract Background: The first cases of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) were published two decades ago. Although the outcomes of singlecentre and national ASA registries have been published, the long-term safety and efficacy of the procedure are still debated. Methods: We report long-term outcomes from the largest multi-centre ASA registry (EuroASA registry). Findings: A total of 1275 (58±14 years, median follow-up 5·0 years) highly symptomatic patients treated with ASA were included. The 30 day post-ASA mortality was 1%. Overall, 171(13%) patients died during follow-up, indicating a post-ASA all-cause mortality rate of 2·42 deaths per 100 patient-years. Survival rates at 1, 3, 5, and 10 years after ASA were 98%, 94%, 89%, and 77%, respectively. In multivariate analysis, independent predictors of allcause mortality were age at ASA (p<0·01), septum thickness before ASA (p<0·01), and NYHA class before ASA (p=0·047); all-cause mortality was also independently associated with the left ventricular (LV) outflow tract gradient at the last clinical check-up (p=0·048). ASA reduced the LV outflow tract gradient from 67±36 to 16±21 mmHg (p<0·001) and NYHA class from 2·9±0·5 to 1·6±0·7 (p<0·001). At the last check-up, 89% of patients reported dyspnoea of NYHA class ≤2, which was independently associated with LV outflow tract gradient (p<0.001). Interpretation: The Euro-ASA registry demonstrated low peri-procedural and long-term mortality after ASA. This intervention provided durable relief of symptoms and a reduction of LV outflow tract obstruction in selected and highly symptomatic patients with obstructive HCM. As the post-procedural obstruction is independently associated with both worse functional status and prognosis, the choice of optimal therapy should be focused on the complete elimination of LV outflow tract gradient. Funding: Supported by MH CZ-DRO, Czech Republic, 00064203.

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Introduction Hypertrophic cardiomyopathy (HCM) is characterised by the presence of an increased thickness of the left ventricular (LV) wall that is not solely explained by abnormal loading conditions, including hypertension and/or valvular diseases (1-2). Two-thirds of patients with HCM have evidence of LV outflow tract obstruction, which is usually based on basal septal hypertrophy in combination with elongated mitral leaflet(s), causing systolic anterior motion of the mitral valve (1-3). In patients who remain highly symptomatic despite optimal medical therapy, surgical myectomy has been traditionally performed to relieve obstruction and its associated symptoms (1-2). Alcohol septal ablation (ASA) was introduced two decades ago by Ulrich Sigwart in The Lancet as an alternative percutaneous technique (4). He demonstrated that the injection of a small amount of desiccated alcohol into an appropriate septal branch of the left anterior descending artery is followed by basal septal necrosis and subsequent shrinkage, resulting in a decrease in LV obstruction. Although encouraging results of single-centre or national ASA registries have been repeatedly published (5-14), the longterm safety and efficacy of the procedure were debated continuously over the following decades (1, 15-16). Twenty years after the introduction of ASA, we therefore report long-term outcomes from the largest multinational ASA registry (Euro-ASA registry) to date. Methods Patients A total of 1275 (58±14 years, 49% females), highly symptomatic, consecutive patients treated with ASA were included. Ablations were performed in ten centres from seven European countries (Bad Oyenhausen – Germany; Prague, Brno, Trinec – Czech Republic; Copenhagen, Gentofte – Denmark; Nieuwegein – the Netherlands; Innsbruck – Austria; Warsaw – Poland; Oslo – Norway) between January 1996 and February 2015. All patients had been prospectively included in institutional registries and subsequently also in the EuroASA registry. Individual centres began with the ASA programme in the years 1996–2005. The diagnosis of obstructive HCM was made by cardiologists experienced in managing patients with this disease, based on typical clinical, electrocardiographic, echocardiographic and/or cardiac magnetic resonance imaging features, with ventricular myocardial hypertrophy (LV wall thickness ≥15 mm) occurring in the absence of any other cardiac or systemic disease that could have been responsible for the hypertrophy. Alcohol septal ablation was offered to highly symptomatic adult patients in functional (NYHA) class III/IV, who were refractory or intolerant to medical therapy. In exceptional cases, patients with severe angina pectoris or

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documented exertional syncope were also included. The maximal (provocable) LV outflow tract gradient had to be ≥50 mmHg in the absence of severe mitral valve disease or other indication for cardiac surgery. Decisions regarding the choice for a transcatheter or surgical approach were made after a detailed multidisciplinary evaluation and a consensus amongst experts in the management of HCM, based on clinical experience at the individual sites. Alcohol septal ablation technique All interventions were performed by experienced interventional cardiologists. Details of the ASA technique have been published in the past (4, 17-18). Although there were some small differences in ASA technique amongst sites, all ablations were guided by myocardial contrast echocardiography and the volume of injected alcohol was gradually decreased over time (1920). Blood was withdrawn for MB fraction of creatine kinase (CK-MB) in the two days postASA. Follow-up There were differences in post-ASA follow-up between centres participating in the registry. Generally, all patients had a routine check-up 3–6 months after ASA and then every year. Patients with an implanted pacemaker or cardioverter-defibrillator (ICD) were evaluated for both implant function and memory, including registration of discharge. The survival of patients treated in the Czech Republic and Denmark were continuously checked in the National Database of the Departed. The survival of patients treated in other countries was updated in 2014–2015, either by clinical visit, telephone call, or mail communication. For deceased patients who died beyond study institutions, interviews or mail communication with the general practitioner or next of kin was performed to discover the cause of death. Endpoints and definitions In this study, we wanted to determine: i) relationships between alcohol dose injected during ASA, improvement of LV outflow tract pressure gradient and the occurrence of complete heart block, ii) clinical outcome in patients treated with ASA, iii) the post-ASA rates of allcause mortality and sudden mortality events, iv) predictors of mortality events and clinical outcome. All-cause mortality was defined as death due to any cause. Sudden mortality events included sudden deaths, appropriate ICD discharges and successful resuscitations. Sudden death was defined as sudden and unexpected death within one hour after a witnessed collapse in a previously stable patient or death that occurred during sleep. In patients with an implanted ICD, device interventions triggered by ventricular fibrillation (VF) or ventricular tachycardia (VT) were considered appropriate. Cardiovascular death was defined as death related to any cardiovascular disease, including heart failure, infective endocarditis or stroke. 190

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The relative delta pressure gradient was used to express the percentage reduction of left ventricular outflow gradient and was defined as follows: (pressure gradient at baseline – pressure gradient at last clinical check-up)/pressure gradient at baseline. Statistical analysis All data was evaluated by two independent statisticians. It was presented as means ± standard deviation (±SD) and/or medians with interquartile range (IQR). Kolmogorov–Smirnov tests, Student t-tests, Wilcoxon tests, Mann–Whitney tests, logistic regression, linear regression, nonparametric regression (LOWESS – locally weighted scatterplot smoothing), median regression, Cox proportional hazard regression, Kaplan–Meier survival analysis, log rank tests for trend and chi-square tests were used as appropriate. The following clinical and echocardiographic variables with a potential impact on patient outcome were chosen and evaluated, firstly in a univariate model: age, gender, baseline and residual dyspnoea in NYHA class, baseline and residual left ventricular pressure gradient, baseline and residual septal thickness, amount of alcohol injected during ASA. Variables with a p value < 0·15 were then entered into a multivariate analysis, which was performed using a backward stepwise multiple Cox’s regression or logistic regression. A probability of less than 0.05 was considered statistically significant. All reported p-values were two-sided. The statistical software GraphPad, release 6·05 (GraphPad Software, La Jolla, CA, USA), was used.

Results Baseline characteristics and ASA procedures A total of 1275 consecutive patients underwent ASA (49% women, 3·7% with implanted pacemaker, 4·1% with implanted ICD). Baseline clinical and echocardiographic characteristics of the patient cohort are summarised in Table 1. Volumes of injected alcohol were 2·2±0·9 ml (median 2 ml, IQR 1·5–2·5 ml) with a subsequent CK-MB peak of 2·9±2·2 µkat/l (Czech centres, upper limit of normal was 0·42 µkat/l) or 141±211 IU/l (remaining centres, upper limit of normal was 80 IU/l). The relationship between alcohol dose and relative delta pressure gradient is expressed in Figure 1. In multivariate analysis, the relative delta pressure gradient was independently associated with the amount of injected alcohol (HR 1·77, 95% CI 1·07-2·47; p<0·001), septum thickness at the last check-up (HR 0·22, -0·37- -0·54; p <0·001), and also NYHA class at the last check-up (HR -1·43,95% CI -2·44- 0·43; p =0·005.). Although higher doses of alcohol were more effective in decreasing LV outflow tract gradient, they were also associated with a

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higher occurrence of the complete heart block (HR 1·19, 95% CI 1·05-1·35; p=0·006) (Figures 1 and 2). A total of 13 (1%) patients died within one month of ASA; four patients died of heart failure, three patients of pulmonary embolism, two patients of cardiac tamponade, one patient of sepsis, one patient of stroke, one patient of carcinoma, and one patient of sudden death (VF). Intra-procedural or early post-procedural (48 hours) sustained VT/VF requiring electrical cardioversion occurred in 16 patients (1·3%) and a further 4 (0·3%) patients required electrical cardioversion between two and 30 days after ASA. The most frequent complication was a transient peri-procedural complete heart block. This occurred in 468 (37%) patients until 30 days after ASA, with 151 (12% of all patients) patients subsequently requiring permanent pacemaker implantation. Clinical outcome At the last clinical check-up (median 3·9 years, IQR 1·4–7·4), ASA had reduced LV outflow tract gradient from 67±36 to 16±21 mmHg (p<0·001) and NYHA class from 2·9±0·5 to 1·6±0·7 (p<0·001) (Table 1); 89% of patients reported dyspnoea of NYHA class ≤2, and 86% of patients experienced improvement of ≥1 class of NYHA. According to multivariate analysis, NYHA class ≤2 at the last clinical check-up with the absence of myectomy or mortality event during follow-up was independently associated with LV outflow tract gradient at the same check-up (HR 0·98, 95% CI 0·97–0·99; p<0.001). Up to the last clinical examination, 87 (7%) patients underwent a re-ASA procedure and 42 (3%) patients primarily treated by ASA subsequently underwent myectomy. Of 110 (9%) patients with an implanted ICD, 52 (4%) patients underwent implantation before and 58 (5%) after ASA. Some clinical data was missing for 105 (8%) patients. Survival after ASA The median of follow-up for survival was 5·0 years, (IQR 2·1–8·2 years). Five (0·4%) patients were lost to long-term follow-up. Overall, 171(13%) patients died during 7057 patient-years of follow-up, indicating a post-ASA all-cause mortality rate of 2·42 deaths per 100 patient-years (95% CI, 2·07–2·82) (Figure 3). Survival rates are summarised in Table 2. According to multivariate analysis, independent predictors of all-cause mortality were higher age at ASA (HR 1·06, 95% CI 1·05–1·08; p<0·001), septum thickness before ASA (HR 1·05, 95% CI 1·01–1·09; p<0·001), and NYHA class before ASA (HR 1.5, 95% CI 1.00–2.10; p=0.047); all-cause mortality was also independently associated with LV outflow tract gradient at the last check-up (HR 1·01, 95% CI 1·00–1·01; p=0·048). The survival of patients, divided in three groups according to LV outflow tract gradient at the last clinical 192

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check-up (≤29 mmHg, 30-59 mmHg, ≥60 mmHg), is available in Figure 4. After adjustment for age at ASA, septum thickness before ASA and NYHA class before ASA, 10-year allcause mortality rates were 75%, 72%, and 55%, respectively. A total of 197 (15%) patients experienced all-cause death or appropriate ICD discharge during 7055 patient-years of follow-up, indicating the rate of mortality events as 2·84 per 100 patient-years (95% CI, 2·46–3·27) (Figure 5). In multivariate analysis, independent predictors of these mortality events were higher age at ASA (HR 1·05, 95% CI 1·04–1·07; p <0·001), and septum thickness before ASA (HR 1·06, 95% CI, 1·03–1·1; p=0·001); mortality events were also independently associated with LV outflow gradient at the last check-up (HR 1·01, 95% CI 1·00–1·01; p=0·02). Figure 6 depicts the mortality events subdivided by cause. Sudden mortality events (sudden death, first appropriate ICD discharge or successful resuscitation) occurred in 68 (5·3%) patients, indicating the rate as 0·98 per 100 patient-years (95% CI, 0·76–1·12) (Figure 7); 43% of these patients survived the first event. The only independent predictor of sudden mortality events was the septum thickness before ASA (HR 1·07, 95% CI 1·01–1·12; p=0·014). Sudden or cardiovascular death occurred in 82 (6·4%) patients, which means an annual mortality rate of 1·16 (95% CI, 0·92–1·44) per 100 patient-years. Mortality events at least partially attributable to HCM (peri-procedural events, sudden mortality events or cardiovascular death) occurred in 108 (8·5%) patients, which means the annual mortality rate 1·58 (95% CI, 1·29–1·90) per 100 patient-years.

Discussion The Euro-ASA Registry was designed as a large, multinational, European registry to identify long-term outcome and its predictors in patients after ASA for highly symptomatic obstructive HCM. Two decades after the introduction of ASA, we can report the following principal findings: i) higher doses of alcohol are more effective in decreasing LV outflow tract gradient, but they are also associated with a higher occurrence of peri-procedural complete heart block; ii) LV outflow gradient is lowered by 76%, and 86% of patients experience improvement of ≥1 class of NYHA; iii) the more pronounced reduction of LV outflow tract gradient is associated with the lower resultant NYHA class; iv) the 30-day postprocedural mortality is 1%, and 12% of treated patients require an early post-procedural pacemaker implantation; v) the annual post-ASA mortality rate is 2.4% and risk of a sudden

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mortality event is 1% per year; vi) the all-cause mortality is independently associated with the residual LV outflow tract gradient. Based on data from smaller studies describing similar haemodynamic results with the use of low or high doses of intracoronary alcohol (19-20), the low doses (1-2 ml) have become standard in most ASA centres. The current registry suggests that higher doses of alcohol were slightly more effective in decreasing LV outflow tract gradient. This has significant clinical consequences, because the lower LV outflow tract gradient was associated both with better functional class and survival. On the other hand, the advantage of higher alcohol doses was balanced by a higher risk of peri-procedural complete heart block. Based on our findings, we believe that doses of alcohol ranging between 1·5 and 2·5 ml are well balanced in terms of efficacy and safety for most patients. Nevertheless, the optimal dose of alcohol can vary for each individual patient depending on the severity of their symptoms, acceptability of procedural risk and LV morphology. Procedure-related mortality was believed to be low even in the first decade after ASA introduction, with a reported mean value of approximately 1·5% (21). In this registry, we found the 30-day post-ASA all-cause mortality to be even lower (1%) including noncardiovascular mortality. On the other hand, the complication rate related to ASA is still not negligible and we have to bear in mind that one-tenth of patients will have to subsequently undergo pacemaker implantation, and some patients (1·6%) will suffer from early postprocedural ventricular arrhythmias. Fortunately, the initial fears of a plethora of late ventricular dysfunction and arrhythmias, or an increased rate of sudden death (15-16) have not been fulfilled in our observation. In this registry, with a follow-up exceeding 7000 patientyears, the rate of sudden mortality events was 1% per year, including 0·6% of sudden deaths, which is less than or similar to results presented in other HCM registries containing HCM patients without previously performed ASA (22-24). The combined rate of sudden and cardiovascular mortality reported here (1·2%) is also relatively low and may not even be entirely attributable to HCM. In the arena of HCM prognostication and choosing the optimal septal reduction therapy, there is still a knowledge gap with regard to post-procedural mortality and comparison of ASA and myectomy. Long-term survival in the current study was comparable with similar reports of patients treated by myectomy. In this study (n=1275, mean age at ASA 58 years) 10-year survival was 77%, compared to two surgical Mayo Clinic studies (25-26) with survival rates of 77% (Schaff et al., 749 patients, mean age at surgery 52 years), and 83% (Ommen et al., 289 patients, mean age at surgery 45 years). Similarly, the North American ASA Registry 194

Euro-‐ASA registry

(874 patients, mean age at ASA 55 years) demonstrated a 9-year survival of 74% (5). An identical 10-year survival of 77% was also reported by Sorajja in 544 consecutive patients with obstructive HCM (mean age 59 years), who were mildly symptomatic or asymptomatic and did not require septal reduction therapy (27). All this data, albeit reported from cohorts with a lower number of patients, seems to be consistent with our results and suggests that the long-term survival of patients treated by both techniques of septal reduction therapy is similar. This view has also been confirmed by several meta-analyses (28-29). Prediction of post-ASA clinical outcome is challenging because of the marked heterogeneity of the treated HCM cohort. In this study, the independent predictors of all-cause mortality were higher age, septum thickness and functional class before ASA, and the only predictor of sudden mortality events was septum thickness before ASA. In the context of known risk factors of long-term mortality for HCM patients these results are not surprising, however, the residual LV outflow tract gradient at the last clinical examination was also independently associated with all-cause mortality and all-cause mortality plus risk of appropriate ICD discharge. Our results thus suggest that the increase in residual LV obstruction by each mmHg was associated with a 1% increase in risk of all-cause death. It is worth noting that in post-myectomy patients an association of incomplete relief of the outflow obstruction with worse survival has also been demonstrated (30). Based on these findings, we may speculate that with the exception of ICD implantation for prevention of sudden cardiac death, the reduction of LV gradient is the most important therapeutic procedure affecting the long-term survival of highly symptomatic obstructive HCM patients, and that the means used to accomplish this are less important. In other words, it does not matter whether the obstruction is eliminated by means of myectomy or ASA, the most important objectives are the safety of the procedure and the final haemodynamic result. We cannot be sure that the current results are entirely generalisable since the patients have been referred to tertiary centres that have great experience with HCM. The key factor influencing the results of ASA is probably the optimal selection of HCM patients who are appropriate for this therapy. Typically, patients with less basal hypertrophy, long mitral leaflets, and marked hypertrophy of (bifid) papillary muscles are good candidates for septal myectomy and surgical procedures on mitral valve and/or papillary muscles (3). On the other hand, patients with hypertrophy localised mainly in the basal part of the septum without elongated mitral leaflets may be effectively and safely treated by ASA.

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Conclusion Patients diagnosed and treated in tertiary centres focusing on HCM have both low periprocedural and long-term mortality after ASA. Higher doses of alcohol are slightly more effective in reducing LV obstruction and result in a higher incidence of peri-procedural complete heart blocks. Since the post-procedural obstruction is independently associated with both worse functional status and prognosis, the choice of optimal therapy should be focused on the complete elimination of LV outflow tract gradient.

196

Euro-‐ASA registry

Research in Context Evidence before the study We searched PubMed on June 26, 2015, for clinical trials with the terms “hypertrophic cardiomyopathy”, “alcohol septal ablation”, “registry” and “survival”, with no language restrictions. We identified a multicentre North American Registry (n=874, mean follow-up 2·1 years) (5) and a German TASH Registry (n=264, in-hospital results) (6). In addition, we found several major institutional and multi-centre studies (7-14) in PubMed. Two-thirds of the patients with HCM display evidence of obstruction in LV at rest or after provocation (1-2). As first demonstrated two decades ago (4), the injection of a small amount of desiccated alcohol into an appropriate septal branch of the left anterior descending artery is followed by basal septal necrosis with its subsequent shrinking and decrease in LV obstruction (alcohol septal ablation – ASA). Although observational data suggested favourable outcomes of ASA (5-6), the long-term results are still a matter of debate (1, 1516). Added value of this study We report long-term outcomes of ASA and their predictors from the largest multi-centre ASA registry (Euro-ASA registry, n=1275, mean follow-up 5·5 years). Doses of alcohol ranging between 1·5 and 2·5 ml were well balanced in terms of efficacy and safety for most patients. ASA lowered LV outflow tract gradient by 76%, and 86% of the patients experienced an improvement of ≥1 of NYHA functional class. The annual post-ASA mortality rate was 2·4% and the risk of sudden mortality event was 1% per year. Both the all-cause mortality and better functional status were independently associated with LV outflow tract gradient at the last clinical examination of the patient. Implications of all available evidence Alcohol septal ablation performed in dedicated centres is a safe and effective procedure for symptomatic obstructive HCM patients. The post-ASA residual obstruction is a significant factor influencing functional status and long-term survival. Appropriate pre-procedural patient selection, and if possible complete elimination of the obstruction, should therefore be pursued for the optimal improvement of long-term survival.

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Acknowledgments The authors are grateful to statisticians Eva Hansvenclova and Dr Marek Maly for their assistance with statistical analysis. The authors also thank colleagues responsible for the HCM clinics in all participated centres. Conflict of interest: None

198

Euro-‐ASA registry

Table 1. Clinical and echocardiographic characteristics at baseline and last clinical check-up.

Baseline Age, years

58 ± 14

63 ± 13

Dyspnoea, NYHA class

2·9 ± 0·5

1·6 ± 0·7

<0·001

Angina, CCS class

1·3 ± 1·2

0·7 ±0·8

<0·001

Left ventricular outflow tract gradient, mmHg

67 ± 36

16 ± 21

<0·001

Left ventricular end-diastolic diameter, mm

43 ± 6

46 ± 6

<0·001

Left ventricular ejection fraction, %

70 ± 10

66 ± 10

<0·001

Basal septum thickness, mm

20 ± 4

15 ± 4

<0·001

Episodes of syncope, %

Follow-up P-value

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Table 2. Event-free survival rates after ASA

Survival rates (95% CI) 1 year All-cause death

3 years

5 years

10 years

98% (96%-98%)

94% (93%-95%)

89% (87%-91%)

77% (73%-80%)

97% (96%-98%)

92% (90%-94%)

87% (85%-89%)

73% (69%-77%)

99% (98%-99%)

97% (95%-98%)

95% (93%-96%)

90% (88%-93%)

All-cause death or appropriate ICD discharge Sudden mortality event

200

Euro-‐ASA registry

Figure 1. Relationship between alcohol dose, relative delta pressure gradient and complete heart block.

201

Chapter 9

Figure 2. Lowess curve describing relationship between alcohol dose and the occurrence of peri-procedural complete heart block.

202

Euro-‐ASA registry

Figure 3. Kaplan-Meier survival curve describing all-cause mortality with 95% confidence intervals.

1.0 0.9

Survival probability

0.8 0.7 0.6 0.5 No. at risk 1275

1107

982

866

744

641

530

444

3 4 5 6 7 Years after alcohol septal ablation

348

262

203

Chapter 9

Figure 4. Relationship between survival in groups divided according to the left ventricular outflow tract pressure gradient (LVOTO) at the last clinical check-up.

204

Euro-‐ASA registry

Figure 5. Kaplan-Meier survival curve describing all mortality events including appropriate ICD discharges and resuscitations with 95% confidence intervals.

1.0 0.9

Survival probability

0.8 0.7 0.6 0.5 No. at risk 1275

1098

969

848

728

624

515

433

3 4 5 6 7 Years after alcohol septal ablation

340

256

205

Chapter 9

Figure 6. Causes of death after ASA.

206

Euro-‐ASA registry

Figure 7. Kaplan-Meier survival curve describing all sudden mortality events including appropriate ICD discharges and resuscitations with 95% confidence intervals.

1.0 0.9

Survival probability

0.8 0.7 0.6 0.5 No. at risk 1275

1098

969

848

728

624

515

433

3 4 5 6 7 Years after alcohol septal ablation

340

256

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Reference List 1.Gersh BJ, Maron BJ, Bonow RO, et al. ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. Circulation 2011; 124:e783-31. 2.Elliott PM, Anastakis A, Borger MA, et al. ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J 2014; 35:2733-79. 3.Patel P, Dhillon A, Popovic ZB, et al. Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients without severe septal hypertrophy. Circ Cardiovasc Imaging 2015; 8: e003132. doi: 10.1161/CIRCIMAGING.115.003132. 4.Sigwart U. Non-surgical myocardial reduction of hypertrophic obstructive cardiomyopathy. Lancet 1995; 346:211-4. 5.Nagueh SF, Groves BM, Schwartz L, et al. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy: A Multicenter North American registry. J Am Coll Cardiol 2011; 58:2322-28. 6.Kuhn H, Seggewiss H, Gietzen FH, Boekstegers P, Neuhaus L, Seipel L. Catheter-based therapy for hypertrophic obstructive cardiomyopathy. First in-hospital outcome analysis of the German TASH Registry. Z Kardiol 2004; 93:23-31. 7.Sorajja P, Ommen SR, Holmes DR Jr., et al. Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2012; 16:2374-80. 8.Veselka J, Krejčí J, Tomašov P, Zemánek D. Long-term survival after alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a comparison with general population. Eur Heart J 2014; 35:2040-5. 9.Jensen MK, Almaas VM, Jacobsson L, et al. Long-term outcome of percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy. Circ Cardiovasc Interv 2011; 4:256-65. 10.Seggewiss H, Rigopoulos A, Welge D, Ziemssen P, Faber L. Long-term follow-up after percutaneous septal ablation in hypertrophic obstructive cardiomyopathy. Clin Res Cardiol 2007; 96:856-63 11.Kwon DH, Kapadia SR, Tuzcu EM, et al. Long-term outcomes in high-risk symptomatic patients with hypertrophic cardiomyopathy undergoing alcohol septal ablation. J Am Coll Cardiol Intv 2008; 1:432-438. 12.Fernandes VL, Nielsen CD, Nagueh SF, et al. Follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy. The Baylor and medical University of South Carolina experience 1996 to 2007. J Am Coll Cardiol Intv 2008; 1:561-70. 208

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13.Faber L, Seggewiss H, Welge D, et al. Echo-guided percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: 7 years of experience. Eur J Echocardiogr 2004; 5:347-55. 14.Steggerda RC, Damman K, Balt JC, Liebregts M, ten Berg JM, van den Berg MP. Periprocedural complications and long-term outcome after alcohol septal ablation versus surgical myectomy in hypertrophic obstructive cardiomyopathy: a single-center experience. JACC Cardiovasc Interv 2014; 7:1227-34. 15.Goodwin JF, Oakley CM. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet 1995; 346:1624. 16.Maron BJ, Yacoub M, Dearani JA. Controversies in cardiovascular medicine. Benefits of surgery in obstructive hypertrophic cardiomyopathy: bring septal myectomy back to European patients. Eur Heart J 2011; 32:1055-8. 17.Veselka J, Zemánek D, Fiedler J, Šváb P. Real-Time Myocardial contrast echocardiography for echo-guided alcohol septal ablation. Arch Med Sci 2009; 5:271-2. 18.Fifer MA, Sigwart U. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation. Eur Heart J 2012; 32:1059-64. 19.Veselka J, Duchoňová R, Procházková Š, Páleníčková J, Sorajja P, Tesař D. Effects of varying ethanol dosing in percutaneous septal ablation for obstructive hypertrophic cardiomyopathy on early hemodynamic changes. Am J Cardiol 2005; 95:675-8. 20.Veselka J, Tomasov P, Zemanek D. Long-term effects of varying alcohol dosing in percutaneous septal ablation for obstructive hypertrophic cardiomyopathy: A randomized study with a follow-up up to 11 years. Can J Cardiol 2011; 27:763-7. 21.Alam M, Dokainish H, Lakkis NM. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy. A systematic review of literature. J Intervent Cardiol 2006; 19:319-27. 22.Elliott PM, Gimeno JR, Thaman R, et al. Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy. Heart 2006; 92:785-91. 23.Elliott PM, Gimeno JR, Tomé MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006; 27:193341. 24.Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013; 381:242-55. 25.Schaff HV, Dearani JA, Ommen SR, Sorajja P, Nishimura RA. Expanding the indications for septal myectomy in patients with hypertrophic cardiomyopathy: results of operation in patients with latent obstruction. J Thorac Cardiovasc Surg 2012; 143:303-9.

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26.Ommen SR, Maron BJ, Olivotto I, et al. Long-term effect of surgical myectomy on survival in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2005; 46:470-6. 27.Sorajja P, Nishimura RA, Gersh BJ, et al. Outcome of mildly symptomatic or asymptomatic obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2009; 54:234241. 28.Agarwal S, Tuzcu EM, Desai MY, et al. Updated meta-analysis of septal alcohol ablation versus myectomy in hypertrophic cardiomyopathy. J Am Coll Cardiol 2010; 55:823-34. 29.Leonardi RA, Kransdorf EP, Simel DL, Wang A. Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment. Circ Cardiovasc Interv 2010; 3:97-104. 30.Mohr R, Schaff HV, Danielson GK, Puga FJ, Pluth JR, Tajik AJ. The outcome of surgical treatment of hypertrophic obstructive cardiomyopathy. Experience over 15 years. J Thorac Cardiovasc Surg 1989; 97:666-74.

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Discussion

211

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The present thesis, current knowledge and practical implications In this Chapter, the data presented in the thesis – combined with relevant previous literature – are discussed in terms of the following four types of context: first, the effectiveness of ASA in terms of gradient and symptom reduction; second, the risk of periprocedural complications – with a focus on PM implantation – after both ASA and surgical myectomy; third, survival and ventricular arrhythmia after ASA and myectomy; and fourth, a comparison between a young and elderly age group in terms of effectiveness, periprocedural risks and survival after ASA. In addition, limitations of the definitions used in the current literature for comparison of ASA and myectomy are discussed, as well as the differences between the current guidelines and recommendations and the results of this thesis. A discussion of the overall “performance” of ASA and a glimpse into the future conclude this thesis.

Symptomatic improvement, gradient after the procedure and reintervention ASA and surgical myectomy are both treatments that aim to improve symptomatic status by relieving obstructed flow in the LVOT of patients with HCM. Both a meta-analysis and recent studies have found short-term symptomatic improvement to be good after both treatments (13). In Chapter 6.1, using a questionnaire administered to patients who had undergone either ASA or myectomy, we found that this beneficial effect was sustained at long-term follow-up. We also found that annual admittance for heart failure was uncommon and the average ejection fraction was good both after myectomy and ASA (61± 11 % vs. 63 ± 8%) (Chapter 6.1). However, despite the fact that ASA and myectomy are comparable with respect to longterm symptomatic status, we found that gradients after ASA were slightly higher than those after a myectomy procedure (19 (10-42) mmHg vs. 10 (7-13) mmHg, P < 0.001). This difference was also seen in a previous meta-analysis (2). The importance of residual gradients after ASA was underscored by the small but significant predictive value of the postprocedural gradient on all-cause mortality (HR1.01, 95% CI 1.00-1.01) that is demonstrated in Chapter 9. During the first series of ASA procedures performed in 1994, it was decided that the first septal branch should be used for the induction of septal infarction. However, as exemplified in Chapter 3.1, the highly variable septal coronary anatomy may limit the technical possibilities of the operator, which perhaps explains the higher gradients found after ASA (Chapter 6.1). This formed the basis of our research in Chapter 3.2, where we found that outcome was far less likely to be successful if the ablated septal branch was more than 20 mm 212

Discussion

distal from the base of the septum and at the same time a more proximal septal branch was present and not ablated. Understanding of this association between underlying septal anatomy and a successful ASA requires further clarification. Since the origin of the LAD is situated in the atrioventricular groove, it is also situated at the level of the beginning of the very basal part of the interventricular septum. The distance from the origin of the LAD to the origin of the ablated septal branch is thus a surrogate for the distance from the base of the septum to the entry point of the ablated septal branch. In the case of unfavourable septal coronary anatomy, a proximal septal branch is not amenable for ablation, so the procedure must take place in a more distally located branch. This can result in a more distal infarct location, thereby providing a possible explanation for the higher gradients seen after ASA. In order to better understand the magnitude of the influence of the location of the infarction, in Chapter 4 we performed an analysis of CMR images from patients who had undergone ASA. A successful outcome was seen in all patients with a basal infarction, whereas patients with a more distal infarction had a higher risk of an unsuccessful outcome. On the other hand, larger infarct size measured with CMR had no influence on outcome after ASA. This again illustrates the importance of the location of the septal infarction and that the correct choice of the septal branch used for ablation plays a crucial part in this. Striving for a small basal infarction seems to lead to the best results in ASA. Even though NYHA class after ASA and myectomy are comparable at long-term follow-up, reinterventions (usually a second ASA procedure) are necessary in about 8% of patients, which is considerably higher than for myectomy (2%) (Table 1). This emphasises the importance of aiming for the most effective ASA procedure.

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Periprocedural complications ASA was introduced as an alternative to surgical myectomy with the advantage of being less invasive and thus more attractive for some patients with symptomatic obstructive HCM. Despite its more invasive nature, surgical myectomy is still considered to be safer by many clinicians and investigators, in the United States in particular. In Chapter 6 we therefore investigated the outcome of ASA and myectomy with special attention for complications associated with ASA and myectomy in a “real world” single-centre cohort study. Periprocedural mortality was found to be around 1-1.5% after both ASA and myectomy. When complications were investigated in detail, more complications were found after surgical myectomy, mostly due to post-operative bleeding. Also the length of in-hospital stay was longer after myectomy (Table 1). In an accompanying editorial, the main reason for the complication rate being higher after myectomy than after ASA was suggested as being limited experience (Chapter 6.2). Indeed, complication rates for myectomy were found to be lower in a highly specialised centre such as the Mayo Clinics (4). Nevertheless, differences between centres in patient characteristics (age, co-morbidity such as presence of coronary artery disease) make this type of comparison difficult. And even though all complications after myectomy presented in Chapter 6.1 were treated successfully, when this single-centre study compared periprocedural complications and length of in-hospital stay, the results favoured ASA, indicating that its less invasive nature could be beneficial. Periprocedural complications after ASA were also investigated in two different age groups in Chapter 8. Not unexpectedly, compared with younger patients, elderly patients had a higher rate of complications after ASA, which in fact supports the notion that ASA should also be considered for younger patients.

214

Discussion

Table 1: Current results of both procedures Myectomy

ASA

95.5%

92%

0.43

10 (7-13)

9 (10-42)

<0.001

1.6% (0.6-2.6)

7.7% (0.6-2.6)

<0.001

1.1%

1.3%

0.75

0.2%

2.2%

0.055

4.4% (2.6-6.2)

10% (7.8-12.1)

<0.001

28%

14%

0.004

9 (4-6)

5 (4-6)

<0.001

1.4%/year

1.5%/year

0.78

0.49%/year

0.41%/year

0.47

0.47%/year

0.34%/year

0.16

Effectiveness Symptomatic relief a Gradient at follow-up (mmHg) Reintervention

Complications Periprocedural mortality a Periprocedural VT/VF PM implantation

All complications*

In-hospital stay (days)

Survival Overall survival a SCD + ICD shock SCD - ICD shock a

a a

: reference 13. : reference Chapter 6.1. ICD: internal cardioverter defibrillator, PM:

pacemaker, SCD: sudden cardiac death, VF: Ventricular Fibrillation, VT: Ventricular Tachycardia. *Includes re-thoracotomy, tamponade, PM implantation, death, CVA, PM infection and mediastinitis.

PM implantation after ASA and myectomy Both after myectomy and after ASA, nodal and infranodal pathways can either be interrupted due to resection of septal myocardium or damaged due to the induction of a septal infarction. There are however some clear differences between the two procedures: after myectomy a left bundle branch block can be found and after ASA a right bundle branch block is usually found. A logical explanation for this difference is the nature of the resection after myectomy, i.e. leftsided septal myocardium is removed, leaving the right bundle branch intact. In contrast, ASA usually creates a transmural infarction involving the right side of the septum (>90% of cases, Chapter 4), thus damaging the right bundle branch. Two possible explanations for why AV block occurs in some patients, but not in others, are preprocedural vulnerability of the AV conduction system, and differences in the size and location of the excised myocardium or induced septal infarction. The exact reasons are however unknown.

215

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In a recent meta-analysis, the post-procedural rate of pacemaker implantation was found to be twice as high after ASA than after myectomy, largely due to the low rate after myectomy in the studies included in this analysis (Table 1). In Chapter 6.1, the rate of pacemaker implantations (9%) observed after myectomy was higher than the rate reported in this meta-analysis. Experience and volume of patients may explain this difference, as also suggested in Chapter 6.2. The rates are for instance higher than the 2.4% reported in a highly specialised U.S. centre (i.e. Mayo Clinics)(4). One must realise however, that the 9% rate of PM implantation found in Chapter 6.1 is a “real world” figure, that is in line with the findings of two other studies – one study extracted data from a large U.S. database and the other from a highly specialised centre (Cleveland Clinics) – which both reported a 9% pacemaker implantation rate (5,6). Apparently, pacemaker rates after myectomy vary in publications and also amongst specialised centres. Another important issue is that there are clear indications that the actual risk of PM implantation in the long-term is higher than the periprocedural risk reported in the current literature after both ASA and myectomy. For instance, the 9% post-operative risk of having a PM implanted after myectomy in the Cleveland Clinics increased to 20% during an eight year follow-up period (6). Also after ASA, the occurrence of late permanent AV block has been reported (7,8). However, studies on this topic are limited. Factors that predict whether some patients do and others do not require a PM after ASA and myectomy are described in Table 2. A higher age, pre-existing LBBB (for ASA) and a pre-existing RBBB (for myectomy) can be seen as indicators of a pre-existing vulnerable conduction system which leads to a higher risk for the need for a PM. In Chapter 6.2, a lack of surgical experience was suggested as being a possible factor influencing the increased rate of PM implantations. Indeed, a detailed description of what techniques an experienced surgeon uses in order to prevent complete heart block, or how periprocedural TEE can be used might be helpful for other centres performing myectomy. Unfortunately these data are not widely available, although risk factors and some periprocedural techniques that are associated with lower rates of PM implantation have been described for ASA (6,7,912, Table2). For example, as described in Chapter 5, whereas the dosage of ethanol did not predict the need for a PM, a slower injection of ethanol instead of bolus injection as well as a lower number of ablated septal branches are known to be associated with a lower need for a PM (Table 2).

216

Discussion

Table 2: Risk factors for permanent AV block pre-existing LBBB a,c,e pre-existing RBBB >1 procedure

a,c

b,f

>1 septal branch ablated

ASA

c,d,g

Alcohol bolus* Advanced age

b,c

Myectomy

LBBB: left bundle branch block, RBBB: right bundle branch block, * fast injection instead of slow injection of alcohol a: reference 6, b: reference 7, c: reference 9, d: reference 10, e: reference 11, f: reference 12, g: Chapter 8.

Survival and ventricular arrhythmia A recent meta-analysis has shown excellent survival rates after both ASA and myectomy (Table 1) (13). The occurrence of ventricular arrhythmia has however been a concern ever since the conception of ASA. Case reports and studies of ICD carriers have shown that ventricular arrhythmia does occur after ASA (14-18). A word of caution was even given when the rate of cardiac death due to ICD shocks was found to be higher after ASA than after myectomy (19). In Chapters 6, 7 and 9, we therefore investigated the occurrence of ventricular arrhythmia as well as survival after both myectomy and ASA. In the single-centre study described in Chapter 6, the annual rates of SCD after ASA and myectomy were both low (0.7% vs. 1.4%, P=0.15), as were the annual rates of death due to any cause: 1.5% after ASA and 2.2% after myectomy (P=0.25). In the multi-centre study described in Chapter 7, the annual SCD rate was 0.96%/year after ASA, 0.75 %/year after myectomy and 1.0 %/year in a control group (P = 0.40). After multivariate analysis, the risk of SCD after ASA was estimated to be significantly higher (HR 2.1 (1.02–4.39), p=0.04). However, 40% of cases of SCD after ASA consisted of an appropriate ICD shock in this study as this was included in the definition of SCD. Considering that appropriate ICD shocks do not necessarily affect survival, this can explain why overall survival was comparable after ASA and myectomy in this multi-centre study (1.9%/year vs. 2.0%/year, P=NS). In the European ASA registry (Chapter 9), an all-cause mortality rate of 2.4 %/year and an SCD rate of 1.2%/year was found in 1275 patients after ASA. A new finding was the independent prediction of mortality

217

Chapter 10

by residual obstructive gradients after ASA, although this effect was rather small (HR 1.01, 95% CI 1.00-1.01; p=0.047). In summary, even after acknowledging that VT/VF may occur after ASA, the incidence of VT/VF is very low and does not affect survival after ASA.

Young versus elderly age group after ASA American guidelines state that if myectomy is viable, ASA should not be performed in younger patients. In Chapter 8, effectiveness, periprocedural risks and survival after ASA were compared between a younger (43 ± 8 years) and an older age group (64 ± 6 years). After the procedure, symptomatic improvement in terms of NYHA class and reduction of the LVOT gradient were comparable in both age groups. However, periprocedural complications in terms of complete AV block and pacemaker implantation were more common in older patients than in the younger age group. Survival rates and risk for ventricular arrhythmia after ASA was found to be independent of age; both young and elderly patients had a survival rate and risk of cardiac death that was similar to their age-matched control groups. The findings in Chapter 8 do not support the notion that ASA should only be performed in the elderly, though a very young age group (<40 years) has not yet been investigated in terms of periprocedural complications, long-term complications effectiveness, and long-term survival.

Limitations of comparing the two techniques and problems with current definitions A randomised controlled trial comparing ASA and surgical myectomy would be the desired method to ultimately decide which technique is preferable. However, such a trial has not yet been performed, for several practical reasons, one of them being the necessity of including a high number of patients (20). Another major issue when comparing ASA and myectomy is that there is no consensus on the definition of success after both ASA and myectomy. Different definitions have meanwhile been used, for instance reduction of the invasive gradient, reduction of the echocardiographic gradient at follow-up and also reduction of the echocardiographic gradient at different time intervals, not to mention symptomatic improvement.

218

Discussion

In order to avoid underestimation of cardiac death, in some studies the definition of cardiac death is stated as being the occurrence of an appropriate ICD shock and death due to unknown causes. Obviously, this in turn leads to an overestimation of death due to ventricular arrhythmia. In conclusion, due to unresolved issues concerning different endpoints, different indications used for the two techniques and the lack of a randomised controlled trial, it remains difficult to directly compare ASA and myectomy and to decide which technique is preferable.

ACC/ESC guideline recommendations and impact of the current thesis The American College of Cardiology’s 2011 guidelines on treatment of HCM state that surgical myectomy should be performed in experienced centres and is the first line of treatment of symptomatic obstructive HCM with a class IIa recommendation. ASA should be regarded as an alternative only for patients in whom surgery is contra-indicated due to serious co-morbidities or advanced age – with a class IIa recommendation– and when the patient expresses preference for ASA after thorough informed consent – only as a class IIb recommendation (21). At variance with the above American guidelines, the more recent European HCM guidelines, issued in 2014, give a class Ib recommendation for both ASA and myectomy as a treatment option. In these European guidelines, surgical myectomy is regarded as a first line treatment (class I recommendation) if other lesions are present that warrant surgery (e.g. mitral valve repair/replacement) (22). As summarised below, the data presented in this thesis do not fully support the recommendations of the American guidelines; instead, they favour and supplement the European guidelines. First, Chapters 3.2 and 4 show that knowledge of septal coronary anatomy can either assist the operator in choosing the correct septal branch and basal location of the infarction or can lead to the conclusion that coronary anatomy is not suitable for ASA and that the patient should be referred for surgical myectomy instead. Therefore, favourable septal coronary anatomy should be incorporated into the guideline recommendations that favour ASA. Second, In Chapters 6 and 7, long-term survival was found to be favourable after both techniques, while both therapies were also equally effective. These results do not support the preference for surgical myectomy given in the American guidelines.

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Third, Chapter 8 does not support the recommendation in the American guidelines that ASA should be confined to older patients, since results in younger patients are also just as good for ASA as for myectomy. It should be noted that for children and adolescents ASA needs further study before ASA can be recommended for this specific age group. Fourth, the heart team should consist of a surgeon experienced with myectomy, an interventional cardiologist experienced with ASA, and an imaging cardiologist. In order for the heart team to make a decision, they must have at their disposal the complete history of the patient, a coronary angiogram (evaluation of suitable septal anatomy and presence of coronary artery disease), an echocardiogram (evaluation of distribution of left ventricular hypertrophy, SAM, concomitant valvular disease) and a CMR report (including the CMR images if echocardiography image quality is inferior). The conditions that give preference to either ASA or myectomy are listed in Table 3 and may aid the heart team in their decision making. Fifth, the fact that rates of periprocedural complications, effectiveness and long-term results are now available for both types of procedures (Chapter 6 and 7), facilitates a process of shared decision making between patient and treating physician, which is at variance with the class IIb recommendation for ASA as stated in the American guidelines of 2011. After the heart team has decided that both procedures are feasible, a process of shared decision between patient and treating physician should be initiated.

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Table 3: Criteria that give preference to either myectomy or ASA Myectomy

ASA

childhood/adolescence

Age<40

+/-

Surgical necessity*

pre-existingLBBB

+/-

pre-existing RBBB

+/-

pre-existing PM

+/-

Increased surgical risk#

+/-

Moderate AOI

Septal anatomy unsuitable

*coronary artery disease requiring surgery or valvular disease requiring surgery (including mitral valve disease with a central or anterior directed mitral insufficiency not due to SAM; elongation of the AMVL; or anterior displacement of papillary muscles). #based on known risk factors (age, hypertension, DM, history of vascular disease, severe pulmonary disease, poor mobility and previous cardiac surgery). AOI: aortic insufficiency, LBBB: left bundle branch block, PM: pacemaker, RBBB: right bundle branch block.

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Performing and improving the ASA procedure In summary, the left coronary artery and the septal anatomy are visualised via arterial access using a guiding catheter and contrast injections in multiple views. The first accessible septal branch is cannulated and an over-the-wire balloon is inserted. After inflation of the balloon, concentrated alcohol (95%) is injected in order to induce a septal infarction. This section summarises how the findings of Chapters 3-8 can be used in practice for optimal efficacy in terms of gradient reduction, minimising periprocedural complications and prevention of ventricular arrhythmia (see also Table 4). This summary includes several tips and tricks that were demonstrated during a EuroPCR 2015 learning session on ASA.

Optimal effectiveness: determining the infarct location using MCE and septal anatomy After injections are made into the left coronary artery (usually a right cranial view), the target septal branch is cannulated and an over-the-wire balloon can be introduced. In the first series of ASA procedures performed in the 1990s, temporary occlusion of the septal branch, by inflating the balloon, was used to induce temporary ischaemia in order to evaluate a pressure drop of the LVOT gradient. However this pressure drop had limited predictive value (23) and was replaced by myocardial contrast echocardiography (MCE). The use of MCE was associated with a reduction in complications (prevention of remote infarction, e.g. in right ventricle) and better outcome after ASA. However, in Chapter 4, CMR revealed that an undesired distal infarction may still occur despite the use of MCE. In order to prevent residual gradients after ASA, the coronary angiogram should be thoroughly inspected. The definitive injection of ethanol should not be given until inspection of the septal coronary anatomy identifies the correct septal branch to be used for ablation and this has been corroborated by MCE showing the correct perfusion area. As shown in Chapter 4, the operator should strive for a small infarction at a basal location and choose the correct septal branch. For septal branches that are difficult to reach, a venture device can be used. Two markers of success that can be used during the procedure are as follows: 1) The MCE shows whitening/infarct location in the correct basal location (Chapter 4). 2) The coronary angiogram shows the correct choice of septal branch (no proximal septal branch and/or the distance from the base of the septum tot the ablated branch is <20 mm) (Chapter 3).

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Prevention of tamponade Tamponade due to temporary pacing is a serious complication that has also led to the periprocedural death of a patient, as described in Chapter 6. This complication can be prevented by the insertion of a regular temporary pacemaker-lead via the subclavian vein by a dedicated electrophysiologist in the PM lab before the procedure (24). This technique will also most likely reduce PM lead infections or loss of capture, relative to a temporary PM lead inserted via the groin.

Prevention of alcohol leakage Leakage of ethanol is the second risk of periprocedural death (Chapter 6) and/or remote infarction. The following factors for preventing alcohol leakage were described during the learning session on ASA at EuroPCR 2015: 1) Choose the correct balloon (short (6-8 mm) and slightly oversized in diameter). 2) Check for complete balloon apposition using contrast injections, both antegrade and retrograde (injection behind the balloon). 3) Give a low-dose injection of ethanol (1-3 ml total, or amount according to septal thickness (0.08 ml/mm)). 4) Inject the ethanol very slowly (rate 0.5-1 ml/min). 5) After ethanol injection, flush with 0.3-0.5 ml saline injection. 6). Wait at least 5 minutes before deflation and removal of the balloon.

Prevention of vascular bleeding Radial instead of femoral access can reduce vascular complications. Although the insertion of a second catheter for continuous gradient monitoring is difficult with this technique, this can also be monitored using echocardiography (24).

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Prevention of ventricular arrhythmia In general, survival after ASA is excellent, with a very low occurrence of ventricular arrhythmia. Survival is also comparable to that in a non-obstructive HCM population (Chapter 7). Nevertheless, case reports and a single-centre study have shown that malignant ventricular arrhythmia may occasionally occur. Suggestions for preventing ventricular arrhythmia were made in Chapters 4 and 5, and are aimed at limiting infarct size: 1) Strive for a small infarction at a basal location (based on septal anatomy and MCE). 2) Avoid large diameter septal branches (instead use a more distal side branch ablation under guidance of MCE). 3) Avoid injecting too large a volume of alcohol.

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Table 4: Performing ASA How to Optimise gradient reduction

Technical approach combined use of MCE and inspection of septal coronary anatomy, striving for basal infarct location

Prevent tamponade

insertion of temporary (subclavian) pacemaker by a dedicated electrophysiologist

Prevent alcohol leakage

- balloon choice (6-8mm short, slightly oversized in diameter) - check balloon apposition using antegrade and retrograde contrast injection - low dose of alcohol (1-3 ml, or 0.08ml/mm of septum) - slow alcohol injection (rate 0.5-1ml/min) - slow flush with 0.3-0.5 ml saline - wait > 5min before deflation/removal of the balloon

Prevent bleeding Prevent ventricular arrhythmia

radial instead of femoral access - low alcohol dosage (1-3 ml, total) - small infarct size, while striving for basal location - avoid large diameter septal branches (using side branches instead)

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How to inform the patient If the heart team considers both procedures to be feasible, the preference for one of the two procedures should be decided jointly by the treating physician and the patient. The results of this thesis and data from the literature enable the patient to be fully informed about the risks and benefits of both options. Information that can be discussed with the patient is presented in Table 3, and, if available, centre-specific results should also be provided. In summary, one should evaluate whether or not the patient has understood the following facts: the nature and invasiveness of both techniques, the good long-term survival after both ASA and myectomy, the effectiveness of both techniques for treatment of symptoms, the higher risk of a PM implantation after ASA relative to myectomy, and the greater need for reintervention after ASA; and, last but not least, the clearly less invasive nature of ASA relative to myectomy.

Future perspectives ASA and myectomy have both evolved into techniques that have excellent long-term survival and a very low risk of SCD. Further improvements in survival are therefore difficult. There are however unresolved issues that do warrant further research. ASA is still associated with slightly higher gradients after the procedure, as well as a higher need for a reintervention and a higher rate of PM necessity compared with myectomy. The development of periprocedural techniques that can prevent these complications is indicated. For instance, case reports on periprocedural use of CT or three-dimensional echocardiography have been presented but need further development and study (24,25). Combining knowledge on the location of conduction pathways and exact location of the septal infarction may allow us to reduce the numbers of patients requiring a pacemaker. A case report and case series have recently been published on a new treatment of obstructive HCM using a mitraclip (26,27). The mitraclip is used to stop the SAM in a direct manner, thereby limiting obstruction in the LVOT. Due to its relatively non-invasive nature, and possibly even lower complication rate (no risk of PM placement), this technique is as promising as ASA and myectomy at the time they were first performed. Future research is required to establish its role as either a conjunctive technique or as a stand-alone technique.

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Reference List: 1.Fifer MA, Sigwart U. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation. Eur Heart J. 2011;32:1059-1064. 2.Alam M, Dokainish H, Lakkis NM. Hypertrophic obstructive cardiomyopathy-alcohol septal ablation vs myectomy: a meta-analysis. Eur Heart J. 2009;30:1080-1087. 3.Sorajja P, Ommen SR, Homes Jr. DR, Dearani JA, Rihal CS, Gersh BJ, Lennon RJ, Nishimura RA (2012). Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 126:2374-2380. 4. H.V. Schaff, J.A. Dearani, S.R. Ommen, P. Sorajja, R.A. Nishimura. Expanding the indications for septal myectomy in patients with hypertrophic cardiomyopathy: results of operation in patients with latent obstruction. J Thorac Cardiovasc Surg 143;2012:303–309. 5. Panaich SS1, Badheka AO2, Chothani A3, Mehta K4, Patel NJ5, Deshmukh A6, Singh V7, Savani GT7, Arora S1, Patel N1, Bhalara V1, Grover P7, Shah N5, Elder M1, Mohamad T1, Kaki A1, Kondur A1, Brown M1, Grines C1, Schreiber T1. Results of ventricular septal myectomy and hypertrophic cardiomyopathy from Nationwide Inpatient Sample [1998-2010]. Am J Cardiol. 2014;114(9):1390-5. 6. Smedira NG, Lytle BW, Lever HM, Rajeswaran J, Krishnaswamy G, Kaple RK, Dolney DOW, Blackstone EH. Current effectiveness and risks of isolated septal myectomy for hypertrophic obstructive cardiomyopathy. Ann Thorac Surg 2008; 85:127-134 7. Schuller JL, Zipse MM, Krantz MJ et al. Incidence and Predictors of Late Complete Heart Block After Alcohol Septal Ablation Treatment of Hypertrophic Obstructive Cardiomyopathy J int Cardiol 2015; 28:90-97. 8. Chen AA, Palacios IF, Mela T, et al. Acute predictors of subacute complete heart block after alcohol septal ablationfor obstructive hypertrophic cardiomyopathy. Am J Cardiol 2006;97:264–269. 9.Chang SM, Nagueh SF, Spencer WH et al. Complete heart block: Determinants and clinical impact in patients with hypertrophic obstructive cardiomyopathy undergoing nonsurgical septal reduction therapy. J Am Coll Cardiol 2003; 42(2); 296-300. 10.Lawrenz T, Lieder F, Bartelsmeier M, et al. Predictors of complete heart block after trancoronary abaltion of septal hypertrophy. J Am Coll Cardiol 2007; 49(24): 2356-2363. 11. El-Jack SS, Nasif M, Blake JW et al. Predictors of Complete Heart Block After Alcohol Septal Ablation for Hypertrophic Cardiomyopathy and the Timing of Pacemaker Implantation. J Interven Cardiol 2007;20:73–76.

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12.ElBardissi AW1, Dearani JA, Nishimura RA, Ommen SR, Stulak JM, Schaff HV. Septal myectomy after previous septal artery ablation in hypertrophic cardiomyopathy. Mayo Clin Proc. 2007 Dec;82(12):1516-22. 13.Liebregts M, Vriesendorp PA, Mahmoodi BK, Schinkel AFL et al. A systematic review and Meta-analysis of long-term Outcomes after septal reduction therapy in patients with hypertrophic cardimyopathy. Submitted 2015 JACC Heart Failure. 14.Hori Y, Ueda M, Nakayama T, et al. Occurrence of de novo sustained monomorphic ventricular tachycardia induced after percutaneous transluminal alcohol septal myocardial ablation for hypertrophic obstructive cardiomyopathy. Int J Cardiol 2007;119:403–7. 15.McGregor JB, Rahman A, Rosanio S, et al. Monomorphic ventricular tachycardia: a late complication of percutaneous alcohol septal ablation for hypertrophic cardiomyopathy. Am J Med Sci 2004;328:185–8. 16.Boltwood CM Jr, Chien W, Ports T. Ventricular tachycardia complicating alcohol septal ablation. N Engl J Med 2004;351:1914–15. 17.Simon RD, Crawford FA III, Spencer WH III, et al. Sustained ventricular tachycardia following alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Pacing Clin Electrophysiol 2005;28:1354–6. 18.Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405– 12. 19. ten Cate FJ, Soliman OI, Michels M, et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail 2010;3: 362–9. 20. I. Olivotto, S.R. Ommen, M.S. Maron, F. Cecchi, B.J. Maron. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Will there ever be a randomized trial? J Am Coll Cardiol 2007;50:831–834. 21.Gersh BJ, Dphil ChB, Maron BJ, Bonow RO et al. 2011ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. J Thoracic and Cardiovasc Surgery 2011;142:e153-203. 22.Elliot PM, Anastasakis A, Borger MA, Borggrefe M et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur H Journal 2014;35:27332779. 23. Knight C, Kurbaan A, Seggewiss H, et al. Nonsurgical septal reduction for hypertrophic obstructive cardiomyopathy. Circulation 1997; 95:2075–81. 228

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24. Cuisset T1, Franceschi F, Prevot S, Ansaldi S, Habib G, Pankert M, Fourcade L, Poyet R, Bonnet JL, Quilici J. Transradial approach and subclavian wired temporary pacemaker to increase safety of alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: the TRASA trial. Arch Cardiovasc Dis. 2011;104(8-9):444-9. 25. Krishnaswamy A, Tuzcu EM, Kapadia SR. Use of intraprocedural CT imaging to guide alcohol septal ablation of hypertrophic cardiomyopathy in the cardiac catheterization laboratory. Catheter Cardiovasc Interv. 2012;80(6):991-4. 26. Moya Mur JL, Salido Tahoces L, Mestre Barceló JL, Rodríguez Muñoz D, Hernández R, Fernández-Golfín C, Zamorano Gómez JL. Alcohol septal ablation in hypertrophic cardiomyopathy. 3D contrast echocardiography allows localization and quantification of the extension of intraprocedural vascular recruitment. Int J Cardiol. 2014 Jul 1;174(3):761-2. 27. Schäfer U, Frerker C, Thielsen T, Schewel D, Bader R, Kuck KH, Kreidel F. Targeting systolic anterior motion and left ventricular outflow tract obstruction in hypertrophic obstructed cardiomyopathy with a MitraClip. EuroIntervention. 2014 Aug 30. pii: 2013031002. 28. Ulrich Scha ̈fer, MD *, Felix Kreidel, MD , Christian Frerker, MD. MitraClip. Implantation as a New Treatment Strategy against Systolic Anterior Motion-induced Outflow Tract Obstruction in Hypertrophic Obstructive Cardiomyopathy. Heart, Lung and Circulation (2014) 23, e131–e135

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Summary:

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Chapter 1 first described the aetiology and pathophysiology of obstructive hypertrophic cardiomyopathy. Next, a description was given on the extensive and ongoing debate of the proper treatment of this patient group. This chapter also described the two main invasive treatment options, ASA and myectomy, their history in terms of associated complications and their improvements over time. Finally, the outline of the thesis was given. In short, the aim was to investigate and compare the two treatment options in terms of clinical outcome, predictors of clinical outcome and complication rates, and to identify possible means of improvement of ASA. Chapter 2 described the background of HCM and the options for treatment. HCM is characterised by idiopathic left ventricular hypertrophy and estimated to have an incidence of 1:500 in the general population. It is inherited in an autosomal dominant fashion, with mutations in genes which encode for the sarcomere. Microscopy demonstrates hypertrophy and disarray of myocytes and interstitial and perivascular fibrosis can also be found. Systolic anterior motion of the anterior mitral valve leaflet with accompanying gradient obstruction in the left ventricular outflow tract can occur in 70% of patients with HCM. The ECG is abnormal in 80% of HCM patients and diagnosis is usually made by echocardiography, if not on cardiovascular magnetic resonance imaging. Symptoms of dyspnoea, angina, vertigo or syncope can occur in both obstructive and non-obstructive HCM patients. The clinical course of HCM patients is mostly favourable, with an annual mortality rate of 1%/year. However, in a high-risk population, the mortality rate can be higher than 5%/year. As sudden cardiac death can occur with no preceding symptoms, a careful risk assessment is necessary. Patients with an increased risk of sudden death can undergo ICD implantation. In non-obstructive HCM patients, symptoms of reduced exercise tolerance can occur due to diastolic dysfunction and ischaemia. In these patients, medical treatment with beta blockers or verapamil usually does not improve – and may even worsen – heart failure symptoms due to negative inotropic effects. In contrast, for patients with symptoms due to obstruction of flow, beta blockers, verapamil and dysopiramide are treatment options as a first line. For patients in whom medical treatment has failed, invasive treatment of the obstruction can be undertaken using either surgical myectomy or – for those with relative contraindications for myectomy – ASA.

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In Chapters 3.1 and 3.2, the relationship between outcome after ASA and septal coronary anatomy was investigated. In Chapter 3.1, a case report illustrated the dependence of the operator on suitable septal anatomy. In cases where the operator was challenged with less favourable anatomy, the first result was inadequate; to achieve a successful outcome a second septal branch that was more proximal and more difficult to approach needed to be ablated. This illustrates the importance of coronary septal anatomy and infarct location for the outcome of the procedure. In Chapter 3.2, predictors of an unsuccessful outcome after ASA were investigated, with a focus on septal anatomy. The definition of a successful outcome was the combination of a resting gradient < 30 mmHg, a provoked gradient < 50 mmHg and an improved NYHA class at follow-up. Coronary angiograms were evaluated for the presence of a septal branch that was more proximal than the ablated septal branch. Also the distance from the origin of the LAD to the origin of the ablated septal branch was measured. Univariate predictors for unsuccessful outcome after ASA were baseline gradient, distance to the ablated branch, and the presence of a non-ablated septal branch more proximal than the ablated branch. In the multivariate analysis, the combination of a non-ablated proximal septal branch with a more distal location of the ablated septal branch (>20 mm ) was associated with an unsuccessful outcome. This confirms the importance of ablating the most proximal septal branch if the next septal branch is too distal. By applying this strategy, the infarction is more likely to encompass the entire basal part of the septum, leading to a wider left ventricular outflow tract (LVOT) and abolition of SAM and obstruction in the LVOT. These findings can be used periprocedurally in conjunction with MCE. And when anatomy is not suitable, patients may be referred for surgical myectomy instead. Chapter 4 used CMR studies to investigate the effects of infarct location and infarct size on outcome after ASA in 47 patients with obstructive HCM. Infarct location was divided into "basal infarction" and "distal infarction". Infarct size was divided into small and large infarctions based on an optimal cut-off value for the distance from the basal septum to the beginning of the infarction. A more basal infarct location was found to be associated with a better outcome after ASA; and at long-term follow-up, patients with a basal infarct location also had lower gradients than those with a distal infarction. The reason for a more distal location of the infarction could be attributed to coronary septal anatomy. In contrast, a larger infarct size was not associated with lower gradients at follow-up. In the future, the best

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strategy therefore seems to be to try and inflict a small basal infarction, which will maximise gradient abolition without risking possible complications seen for larger infarctions. In Chapter 5, the relationship between alcohol dosage and infarct size, and cardiac death after ASA was investigated. The main finding was that alcohol dosage could not predict either ventricular arrhythmia or cardiac death. However, an association was found between infarct size and cardiac death. As it turned out, baseline septal thickness and larger septal branches were associated with infarct size, whereas alcohol dosage was not. Despite the lack of an association between alcohol dosage and cardiac death, a larger alcohol dosage was not associated with better gradient abolition, and thus it seems sensible to keep infarct size small and total alcohol dosage low. In Chapter 6.1, in a single-centre study, a group of patients was investigated for periprocedural complications, symptoms of heart failure and long-term survival after ASA or myectomy. The rate of periprocedural complications after ASA was lower than that after myectomy and median in-hospital stay was shorter. The longer in-hospital stay and the higher rate of complications seen in myectomy are probably a reflection of the fact that this surgical procedure is more invasive than ASA. Survival, annual rate of cardiac death, symptomatic status at long-term follow-up, and rate of re-hospitalisation for heart failure were comparable between the two groups. However, the lower complication rate after ASA was offset by higher gradients after the procedure. In Chapter 6.2, an editorial comment by Geske JB and Gersh BJ is given on the findings of Chapter 6.1, commenting on the fact that operative mortality, ischaemic stroke, need for rethoracotomy due to bleeding and the need for PM implantation were relatively high compared with results from other high-volume centres (e.g. Cleveland Clinics and Mayo Clinic). The main probable reason as suggested by the authors is the difference in the surgeon’s level of experience.

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In Chapter 7.1, ASA and myectomy were compared in a multi-centre study. A control group consisting of patients with non-obstructive HCM was used for comparison. The annual rate of “cardiac death” was slightly higher after ASA than after myectomy and was mainly due to appropriate ICD shocks. However, overall survival was good and comparable after both ASA and myectomy. Both the reintervention rate and the gradient at follow-up were higher after ASA than after myectomy. In Chapter 7.2, an editorial comment by Maron BJ and Nishimura RA is given on the findings of Chapter 7.1. The authors state that the American guidelines unanimously judge septal myectomy to be the primary treatment option for most patients with HCM. ASA is regarded as an alternative to myectomy only for patients with a very high perioperative risk or for patients of advanced age. They consider the two-fold increase in risk of sudden death after ASA to be an indicator of increased arrhythmogenicity due to the infarct induction with alcohol. They believe this to be an important reason why surgical myectomy should remain the primary treatment option. In Chapter 8, the outcome after ASA was compared between a younger population (average 43 ± 8 years) and an older population (average 64 ± 6 years) and compared with age-matched control groups of pharmacologically treated HCM patients. The survival rate after ASA was similar in the two age groups and also similar to the respective control groups. Reduction of the gradient and post-procedural NYHA class after ASA were comparable between the young and older age groups. Regarding periprocedural complications, more PM implantations and a higher frequency of AV block were found in the older population. Chapter 9 described the outcome after ASA of patients included in the European ASA registry, which included 1275 patients from ten centres in seven different countries. Perioperative mortality was 1% and survival rates after ASA were 98% at 1 year, 94% at 3 years, 89% at 5 years and 77% at 10 years. A small but significant association was found between residual obstruction and worse functional status. This illustrates the importance of completely eliminating the LVOT gradient.

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Dankwoord Graag wilde ik iedereen bedanken die op directe of indirecte wijze heeft meegeholpen aan het tot stand komen van dit proefschrift. In het bijzonder wilde ik een aantal mensen hieronder nogmaals bedanken. Ten eerste mijn promotor Maarten van den Berg en copromotoren Jurriën ten Berg en Kevin Damman; Beste Maarten, bedankt voor de begeleiding die je hebt gegeven tijdens mijn promotietraject. Je hulp en alle ideeën die je hebt gegeven voor het onderzoek en je hulp bij het schrijven en herhaaldelijk corrigeren van alle stukken hebben dit manuscript mogelijk gemaakt. Beste Jur, ik wilde je bedanken voor alle mogelijkheden die je me hebt aangeboden voor dit onderzoek en de inspiratie die ik verkreeg uit alle werk dat je hiervoor hebt gedaan. Beste Kevin graag wilde ik je bedanken voor al je hulp bij het corrigeren en analyseren van de stukken en je hulp bij mijn promotietraject. Mijn dank gaat uit naar alle leden van de maatschap cardiologie van Nieuwegein. Dank voor de tijd toen ik werkte als arts-assistent bij jullie en de mogelijkheid mijn onderzoek te starten. Aan alle oud-assistenten van het Antonius ziekenhuis met wie ik heb samengewerkt: De tijd die ik met jullie heb samengewerkt was echt een goede tijd, dank daarvoor. Voor Max Liebregts; Beste Max, ik wens je veel succes met je aankomende promotie op het hetzelfde onderwerp. Bedankt voor het werk dat we samen hebben kunnen doen. Hierbij wil ik tevens de werkgroep van het Erasmus MC uit Rotterdam en van het Universitair ziekenhuis te Leuven (België) bedanken voor hun samenwerking. Alle leden van de maatschap cardiologie van het Martini ziekenhuis: Leo Schrijvers, Addy Lubbert-Verberkmoes, Jan Posma, Robert Tieleman, Marco Willemsen, Louis Bartels, Raymond Huijskes, Bert Takens, Christiane Geluk wil ik bedanken voor jullie ondersteuning. In het bijzonder wil ik Chris bedanken voor alle hulp met de statistieken en correcties van de stukken. Voor alle leden van de MRI werkgroep uit het VUMC, met in het bijzonder Wessel Brouwer en Albert van Rossum: Dank voor alle samenwerking en jullie eerdere werk op dit gebied die het huidige onderzoek mogelijk hebben gemaakt.

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Beste Ritsert, bedankt voor je hulp aan het einde van het proefschrift. Verder ook bedankt voor het doorsturen van die speedboot; Een 50N vestje is blijkbaar toch wel voldoende op het ijsselmeer. Beste Jippe, ik wilde je bedanken voor al je hulp met de data en het schrijven en je tips om door te zetten. Alberto é Riri grazie per la compagnia a Framura e anche per avermi lasciato lavorare; e sempre un piacere stare con voi. Grazie per il limoncello, Alberto e grazie per tutto il cibo, Riri. Mijn vrouw; Lieve Valentina, dankje voor je ondersteuning en je begrip voor wanneer ik weer achter de computer ging zitten. Voor mijn kinderen Livia en Irene, jullie zijn gewoon de liefste schatjes.

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Curriculum Vitae Robbert Steggerda is in 1974 geboren in Utrecht en opgegroeid in Echt, waar hij zijn vwo diploma in 1992. Hierna heeft hij in Antwerpen geneeskunde gestudeerd van 1992 tot 1997. Van 1997 tot 2001 heeft hij zijn opleiding geneeskunde afgerond aan de Vrije Universiteit in Amsterdam. Van 2002 tot 2003 heeft hij gewerkt als AGNIO in het St Elisabeth ziekenhuis te Haarlem en in het VU ziekenhuis te Amsterdam. Zijn opleiding tot cardioloog heeft hij aanvankelijk gestart in het VU ziekenhuis in 2004 en nadien van 2005 tot 2010 in het St Antonius ziekenhuis te Nieuwegein afgerond. Tijdens zijn opleiding tot cardioloog is hij onder begeleiding van dr. JM ten Berg gestart met onderzoek naar patiënten met obstructieve hypertrofische cardiomyopathy die ofwel behandeld waren geweest met alcohol septum ablatie ofwel met een chirurgische myectomy. Nadat hij vanaf 2011 in het Martini ziekenhuis ging werken als cardioloog heeft hij dit onderzoek voortgezet, nu tevens onder begeleiding van Prof. MP van den Berg van het UMCG Groningen. Zijn hobby’s zijn catamaran zeilen en surfen. Hij is getrouwd met Valentina Gracchi en heeft twee dochters, Irene en Livia.

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