Proefschrift van den Brom by Nicole Nijhuis

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury in rats

UITNODIGING voor het bijwonen van de openbare verdediging van het proefschrift

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury in rats door Charissa van den Brom

in rats

Donderdag 30 januari 2014 om 15.45 uur In de aula van het Hoofdgebouw Vrije Universiteit De Boelelaan 1105 te Amsterdam Receptie na afloop van de promotie

Charissa EsmĂŠ van den Brom

Paranimfen Ester Weijers e.weijers@vumc.nl Marianne de Gruil-van Eldik eldik400@hotmail.com

Charissa EsmĂŠ van den Brom

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury in rats

Charissa EsmĂŠ van den Brom

Het effect van dieetsamenstelling en sevofluraan op de perfusie, functie en ischemische schade van het hart in ratten

Printed by: Gildeprint Drukkerijen Âą www.gildeprint.nl ISBN: 978-90-9027989-3 Copyright ÂŠ 2013 by C.E. van den Brom (c.vandenbrom@vumc.nl) All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, without prior written permission of the author. The

work

presented

this

thesis

was

performed

the

Department

Anesthesiology and Laboratory for Physiology, VU University Medical Center / Institute of Cardiovascular Research (ICaR-VU), Amsterdam, the Netherlands. Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. Additional financial support for this thesis was kindly provided by the following sponsors: UNO roestvaststaal B.V. and AbbVie B.V.

VRIJE UNIVERSITEIT

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury in rats

ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. F.A. van der Duyn Schouten, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op donderdag 30 januari 2014 om 15.45 uur in de aula van de universiteit, De Boelelaan 1105

door

Charissa EsmĂŠ van den Brom geboren te Nijkerk

promotor:

prof.dr. S.A. Loer

copromotoren:

dr. C. Boer dr. R.A. Bouwman

Voor papa

Contents Chapter 1:

General introduction & Outline of this thesis Chapter 2:

Metabolic disease and perioperative ischemia in the experimental setting: Consequences of derangements in myocardial substrate metabolism Chapter 3:

High fat diet-induced glucose intolerance impairs myocardial function, but not myocardial perfusion during hyperemia: a pilot study Chapter 4:

Sevoflurane impairs myocardial systolic function, but not myocardial perfusion in diet-induced prediabetic rats Chapter 5:

Diet composition modulates sevoflurane-induced myocardial depression in rats Chapter 6:

109

Western diet modulates the susceptibility of the heart to ischemic injury and sevoflurane-induced cardioprotection in rats Chapter 7:

129

Conclusions & General discussion Chapter 8:

143

Summary Chapter 9:

149

Samenvatting List of abbreviations

155

Dankwoord

161

List of publications

167

Curriculum Vitae

177

1 General introduction & Outline of this thesis

Introduction

Perioperative cardiovascular risks In the Netherlands, about 1.3 million surgical procedures are performed every year under general or locoregional anesthesia. Surgery and anesthesia are associated with alterations in systemic and regional perfusion and oxygenation. These alterations are due to the cardiovascular effects of anesthetics, loss and replacement of intravascular volume, mechanical positive pressure ventilation and application of vasoactive drugs. Although the mortality risk of surgery and anesthesia is nowadays considerably

low,

patients

are

still

risk

for

perioperative

cardiovascular

complications. Bainbridge et al. showed a total perioperative mortality of 0.12% and anesthetic-related mortality of 0.0034% in the 1990s-2000s in developed and developing countries.1 The risk for cardiovascular complications increases with age and in the presence of comorbidities like heart disease, pulmonary disease or diabetes

mellitus.2-4

Other

well-known

predictors

perioperative

cardiac

complications are coronary disease, angina pectoris, prior myocardial infarction, heart failure, stroke/transient ischemic attack, renal dysfunction and diabetes mellitus requiring insulin therapy.4;5 It is estimated that cardiovascular complications like myocardial infarction and cardiac arrest occur in 2-5% of all noncardiac surgical procedures, and globally affect 5-12 million patients each year.4;5

Myocardial ischemia and reperfusion The most common cardiovascular complication during or after noncardiac surgery is the development of myocardial ischemia,4;5 which is associated with a significant risk for morbidity and mortality. Myocardial ischemia occurs when coronary perfusion is inadequate to maintain a sufficient oxygen supply/demand ratio in the heart. During surgery, maintenance of the myocardial oxygen balance is challenged by anesthetics and surgical stress, which directly affect myocardial oxygen supply and consumption. This altered balance may increase the risk of myocardial ischemia.6;7 While the silent nature of perioperative myocardial ischemia hampers its diagnosis, Landesberg et al. showed that patients with a large increase in troponin following major surgery are at risk for cardiac complications and unfavorable outcome.8 More recently, McFalls et al. described that perioperative elevated cardiac troponin levels strongly predict long-term mortality.9 From these findings it might be concluded that myocardial ischemia is often present during and after surgery, and prevention of an oxygen supply/demand mismatch may contribute to improved

postoperative

outcome.

Volatile anesthesia There is an ongoing debate whether the type of anesthesia could modulate the risk of perioperative cardiovascular complications. Surgical procedures under general

Chapter 1

anesthesia are either performed using intravenous anesthetics, like propofol, or inhalational anesthesics using volatile agents like isoflurane or sevoflurane. Volatile anesthetics are acknowledged for their cardioprotective effects, which consist of preservation of cardiovascular function in case of reduced tissue oxygenation. Volatile anesthetics exert several effects on the heart, peripheral vasculature and the autonomic nervous system. Sevoflurane alters calcium (Ca2+) handling in the heart. To be more specific, sevoflurane reduces myocardial Ca2+ availability and increases sarcoplasmic reticulum Ca2+ content,10 depresses Ca2+ currents,11 reduces Ca2+ influx via the L-type Ca2+ channels12 and increases Na+/Ca2+ exchangermediated Ca2+ influx.13 In addition, sevoflurane prolongs the QT interval, thereby prolonging ventricular repolarization.14;15 Moreover, inhalation of volatile anesthetics causes a dose-dependent decrease in blood pressure, mainly due to a reduction in systemic vascular resistance.16 In healthy humans, sevoflurane decreases myocardial blood volume and hyperemic blood flow, while myocardial blood flow during baseline conditions is not affected.17 Further effects of volatile anesthetics on the heart are negative inotropic effects, such as depressed myocardial contractility and lusitropic effects reflected by early diastolic dysfunction.18-20 One might expect that, due to the general effects of volatile anesthetics on the heart, anesthesia may be associated with a changed balance between myocardial pefusion and function, although this has been rarely investigated.

Cardiometabolic disease Patients with lifestyle risk factors, such as excessive caloric intake and a sedentary lifestyle, which both contribute to the development of obesity and type 2 diabetes mellitus, even show a higher risk for postoperative morbidity and mortality in case of perioperative myocardial ischemia.3;4;9;21 Worldwide, more that 1.4 billion adults were overweight in 2008, and of these over 500 million people were obese. Moreover, 344 million people suffer from impaired glucose tolerance, whereas 366 million patients are diagnosed with type 2 diabetes mellitus.22 It is expected that by the year 2030 almost 400 million people suffer from impaired glucose tolerance and 552 million people from diabetes.22 The higher risk for the development of perioperative myocardial ischemia in patients with obesity and type 2 diabetes mellitus may partly be due to reduced coronary vasodilation in response to pharmacological stimuli, atherosclerosis, oxidative stress and insulin resistance.23-25 With the expanding epidemic of obesity and type 2 diabetes mellitus it is therefore expected that the number of patients that are prone to develop perioperative myocardial ischemia will increase within the next decades. The number of studies focusing on the impact of cardiometabolic disease on myocardial perfusion and function during anesthesia is however limited, and the underlying pathophysiology is not well understood.

Introduction

Dietary intake While obesity and type 2 diabetes mellitus are acknowledged as factors that accelerate the risk of perioperative myocardial ischemia, there is only limited information available with respect to the association between the development of cardiometabolic disease with myocardial perfusion, function and ischemia and reperfusion injury. It is commonly acknowledged that excessive caloric intake, in combination with a sedentary lifestyle, is the main contributor to the development of obesity and type 2 diabetes mellitus. Most lifestyle programs therefore focus on changes in dietary behavior in combination with physical activity. In addition to the number of calories that contribute to the development of cardiometabolic disease, there is increasing interest in the role of dietary composition on the development of cardiometabolic disease. A western or cafetaria diet, which is characterized by a high percentage of saturated fatty acids and simple carbohydrates such as fructose or sucrose, is one of the most common causes for overweight, obesity and diabetes mellitus. Animal studies provide evidence that excessive availability of dietary lipids or simple carbohydrates leads to accumulation of metabolic intermediates, thereby inducing myocardial insulin resistance and impairment of myocardial function.26-29 In humans, myocardial triglyceride accumulation is associated with alterations in myocardial function and has been demonstrated to occur in the diabetic heart.30 During normal physiologic conditions the heart derives its energy requirements from fatty acid oxidation (60-70%), glucose oxidation (30-40%) and amongst others, lactate (10%). However, this process is restricted as myocardial substrate metabolism is largely determined by the availability of the substrate.31-35 The above described observations contribute to the emerging concept that myocardial substrate metabolism is closely related to myocardial function. Moreover, in case of surgical stress and anesthesia, diet-induced alterations in myocardial substrate metabolism may become more abundant with respect to the balance between the supply and demand of oxygen and cellular nutrients. It might therefore be interesting to investigate how modulation of dietary intake influences the susceptibiltiy of the heart to injury, and whether the protective effects of anesthetic strategies may be altered by dietary composition.31-35 Interestingly, while the negative consequences of obesity and type 2 diabetes mellitus for the development of cardiometabolic diseases are well acknowledged, there is increasing evidence that overweight and obesity may also be protective in case of postoperative risks,36 the so-called obesity paradox. The counterintuitive observations suggest that the unfavorable cardiometabolic effects of high intake of saturated fatty acids may shift towards a beneficial condition in case of stress. Moreover, recent studies suggest that a change in diet before surgery and anesthesia may be of influence on the risk of postoperative complications.37 Animal studies further showed that short-term dietary restrictions before surgical stress are

Chapter 1

associated

with

improved

insulin

sensitivity,

oxidative protection and

organ

preservation during ischemia and reperfusion injury.38;39 It is however unknown whether dietary changes in the period before exposure to an anesthetic procedure may alter the effects of volatile anesthetics on myocardial perfusion, function and injury.

Aim of this thesis In the light of these considerations, the present thesis particularly focuses on the interaction of the volatile anesthetic sevoflurane with myocardial perfusion, systolic function as well as ischemia and reperfusion injury in rats exposed to a normal healthy or a western diet. Myocardial perfusion and function were studied using echocardiography as a noninvase technique for the monitoring of myocardial systolic and diastolic function. The use of a contrast agent expands the use of the technique for determination of myocardial perfusion. We hypothesized that sevoflurane-induced changes in myocardial perfusion and function are distinctly influenced by preoperative dietary composition. Moreover, we tested the hypothesis that a high intake of saturated fatty acids in combination with simple carbohydrates alters the cardioprotective effects of sevoflurane in case of myocardial ischemia and reperfusion. The specific aims per chapter are summarized below.

Outline of the thesis This thesis focuses on the effect of dietary changes on myocardial function, perfusion and injury during sevoflurane anesthesia. In chapter 2 the effects of volatile anesthetics,

diabetes

and

perioperative

ischemia

myocardial

substrate

metabolism are reviewed. In chapter 3, we studied the effect of high fat diet feeding on myocardial perfusion and function with (contrast) echocardiography. We used dipyridamole infusion to induce conditions of hyperemia. Chapter 4 describes the effects of a more severe, western diet on myocardial perfusion and function. Additionally, the effects of sevoflurane were studied. Furthermore, we studied the effect of changing dietary intake on myocardial function and myocardial ischemia and reperfusion injury. Chapter 5 was designed to study the effect of dietary alterations in combination with sevoflurane exposure on myocardial function. In Chapter 6 the hypothesis that the cardioprotective effects of sevoflurane on myocardial ischemia and reperfusion injury are reduced by western diet-feeding has been tested. Finally, Chapter 7 provides a general discussion of the findings presented in this thesis and places these findings in perspective.

Introduction

References 1. Bainbridge D, Martin J, Arango M, Cheng D: Perioperative and anaesthetic-related mortality in developed and developing countries: a systematic review and meta-analysis. Lancet 2012, 380:1075-1081. 2. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999, 100:1043-1049. 3. Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, Fleisher LA, Froehlich JB, Gusberg RJ, Leppo JA, Ryan T, Schlant RC, Winters WL, Jr., Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC, Jr.: ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery-Executive Summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg 2002, 94:1052-1064. 4. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith SC, Jr., Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA et al.: ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation

and

care

for

noncardiac

surgery:

report

the

American

College

Chapter 1

11.Fassl J, Halaszovich CR, Huneke R, Jungling E, Rossaint R, Luckhoff A: Effects of inhalational anesthetics on L-type Ca2+ currents in human atrial cardiomyocytes during beta-adrenergic stimulation. Anesthesiology 2003, 99:90-96. 12.Hanley PJ, ter Keurs HE, Cannell MB: Excitation-contraction coupling in the heart and the negative inotropic action of volatile anesthetics. Anesthesiology 2004, 101:999-1014. 13.Bouwman RA, Salic K, Padding FG, Eringa EC, van Beek-Harmsen BJ, Matsuda T, Baba A, Musters RJ, Paulus WJ, de Lange JJ, Boer C: Cardioprotection via activation of protein kinase Cdelta depends on modulation of the reverse mode of the Na+/Ca2+ exchanger. Circulation 2006, 114:I226-I232. 14.Kang J, Reynolds WP, Chen XL, Ji J, Wang H, Rampe DE: Mechanisms underlying the QT interval-prolonging effects of sevoflurane and its interactions with other QT-prolonging drugs. Anesthesiology 2006, 104:1015-1022. 15.Nakao S, Hatano K, Sumi C, Masuzawa M, Sakamoto S, Ikeda S, Shingu K: Sevoflurane causes greater QTc interval prolongation in elderly patients than in younger patients. Anesth Analg 2010, 110:775-779. 16.Malan TP, Jr., DiNardo JA, Isner RJ, Frink EJ, Jr., Goldberg M, Fenster PE, Brown EA, Depa R, Hammond LC, Mata H: Cardiovascular effects of sevoflurane compared with those of isoflurane in volunteers. Anesthesiology 1995, 83:918-928. 17.Bulte CS, Slikkerveer J, Kamp O, Heymans MW, Loer SA, de Marchi SF, Vogel R, Boer C, Bouwman RA: General anesthesia with sevoflurane decreases myocardial blood volume and hyperemic blood flow in healthy humans. Anesth Analg 2013, 116:767-774. 18.Humphrey LS, Stinson DC, Humphrey MJ, Finney RS, Zeller PA, Judd MR, Blanck TJ: Volatile anesthetic effects on left ventricular relaxation in swine. Anesthesiology 1990, 73:731-738. 19.Yamada T, Takeda J, Koyama K, Sekiguchi H, Fukushima K, Kawazoe T: Effects of sevoflurane, isoflurane, enflurane, and halothane on left ventricular diastolic performance in dogs. J Cardiothorac Vasc Anesth 1994, 8:618-624. 20.Harkin CP, Pagel PS, Kersten JR, Hettrick DA, Warltier DC: Direct negative inotropic and lusitropic effects of sevoflurane. Anesthesiology 1994, 81:156-167. 21.Preis SR, Pencina MJ, Hwang SJ, D'Agostino RB, Sr., Savage PJ, Levy D, Fox CS: Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation 2009, 120:212-220. 22.Unwin N, Whiting D, Guariguata L, Hennis A, Husseini A, Ji L, Kissimova-Skarbek K, Libman I, Mayer-Davis E, Motala A, Narayan V, Ramachandran A, Roglic G, Sham J, Wareham N, Zhang P. IDF diabetes atlas 2011. 5th ed. Brussels: International Diabetes Federation; 2011. 23.Ansley DM, Wang B: Oxidative stress and myocardial injury in the diabetic heart. J Pathol 2013, 229:232-241. 24.Candiotti K, Sharma S, Shankar R: Obesity, obstructive sleep apnoea, and diabetes mellitus: anaesthetic implications. Br J Anaesth 2009, 103 Suppl 1:i23-i30. 25.Bagry HS, Raghavendran S, Carli F: Metabolic syndrome and insulin resistance: perioperative considerations. Anesthesiology 2008, 108:506-523. 26.Ouwens DM, Diamant M, Fodor M, Habets DD, Pelsers MM, El Hasnaoui M, Dang ZC, van den Brom CE, Vlasblom R, Rietdijk A, Boer C, Coort SL, Glatz JF, Luiken JJ: Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36mediated fatty acid uptake and esterification. Diabetologia 2007, 50:1938-1948. 27.Davidoff AJ, Mason MM, Davidson MB, Carmody MW, Hintz KK, Wold LE, Podolin DA, Ren J: Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments. Am J Physiol Endocrinol Metab 2004, 286:E718-E724.

Introduction

28.Marsh SA, Dell'Italia LJ, Chatham JC: Interaction of diet and diabetes on cardiovascular function in rats. Am J Physiol Heart Circ Physiol 2009, 296:H282-H292. 29.Gonsolin D, Couturier K, Garait B, Rondel S, Novel-Chate V, Peltier S, Faure P, Gachon P, Boirie Y, Keriel C, Favier R, Pepe S, DeMaison L, Leverve X: High dietary sucrose triggers hyperinsulinemia, increases myocardial beta-oxidation, reduces glycolytic flux and delays postischemic contractile recovery. Mol Cell Biochem 2007, 295:217-228. 30.van der Meer RW, Rijzewijk LJ, Diamant M, Hammer S, Schar M, Bax JJ, Smit JW, Romijn JA, de Roos A, Lamb HJ: The ageing male heart: myocardial triglyceride content as independent predictor of diastolic function. Eur Heart J 2008, 29:1516-1522. 31.Stanley WC, Lopaschuk GD, McCormack JG: Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 1997, 34:25-33. 32.Carley AN, Severson DL: Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim Biophys Acta 2005, 1734:112-126. 33.Neely JR, Rovetto MJ, Oram JF: Myocardial utilization of carbohydrate and lipids. Prog Cardiovasc Dis 1972, 15:289-329. 34.van den Brom CE, Bosmans JW, Vlasblom R, Handoko ML, Huisman MC, Lubberink M, Molthoff CF, Lammertsma AA, Ouwens DM, Diamant M, Boer C: Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle. Cardiovasc Diabetol 2010, 9:25. 35.van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, Van der Velden J, Boer C, Ouwens DM, Diamant M: Altered myocardial substrate

metabolism

associated

with

myocardial

dysfunction

early

diabetic

cardiomyopathy in rats: studies using positron emission tomography. Cardiovasc Diabetol 2009, 8:39. 36.Valentijn TM, Galal W, Tjeertes EK, Hoeks SE, Verhagen HJ, Stolker RJ: The obesity paradox in the surgical population. Surgeon 2013, 11:169-176. 37.Mitchell JR, Beckman JA, Nguyen LL, Ozaki CK: Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery 2013, 153:594-598. 38.Mitchell JR, Verweij M, Brand K, van d, V, Goemaere N, van den Engel S, Chu T, Forrer F, Muller C, de JM, van IW, IJzermans JN, Hoeijmakers JH, de Bruin RW: Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell 2010, 9:40-53. 39.Shinmura K, Tamaki K, Bolli R: Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol 2005, 39:285-296.

2 Metabolic disease and perioperative ischemia in the experimental setting: Consequences of derangements in myocardial substrate metabolism CE van den Brom, CSE Bulte, SA Loer, RA Bouwman, C Boer Cardiovascular Diabetology, 2013 12:47

Metabolic disease and perioperative ischemia

Abstract Volatile anesthetics exert protective effects on the heart against perioperative ischemic injury. However, there is growing evidence that these cardioprotective properties are reduced in case of type 2 diabetes mellitus. A strong predictor of postoperative cardiac function is myocardial substrate metabolism. In the type 2 diabetic heart, substrate metabolism is shifted from glucose utilization to fatty acid oxidation, resulting in metabolic inflexibility and cardiac dysfunction. The ischemic heart also loses its metabolic flexibility and can switch to glucose or fatty acid oxidation as its preferential state, which may deteriorate cardiac function even further in case of type 2 diabetes mellitus. Recent experimental studies suggest that the cardioprotective properties of volatile anesthetics partly rely on changing myocardial substrate metabolism. Interventions that

target

restoration

metabolic

derangements,

lifestyle

and

pharmacological interventions, may therefore be an interesting candidate to reduce perioperative complications. This review will focus on the current knowledge regarding myocardial substrate metabolism during volatile anesthesia in the obese and type 2 diabetic heart during perioperative ischemia.

Chapter 2

Introduction Perioperative cardiac complications occur in 2-5% of all non-cardiac surgical procedures, which globally affect 5-12 million patients each year.1 More specifically, 0.65% of these patients develop perioperative myocardial infarction or cardiac arrest.2 Perioperative cardiac complications are an economical, medical and social burden that warrants optimization of perioperative health and cardiovascular care to improve patient outcome and reduce health care costs. There are several well-known predictors for perioperative cardiac complications identified, such as type of surgery, ASA classification and increasing age.1,2 Additionally, lifestyle risk factors associated with metabolic alterations, such as excessive dietary intake and physical inactivity, are

strongly

associated

with

clinical

risk

factors

that

predict

perioperative

cardiovascular complications.1 Lifestyle risk factors related to obesity and type 2 diabetes mellitus (T2DM) have become an epidemic over the last decade. Worldwide, 366 million people have T2DM.3 It is predicted that in the year 2030 about 552 million people will have overt diabetes, mainly T2DM.3 Patients with T2DM are more likely to develop coronary artery disease and myocardial ischemia4 and have an increased cardiovascular complication rate after major non-cardiac surgery.5 In addition to prevention programs to reduce the burden of metabolic disease on the perioperative process, there are intraoperative cardioprotective strategies available that may reduce the impact of ischemic injury during and after surgery, like the application of the volatile anesthetics sevoflurane and isoflurane. These volatile anesthetics exert multiple protective effects that enhance perioperative preservation of the heart in patients6 and rats.7 Although exposure to volatile anesthetics reduced infarct

size

and

improved

post-ischemic

recovery

healthy

rats,7

the

cardioprotective effects of these agents are reduced in obese and hyperglycemic9 rats. Derangements in myocardial substrate metabolism are one of the hypothetical mechanisms that may explain the suppressed cardioprotective capacity in T2DM.10-12 It is however not yet understood how these myocardial metabolic alterations affect intraoperative cardioprotective mechanisms. In order to elucidate the impact of altered myocardial substrate metabolism on intraoperative myocardial protection, this review will focus on available preclinical knowledge regarding myocardial substrate metabolism during volatile anesthesia in the obese/T2DM heart under normal conditions and in the context of ischemia. We first describe myocardial substrate metabolism under healthy, obese/T2DM and ischemic conditions, followed by an overview of the interaction between substrate metabolism and volatile anesthetics in the context of perioperative ischemia and reperfusion injury. Finally, we propose strategies to modulate myocardial substrate

Metabolic disease and perioperative ischemia

metabolism that may contribute to an improvement of myocardial protective capacity and perioperative and postoperative outcome in obesity and T2DM.

Myocardial substrate metabolism Fatty acids and carbohydrates are essential for the pump function of the heart.13 Under physiological conditions, myocardial contractile function relies on oxidation of fatty acids (60-70%), glucose (30-40%) and to a lesser extent lactate, ketones, amino acids and pyruvate (10%) to generate adenosine triphosphate (ATP).14-16 The heart exerts a metabolic flexibility, and myocardial substrate utilization depends on substrate availability, nutritional status, and exercise level. With glucose as the more energetically efficient substrate, the healthy heart is able to switch to glucose under conditions of stress, such as ischemia, pressure overload or in heart failure. Glucose metabolism is regulated through multiple steps, including uptake, glycolysis and pyruvate decarboxylation. Myocardial glucose supply is regulated 1) via circulating glucose levels or 2) by release of glucose from intracellular glycogen stores.17 Myocardial glucose uptake depends on the sarcolemmal glucose transporter GLUT1 (insulin-independent) and the dominant glucose transporter GLUT4 (insulindependent) (Figure 2.1).18 After uptake, glucose is broken down into pyruvate by glycolysis, consumed by the mitochondria and decarboxylated into acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA enters the tricarboxylic acid cycle with entry of reducing equivalents to the electron transport chain and oxidative phosphorylation, which finally leads to ATP formation (Figure 2.1). Fatty acid metabolism consists of uptake, oxidation and esterification. There are two sources of fatty acids for myocardial metabolism: 1) circulating albumin bound fatty acids derived from adipose tissue via lipolysis or 2) released from triglyceriderich lipoproteins from the liver.19 Fatty acids enter cardiomyocytes by simple diffusion and via transport through three different membrane fatty acid transporters Âą fatty acid translocase (FAT)/CD36, fatty acid transport protein (FATP1/6) and plasma membrane fatty acid binding protein (FABPpm) (Figure 2.1).19 After sarcolemmal uptake, intracellular fatty acids are activated to form fatty acyl-CoA, which

can

undergo

triglycerides.20

Fatty

beta-oxidation acid

oxidation

esterification

requires

fatty

form

acyl-CoA

intracellular

entry

into

the

mitochondria, which is dependent on the activity of carnitine palmitoyl transferase (CPT-1).21 After translocation into the mitochondria, fatty acyl-CoA can enter the beta-oxidation pathway to form acetyl-CoA and subsequently ATP (Figure 2.1). Under physiological conditions, 70-90% of the fatty acids that enter cardiomyocytes are oxidized for ATP generation, whereas 10-30% is converted to triglycerides by lipoprotein lipase.22 In case of energy expenditure, intracellular triglyceride stores can be hydrolyzed as an endogenous fatty acid source, which is explanatory for 10% of the total fatty acid utilization in the heart.23

Chapter 2

Figure 2.1: Glucose and fatty acid metabolism in the cardiomyocyte Glucose uptake into the cell occurs through the glucose transporters GLUT1 and GLUT4. Once inside, glucose is broken down into pyruvate by glycolysis. Pyruvate is subsequently transported into the mitochondria and decarboxylated to acetyl-CoA. Non-esterified fatty acids are taken up through fatty acid transporter (FAT)/CD36, fatty acid transport protein (FATP) and plasma membrane fatty acid binding protein (FABPpm). Intracellular fatty acids form fatty acyl-CoA and can either be esterified into triglycerides (TG) or enter the mitochondria via carnitine palmitoyl transferase (CPT-1). Fatty acyl-&R$ HQWHUV WKH Ç&#x192;-oxidation pathway, forming acetyl-CoA. Glucose or fatty acid-derived acetyl-CoA enters the tricarboxylic acid (TCA) cycle with entry of reducing equivalents to the electron transport chain and oxidative phosphorylation, and finally ATP is formed.

Metabolic disease and perioperative ischemia

Type 2 diabetes mellitus Alterations in myocardial substrate metabolism in T2DM hearts are extensively reviewed by others.15,22,24 In short, myocardial fatty acid metabolism is initially enhanced in T2DM hearts, with increased rates of fatty acid oxidation and esterification.25,26 There are two proposed mechanisms that may underlie this derangement: 1) increased fatty acid uptake due to increased substrate supply and augmented expression and localization of sarcolemmal fatty acid transporters26 and 2) increased oxidation and esterification due to changes in regulation at both the enzymatic and transcriptional level.26 In addition, a decreased myocardial glucose metabolism is a concomitant feature of the T2DM heart.25,26 The slow rate of glucose transport across the sarcolemmal membrane due to decreased glucose transporters leads to a restriction of glucose oxidation. Accordingly, fatty acid oxidation has an inhibitory effect on the pyruvate dehydrogenase complex due to increased fatty acid supply. Taken together, the T2DM heart has a distinct metabolic phenotype, characterized by enhanced myocardial fatty acid metabolism and a concomitant reduction in myocardial glucose metabolism. Ischemia Myocardial ischemia occurs when coronary perfusion is inadequate to maintain a sufficient

oxygen

supply/demand

ratio.

Ischemia

influences

both

myocardial

substrate metabolism and myocardial function. The pathophysiological mechanisms underlying this phenomenon have been reviewed previously.24,27 In the event of ischemia, high-energy phosphates are depleted, ionic homeostasis is disturbed and contractile dysfunction is caused. The energetic demand of the heart changes in case of myocardial ischemia. The heart usually responds to injury by increasing myocardial glucose metabolism to improve its energetic efficiency.22,24 However, increased adipose tissue lipolysis results in increased plasma free fatty acid concentrations,

which

may

increase

myocardial

fatty

acid

utilization

and

esterification.27 In this context, glycolysis becomes an important source of energy due to its ATP-generating ability in the absence of oxygen. It is also suggested that in the early phase of ischemia, fatty acid oxidation shifts to the more efficient glucose oxidation, followed by a decrease in total substrate oxidation.24 Increased glycolysis can parallel depression of myocardial glucose and fatty acid oxidation depending on the severity of ischemia. Overall, the ischemic heart favors the energetically more efficient glucose (3.17 ATP/oxygen molecule) over fatty acid oxidation (2.83 ATP/oxygen molecule).28 This flexibility additionally depends on substrate

availability,

oxygen

supply,

tissue

vascularization

and

myocardial

workload. In conclusion, the metabolic state of the ischemic heart is characterized by

Chapter 2

imbalances in substrate availability and utilization and is also influenced the severity of ischemia. The combination of type 2 diabetes mellitus and ischemia The cardiometabolic profile of patients with T2DM makes them more prone to develop plaque formation and intravascular stenosis, leading to the development of stroke or myocardial infarction. In addition, these patients are more susceptible to subsequent episodes of ischemia.29,30 Whereas the metabolic undisturbed heart usually responds to injury by increasing myocardial glucose metabolism,22,24 this adaptive response is inhibited by insulin resistance, which is a characteristic of obesity and T2DM. This inhibition results in increased myocardial fatty acid metabolism,31;32 increased oxygen consumption, decreased cardiac efficiency31 and altered myocardial perfusion.33 In obese or T2DM animals subjected to myocardial ischemia the findings are inconclusive. It has been shown that obesity reduced ischemia and reperfusion injury34 and myocardial function during ischemia (and reperfusion),35-40 but also similar ischemia and reperfusion injury was found.41 Additionally, increased glucose oxidation and decreased fatty acid oxidation after myocardial infarction was found, which was ameliorated in obese rats.40 Obese rats with insulin resistance resulted in preserved myocardial function36 or aggravated36,4244

ischemia and reperfusion injury. Moreover, the combination of insulin resistance,

dyslipidaemia and hypertension in obese animals seems to increase the susceptibility of the heart to ischemia (and reperfusion) injury.45-48 Others however reported that myocardial injury during ischemia was unaffected in T2DM rats, independent of the severity of T2DM.49 In case of genetically induced T2DM rats in combination with a high cholesterol diet, ischemic injury was however exacerbated.50 As stated earlier, these inconclusive results in animal experiments suggest that the type and severity of T2DM may influence the sensitivity of the heart to ischemic insults. With regard to myocardial substrate metabolism, endogenous glycogen stores may support increased glucose availability as substrate for the heart, and may thus be beneficial in case of ischemic injury. However, whether pre-ischemic glycogen levels are beneficial or detrimental depends on the duration of T2DM51 and to the extent of glycogen depletion during ischemia.52 Overall, the effects of imbalanced myocardial substrate metabolism during ischemia in T2DM are inconclusive. These observed contrasts may be due to differences in the severity of ischemia, the measured outcome parameter, exogenous circumstances and the severity of the experimental model for T2DM.32,53

Metabolic disease and perioperative ischemia

Effects of volatile anesthetics in animals Cardioprotective effects during ischemia Sevoflurane and isoflurane are commonly used volatile anesthetics. Sevoflurane and isoflurane make the rat heart more resistant to ischemia and reperfusion injury.54-58 It has been shown that proteins related to myocardial substrate metabolism are, amongst others, affected by sevoflurane-induced cardioprotection. PI3K and Akt, which regulate translocation of glucose transporter 4 (GLUT4) to the sarcolemma for glucose uptake, are increased during sevoflurane in the isolated ischemic rat heart.59 Moreover, sevoflurane enhances GLUT4 expression in lipid rafts, increases glucose oxidation and decreases fatty acid oxidation after ischemia and reperfusion injury in isolated working rat hearts compared to untreated ischemic hearts.10 In the same study, no alterations in AMP activated protein kinase (AMPK) phosphorylation, pyruvate dehydrogenase activity and glycogen content were found, whereas sevoflurane

decreased

triglycerides

and ceramide

levels

after

ischemia

and

reperfusion injury.

Moreover, volatile anesthetics are also known to alter mitochondrial function, which is nicely reviewed by Stadnicka et al.60 In short, it has been shown that sevoflurane and

isoflurane 61,62

channels,

metabolism.

open

mitochondrial

ATP-activated

activates reactive oxygen species

potassium

(mito

K+ATP)

and thereby alters mitochondrial

Together, these results suggest a role for myocardial substrate metabolism in the cardioprotective effects of volatile anesthesia during ischemia and reperfusion injury in animals, although evidence is limited. Myocardial substrate metabolism during volatile anesthesia In rats, it has been shown that in vivo myocardial glucose uptake was increased in the heart during isoflurane (2 vol%) when compared to sevoflurane (3.5 vol%).64 An explanation could be the differences by more stable blood glucose levels during sevoflurane. However, a limitation of this study was that the effects were not compared with findings in awake rats or using non-volatile anesthetics. Others found that isoflurane (2 vol%) increased myocardial glucose uptake compared to awake mice.65 The effects of sevoflurane on myocardial substrate metabolism have only been studied ex vivo. Sevoflurane (2 vol%) decreased FAT/CD36 in lipid rafts and fatty acid oxidation in isolated rat hearts.12 And, although studied in skeletal muscle cells, sevoflurane (2.6-5.2%) increased glucose uptake.66 Altogether, these results suggest that isoflurane and sevoflurane might switch myocardial metabolism to glucose as energetically more efficient substrate.

Chapter 2

Volatile anesthesia is also known to affect pancreatic insulin release. In isolated rat pancreatic islets, enflurane67 and isoflurane68 have an inhibitory effect on glucosestimulated insulin release. In rats, isoflurane impaired glucose-induced insulin release,69 whereas sevoflurane impaired glucose tolerance,70 which both resulted in hyperglycemia. Therefore it seems that impaired insulin release during volatile anesthesia might have a negative effect on substrate metabolism. However, the beneficial cardioprotective effects may outweigh the adverse effects of impaired insulin

secretion,

the

American

Heart

Association

2007

guidelines

ÂľSHULRSHUDWLYH FDUGLRYDVFXODU HYDOXDWLRQ DQG FDUH IRU QRQ FDUGLDF VXUJHU\Âś VXJJHVWHG that it can be beneficial to use volatile anesthetics during non cardiac surgery for maintenance of general anesthesia in hemodynamically stable patients at risk for myocardial ischemia.1 Alterations in cardioprotective mechanisms in the metabolic altered heart The healthy heart is capable of protecting itself against stressors like ischemia by the flexibility to switch between circulating substrates. These cardioprotective properties might be enlarged during volatile anesthesia. On the other hand, the obese/T2DM heart is less capable of switching between circulating substrates, which may contribute to a reduced intrinsic protective capacity. It is generally acknowledged that the incidence of perioperative cardiovascular complications is increased in patients

with

T2DM

after

non-cardiac

surgery.5

Accordingly,

blood

glucose

concentrations at admission correlated with long-term mortality in diabetic patients with acute myocardial infarction,71 suggesting that T2DM may affect perioperative cardiovascular risk. The next paragraphs focus on available experimental knowledge whether obesity, insulin resistance, hyperlipidemia and hyperglycemia, important hallmarks of T2DM, exert a cumulative effect on endogenous and exogenous cardioprotective mechanisms. Obesity and insulin resistance It has been shown that obesity and insulin resistance inhibit the cardioprotective effects of ischemic pre-72 and postconditioning.73 In high fat diet-induced obese rats, sevoflurane preconditioning failed to induce cardioprotection during myocardial ischemia and reperfusion injury.41 Moreover, sevoflurane postconditioning did not protect the heart against myocardial and reperfusion injury in obese and insulin resistant Zucker rats,8 however, more research is necessary to draw a conclusion. Hyperlipidemia The hyperlipidemic heart has difficulties to adapt to stressors like ischemia, suggesting that cardioprotective mechanisms are impaired. In rats it has been shown that pacing-induced cardioprotection74 and ischemic-induced preconditioning75 was inhibited by hypercholesterolemia. Sevoflurane preconditioning reduced myocardial

Metabolic disease and perioperative ischemia

infarct size in normocholesterolemic rats, which was blocked in hypercholesterolemic rats.76 Further research is warranted to study the impact of hyperlipidemia on anesthesia-induced cardioprotection. Acute hyperglycemia Hyperglycemia

independent

predictor

cardiovascular

risk.71

The

glycometabolic state upon hospital admission is associated with the mortality risk in T2DM patients with acute myocardial infarction.77 It has further been shown that hyperglycemia inhibits the cardioprotective capacity during desflurane-induced preconditioning,78 isoflurane-induced preconditioning,9,79 and sevoflurane-induced postconditioning in the experimental setting.80 Accordingly, infarct size was directly related to the severity of hyperglycemia,81;82 whereas the inhibited cardioprotective effects of isoflurane-induced preconditioning are concentration dependent and related to the severity of acute hyperglycemia.9 Moreover, it has been shown that hyperglycemia attenuated cardioprotection via inhibition of Akt and endothelial nitric oxide

synthase

(eNOS)

phosphorylation.83

However,

interpretation

abovementioned findings in relation to T2DM is difficult, because experiments were performed during acute hyperglycemia in otherwise healthy animals without the typical characteristics of T2DM, such as obesity and insulin resistance. Type 2 diabetes mellitus T2DM hinders the cardioprotective effects of ischemic preconditioning,84 which has been reviewed by Miki et al.85 However, the diabetic rat heart may still benefit when the preconditioning stimulus is enlarged.86 The effects of anesthesia-induced cardioprotection in T2DM have however never been studied. In type 1 diabetes, the protective effects of isoflurane-induced preconditioning were inhibited in case of low isoflurane concentrations, but not at high concentrations.82 Further, sevofluraneinduced postconditioning in the type 1 diabetic heart was disturbed, whereas insulin treatment to reach normoglycemia did not restore the cardioprotective capacity.87 Mechanisms that are suggested to be involved include the inhibition of PI3K/Akt 86,87 and inactivity of mito K+ATP.87 Furthermore, AMPK activation during ischemia protects the non-obese T2DM Goto-Kakizaki rat heart against reperfusion injury,88 suggesting a role for AMPK in the cardioprotective properties of the diabetic heart. A limitation of the above-described studies is that anesthesia-induced cardioprotection is only studied in type 1 diabetes with insulinopenia and hyperglycemia, but without characteristics such as obesity, insulin resistance and hyperinsulinemia. Although current findings suggest that the degree of T2DM, dependent on the presence and severity of hyperglycemia and hyperlipidemia, is of influence for the cardioprotective capacity of anesthetics, there are no direct studies available that investigated cardioprotective strategies in animals with this diabetic entity.

Chapter 2

Figure 2.2: (Hypothetical) Glucose and fatty acid metabolism under different conditions Glucose and fatty acid metabolism in the healthy heart (A), during volatile anesthesia (B), in the metabolic altered heart (C), in the ischemic heart (D), during volatile anesthesia in the ischemic heart (E) and during volatile anesthesia in the ischemic metabolic altered heart (F). The healthy heart utilizes 70% of fatty acids and 30% of glucose for ATP generation (A). We hypothesize that one of the mechanisms of volatile anesthesia is the effect on increased glucose metabolism (B). In the metabolic altered heart it is suggested that myocardial substrate metabolism is shifted to increased fatty acid metabolism (C), whereas it is suggested that the ischemic heart is shifted to increased glucose metabolism, however, also contrasting results exist (D). We hypothesize that exposure of volatile anesthetics in the ischemic heart might increase myocardial glucose metabolism even more (E), which is disturbed in the ischemic and metabolic altered heart (F).

Metabolic disease and perioperative ischemia

Experimental

options

improve

perioperative

myocardial

metabolism The reduced adaptability of the metabolic altered heart to ischemic injury and cardioprotective interventions warrants further investigation of treatment strategies that optimize myocardial substrate metabolism before surgery. It is suggested that volatile anesthesia induces a switch from myocardial fatty acid to glucose metabolism. In the metabolically altered heart, however, myocardial substrate metabolism is shifted to increased fatty acid and decreased glucose metabolism. Accordingly, the effect of volatile anesthetics seems blunted in the metabolic altered heart. As a consequence, an improvement of the metabolic flexibility of the heart may be an important target. Figure 2.2 shows a hypothetical overview of the effects of different conditions on myocardial substrate metabolism. Pharmacological interventions Improvement of myocardial metabolic flexibility may be achieved by shifting myocardial substrate metabolism to glucose metabolism. This can be induced by 1) altering substrate supply, 2) inhibition of fatty acid oxidation and/or 3) improving insulin sensitivity. The next paragraphs provide an overview of pharmacological interventions in the experimental setting in the treatment of T2DM and/or myocardial

ischemic

injury,

which

might

reduce

perioperative

risk

due

normalization of metabolic derangements (Table 2.1). Inhibition of fatty acid metabolism Carnitine palmitoyl transferase 1 (CPT-1) is a rate-limiting step of fatty acid oxidation. Several inhibitors of CPT-1 have shown beneficial effects during ischemia and reperfusion in rats, such as etomoxir,89-91 perhexiline92 and oxfenicine.92;93 However, not all of these variants of CPT-1 inhibitors are yet registered for clinical use. Other possibilities to reduce fatty acid oxidation are trimetazidine (3-ketoacyl CoA thiolase inhibitor),94,95 ranolazine (partial fatty acid oxidation inhibitor)96,97 and dichloroacetate (DCA; pyruvate dehydrogenase kinase inhibitor),98 which have protective characteristics during myocardial ischemia in rats. One of the suggested mechanisms underlying the beneficial effects of these substances is the stimulation of myocardial glucose oxidation.96,98,99 However, as insulin resistance is a hallmark of the metabolic altered heart, stimulation of glucose metabolism via inhibition of fatty acid metabolism may be blunted during insulin resistance. Unfortunately, the effect of volatile anesthesia in combination with inhibition of fatty acid metabolism on ischemic injury in T2DM hearts has not been studied yet, however, based on the use of these fatty acid inhibitors in models of T2DM it may be deduced that insulin

Chapter 2

resistance might be improved, thereby improving the impact of anesthesia-induced cardioprotection. Insulin Glucose-insulin-potassium (GIK) infusion has been shown to reduce mortality in nondiabetic100,101 and diabetic patients,102 and to reduce infarct size in rats.103 However, also other results exist.104,105 In the perioperative context, GIK infusion lowered glucose levels and other metabolic parameters106 and improved perioperative outcomes, enhanced survival, decreased the incidence of ischemic events107 in T2DM patients during coronary artery bypass grafting (CABG). The beneficial effects of GIK include increasing myocardial glucose uptake and glycogen

content.

suggested

that

insulin

itself

might

the

major

cardioprotective component. In isolated rat hearts, administration of insulin protected against ischemia and reperfusion injury.108,109 However, insulin treatment was not able to restore the lost cardioprotective capacity of sevoflurane in the type 1 diabetic heart.87 Disadvantages of insulin infusion might be hypoglycemia, which could be circumvented by additional glucose infusion (hyperinsulinemic euglycemic clamping). Insulin and dextrose infusion normalized postoperative whole body insulin sensitivity and substrate utilization in healthy patients during elective surgery.110 During cardiac surgery, insulin and dextrose infusion maintained normoglycemia in healthy111 and T2DM112 patients, however, hypolipidemia was observed.113 Further, it was shown in diabetic patients that isoflurane reduced postoperative markers of ischemic injury after CABG, indicating a cardioprotective effect of isoflurane.114 Preoperative treatment with glibenclamide prevented this protective effect, which was restored by changing glibenclamide preoperatively to insulin.114 Taken together, these data suggest that perioperative glucose control by insulin may decrease the risk of postoperative mortality and morbidity. Peroxisome proliferator-activated receptor agonists Fibrates are selective peroxisome proliferator-activated receptor 33$5 ÄŽ DJRQLVWV which have lipid lowering effects, thereby improving insulin sensitivity. PPARÄŽ activation has been shown to reduce myocardial ischemia and reperfusion injury in rat hearts.115,116 $FWLYDWLRQ RI 33$5ÄŽ LQ 7 '0 *RWR-Kakizaki rat hearts reduced ischemic injury,117 whereas in T2DM db/db PLFH 33$5ÄŽ DFWLYDWLRQ GLG QRW DIIHFW WKH sensitivity to ischemia and reperfusion even while myocardial glucose oxidation was increased and myocardial fatty acid oxidation reduced.47 Moreover, sevoflurane UHGXFHG 33$5ÄŽ LQ ZKROH EORRG FRPSDUHG WR EDVHOLQH,118 whereas during CABG VHYRIOXUDQH UHGXFHG 33$5ÄŽ LQ right atrial tissue compared to propofol.11 Based on WKHVH FRQWUDVWLQJ UHVXOWV LW PLJKW EH LQWHUHVWLQJ WR VWXG\ WKH HIIHFWV RI 33$5ÄŽ agonists combined with volatile anesthesia.

Metabolic disease and perioperative ischemia

Insulin-sensitizing drugs, such as thiazolidinediones have beneficial effects by DFWLYDWLRQ RI 33$5Ǆ 5RVLJOLWD]RQH LV WKH PRVW VHOHFWLYH 33$5Ǆ DJRQLVW DQG LV ZLGHO\ XVHG LQ WKH WUHDWPHQW RI 7 '0 33$5Ǆ DJRQLVWV KDYH EHHQ VKRZQ WR UHGXFH myocardial ischemia and reperfusion injury in rats.48,115,119,120 Rosiglitazone has been shown to increase myocardial GLUT4 translocation121 and glucose metabolism122 in healthy and T2DM rat hearts. During myocardial ischemia and reperfusion, it was shown that rosiglitazone treatment normalized ischemic injury by improvement of the reduced glucose uptake in obese Zucker rats,44 and reduced ischemic injury by improved myocardial insulin sensitivity and glucose oxidation in T2DM Zucker diabetic fatty rats,48 suggesting a role fRU 33$5Ǆ WR LQIOXHQFH P\RFDUGLDO VXEVWUDWH metabolism to optimize metabolic flexibility during myocardial ischemia and reperfusion. Accordingly, it was shown that desflurane-induced cardioprotection during ischemia DQG UHSHUIXVLRQ ZDV DEROLVKHG E\ 33$5Ǆ LQhibition in rabbits,123 VXJJHVWLQJ D UROH IRU 33$5Ǆ LQ LPSURYHPHQW RI PHWDEROLF IOH[LELOLW\ Metformin Metformin, a biguanide with antihyperglycemic properties, has been widely used in the treatment of obesity and T2DM and exerts its actions by enhancing insulin sensitivity. It is suggested that the glucose-lowering effects of metformin are mediated through the activation of AMPK, which has also been indicated to play an important protective role in the ischemic mouse heart.124,125 In non-diabetic rat hearts, metformin protects against ischemic injury.126,127 Accordingly, metformin provides cardioprotection against ischemic injury in T2DM hearts from animals in vivo,125 but not in vitro.128 The effects of volatile anesthesia and metformin in ischemic and T2DM hearts has not been studied yet. However, it has been shown that AMPK is involved in anesthetic cardioprotection.41;129 Glucagon-like peptide 1 Glucagon-like peptide 1 (GLP1) is a gut incretin hormone that is released in response to nutrient intake, stimulates insulin secretion and exerts insulinotropic and insulinomimetic properties. GLP1 has been shown to be protective in ischemic rat hearts.130 GLP1 has a short half-life of several minutes, due to rapid breakdown by dipeptidyl peptidase IV (DPP4). Exendin-4 is a peptide derived from the saliva of the gila monster which mimics GLP1, but is resistant to degradation by DPP4. Exenatide and liraglutide are synthetic GLP1 analogues, which mimic human GLP1 and are currently used for blood glucose-lowering therapy in T2DM. Exendin-4,131 exenatide132 and liraglutide133 have been shown to reduce infarct size in animals, but also a neutral effect of liraglutide on myocardial infarct size was found.134 Another possibility to circumvent the rapid breakdown of GLP1 is the use of a DPP4 inhibitor. However, inhibition of DPP4 by valine pyrrolidide in rats130 or in DPP4 knockout mice135 was not

Chapter 2

protective during myocardial infarction. It is suggested that the cardioprotective effect is a consequence of insulin, however, GLP1 has cardioprotective effects both in vivo and in vitro, whereby the latter is in absence of circulating insulin levels,130 suggesting a role for GLP1 in cardioprotection. The mechanism behind the cardioprotective properties of GLP1 may, amongst others,136 rely on improving myocardial glucose metabolism. GLP1 increased glucose uptake

isolated

ischemic/reperfused

138

mouse137

and

isolated

healthy,138

hypertensive139

and

rat hearts. Moreover, exenatide increased myocardial glucose

uptake in healthy140 and insulin resistant dilated cardiomyopathy141 mice, whereas it did not alter myocardial glucose uptake in type 2 diabetic patients.142 Exposure of healthy rats to isoflurane anesthesia decreased GLP1 levels, without affecting DPP4 activity, insulin and glucose levels,143 suggesting impaired GLP1 secretion during isoflurane anesthesia. However, the effect of volatile anesthetics on GLP1 is scarcely studied and therefore no conclusion van be drawn. Taken together, the above-discussed pharmacological interventions suggest that improving insulin sensitivity, and thereby improving myocardial flexibility, may be the most beneficial option in metabolically altered hearts in order to restore cardioprotective mechanisms. However, according to current clinical practice, oral hypoglycemic agents are usually withheld before surgery in order to avoid associated adverse effects, such as perioperative hypoglycemia or lactic acidosis. Therefore the (clinical) feasibility and safety of the proposed interventions should be carefully studied and weighted against the potential risk of these adverse effects.

infarction130 infarction131 infarction132 infarction133,134

GLP1 GLP1 Exendin-4 Exenatide Liraglutide

glucose glucose glucose glucose glucose glucose

oxidation99 oxidation oxidation oxidation oxidation96 oxidation98

Reduction Reduction Reduction Reduction

glucose glucose glucose glucose

Stimulation glucose oxidation

Reduction lipids Reduction lipids Insulin sensitizer Insulin sensitizer

Stimulation glucose oxidation Reduction glucose Stimulation glucose oxidation levels

Stimulation Stimulation Stimulation Stimulation Stimulation Stimulation

Advantages

T2DM, type 2 diabetes mellitus; PPAR, peroxisome proliferators-activated receptor; GLP-1, glucagon-like peptide 1.

T2DM, T2DM, T2DM, T2DM,

T2DM, infarction125-128

T2DM47 Infarction115-117 T2DM121,122 Infarction44,48,115,119,120

Infarction103 T2DM Infarction108,109

Biguanide Metformin

7KLR]ROLGLQHGLRQHV 33$5Ç&#x201E;

PPAR agonists )LEUDWHV 33$5ÄŽ

Insulin Glucose-insulin-potassium Insulin

infarction89-91 infarction92 infarction92,93 infarction94,95 infarction96,97 infarction98

Applicability

Fatty acid metabolism inhibitors Etomoxir T2DM, Perhexiline T2DM, Oxfenicine T2DM, Trimetazidine T2DM, Ranolazine T2DM, Dichloroacetate T2DM,

Drug

Table 2.1: Overview of pharmacological interventions in the experimental setting

Short half-life Hypoglycemia Hypoglycemia Hypoglycemia

Lactic acidosis

Myopathy Myopathy Increased risk heart attacks Increased risk heart attacks

Hypoglycemia Hypoglycemia Hypoglycemia

Side-effects

Metabolic disease and perioperative ischemia 35

Chapter 2

Preoperative health risk improvement Based on 7 risk factors (physical inactivity, dietary pattern, obesity, smoking, high cholesterol, hypertension and elevated blood glucose levels), the 2020 impact goal of the American Heart Association is: "to improve the cardiovascular health by 20% while reducing deaths from cardiovascular diseases and stroke by 20%".144 Another possibility besides pharmacological intervention is preoperative lifestyle intervention, such as changing the dietary intake and stimulation of physical activity thereby losing weight and improving insulin sensitivity. It has been shown by reducing dietary fat in rodents that diet-induced obesity is reversible.145-147 In contrast, diet-induced obesity was not reversed by withdrawal of an energy dense diet.148 Reversibility of diet-induced obesity is independent of the duration of the obese state,146 whereas long-term diet feeding did not reversed obesity.145 Overall, these data suggest that changing dietary intake may have beneficial effects on health. However, there is only limited literature available that describes the effects of changing dietary balance on the heart. In western diet-fed rats, lowering caloric intake improved systolic and diastolic function and prevented sevoflurane-induced cardiodepression (van den Brom et al., unpublished observations). Accordingly, pacing-induced cardioprotection was lost by diet-induced hypercholesterolemia, but restored after reversion to control diet,149 whereas caloric restriction by itself in healthy rats also has cardioprotective properties.150 In conclusion, restriction of dietary fat seems an effective treatment to improve metabolic flexibility of the heart and thereby may be a possibility to reduce perioperative risk. Obesity and T2DM are closely related to physical inactivity, and exercise could be a possible lifestyle intervention to reduce perioperative risk. The benefits of exercise with respect to obesity and T2DM are already recognized clinically.151 However, the effects of exercise on myocardial infarction are contradictory. Exercise did not reduce myocardial ischemic injury in rats,152 whereas others showed that exercise had protective effects in rat hearts.153-155 The question remains if exercise has beneficial effects in obese and T2DM on myocardial function and ischemia and reperfusion injury. Exercise was shown to reverse diet-induced obesity, insulin resistance and cardiomyocyte dysfunction,147 however, the effects of exercise on myocardial infarction in obese and T2DM with and without the effects of volatile anesthesia is not known. Based on the above described results exercise might be a possible lifestyle intervention to reduce perioperative risk.

Metabolic disease and perioperative ischemia

Conclusions Over the years, several mechanisms that are involved in anesthesia-induced cardioprotection have been evaluated in the experimental setting. The existing evidence suggests that the obese and/or T2DM heart is less adaptable to cardioprotective interventions and that anesthesia-induced cardioprotection is just a ÂłKHDOWK\ KHDUW SKHQRPHQRQÂ´ Differences between experimental models, the type of metabolic disease and the severity of myocardial substrate derangements challenge the identification of unifying mechanisms related to anesthesia-induced cardioprotection in cases of obesity and T2DM. It might be deduced that interventional options should focus on recovery of the metabolic flexibility of the heart, especially by improving insulin sensitivity. Although changing lifestyle seems promising to reduce the susceptibility of the heart to intraoperative ischemia and reperfusion injury, experimental data has not been translated into clinical data. Therefore more studies are required to elucidate whether these interventions have beneficial effects on perioperative outcome.

Chapter 2

References 1. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith SC, Jr., Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA et al.: ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation

and

care

for

noncardiac

surgery:

report

the

American

College

Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation 2007, 116:e418-e499. 2. Gupta PK, Gupta H, Sundaram A, Kaushik M, Fang X, Miller WJ, Esterbrooks DJ, Hunter CB, Pipinos II, Johanning JM, Lynch TG, Forse RA, Mohiuddin SM, Mooss AN: Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circulation 2011, 124:381-387. 3. Unwin N, Whiting D, Guariguata L, Hennis A, Husseini A, Ji L, Kissimova-Skarbek K, Libman I, Mayer-Davis E, Motala A, Narayan V, Ramachandran A, Roglic G, Sham J, Wareham N, Zhang P. IDF diabetes atlas 2011. 5th ed. Brussels: International Diabetes Federation; 2011. 4. Preis SR, Pencina MJ, Hwang SJ, D'Agostino RB, Sr., Savage PJ, Levy D, Fox CS: Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation 2009, 120:212-220. 5. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999, 100:1043-1049. 6. Frassdorf J, De Hert S, Schlack W: Anaesthesia and myocardial ischaemia/reperfusion injury. Br J Anaesth 2009, 103:89-98. 7. De Hert SG, Preckel B, Hollmann MW, Schlack WS: Drugs mediating myocardial protection. Eur J Anaesthesiol 2009, 26:985-995. 8. Huhn R, Heinen A, Hollmann MW, Schlack W, Preckel B, Weber NC: Cyclosporine A administered during reperfusion fails to restore cardioprotection in prediabetic Zucker obese rats in vivo. Nutr Metab Cardiovasc Dis 2010, 20:706-712. 9. Kehl F, Krolikowski JG, Mraovic B, Pagel PS, Warltier DC, Kersten JR: Hyperglycemia prevents isoflurane-induced preconditioning against myocardial infarction. Anesthesiology 2002, 96:183188. 10.Lucchinetti E, Wang L, Ko KW, Troxler H, Hersberger M, Zhang L, Omar MA, Lopaschuk GD, Clanachan AS, Zaugg M: Enhanced glucose uptake via GLUT4 fuels recovery from calcium overload after ischaemia-reperfusion injury in sevoflurane- but not propofol-treated hearts. Br J Anaesth 2011, 106:792-800. 11.Lucchinetti E, Hofer C, Bestmann L, Hersberger M, Feng J, Zhu M, Furrer L, Schaub MC, Tavakoli R, Genoni M, Zollinger A, Zaugg M: Gene regulatory control of myocardial energy metabolism predicts postoperative cardiac function in patients undergoing off-pump coronary artery bypass graft surgery: inhalational versus intravenous anesthetics. Anesthesiology 2007, 106:444-457. 12.Wang L, Ko KW, Lucchinetti E, Zhang L, Troxler H, Hersberger M, Omar MA, Posse de Chaves EI, Lopaschuk GD, Clanachan AS, Zaugg M: Metabolic profiling of hearts exposed to sevoflurane

Metabolic disease and perioperative ischemia

and propofol reveals distinct regulation of fatty acid and glucose oxidation: CD36 and pyruvate dehydrogenase as key regulators in anesthetic-induced fuel shift. Anesthesiology 2010, 113:541-551. 13.Winterstein H: Ueber die Sauerstoffatmung des isolierten Saeugetierherzens. Z Allg Physiol 1904, 4:339-359. 14.Stanley WC, Lopaschuk GD, McCormack JG: Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 1997, 34:25-33. 15.Carley AN, Severson DL: Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim Biophys Acta 2005, 1734:112-126. 16.Neely JR, Rovetto MJ, Oram JF: Myocardial utilization of carbohydrate and lipids. Prog Cardiovasc Dis 1972, 15:289-329. 17.Taegtmeyer H: Glycogen in the heart--an expanded view. J Mol Cell Cardiol 2004, 37:7-10. 18.Shepherd PR, Kahn BB: Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med 1999, 341:248-257. 19.Coort SL, Bonen A, van der Vusse GJ, Glatz JF, Luiken JJ: Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters. Mol Cell Biochem 2007, 299:5-18. 20.Lewin TM, Coleman RA: Regulation of myocardial triacylglycerol synthesis and metabolism. Biochim Biophys Acta 2003, 1634:63-75. 21.Kerner J, Hoppel C: Fatty acid import into mitochondria. Biochim Biophys Acta 2000, 1486:117. 22.Stanley WC, Recchia FA, Lopaschuk GD: Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005, 85:1093-1129. 23.Saddik M, Lopaschuk GD: Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 1991, 266:8162-8170. 24.Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC: Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010, 90:207-258. 25.van den Brom CE, Bosmans JW, Vlasblom R, Handoko ML, Huisman MC, Lubberink M, Molthoff CF, Lammertsma AA, Ouwens DM, Diamant M, Boer C: Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle. Cardiovasc Diabetol 2010, 9:25. 26.van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, Van der Velden J, Boer C, Ouwens DM, Diamant M: Altered myocardial substrate

metabolism

associated

with

myocardial

dysfunction

early

diabetic

cardiomyopathy in rats: studies using positron emission tomography. Cardiovasc Diabetol 2009, 8:39. 27.Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD: Targeting fatty acid and carbohydrate oxidation--a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta 2011, 1813:1333-1350. 28.Opie LH. The heart: Physiology and Metabolism. New York Raven Press; 1991. 29.Kannel WB, Hjortland M, Castelli WP: Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974, 34:29-34. 30.Rennert G, Saltz-Rennert H, Wanderman K, Weitzman S: Size of acute myocardial infarcts in patients with diabetes mellitus. Am J Cardiol 1985, 55:1629-1630. 31.How OJ, Aasum E, Severson DL, Chan WY, Essop MF, Larsen TS: Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 2006, 55:466-473. 32.Paulson DJ: The diabetic heart is more sensitive to ischemic injury. Cardiovasc Res 1997, 34:104-112.

Chapter 2

33.van den Brom CE, Bulte CS, Kloeze BM, Loer SA, Boer C, Bouwman RA: High fat diet-induced glucose

intolerance

impairs

myocardial

function,

but

not

myocardial

perfusion

during

hyperaemia: a pilot study. Cardiovasc Diabetol 2012, 11:74. 34.Ivanova M, Janega P, Matejikova J, Simoncikova P, Pancza D, Ravingerova T, Barancik M: Activation of Akt kinase accompanies increased cardiac resistance to ischemia/reperfusion in rats after short-term feeding with lard-based high-fat diet and increased sucrose intake. Nutr Res 2011, 31:631-643. 35.Rennison JH, McElfresh TA, Chen X, Anand VR, Hoit BD, Hoppel CL, Chandler MP: Prolonged exposure to high dietary lipids is not associated with lipotoxicity in heart failure. J Mol Cell Cardiol 2009, 46:883-890. 36.Jordan JE, Simandle SA, Tulbert CD, Busija DW, Miller AW: Fructose-fed rats are protected against ischemia/reperfusion injury. J Pharmacol Exp Ther 2003, 307:1007-1011. 37.Morgan EE, Rennison JH, Young ME, McElfresh TA, Kung TA, Tserng KY, Hoit BD, Stanley WC, Chandler MP: Effects of chronic activation of peroxisome proliferator-activated receptor-alpha or high-fat feeding in a rat infarct model of heart failure. Am J Physiol Heart Circ Physiol 2006, 290:H1899-H1904. 38.Rennison JH, McElfresh TA, Okere IC, Vazquez EJ, Patel HV, Foster AB, Patel KK, Chen Q, Hoit BD, Tserng KY, Hassan MO, Hoppel CL, Chandler MP: High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction. Am J Physiol Heart Circ Physiol 2007, 292:H1498-H1506. 39.Mozaffari MS, Patel C, Ballas C, Schaffer SW: Effects of excess salt and fat intake on myocardial function and infarct size in rat. Life Sci 2006, 78:1808-1813. 40.Berthiaume JM, Young ME, Chen X, McElfresh TA, Yu X, Chandler MP: Normalizing the metabolic phenotype after myocardial infarction: impact of subchronic high fat feeding. J Mol Cell Cardiol 2012, 53:125-133. 41.Song T, Lv LY, Xu J, Tian ZY, Cui WY, Wang QS, Qu G, Shi XM: Diet-induced obesity suppresses sevoflurane preconditioning against myocardial ischemia-reperfusion injury: role of AMPactivated protein kinase pathway. Exp Biol Med (Maywood ) 2011, 236:1427-1436. 42.Morel S, Berthonneche C, Tanguy S, Toufektsian MC, Perret P, Ghezzi C, de Leiris J, Boucher F: Early pre-diabetic state alters adaptation of myocardial glucose metabolism during ischemia in rats. Mol Cell Biochem 2005, 272:9-17. 43.Maddaford TG, Russell JC, Pierce GN: Postischemic cardiac performance in the insulin-resistant JCR:LA-cp rat. Am J Physiol 1997, 273:H1187-H1192. 44.Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke K: Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. Diabetes 2002, 51:1110-1117. 45.Mozaffari MS, Schaffer SW: Myocardial ischemic-reperfusion injury in a rat model of metabolic syndrome. Obesity (Silver Spring) 2008, 16:2253-2258. 46.Thakker GD, Frangogiannis NG, Zymek PT, Sharma S, Raya JL, Barger PM, Taegtmeyer H, Entman ML, Ballantyne CM: Increased myocardial susceptibility to repetitive ischemia with highfat diet-induced obesity. Obesity (Silver Spring) 2008, 16:2593-2600. 47.Aasum E, Hafstad AD, Severson DL, Larsen TS: Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. Diabetes 2003, 52:434441. 48.Yue TL, Bao W, Gu JL, Cui J, Tao L, Ma XL, Ohlstein EH, Jucker BM: Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes 2005, 54:554-562.

Metabolic disease and perioperative ischemia

49.Wang P, Chatham JC: Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart. Am J Physiol Endocrinol Metab 2004, 286:E725-E736. 50.Hoshida S, Yamashita N, Otsu K, Kuzuya T, Hori M: Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol 2000, 278:H256-H262. 51.Higuchi M, Miyagi K, Nakasone J, Sakanashi M: Role of high glycogen in underperfused diabetic rat hearts with added norepinephrine. J Cardiovasc Pharmacol 1995, 26:899-907. 52.Cross HR, Opie LH, Radda GK, Clarke K: Is a high glycogen content beneficial or detrimental to the ischemic rat heart? A controversy resolved. Circ Res 1996, 78:482-491. 53.Feuvray D, Lopaschuk GD: Controversies on the sensitivity of the diabetic heart to ischemic injury: the sensitivity of the diabetic heart to ischemic injury is decreased. Cardiovasc Res 1997, 34:113-120. 54.Yao YT, Fang NX, Shi CX, Li LH: Sevoflurane postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Chin Med J (Engl ) 2010, 123:1320-1328. 55.Bouwman RA, Vreden MJ, Hamdani N, Wassenaar LE, Smeding L, Loer SA, Stienen GJ, Lamberts RR: Effect of bupivacaine on sevoflurane-induced preconditioning in isolated rat hearts. Eur J Pharmacol 2010, 647:132-138. 56.Tosaka S, Tosaka R, Matsumoto S, Maekawa T, Cho S, Sumikawa K: Roles of cyclooxygenase 2 in sevoflurane- and olprinone-induced early phase of preconditioning and postconditioning against myocardial infarction in rat hearts. J Cardiovasc Pharmacol Ther 2011, 16:72-78. 57.Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B, Schlack W: The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg 2005, 101:1252-1260. 58.Lang XE, Wang X, Jin JH: Mechanisms of cardioprotection by isoflurane against I/R injury. Front Biosci 2013, 18:387-393. 59.Yao Y, Li L, Li L, Gao C, Shi C: Sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by activation of pro-survival kinases and inhibition of mitochondrial permeability transition pore opening upon reperfusion. Biol Pharm Bull 2009, 32:1854-1861. 60.Stadnicka A, Marinovic J, Ljubkovic M, Bienengraeber MW, Bosnjak ZJ: Volatile anestheticinduced cardiac preconditioning. J Anesth 2007, 21:212-219. 61.Lattermann R, Schricker T, Wachter U, Georgieff M, Goertz A: Understanding the mechanisms by which isoflurane modifies the hyperglycemic response to surgery. Anesth Analg 2001, 93:121-127. 62.Bouwman RA, Musters RJ, van Beek-Harmsen BJ, de Lange JJ, Boer C: Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection. Anesthesiology 2004, 100:506-514. 63.Costa AD, Quinlan CL, Andrukhiv A, West IC, Jaburek M, Garlid KD: The direct physiological effects of mitoK(ATP) opening on heart mitochondria. Am J Physiol Heart Circ Physiol 2006, 290:H406-H415. 64.Flores JE, McFarland LM, Vanderbilt A, Ogasawara AK, Williams SP: The effects of anesthetic agent and carrier gas on blood glucose and tissue uptake in mice undergoing dynamic FDG-PET imaging: sevoflurane and isoflurane compared in air and in oxygen. Mol Imaging Biol 2008, 10:192-200. 65.Toyama H, Ichise M, Liow JS, Vines DC, Seneca NM, Modell KJ, Seidel J, Green MV, Innis RB: Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart using small animal PET. Nucl Med Biol 2004, 31:251-256.

Chapter 2

66.Kudoh A, Katagai H, Takazawa T: Sevoflurane increases glucose transport in skeletal muscle cells. Anesth Analg 2002, 95:123-8. 67.Ewart RB, Rusy BF, Bradford MW: Effects of enflurane on release of insulin by pancreatic islets in vitro. Anesth Analg 1981, 60:878-884. 68.Tanaka K, Kawano T, Tsutsumi YM, Kinoshita M, Kakuta N, Hirose K, Kimura M, Oshita S: Differential effects of propofol and isoflurane on glucose utilization and insulin secretion. Life Sci 2011, 88:96-103. 69.Zuurbier CJ, Keijzers PJ, Koeman A, Van Wezel HB, Hollmann MW: Anesthesia's effects on plasma glucose and insulin and cardiac hexokinase at similar hemodynamics and without major surgical stress in fed rats. Anesth Analg 2008, 106:135-42. 70.Kitamura T, Ogawa M, Kawamura G, Sato K, Yamada Y: The effects of sevoflurane and propofol on glucose metabolism under aerobic conditions in fed rats. Anesth Analg 2009, 109:14791485. 71.Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y, Havranek EP, Krumholz HM: Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation 2005, 111:3078-3086. 72.Katakam

PV,

Jordan

JE,

Snipes

JA,

Tulbert

CD,

Miller

AW,

Busija

DW:

Myocardial

preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol 2007, 292:R920-R926. 73.Wagner C, Kloeting I, Strasser RH, Weinbrenner C: Cardioprotection by postconditioning is lost in WOKW rats with metabolic syndrome: role of glycogen synthase kinase 3beta. J Cardiovasc Pharmacol 2008, 52:430-437. 74.Ferdinandy P, Szilvassy Z, Horvath LI, Csont T, Csonka C, Nagy E, Szentgyorgyi R, Nagy I, Koltai M, Dux L: Loss of pacing-induced preconditioning in rat hearts: role of nitric oxide and cholesterol-enriched diet. J Mol Cell Cardiol 1997, 29:3321-3333. 75.Kocic

Konstanski

Kaminski

Dworakowska

Dworakowski

Experimental

hyperlipidemia prevents the protective effect of ischemic preconditioning on the contractility and responsiveness to phenylephrine of rat-isolated stunned papillary muscle. Gen Pharmacol 1999, 33:213-219. 76.Zhang FJ, Ma LL, Wang WN, Qian LB, Yang MJ, Yu J, Chen G, Yu LN, Yan M: Hypercholesterolemia

abrogates

sevoflurane-induced

delayed

preconditioning

against

myocardial infarct in rats by alteration of nitric oxide synthase signaling. Shock 2012, 37:485491. 77.Malmberg K, Norhammar A, Wedel H, Ryden L: Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999, 99:2626-2632. 78.Weber NC, Goletz C, Huhn R, Grueber Y, Preckel B, Schlack W, Ebel D: Blockade of anaestheticinduced preconditioning in the hyperglycaemic myocardium: the regulation of different mitogenactivated protein kinases. Eur J Pharmacol 2008, 592:48-54. 79.Kehl F, Krolikowski JG, Weihrauch D, Pagel PS, Warltier DC, Kersten JR: N-acetylcysteine restores isoflurane-induced preconditioning against myocardial infarction during hyperglycemia. Anesthesiology 2003, 98:1384-1390. 80.Huhn R, Heinen A, Weber NC, Hollmann MW, Schlack W, Preckel B: Hyperglycaemia blocks sevoflurane-induced postconditioning in the rat heart in vivo: cardioprotection can be restored by blocking the mitochondrial permeability transition pore. Br J Anaesth 2008, 100:465-471.

Metabolic disease and perioperative ischemia

81.Kersten JR, Toller WG, Gross ER, Pagel PS, Warltier DC: Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality. Am J Physiol Heart Circ Physiol 2000, 278:H1218-H1224. 82.Tanaka K, Kehl F, Gu W, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR: Isoflurane-induced preconditioning is attenuated by diabetes. Am J Physiol Heart Circ Physiol 2002, 282:H2018H2023. 83.Raphael J, Gozal Y, Navot N, Zuo Z: Hyperglycemia inhibits anesthetic-induced postconditioning in the rabbit heart via modulation of phosphatidylinositol-3-kinase/Akt and endothelial nitric oxide synthase signaling. J Cardiovasc Pharmacol 2010, 55:348-357. 84.Kristiansen SB, Lofgren B, Stottrup NB, Khatir D, Nielsen-Kudsk JE, Nielsen TT, Botker HE, Flyvbjerg A: Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 2004, 47:1716-1721. 85.Miki T, Itoh T, Sunaga D, Miura T: Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning. Cardiovasc Diabetol 2012, 11:67. 86.Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM: Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes 2005, 54:2360-2364. 87.Drenger B, Ostrovsky IA, Barak M, Nechemia-Arbely Y, Ziv E, Axelrod JH: Diabetes Blockade of Sevoflurane Postconditioning Is Not Restored by Insulin in the Rat Heart: Phosphorylated Signal Transducer and Activator of Transcription 3- and Phosphatidylinositol 3-Kinase-mediated Inhibition. Anesthesiology 2011, 114:1364-1372. 88.Paiva MA, Rutter-Locher Z, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, Mocanu MM: Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. Am J Physiol Heart Circ Physiol 2011, 300:H2123-H2134. 89.Penna

Mancardi

Gattullo

Pagliaro

Myocardial

protection

from

ischemic

preconditioning is not blocked by sub-chronic inhibition of carnitine palmitoyltransferase I. Life Sci 2005, 77:2004-2017. 90.Lopaschuk GD, Spafford MA, Davies NJ, Wall SR: Glucose and palmitate oxidation in isolated working rat hearts reperfused after a period of transient global ischemia. Circ Res 1990, 66:546-553. 91.Lopaschuk GD, Saddik M: The relative contribution of glucose and fatty acids to ATP production in hearts reperfused following ischemia. Mol Cell Biochem 1992, 116:111-116. 92.Kennedy JA, Kiosoglous AJ, Murphy GA, Pelle MA, Horowitz JD: Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J Cardiovasc Pharmacol 2000, 36:794-801. 93.Molaparast-Saless F, Liedtke AJ, Nellis SH: Effects of the fatty acid blocking agents, oxfenicine and 4-bromocrotonic acid, on performance in aerobic and ischemic myocardium. J Mol Cell Cardiol 1987, 19:509-520. 94.Kara AF, Demiryurek S, Celik A, Tarakcioglu M, Demiryurek AT: Effects of trimetazidine on myocardial preconditioning in anesthetized rats. Eur J Pharmacol 2004, 503:135-145. 95.Mouquet F, Rousseau D, Domergue-Dupont V, Grynberg A, Liao R: Effects of trimetazidine, a partial inhibitor of fatty acid oxidation, on ventricular function and survival after myocardial infarction and reperfusion in the rat. Fundam Clin Pharmacol 2010, 24:469-476. 96.McCormack JG, Barr RL, Wolff AA, Lopaschuk GD: Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 1996, 93:135-142. 97.Wang P, Fraser H, Lloyd SG, McVeigh JJ, Belardinelli L, Chatham JC: A comparison between ranolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion. J Pharmacol Exp Ther 2007, 321:213-220.

Chapter 2

98.McVeigh JJ, Lopaschuk GD: Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. Am J Physiol 1990, 259:H1079-H1085. 99.Lopaschuk GD, McNeil GF, McVeigh JJ: Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. Mol Cell Biochem 1989, 88:175-179. 100.Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G: Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation 1998, 98:2227-2234. 101.Di MS, Boldrini B, Conti U, Marcucci G, Morgantini C, Ferrannini E, Natali A: Effects of GIK (glucose-insulin-potassium) on stress-induced myocardial ischaemia. Clin Sci (Lond) 2010, 119:37-44. 102.Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wedel H: Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. DIGAMI Study Group. Diabetes Insulin-Glucose in Acute Myocardial Infarction. Eur Heart J 1996, 17:1337-1344. 103.Jonassen AK, Aasum E, Riemersma RA, Mjos OD, Larsen TS: Glucose-insulin-potassium reduces infarct size when administered during reperfusion. Cardiovasc Drugs Ther 2000, 14:615-623. 104.Ceremuzynski L, Budaj A, Czepiel A, Burzykowski T, Achremczyk P, Smielak-Korombel W, Maciejewicz J, Dziubinska J, Nartowicz E, Kawka-Urbanek T, Piotrowski W, Hanzlik J, Cieslinski A, Kawecka-Jaszcz K, Gessek J, Wrabec K: Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial. Cardiovasc Drugs Ther 1999, 13:191-200. 105.van der Horst IC, Zijlstra F, van 't Hof AW, Doggen CJ, de Boer MJ, Suryapranata H, Hoorntje JC, Dambrink JH, Gans RO, Bilo HJ: Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol 2003, 42:784-791. 106.Thomas DJ, Platt HS, Alberti KG: Insulin infusion (GIK) in the treatment of type 2 (non-insulin dependent) diabetes during the perioperative period. Br J Surg 1986, 73:898-901. 107.Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS: Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 2004, 109:1497-1502. 108.Doenst T, Richwine RT, Bray MS, Goodwin GW, Frazier OH, Taegtmeyer H: Insulin improves functional and metabolic recovery of reperfused working rat heart. Ann Thorac Surg 1999, 67:1682-1688. 109.Jonassen AK, Sack MN, Mjos OD, Yellon DM: Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 2001, 89:1191-1198. 110.Nygren JO, Thorell A, Soop M, Efendic S, Brismar K, Karpe F, Nair KS, Ljungqvist O: Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery. Am J Physiol 1998, 275:E140-E148. 111.Sato H, Carvalho G, Sato T, Bracco D, Codere-Maruyama T, Lattermann R, Hatzakorzian R, Matsukawa T, Schricker T: Perioperative tight glucose control with hyperinsulinemicnormoglycemic clamp technique in cardiac surgery. Nutrition 2010, 26:1122-1129. 112.Carvalho G, Moore A, Qizilbash B, Lachapelle K, Schricker T: Maintenance of normoglycemia during cardiac surgery. Anesth Analg 2004, 99:319-24.

Metabolic disease and perioperative ischemia

113.Zuurbier CJ, Hoek FJ, van Dijk J, Abeling NG, Meijers JC, Levels JH, de Jonge E, de Mol BA, Van Wezel HB: Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery. Br J Anaesth 2008, 100:442-450. 114.Forlani S, Tomai F, De Paulis R, Turani F, Colella DF, Nardi P, De Notaris S, Moscarelli M, Magliano G, Crea F, Chiariello L: Preoperative shift from glibenclamide to insulin is cardioprotective in diabetic patients undergoing coronary artery bypass surgery. J Cardiovasc Surg (Torino) 2004, 45:117-122. 115.Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C: Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 2002, 16:1027-1040. 116.Yue TL, Bao W, Jucker BM, Gu JL, Romanic AM, Brown PJ, Cui J, Thudium DT, Boyce R, BurnsKurtis CL, Mirabile RC, Aravindhan K, Ohlstein EH: Activation of peroxisome proliferatoractivated receptor-alpha protects the heart from ischemia/reperfusion injury. Circulation 2003, 108:2393-2399. 117.Bulhak AA, Jung C, Ostenson CG, Lundberg JO, Sjoquist PO, Pernow J: PPAR-alpha activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway. Am J Physiol Heart Circ Physiol 2009, 296:H719-H727. 118.Lucchinetti E, Aguirre J, Feng J, Zhu M, Suter M, Spahn DR, Harter L, Zaugg M: Molecular evidence of late preconditioning after sevoflurane inhalation in healthy volunteers. Anesth Analg 2007, 105:629-640. 119.Yue TL, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu JL, Boyce R, Zimmerman DM,

Hart

TK,

Buckingham

RE,

Ohlstein

EH:

vivo

myocardial

protection

from

ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 2001, 104:2588-2594. 120.Ito H, Nakano A, Kinoshita M, Matsumori A: Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates myocardial ischemia/reperfusion injury in a rat model. Lab Invest 2003, 83:1715-1721. 121.Khandoudi N, Delerive P, Berrebi-Bertrand I, Buckingham RE, Staels B, Bril A: Rosiglitazone, a peroxisome

proliferator-activated

receptor-gamma,

inhibits

the

Jun

NH(2)-terminal

kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. Diabetes 2002, 51:1507-1514. 122.Shoghi KI, Finck BN, Schechtman KB, Sharp T, Herrero P, Gropler RJ, Welch MJ: In vivo metabolic phenotyping of myocardial substrate metabolism in rodents: differential efficacy of metformin and rosiglitazone monotherapy. Circ Cardiovasc Imaging 2009, 2:373-381. 123.Lotz C, Lange M, Redel A, Stumpner J, Schmidt J, Tischer-Zeitz T, Roewer N, Kehl F: Peroxisome-proliferator-activated

receptor

gamma

mediates

the

second

window

anaesthetic-induced preconditioning. Exp Physiol 2011, 96:317-324. 124.Russell RR, III, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH: AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 2004, 114:495-503. 125.Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ: Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 2008, 57:696-705. 126.Yin M, van der Horst I, van Melle JP, Qian C, van Gilst WH, Sillje HH, de Boer RA: Metformin improves cardiac function in a non-diabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 2011, 301:459-468.

Chapter 2

127.Paiva MA, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, Mocanu MM: Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction. Cardiovasc Drugs Ther 2010, 24:25-32. 128.Lavanchy N, Christe G, Cand F, Wiernsperger N, Verdetti J: Effects of chronic treatment with glibenclamide and/or metformin on the resistance to ischaemia of isolated hearts from Zucker diabetic fatty rats (ZDF/GMI-fa/fa). Br J Diabetes Vasc Dis 2003, 3:375-380. 129.Lamberts RR, Onderwater G, Hamdani N, Vreden MJ, Steenhuisen J, Eringa EC, Loer SA, Stienen GJ, Bouwman RA: Reactive oxygen species-induced stimulation of 5'AMP-activated protein kinase mediates sevoflurane-induced cardioprotection. Circulation 2009, 120:S10-S15. 130.Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM: Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 2005, 54:146-151. 131.Sonne DP, Engstrom T, Treiman M: Protective effects of GLP-1 analogues exendin-4 and GLP1(9-36) amide against ischemia-reperfusion injury in rat heart. Regul Pept 2008, 146:243249. 132.Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, Verlaan CW, Kerver M, Piek JJ, Doevendans PA, Pasterkamp G, Hoefer IE: Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol 2009, 53:501-510. 133.Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, Baggio LL, Henkelman RM, Husain M, Drucker DJ: GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009, 58:975983. 134.Kristensen J, Mortensen UM, Schmidt M, Nielsen PH, Nielsen TT, Maeng M: Lack of cardioprotection from subcutaneously and preischemic administered liraglutide in a closed chest porcine ischemia reperfusion model. BMC Cardiovasc Disord 2009, 9:31. 135.Sauve M, Ban K, Momen MA, Zhou YQ, Henkelman RM, Husain M, Drucker DJ: Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes 2010, 59:1063-1073. 136.Ravassa S, Zudaire A, Diez J: GLP-1 and cardioprotection: from bench to bedside. Cardiovasc Res 2012, 94:316-323. 137.Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M: Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagonlike peptide 1 receptor-dependent and -independent pathways. Circulation 2008, 117:23402350. 138.Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen YT, Shannon RP: Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther 2006, 317:1106-1113. 139.Poornima I, Brown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP: Chronic glucagonlike-peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneosly hypertensive, heart failure prone rat. Circ Heart Fail 2008, 1:153-160. 140.Wang D, Luo P, Wang Y, Li W, Wang C, Sun D, Zhang R, Su T, Ma X, Zeng C, Wang H, Ren J, Cao F: Glucagon-Like Peptide-1 Protects Against Cardiac Microvascular Injury in Diabetes Via a cAMP/PKA/Rho-Dependent Mechanism. Diabetes 2013. 141.Vyas AK, Yang KC, Woo D, Tzekov A, Kovacs A, Jay PY, Hruz PW: Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy. PLoS One 2011, 6:e17178. 142.Gejl M, Sondergaard HM, Stecher C, Bibby BM, Moller N, Botker HE, Hansen SB, Gjedde A, Rungby J, Brock B: Exenatide alters myocardial glucose transport and uptake depending on

Metabolic disease and perioperative ischemia

insulin resistance and increases myocardial blood flow in patients with type 2 diabetes. J Clin Endocrinol Metab 2012, 97:E1165-E1169. 143.Kawano T, Tanaka K, Chi H, Eguchi S, Yamazaki F, Kitamura S, Kumagai N, Yokoyama M: Biophysical and pharmacological properties of glucagon-like peptide-1 in rats under isoflurane anesthesia. Anesth Analg 2012, 115:62-69. 144.Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van HL, Greenlund K, Daniels S, Nichol G, Tomaselli GF, Arnett DK, Fonarow GC, Ho PM, Lauer MS, Masoudi FA, Robertson RM, Roger V, Schwamm LH, Sorlie P, Yancy CW, Rosamond WD: Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic Impact Goal through 2020 and beyond. Circulation 2010, 121:586-613. 145.Hill JO, Dorton J, Sykes MN, DiGirolamo M: Reversal of dietary obesity is influenced by its duration and severity. Int J Obes 1989, 13:711-722. 146.Bartness TJ, Polk DR, McGriff WR, Youngstrom TG, DiGirolamo M: Reversal of high-fat dietinduced obesity in female rats. Am J Physiol 1992, 263:R790-R797. 147.Davidoff AJ, Mason MM, Davidson MB, Carmody MW, Hintz KK, Wold LE, Podolin DA, Ren J: Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments. Am J Physiol Endocrinol Metab 2004, 286:E718-E724. 148.Llado I, Proenza AM, Serra F, Palou A, Pons A: Dietary-induced permanent changes in brown and white adipose tissue composition in rats. Int J Obes 1991, 15:415-419. 149.Szilvassy Z, Ferdinandy P, Szilvassy J, Nagy I, Karcsu S, Lonovics J, Dux L, Koltai M: The loss of pacing-induced preconditioning in atherosclerotic rabbits: role of hypercholesterolaemia. J Mol Cell Cardiol 1995, 27:2559-2569. 150.Shinmura K, Tamaki K, Bolli R: Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol 2005, 39:285-296. 151.Hamdy O, Goodyear LJ, Horton ES: Diet and exercise in type 2 diabetes mellitus. Endocrinol Metab Clin North Am 2001, 30:883-907. 152.Veiga EC, Antonio EL, Bocalini DS, Murad N, Abreu LC, Tucci PJ, Sato MA: Prior exercise training does not prevent acute cardiac alterations after myocardial infarction in female rats. Clinics (Sao Paulo) 2011, 66:889-893. 153.Burelle Y, Wambolt RB, Grist M, Parsons HL, Chow JC, Antler C, Bonen A, Keller A, Dunaway GA, Popov KM, Hochachka PW, Allard MF: Regular exercise is associated with a protective metabolic phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2004, 287:H1055H1063. 154.McElroy CL, Gissen SA, Fishbein MC: Exercise-induced reduction in myocardial infarct size after coronary artery occlusion in the rat. Circulation 1978, 57:958-962. 155.Freimann S, Scheinowitz M, Yekutieli D, Feinberg MS, Eldar M, Kessler-Icekson G: Prior exercise training improves the outcome of acute myocardial infarction in the rat. Heart structure, function, and gene expression. J Am Coll Cardiol 2005, 45:931-938.

3 High fat diet-induced glucose intolerance impairs myocardial function, but not myocardial perfusion during hyperemia: a pilot study CE van den Brom, CSE Bulte, BM Kloeze, SA Loer, C Boer, RA Bouwman Cardiovascular Diabetology 2012, 11:74

Myocardial function and perfusion during glucose intolerance

Abstract Introduction Glucose intolerance is a major health problem and is associated with increased risk of progression to type 2 diabetes mellitus and cardiovascular disease. However, whether glucose intolerance is related to impaired myocardial perfusion is not known. The purpose of the present study was to study the effect of diet-induced glucose intolerance on myocardial function and perfusion during baseline and pharmacological induced hyperemia. Methods Male Wistar rats were randomly exposed to a high fat diet (HFD) or control diet (CD) (n=8 per group). After 4 weeks, rats underwent an oral glucose tolerance test. Subsequently, rats underwent (contrast) echocardiography to determine myocardial function and perfusion during baseline and dipyridamole-induced hyperemia (20 mg/kg for 10 min). Results Four weeks of HFD feeding resulted in glucose intolerance compared to CD-feeding. Contractile function as represented by fractional shortening was not altered in HFDfed rats compared to CD-fed rats under baseline conditions. However, dipyridamole increased fractional shortening in CD-fed rats, but not in HFD-fed rats. Basal myocardial perfusion, as measured by estimate of perfusion, was similar in CD- and HFD-fed rats, whereas dipyridamole increased estimate of perfusion in CD-fed rats, but not in HFD-fed rats. However, flow reserve was not different between CD- and HFD-fed rats. Conclusions Diet-induced glucose intolerance is associated with impaired myocardial function during conditions of hyperemia, but myocardial perfusion is maintained. These findings may result in new insights into the effect of glucose intolerance on myocardial function and perfusion during hyperemia.

Chapter 3

Introduction Glucose intolerance defines the intermittent stage between transition from normal glucose levels to type 2 diabetes mellitus.1 Glucose intolerance is a predictor of cardiovascular disease2,3 and known to associate with vascular dysfunction and consequent impairment of organ perfusion as one of the appearing consequences.4 Myocardial perfusion in combination with myocardial performance plays a central role in the balance between myocardial energy supply and demand. Under physiological conditions,

myocardial

blood

flow

and

function

are

balance,5

while

pathophysiological conditions leading to vascular dysfunction, such as glucose intolerance, could alter balance between energy supply and demand. Although glucose intolerance-induced vascular dysfunction may impair organ perfusion, data elucidating the effects of glucose intolerance on the perfusion of vital organs like the heart are limited. Up to now, only one group showed that insulin resistance in prediabetic patients was associated with myocardial perfusion defects.6,7 Contrast

echocardiography

non-invasive

method

for

assessment

and

quantification of myocardial perfusion that is clinically applied for specific indications in the cardiology setting. Using this technique it has been shown that myocardial blood flow reserve, as a measure for vascular function, is reduced in type 1 diabetic rats8 and type 1 diabetic patients9 when compared to normoglycemic controls. There are currently limited data available on myocardial perfusion in glucose intolerance. In the present study we therefore studied myocardial function and perfusion under baseline and pharmacological-induced hyperemic conditions in a rat model for dietinduced glucose intolerance using contrast echocardiography. Our hypothesis is that glucose intolerance reduces the myocardial vasodilating capacity, which blunts the increase in myocardial perfusion during hyperemia. This study demonstrates that diet-induced glucose intolerance is associated with impaired myocardial function during conditions of hyperemia, but not myocardial perfusion.

Myocardial function and perfusion during glucose intolerance

rats

underwent

oral

glucose

tolerance

test

and

(contrast)

echocardiography during baseline and after dipyridamole infusion. Diets High fat diet was obtained from Research Diets (D12451, New Brunswick, NJ). The HFD consisted of 24 wt% protein, 24 wt% fat and 41 wt% carbohydrates (8.5 wt% starch, 20.1 wt% sucrose). Control diet (Teklad 2016) was obtained from Harlan (Horst, The Netherlands) and consisted of 17 wt% protein, 4 wt% fat and 61 wt% carbohydrates (45.1 wt% starch, 5.0 wt% sucrose). Oral glucose tolerance test Rats fasted overnight received an oral glucose load (2 g/kg of body weight). Blood glucose levels were measured from tail bleeds with a Precision Xceed Blood Glucose monitoring system (MediSense, UK) before (0) and 15, 30, 60, 90 and 120 min after glucose ingestion.12 At similar time points, plasma insulin (LINCO research, St. Charles, Missouri) levels were measured as described previously.12 Plasma measurements Plasma hematocrit levels were determined using microcentrifugation. Plasma free fatty acids (WAKO NEFA-C, Wako Pure Chemical Industries, Osaka, Japan), plasma high-density lipoprotein (HDL) cholesterol and plasma low-density lipoprotein (LDL)/very-low-density lipoprotein (VLDL) cholesterol (Abcam, Cambridge, MA) were measured after overnight fasting as previously described.13,14

Chapter 3

Cannulation of the jugular vein For infusion of the contrast agent for echocardiography, a catheter was placed in the jugular vein under S-Ketamine (KetanestÂŽ, 150 mg/kg, Pfizer, the Netherlands) and diazepam (3 mg/kg, Centrafarm, the Netherlands) anesthesia intraperitoneally. After surgery, echocardiography and contrast echocardiography to determine myocardial function

and

perfusion,

respectively,

were

performed

during

baseline

and

dipyridamole-induced hyperemia (20 mg/kg for 10 minutes) (Figure 3.1).

Figure 3.1: Protocol (contrast) echocardiography After 4 weeks of control diet (CD) or high fat diet (HFD) feeding, rats received anesthesia for cannulation of the jugular vein followed by echocardiography (echo) and contrast echocardiography (contrast echo) during baseline and dipyridamole-induced hyperemia.

Echocardiography Echocardiography (Siemens, ACUSON, Sequoia 512) was performed as previously described.14 Briefly, wall thickness (WT) and left ventricular (LV) dimensions during end-systole (ES) and end-diastole (ED) were determined in the M- (motion) mode of the parasternal short-axis view at the level of the papillary muscles. Left ventricular contractile

function

was

calculated

the

fractional

shortening

(EDD-

ESD)/E''Ć&#x160; $QDO\VHV ZHUH SHUIRUPHG RII-line (Image-Arena 2.9.1, TomTec Imaging Systems, Unterschleissheim / Munich, Germany). All parameters were averaged over at least three cardiac contractile cycles. Myocardial contrast echocardiography Contrast echocardiography was performed using a Siemens (ACUSON, Sequoia 512) equipped with a 14 MHz linear array transducer (Philips Healthcare, Best, The Netherlands). The contrast agent SonovueÂŽ (Bracco Imaging, Italy), which contains 2x108-5x108/ml sulphur hexafluoride-filled, phospholipid-coated microbubbles with a diameter of 1Âą Ç&#x2039;P ZDV SUHSDUHG DFFRUGLQJ WKH PDQXIDFWXUHUÂśV LQVWUXFWLRQV DQG diluted twice by adding 5 ml NaCl (0.9%). Microbubbles were continuously infused LQWR WKH MXJXODU YHLQ ZLWK D UDWH RI Ç&#x2039;O PLQ using a dedicated syringe pump (Vueject, Bracco SA, Switzerland). After two minutes of microbubble infusion, perfusion images were taken of the short axis view of the left ventricle at the level of the papillary muscles.

Myocardial function and perfusion during glucose intolerance

Low acoustic power (mechanical index [MI] 0.20 max) was used for microbubble detection. A perfusion sequence consisted of about 10 cardiac cycles of low MI imaging, followed by a burst of high acoustic power (MI 1.8) for complete contrast destruction. Subsequently, on average 20 cardiac cycles of low MI images were acquired at a frame rate of 14 Hz to allow contrast replenishment in the myocardium. All data were stored for offline analysis. Myocardial contrast echocardiography analysis Custom-designed software was used for analysis of the estimate of perfusion (Matlab, 7.10, R2010A, MathWorks Inc. Massachusetts, USA) with special thanks to R. Meijer. For each cardiac cycle the end-systolic frame was selected manually and regions of interest were drawn in the posterior wall in the short axis view of the left ventricle. Myocardial signal intensity extracted from the frames before microbubble destruction were used to calculate microvascular blood volume A. Myocardial signal intensities from the frames after microbubble destruction were corrected for background noise by subtracting the signal intensity of the first frame after microbubble destruction (Y0). These intensities were then fitted (Y=Y0+(A-Y0)*(1exp(-Ç&#x192; [ ) for calculation of the microvascular filling velocity Ç&#x192; ZKLFK ZDV WUDQVIRUPHG into min-1 for further analysis (Figure 3.2). The estimate of perfusion was calculated as A * Ă&#x;. The flow reserve was calculated as the ratio of hyperemic and baseline estimate of perfusion. Statistical analysis All data are presented as meanÂąSD. Between group comparisons (CD vs. HFD) were performed using a student t-test, whereas baseline vs. dipyridamole intervention was tested with a paired student t-test. Oral glucose tolerance test was tested with one-way ANOVA with repeated measurements and Bonferroni post-hoc test. p<0.05 was considered as statistically significant.

Chapter 3

Figure 3.2: Typical example of contrast echocardiography with replenishment curve in rats

Myocardial function and perfusion during glucose intolerance

Results Short-term high fat diet feeding results in mild glucose intolerance Characteristics of rats after the diet intervention are summarized in Table 3.1. HFD feeding did not affect body weight, but increased perirenal and epidydimal fat weight. No changes were found in heart weight and tibia length between groups. Haematocrit, blood glucose, plasma insulin, free fatty acid and LDL/VLDL cholesterol levels were unaltered, whereas plasma HDL cholesterol levels were significantly decreased compared to controls. Post-load blood glucose levels were increased in HFD-fed rats compared to CD-fed rats, whereas post-load plasma insulin levels remained unchanged after HFD and CD feeding (Figure 3.3), indicating mild glucose intolerance. Table 3.1: Characteristics after short-term diet intervention Control diet

High fat diet

Body weight (g)

400±18

408±9

Perirenal fat (g)

6.3±1.5

7.5±1.2

Epidydimal fat (g)

7.4±1.2

9.4±1.4 *

Heart weight (g)

1.22±0.13

1.31±0.18

Tibia length (cm)

3.97±0.15

3.89±0.15

Hematocrit (%)

45.2±1.9

44.8±1.9

Blood glucose (mmol/L)

4.4±0.5

4.5±0.6

Plasma insulin (pmol/L)

95.2±37.4

130.8±82.4

Plasma free fatty acid (mmol/L)

1.22±0.21

1.09±0.19

Plasma HDL cholesterol (mg/dL)

318.7±23.9

242.6±40.8 *

Plasma LDL/VLDL cholesterol (mg/dL)

7.73±2.13

7.45±1.40

Body composition

Blood/plasma characteristics

Data are mean±SD, n=8, student t-test, * p<0.05 vs. control diet.

Chapter 3

Figure 3.3: High fat diet-feeding induced mild glucose intolerance Blood glucose (A,B) and plasma insulin levels (C,D) following an oral glucose load in rats fed a control diet (CD) or high fat diet (HFD). Data are expressed as meanÂąSD, n=7-8. One-way ANOVA with repeated measurements and Bonferroni post-hoc test (A,C) or student t-test (B,D), * p<0.05 vs. CD.

1.30±0.12 2.96±0.39

Diastolic WT (mm)

Systolic WT (mm)

end-systolic; WT, wall thickness.

Data are mean±SD, n=8, student t-test, * p<0.05 diet effect,

3.18±0.54

ES lumen diameter (mm)

1.34±0.25 2.85±0.37

# #

2.99±0.78

6.50±0.70 *

3.10±0.24 *

1.42±0.11

2.89±0.49

7.07±0.79

Hyperemia

p<0.05 hyperemia effect. CD, control diet; HFD, high fat diet; ED, end-diastolic; ES,

3.40±0.16

1.41±0.14

2.58±0.49

7.46±0.35

Baseline

7.41±0.53

ED lumen diameter (mm)

HFD Hyperemia

CD Baseline

Table 3.2: Echocardiographic parameters after short-term diet intervention

Myocardial function and perfusion during glucose intolerance 59

Chapter 3

High fat diet feeding impaired contractile function during dipyridamoleinduced hyperemia Table 3.2 shows a summary of the echocardiographic parameters measured after 4 weeks of HFD feeding during baseline and dipyridamole-induced hyperemia. HFD feeding resulted in decreased lumen diameter during end diastole at baseline and reduced systolic wall thickness after dipyridamole infusion. Dipyridamole infusion increased systolic and diastolic wall thickness in CD-fed rats, whereas in HFD-fed rats the end diastolic lumen diameter was increased. Contractile function, as represented by fractional shortening, was unaffected by HFD feeding under baseline conditions (Figure 3.4). During dipyridamole infusion, fractional shortening was increased in CD-fed rats, but not in HFD-fed rats, whereas fractional shortening was even decreased in HFD vs. CD-fed rats, suggesting impaired contractile function during dipyridamole-induced hyperemia.

Figure 3.4: Contractile function during baseline and dipyridamole-induced hyperemia Representative examples of the m-mode of the left ventricle at the level of the papillary muscle (A). Contractile function, as represented by the fractional shortening, measured in rats fed a control diet (CD) and high fat diet (HFD) for 4 weeks during baseline and dipyridamole-induced hyperemia (B). Data are expressed as meanÂąSD, n=6-8, (paired) student t-test, * p<0.05 diet effect,

p<0.05 hyperemia effect.

Myocardial function and perfusion during glucose intolerance

Unchanged myocardial perfusion after high fat diet feeding HFD-feeding did not alter microvascular blood volume A, microvascular filling velocity Ç&#x192; DQG the estimate of perfusion compared to CD-fed rats (Figure 3.5A-C). Dipyridamole infusion increased microvascular blood volume A, microvascular filling velocity Ç&#x192; DQG the estimate of perfusion in CD-fed rats (Figure 3.5A-C), however, failed to reach significance. In HFD-IHG UDWV RQO\ Ç&#x192; ZDV VLJQLILFDQWO\ LQFUHDVHG DIWHU dipyridamole infusion (Figure 3.5A-C). No differences were found in flow reserve between CD- and HFD-fed rats (Figure 3.5D), suggesting unaltered myocardial perfusion after 4 weeks of HFD feeding.

Figure 3.5: Myocardial perfusion measured with contrast echocardiography Microvascular blood volume A (A), microvascular filling velocity Ç&#x192; B), estimate of perfusion (C) and flow reserve (D) in rats fed a control (CD) or high fat diet (HFD) measured during baseline and dipyridamole-induced hyperemia. Data are expressed as meanÂąSD, n=4-8, (paired) student t-test, #

p<0.05 vs. CD.

Chapter 3

Discussion In the present study, we examined the effect of glucose intolerance on myocardial function and perfusion. We found that short-term high fat diet feeding resulted in glucose intolerance without affecting myocardial function and perfusion under baseline conditions. Diet-induced glucose intolerance impaired myocardial contractile function during conditions of hyperemia, in the absence of alterations in myocardial perfusion. The present study showed that short-term high fat diet feeding resulted in glucose intolerance without obesity affecting myocardial contractile function under resting conditions. Our results confirm previous findings, showing that 4 weeks of high fat diet feeding in rats resulted in glucose intolerance without affecting function,15 whereas 8 weeks of high fat diet feeding resulted in glucose intolerance with mildly impaired contractile function.15 One of the suggested mechanisms that may contribute to alterations in myocardial blood flow during prediabetes or diabetes are changes in nitric oxide availability. High fat diet feeding in male rats decreased nitric oxide availability,16 whereas increased nitric oxide bioavailability in eNOS-/- mice has been shown to attenuate high fat diet-induced metabolic alterations associated with insulin resistance.17 Taken together, these results suggest that 4 weeks of high fat diet feeding in a rat results in a mild model of glucose intolerance without impaired myocardial function. Under physiological conditions, myocardial perfusion and function are in balance.5 However, a perfusion-contraction mismatch might exist in glucose intolerance. In the present study, diet-induced glucose intolerance did not affect myocardial perfusion measured with contrast echocardiography during baseline conditions. These results are in agreement with Menard et al.,18 who found no differences in myocardial perfusion index measured by [13N] ammonia PET in rats fed a high fructose and high fat diet with additional streptozotocin. Accordingly, in patients with insulin resistance or glucose tolerance it was found that insulin resistance was associated with a defect in myocardial perfusion measured by single photon emission computed tomography, which was independent of glucose tolerance and obesity.6 Together, these results suggest that under baseline conditions diet-induced glucose intolerance does not affect myocardial function and perfusion. Dipyridamole

used

pharmacologically

induce

maximal

vasodilation.

Dipyridamole blocks the uptake of adenosine, thereby increasing the circulating levels of adenosine, which results in maximal coronary blood flow due to decreased coronary vascular resistance.19 During hyperemia, myocardial contractile function was increased in healthy rats, but not in rats with diet-induced glucose intolerance. On the contrary, this hyperemic-induced increase in contractile function was not seen in healthy and type 1 diabetic rats.8 Besides glucose intolerance, several variables

Myocardial function and perfusion during glucose intolerance

could be associated with alterations in myocardial function. Our experimental rat model with high fat diet feeding resulted in development of glucose intolerance, but rats did not become obese. Consequently, obesity cannot be explanatory for the findings of the effect of high fat diet feeding on myocardial function. Myocardial blood flow reserve is the increase in blood flow that can be achieved from basal perfusion to maximal vasodilatation, and is therefore a measurement of the ability of the microvasculature to respond to an increase in oxygen demand. In type 1 diabetic rats8 and patients9 it was shown that myocardial blood flow reserve measured with contrast echocardiography was decreased compared to healthy controls. In the present study, myocardial blood flow reserve was unchanged between healthy rats and rats with glucose intolerance, suggesting that glucose intolerance does not reduce the vasodilating capacity of the myocardium. Increases in myocardial contractile function will lead to a metabolically-mediated increase in myocardial blood flow, however, an increase in coronary perfusion does not have to increase myocardial contractile function,5 which might explain the hyperemic-induced differences in myocardial function and perfusion in rats with glucose intolerance. A limitation of this study is the small amount of rats used. Although this is a pilot study, ideally, this data set should have been analyzed with a two-way ANOVA with Bonferronni post-hoc testing for multiple group comparisons. In conclusion, the present data demonstrate that diet-induced glucose intolerance is associated with impaired myocardial function during conditions of hyperemia, but not myocardial perfusion. These findings may result in new insights into the effect of glucose intolerance on myocardial function and perfusion during hyperemia.

Chapter 3

References 1.

Zimmet PZ, Gareeboo H, Hemraj F, Tuomilehto J, Alberti KG: Impaired fasting glucose or impaired glucose tolerance. What best predicts future diabetes in Mauritius? Diabetes Care 1999, 22:399±402.

de Veire van, de Winter O, Gillebert TC, de Sutter J: Diabetes and impaired fasting glucose as predictors of morbidity and mortality in male coronary artery disease patients with reduced left ventricular function. Acta Cardiol 2006, 61:137±143.

Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A: Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999, 22:920±924.

DeFronzo RA, bdul-Ghani M: Assessment and treatment of cardiovascular risk in prediabetes:

Heusch G, Schulz R: The relation of contractile function to myocardial perfusion. Perfusion-

impaired glucose tolerance and impaired fasting glucose. Am J Cardiol 2011, 108:3B±24B. contraction match and mismatch. Herz 1999, 24:509±514. 6.

Nasr G, Sliem H: Silent myocardial ischemia in prediabetics in relation to insulin resistance. J Cardiovasc Dis Res 2010, 1:116±121.

Nasr G, Sliem H: Silent ischemia in relation to insulin resistance in normotensive prediabetic adults: early detection by single photon emission computed tomography (SPECT). Int J Cardiovasc Imaging 2011, 27:335±341.

Cosyns B, Droogmans S, Hernot S, Degaillier C, Garbar C, Weytjens C, Roosens B, Schoors D, Lahoutte T, Franken PR, Van Camp G: Effect of streptozotocin-induced diabetes on myocardial blood flow reserve assessed by myocardial contrast echocardiography in rats. Cardiovasc Diabetol 2008, 7:26.

Rana O, Byrne CD, Kerr D, Coppini DV, Zouwail S, Senior R, Begley J, Walker JJ, Greaves K: Acute hypoglycemia decreases myocardial blood flow reserve in patients with type 1 diabetes mellitus and in healthy humans. Circulation 2011, 124:1548±1556.

10. http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31986L0609:EN:NOT. 11. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010, 8:e1000412. 12. Ouwens DM, Boer C, Fodor M, de Galan P, Heine RJ, Maassen JA, Diamant M: Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 2005, 48:1229±1237. 13. van den Brom CE, Bosmans JW, Vlasblom R, Handoko ML, Huisman MC, Lubberink M, Molthoff CF, Lammertsma AA, Ouwens DM, Diamant M, Boer C: Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle. Cardiovasc Diabetol 2010, 9:25. 14. van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, Van der Velden J, Boer C, Ouwens DM, Diamant M: Altered myocardial substrate

metabolism

associated

with

myocardial

dysfunction

early

diabetic

cardiomyopathy in rats: studies using positron emission tomography. Cardiovasc Diabetol 2009, 8:39. 15. Ouwens DM, Diamant M, Fodor M, Habets DD, Pelsers MM, El Hasnaoui M, Dang ZC, van den Brom CE, Vlasblom R, Rietdijk A, Boer C, Coort SL, Glatz JF, Luiken JJ: Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36mediated fatty acid uptake and esterification. Diabetologia 2007, 50:1938±1948.

Myocardial function and perfusion during glucose intolerance

16. Monteiro PF, Morganti RP, Delbin MA, Calixto MC, Lopes-Pires ME, Marcondes S, Zanesco A, Antunes E: Platelet hyperaggregability in high-fat fed rats: a role for intraplatelet reactiveoxygen species production. Cardiovasc Diabetol 2012, 11:5. 17. Razny U, Kiec-Wilk B, Wator L, Polus A, Dyduch G, Solnica B, Malecki M, Tomaszewska R, Cooke JP, mbinska-Kiec A: Increased nitric oxide availability attenuates high fat diet metabolic alterations and gene expression associated with insulin resistance. Cardiovasc Diabetol 2011, 10:68. 18. Menard SL, Croteau E, Sarrhini O, Gelinas R, Brassard P, Ouellet R, Bentourkia M, van Lier JE, Des RC, Lecomte R, Carpentier AC: Abnormal in vivo myocardial energy substrate uptake in diet-induced type 2 diabetic cardiomyopathy in rats. Am J Physiol Endocrinol Metab 2010, 298:E1049ÂąE1057. 19. Leppo JA: Dipyridamole myocardial perfusion imaging. J Nucl Med 1994, 35:730Âą733.

4 Sevoflurane impairs myocardial systolic function, but not myocardial perfusion in diet-induced prediabetic rats CE van den Brom, CA Boly, CSE Bulte, RPF van den Akker, RFJ Kwekkeboom, SA Loer, C Boer, RA Bouwman Submitted

Sevoflurane and myocardial perfusion in prediabetes

Abstract Introduction Preservation of myocardial perfusion is particularly important in patients with increased risk for perioperative cardiac complications, such as patients with diabetes. Knowledge regarding regulation of myocardial perfusion and function during anesthesia in subjects with cardiometabolic disease is however limited. In this study we therefore investigated whether the effect of sevoflurane on myocardial perfusion and function is altered in healthy and diet-induced prediabetic rats. Methods Male Wistar rats were randomly exposed to a western diet (WD; n=18) or control diet (CD; n=18). After 8 weeks, rats underwent (contrast) echocardiography to determine myocardial perfusion and function during baseline conditions and sevoflurane (2%) exposure. Myocardial perfusion was estimated based on the product of microvascular filling velocity (Ç&#x192; and microvascular blood volume (A), whereas myocardial function was determined by fractional shortening and fractional area change. Results Eight weeks of WD feeding resulted in obesity and hyperglycemia compared to CDfeeding. At baseline, WD decreased estimate of perfusion compared to control rats. Systolic function was significantly impaired compared to CD-fed rats. Exposure to sevoflurane increased the microvascular filling velocity in healthy controls, whereas the overall estimate of myocardial perfusion remained unchanged in both diet groups. Moreover, sevoflurane impaired systolic function in both diet groups. Conclusions Diet-induced prediabetes is associated with impaired myocardial perfusion and function in rats. While sevoflurane further impaired systolic function, it did not affect myocardial perfusion in prediabetic rats. Our findings suggest that sevoflurane leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state.

Chapter 4

Introduction Myocardial perfusion in relation with myocardial function determines the balance between myocardial energy supply and demand. During surgery, maintenance of the myocardial oxygen balance is challenged, because extrinsic factors, like anesthetics and surgical stress, and intrinsic factors, like metabolic alterations, affect myocardial oxygen supply and consumption. This altered balance may increase the vulnerability of the heart for an oxygen supply and demand mismatch and consequent ischemia.1;2 Sevoflurane has vasodilating properties and is known to reduce coronary vascular resistance3 and perfusion pressure.4;5 We recently showed that sevoflurane did not affect myocardial blood flow in healthy patients, while myocardial flow reserve was decreased.6 Animal studies however showed that sevoflurane, when perfusion pressure remained constant, increased coronary blood flow in hearts of dogs7 and decreased coronary flow reserve in isolated rat hearts.5 In contrast, sevoflurane lowered blood pressure and decreased myocardial blood flow in healthy rats,8 dogs9 and pigs.10 While sevoflurane exerts contrasting effects on myocardial perfusion in healthy subjects,

its

vasodilatory

impact

may

abundant

patients

with

cardiometabolic disease, like type 2 diabetes mellitus (T2DM). T2DM patients are more

likely

cardiovascular

develop

coronary

complication

rate

artery

after

disease11

major

and

non-cardiac

have

surgery.12

increased Because

myocardial substrate metabolism and myocardial oxygen balance is altered in T2DM,13 the regulation of myocardial perfusion in these patients is particularly important during normal and intraoperative circumstances. The number of studies focusing on myocardial perfusion during anesthesia in subjects with cardiometabolic disease is however limited. Previously, we found that myocardial perfusion, but not myocardial function, is preserved during hyperemia in glucose intolerant rats,14 while others

showed

myocardial

perfusion

defects

prediabetic

insulin

resistant

patients15;16 or T2DM patients during the postprandial state.17;18 The aforementioned data suggest that a cardiometabolic-compromised state may be associated with more severe alterations in myocardial perfusion during anesthesia. Therefore, the purpose of the present study was to investigate the effect of sevoflurane on myocardial function and perfusion in diet-induced prediabetic rats. While the effects in healthy subjects seem apparently conflicting, we hypothesized WKDW VHYRIOXUDQHÂśV YDVRGLODWRU\ LPSDFW PD\ EH PRUH DEXQGDQW LQ WKH SUHVHQFH RI cardiometabolic disease and thereby challenging myocardial perfusion regulation.

Sevoflurane and myocardial perfusion in prediabetes

Methods Animals and experimental set-up All experiments were approved by the Institutional Animal Care and Use Committee of the VU University, and were conducted following the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes. Adult male Wistar rats (n=36; body weight 265±7 g; Charles River Laboratories, France) were fed a western diet (WD) for a period of 8 weeks (n=18). Rats that received a diet low in fat and sugars (control diet; CD) for 8 weeks served as controls (n=18). Animals were housed in a temperature-controlled room (20-23°C; 40-60% humidity) under a 12/12h light/dark cycle starting at 6.00 am. Body weight was determined on a weekly basis. After 8 weeks, rats underwent (contrast) echocardiography during baseline conditions and during sevoflurane (AbbVie, the Netherlands) exposure, starting after 5 minutes of sevoflurane. Diets CD (Teklad 2016, Harlan, Horst, the Netherlands) consisted of 20 %kcal protein, 9 %kcal fat and 74 %kcal carbohydrates (1804 kcal/kg starch, 200 kcal/kg sugars), whereas WD (D12451, Research Diets, New Brunswick, NJ) consisted of 20 %kcal protein, 45 %kcal fat and 35 %kcal carbohydrates (291 kcal/kg starch, 691 kcal/kg sugars) with 20% sucrose water (800 kcal/kg), totally containing 3300 kcal/kg and 4857 kcal/kg for CD and WD with sucrose water, respectively. Surgery After 8 weeks of diet exposure, rats were anesthetized with 125 mg/kg S-Ketamine (Ketanest®, Pfizer, the Netherlands) and 4 mg/kg diazepam (Centrafarm, the Netherlands) intraperitoneally and were intubated and mechanically ventilated (UNO, the Netherlands; positive end-expiratory pressure, 1-2 cm H2O; respiratory rate, ~65 breaths/min; tidal volume, ~10 ml/kg) with oxygen-enriched air (40% O2/60% N2). Anesthesia was maintained by continuous infusion of 50 mg/kg/h S-Ketamine and 1.3 mg/kg/h diazepam intravenously via the tail vein. Respiratory rate was adjusted to maintain pH and partial pressure of carbon dioxide within physiological limits. Body temperature was maintained stable (36.7±1.2°C) using a warm water underbody heating pad. A catheter was placed in the right jugular vein for infusion of the contrast agent. The left carotid artery was cannulated for blood sampling, blood gas analyses (ABL50, radiometer, Copenhagen, Denmark) and for measurements of arterial blood pressure (Safedraw Transducer Blood Sampling Set, Argon Medical Devices, Texas, USA). Arterial blood pressure, ECG and heart rate were continuously recorded using

Chapter 4

PowerLab software (PowerLab 8/35, Chart 7.0; ADInstruments Pty, Ltd., Castle Hill, Australia). Mean arterial blood pressure was calculated according the following IRUPXOD Ć&#x160;GLDVWROLF EORRG SUHVVXUH Ć&#x160;V\VWROLF EORRG SUHVVXUH 5DWH SUHVVXUH product (RPP) was calculated by the product of heart rate and systolic blood pressure and was used as an estimate of myocardial oxygen demand. Echocardiography After surgery, (contrast) echocardiography was performed to determine myocardial function and perfusion during baseline conditions and after 5 minutes of sevoflurane (2%) exposure. Echocardiography (Siemens, ACUSON, Sequoia 512) was performed as previously described.13 Briefly, left ventricular (LV) dimensions during end-systole (ES) and end-diastole (ED) were determined in the M-(motion) mode of the parasternal short-axis view at the level of the papillary muscles. LV systolic function is represented by fractional shortening (FS) and fractional area change (FAC), which were calculated by the equations: FS = (EDD-(6' (''Ć&#x160; DQG )$& 2

(''2-

ESD )/EDD Ć&#x160;100). All parameters were averaged over at least three cardiac contractile cycles. Preparation of microbubbles Microbubbles were prepared from perfluorobutane gas and stabilized with a monolayer of distearoyl phosphatidylcholine and PEG stearate. 1,2-distearoyl-snglycero-3-phosphocholine

(DSPC;

Avanti

Polar

Lipids,

Alabama,

USA)

and

polyoxyethylene stearate (PEG40; Sigma, St Louis, MO, USA) were dissolved in glycerol (10 mg/ml) and sonicated (Decon FS200, Decon Ultrasonics Ltd, Sussex, UK) at 40 kHz in an atmosphere of perfluorobutane (F2 Chemicals Ltd, Lancashire, UK) and vials were shaken a Vialmix at 4500 rpm (Bristol-Myers Squibb Medical Imaging, Massachusetts, USA). As the gas was dispersed in the aqueous phase, microbubbles

were

formed,

which

were

stabilized

with

self-assembled

lipid/surfactant monolayer. Freshly made bubbles were then washed twice to remove excessive DSPC and PEG40 and stored refrigerated in sealed vials in perfluorobutane atmosphere. A Multisizer 3 coulter counter (Beckman Coulter Inc., Miami, FL, USA) was used to measure the particle size distribution as well as the number of particles. The average bubble concentration was 1.578Ă&#x161;109 Âą 0.364Ă&#x161;109 and the particle range was between 1 and 10 Ç&#x2039;P Microbubbles were diluted to a concentration of 200Ă&#x161;106 with ungassed water.

Sevoflurane and myocardial perfusion in prediabetes

Myocardial contrast echocardiography Contrast echocardiography was performed using a Siemens (ACUSON, Sequoia 512) equipped with a 14 MHz linear array transducer (Philips Healthcare, Best, The Netherlands).14 Microbubbles were continuously infused into the jugular vein with a rate of 300 μl/min using a dedicated syringe pump (Vueject, Bracco SA, Switzerland). After two minutes of microbubble infusion, perfusion images were taken from the long axis view of the left ventricle. Low acoustic power (mechanical index [MI] 0.20) was used for microbubble detection with a dynamic range of 50 dB. A perfusion sequence consisted of about 10 cardiac cycles of low MI imaging, followed by a burst of high acoustic power (MI 1.8) for complete contrast destruction. Subsequently, on average 20 cardiac cycles of low MI images were acquired to allow contrast replenishment in the myocardium. All data were stored for offline analysis. Myocardial contrast echocardiography analysis Custom-designed software was used for analysis of the estimate of perfusion (Matlab, 7.10, R2010A, MathWorks Inc. Massachusetts, USA).6;14 For each cardiac cycle, regions of interest were drawn in the end-systolic frame in the posterior wall in the long axis view of the left ventricle. Myocardial signal intensities from the frames after microbubble destruction were corrected for background noise by subtracting the signal intensity of the first frame after microbubble destruction (Y0). These intensities were then

fitted (Y=Y0

+ (A-Y0)Ú(1-exp(-ßÚx)))

for

calculation

microvascular blood volume A and the microvascular filling velocity ß, which corresponds to the capillary blood exchange rate. The estimate of perfusion was calculated as the product of A and ß.19 Statistical analysis Data were analyzed using Graphpad Prism 5.0 (La Jolla, USA) and presented as mean±SD. Between group comparisons (CD vs. WD) were performed using a student t-test, whereas the effect of sevoflurane exposure was tested with a twoway ANOVA with Bonferonni as post-hoc test. p<0.05 was considered as statistically significant.

Chapter 4

Results Western diet feeding resulted in obesity and hyperglycemia After 8 weeks of western diet feeding, bodyweight was significantly increased compared to control rats (Table 4.1), whereas heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure remained unchanged (Figure 4.1). After sacrifice, blood glucose levels and left ventricular weights were higher in western diet- compared to control diet-fed rats (Table 4.1).

Table 4.1: Characteristics after 8 weeks of diet intervention

Body weight (g)

Control diet

Western diet

420±25

450±20 *

Blood glucose after sacrifice (mmol/L)

14.6±5.1

19.3±3.6 *

Tibia length (mm)

42.7±1.0

43.1±0.6

Left ventricular weight (g)

0.53±0.06

0.57±0.08 *

Data are mean±SD, n=18, student t-test, * p<0.05 vs. control diet.

Sevoflurane and myocardial perfusion in prediabetes

Figure 4.1: Hemodynamics during sevoflurane exposure Systolic blood pressure (A), diastolic blood pressure (B), mean arterial pressure (C), heart rate (D) and rate pressure product (E) during baseline conditions, before sevoflurane exposure, after 5 minutes of sevoflurane and after 5 minutes of washout period in rats fed a control diet (CD) or western diet (WD) for 8 weeks. Data are meanÂąSD, n=16-18, two-way ANOVA with repeated measurements and Bonferonni post-hoc analyses, # p<0.05 sevoflurane effect, $ p<0.05 washout effect.

Chapter 4

Impaired myocardial perfusion and systolic function in prediabetic rats Compared

healthy

controls,

western

diet

feeding

tended

decrease

PLFURYDVFXODU ILOOLQJ YHORFLW\ ǃ DQG VLJQLILFDQWO\ GHFUHDVHG PLFURYDVFXODU EORRG volume (A), which resulted in a significant reduction in the estimate of perfusion (Figure 4.2). Western diet feeding significantly increased end-systolic lumen diameter and diastolic wall thickness, but did not affect end-diastolic lumen diameter and wall thickness during systole compared to control rats (Table 4.2). Fractional shortening and fractional area change were significantly decreased in western diet-fed rats compared to control animals, suggesting impaired systolic function (Figure 4.3).

Table 4.2: Myocardial function after 8 weeks during baseline and after sevoflurane exposure Baseline

Sevoflurane

Diastolic lumen diameter (mm)

5.7±0.6

5.5±0.8

5.4±0.8

5.5±0.8

Systolic lumen diameter (mm)

2.0±0.4

2.7±0.7*

2.3±0.5

3.4±0.6*#

Diastolic wall thickness (mm)

1.8±0.1

1.9±0.2*

1.6±0.2

1.9±0.2*

Systolic wall thickness (mm)

3.3±0.3

3.1±0.4

3.0±0.4

2.9±0.2

Data are mean±SD, n=9-18, two-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 diet effect, # p<0.05 sevoflurane effect. CD, control diet; WD, western diet.

Sevoflurane and myocardial perfusion in prediabetes

Figure 4.2: Effect of sevoflurane on myocardial perfusion in prediabetic rats Microvascular blood volume A (A), microvascular filling velocity Ç&#x192; B) and estimate of perfusion (C) measured with contrast echocardiography in rats fed a control diet (CD) or western diet (WD) for 8 weeks during baseline conditions and after 5 minutes of sevoflurane exposure. Data are expressed as meanÂąSD, n=9-13, two-way ANOVA with Bonferonni post-hoc analyses, * p<0.05 diet effect, # p<0.05 sevoflurane effect.

Chapter 4

Sevoflurane further impaired systolic function, but not myocardial perfusion Blood pressure, heart rate and rate pressure product were significantly decreased after 5 minutes of sevoflurane exposure and significantly restored after a 5-minute washout period, without differences among diet groups (Figure 4.1). Compared to baseline conditions, sevoflurane decreased the microvascular filling YHORFLW\ Ç&#x192; DQG tended to increase microvascular blood volume (A) in controls, while this observation was absent in western diet-fed animals. Overall, this resulted in an unchanged estimate of perfusion in both diet groups (Figure 4.2). Sevoflurane additionally increased end-systolic lumen diameter in western diet-fed rats compared to baseline conditions (Table 4.2), which resulted in further impaired systolic function in western diet-fed rats compared to control rats (Figure 4.3).

Figure 4.3: Effect of sevoflurane on systolic function in prediabetic rats Systolic function, as represented by the fractional shortening (A) and fractional area change (B), measured with echocardiography in rats fed a control diet (CD) or western diet (WD) for 8 weeks during baseline conditions and after 5 minutes of sevoflurane exposure. Data are expressed as meanÂąSD, n=9-18, two-way ANOVA with Bonferonni post-hoc analyses, * p<0.05 diet effect, # p<0.05 sevoflurane effect.

Sevoflurane and myocardial perfusion in prediabetes

Discussion In the present study, we examined the effect of sevoflurane on myocardial perfusion and function in western diet-fed rats. We found that short-term western diet feeding resulted in a prediabetic phenotype characterized by obesity and hyperglycemia. Further, diet-induced prediabetes was associated with impaired myocardial perfusion and systolic dysfunction. Sevoflurane had no overall effect on myocardial perfusion in healthy and prediabetic rats, while systolic function was even further impaired. These results suggest that sevoflurane leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state. Sevoflurane did not affect myocardial perfusion, despite of decreased arterial blood pressure, heart frequency and rate pressure product in healthy rats. Previously it has indeed been shown that sevoflurane did not alter myocardial blood flow in healthy rats20 and healthy subjects6 compared to the awake condition. In contrast, others however described decreased myocardial blood flow in healthy rats,8 dogs9 and pigs.10 In addition to species variation and the use of different experimental techniques,19 administration of general anesthetics may explain the contrasting observations, as this may distinctly alter hemodynamics compared to the awake state. While myocardial perfusion remained unchanged, sevoflurane decreased the PLFURYDVFXODU ILOOLQJ YHORFLW\ Ç&#x192; DQG LQFUHDVHG PLFURYDVFXODU EORRG YROXPH A). The microvascular filling velocity is a parameter of the capillary exchange rate providing an estimate of the speed of erythrocytes through the capillaries, while microvascular blood volume suggests the surface area for exchange of nutrients and correlates with oxygen consumption. Our observations are in contrast with a previously performed study in healthy subjects by our group, where we showed that sevoflurane decreased myocardial blood volume and increased the microvascular filling velocity.6 A possible mechanism to explain these differences may be derived by the differences in heart rate among species. We found a decrease in heart rate, while in healthy subjects an increase in heart rate was shown.6 However, also decreased8 or unchanged20 heart rate in rats are found. Taken together, although sevoflurane impaired the microvascular filling velocity, myocardial perfusion was not affected in healthy rats. Moreover, the present study showed that myocardial perfusion and function were both decreased in prediabetic rats compared to healthy controls. In detail, microvascular blood volume was decreased, which resulted in impairment of myocardial perfusion. Previously, we found that myocardial perfusion was maintained during baseline conditions in high fat diet-induced glucose intolerant rats.14 The present study used a more severe diet, which resulted in more pronounced disturbances in the cardiometabolic condition of the rats. Independent of glucose tolerance and obesity, myocardial perfusion defects were found in prediabetic insulin resistant patients.15;16 In T2DM patients, no differences in myocardial blood flow were found during fasting conditions.17;18 However, during the postprandial state

Chapter 4

decreased myocardial blood flow was found in T2DM patients,17;18 which is in agreement with the present study showing decreased myocardial perfusion in nonfasted prediabetic rats. An underlying mechanism of this impaired myocardial perfusion might be alterations in insulin-mediated recruitment of the capillaries. In healthy subjects, insulin increased basal21 and adenosine-stimulated22 myocardial perfusion. Moreover, insulin directly affects myocardial perfusion by enhancing hyperemic myocardial blood flow in a dose-dependent manner in healthy subjects.23 However, insulin resistance may block insulin-mediated capillary recruitment.24 In T2DM patients, the use of an insulin analog partially reversed myocardial perfusion abnormalities.18 As far as we know, we are the first to study the effect of sevoflurane anesthesia on myocardial perfusion in prediabetic rats. Our results show that sevoflurane has a stronger cardiodepressive effect in prediabetic rats, whereas myocardial perfusion remained unaffected. Under physiological conditions, myocardial blood flow and function are in balance.25 In our prediabetic rats, myocardial perfusion as well as myocardial

function

are

decreased.

However,

during

sevoflurane

myocardial

perfusion is maintained, while myocardial function is decreased in healthy and prediabetic rats. This uncoupling of perfusion and function suggests that despite of increased microvascular blood volume and decreased microvascular filling velocity, myocardial function cannot be maintained. In conclusion, the present study showed impaired myocardial function and perfusion in diet-induced prediabetic rats. Moreover, sevoflurane further impaired systolic function, but myocardial perfusion was maintained. These results suggest that sevoflurane leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state of the heart.

Sevoflurane and myocardial perfusion in prediabetes

References 1. Dole WP: Autoregulation of the coronary circulation. Prog Cardiovasc Dis 1987, 29:293-323. 2. Hoffman JI, Spaan JA: Pressure-flow relations in coronary circulation. Physiol Rev 1990, 70:331-390. 3. Malan TP, Jr., DiNardo JA, Isner RJ, Frink EJ, Jr., Goldberg M, Fenster PE, Brown EA, Depa R, Hammond LC, Mata H: Cardiovascular effects of sevoflurane compared with those of isoflurane in volunteers. Anesthesiology 1995, 83:918-928. 4. Park KW: Cardiovascular effects of inhalational anesthetics. Int Anesthesiol Clin 2002, 40:1-14. 5. Larach DR, Schuler HG: Direct vasodilation by sevoflurane, isoflurane, and halothane alters coronary flow reserve in the isolated rat heart. Anesthesiology 1991, 75:268-278. 6. Bulte CS, Slikkerveer J, Kamp O, Heymans MW, Loer SA, de Marchi SF, Vogel R, Boer C, Bouwman RA: General anesthesia with sevoflurane decreases myocardial blood volume and hyperemic blood flow in healthy humans. Anesth Analg 2013, 116:767-774. 7. Crystal GJ, Zhou X, Gurevicius J, Czinn EA, Salem MR, Alam S, Piotrowski A, Hu G: Direct coronary

vasomotor

effects

sevoflurane

and

desflurane

situ

canine

hearts.

Anesthesiology 2000, 92:1103-1113. 8. Conzen PF, Vollmar B, Habazettl H, Frink EJ, Peter K, Messmer K: Systemic and regional hemodynamics of isoflurane and sevoflurane in rats. Anesth Analg 1992, 74:79-88. 9. Hirano M, Fujigaki T, Shibata O, Sumikawa K: A comparison of coronary hemodynamics during isoflurane and sevoflurane anesthesia in dogs. Anesth Analg 1995, 80:651-656. 10.Manohar M, Parks CM: Porcine systemic and regional organ blood flow during 1.0 and 1.5 minimum alveolar concentrations of sevoflurane anesthesia without and with 50% nitrous oxide. J Pharmacol Exp Ther 1984, 231:640-648. 11.Preis SR, Pencina MJ, Hwang SJ, D'Agostino RB, Sr., Savage PJ, Levy D, Fox CS: Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation 2009, 120:212-220. 12.Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999, 100:1043-1049. 13.van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, Van der Velden J, Boer C, Ouwens DM, Diamant M: Altered myocardial substrate

metabolism

associated

with

myocardial

dysfunction

early

diabetic

cardiomyopathy in rats: studies using positron emission tomography. Cardiovasc Diabetol 2009, 8:39. 14.van den Brom CE, Bulte CS, Kloeze BM, Loer SA, Boer C, Bouwman RA: High fat diet-induced glucose

intolerance

impairs

myocardial

function,

but

not

myocardial

perfusion

during

hyperaemia: a pilot study. Cardiovasc Diabetol 2012, 11:74. 15.Nasr G, Sliem H: Silent myocardial ischemia in prediabetics in relation to insulin resistance. J Cardiovasc Dis Res 2010, 1:116-121. 16.Nasr G, Sliem H: Silent ischemia in relation to insulin resistance in normotensive prediabetic adults: early detection by single photon emission computed tomography (SPECT). Int J Cardiovasc Imaging 2011, 27:335-341. 17.Scognamiglio R, Negut C, De Kreutzenberg SV, Tiengo A, Avogaro A: Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation 2005, 112:179-184.

Chapter 4

18.Scognamiglio R, Negut C, De Kreutzenberg SV, Tiengo A, Avogaro A: Effects of different insulin regimes on postprandial myocardial perfusion defects in type 2 diabetic patients. Diabetes Care 2006, 29:95-100. 19.Bulte CS, Slikkerveer J, Meijer RI, Gort D, Kamp O, Loer SA, de Marchi SF, Vogel R, Boer C, Bouwman RA: Contrast-enhanced ultrasound for myocardial perfusion imaging. Anesth Analg 2012, 114:938-945. 20.Crawford MW, Lerman J, Saldivia V, Carmichael FJ: Hemodynamic and organ blood flow responses to halothane and sevoflurane anesthesia during spontaneous ventilation. Anesth Analg 1992, 75:1000-1006. 21.Liu Z: Insulin at physiological concentrations increases microvascular perfusion in human myocardium. Am J Physiol Endocrinol Metab 2007, 293:E1250-E1255. 22.Laine H, Nuutila P, Luotolahti M, Meyer C, Elomaa T, Koskinen P, Ronnemaa T, Knuuti J: Insulininduced increment of coronary flow reserve is not abolished by dexamethasone in healthy young men. J Clin Endocrinol Metab 2000, 85:1868-1873. 23.Sundell J, Nuutila P, Laine H, Luotolahti M, Kalliokoski K, Raitakari O, Knuuti J: Dose-dependent vasodilating effects of insulin on adenosine-stimulated myocardial blood flow. Diabetes 2002, 51:1125-1130. 24.Zhang L, Vincent MA, Richards SM, Clerk LH, Rattigan S, Clark MG, Barrett EJ: Insulin sensitivity of muscle capillary recruitment in vivo. Diabetes 2004, 53:447-453. 25.Heusch G, Schulz R: The relation of contractile function to myocardial perfusion. Perfusioncontraction match and mismatch. Herz 1999, 24:509-514.

5 Diet composition modulates sevofluraneinduced myocardial depression in rats CE van den Brom, C Boer, RPF van den Akker, J van der Velden, SA Loer, RA Bouwman Submitted

Dietary effects on the heart during sevoflurane

Abstract Introduction Cardiometabolic diseases like obesity and/or diabetes mellitus may alter the effects of sevoflurane on the heart, but current evidence is limited to in vitro studies. This study evaluated the influence of western diet-induced obesity with glucose intolerance on the myocardial response to sevoflurane, and further elaborated whether lowering caloric intake can modulate this effect. Methods Male Wistar rats were exposed to a western diet (WD) or control diet (CD) for 8 weeks. A third group of WD-fed rats reversed after 4 weeks to CD for 4 consecutive weeks. Study parameters included an oral glucose tolerance test, echocardiography

and protein analyses before and after exposure to 2% sevoflurane. Results Eight weeks of WD-feeding resulted in a prediabetic phenotype with obesity, glucose intolerance,

mild

hyperglycemia,

hyperinsulinemia,

dyslipidemia

and

reduced

myocardial systolic and diastolic function. While sevoflurane did not alter myocardial contractile function in healthy control animals, systolic function in WD-fed rats was further impaired after sevoflurane exposure. Reversion of WD to control diet normalized the prediabetic phenotype, and restored myocardial function during baseline and after sevoflurane exposure to control values. Western diet and diet reversal exerted distinct effects on myocardial calcium handling proteins, while changes in proteins related to substrate metabolism were only minimal. Conclusions Sevoflurane is a stronger cardiodepressant in prediabetic than in control rats, which could be restored by lowering caloric intake. These results suggest that normalization of the cardiometabolic profile by dietary changes are of direct influence on the myocardial response to sevoflurane in rats.

Chapter 5

Introduction Patients with obesity and type 2 diabetes mellitus (T2DM) due to excessive caloric intake may exert a different response to anesthesia and surgery than healthy subjects. In healthy subjects, volatile anesthetics like sevoflurane exhibit negative inotropic effects as shown by depressed myocardial contractility,1;2 lusitropic effects as reflected by early diastolic dysfunction1;3 and decreased systemic vascular resistance.3 While it may be expected that cardiometabolic alterations induced by obesity and/or diabetes mellitus alter the response of the heart to volatile anesthetics, most studies focusing on this relationship are limited by their in vitro nature and the use of models for type 1 diabetes mellitus. Moreover, the results are conflicting, showing either augmentation4 or suppression5 of the cardiodepressive effects of volatile anesthetics in papillary muscles of type 1 diabetic rats. A third study suggested that the inotropic effects of several volatile anesthetics were not altered in single ventricular myocytes from type 1 diabetic rats.6 These findings warrant further exploration of the effects of obesity and/or diabetes mellitus on the interaction of volatile anesthetics with the heart. Moreover, increasing evidence suggests that preoperative alterations in dietary composition and intake may alter the susceptibility of the cardiovascular system to surgical and anesthetic stress.7 It has indeed been shown that diet-induced obesity8-11 and T2DM12;13 in small rodents is reversible by reducing caloric intake, which resulted in weight loss and improved insulin sensitivity. In obese and T2DM patients, a low caloric diet decreased myocardial fatty acid uptake14 and improved diastolic function,15

respectively.

Additionally,

preoperative

dietary

restriction

exerted

favorable effects on surgery-related inflammation, oxidative stress and ischemia.7;16 It is however unknown whether the interaction of volatile anesthesia with myocardial function can be altered by dietary intake. In the present study we therefore investigated whether western diet-induced obesity with glucose intolerance alters the effects of the volatile anesthetic sevoflurane on myocardial function and calcium handling proteins in rats, and whether changing diet composition can modulate these alterations.

Dietary effects on the heart during sevoflurane

Methods Animals and experimental set-up All animal experiments were approved by the Institutional Animal Care and Use Committee of the VU University, and were conducted following the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes, and the guide for the Care and Use of Laboratory Animals. The performed research is in compliance with the modern ARRIVE guidelines on animal research.17 The first part of the study was performed in a group of 24 male Wistar rats (baseline body weight: 264±5 g; Charles River Laboratories, France). Rats were exposed to a western diet in combination with sucrose water (20%) (WD, n=16) or control diet (CD, n=8) for a period of 8 weeks. Four weeks after the start of the diet exposure, WD (n=8) exposed rats reversed to CD for 4 consecutive weeks. Rats were housed in a temperature-controlled room (20-23°C; 40-60% humidity) under a 12/12h light/dark cycle starting at 6.00 am. Body weight and caloric intake were determined on a weekly basis. After 4 and 8 weeks of diet exposure, rats underwent an oral glucose tolerance test and echocardiography. After a 6h fasting period, rats were sacrificed by decapitation, trunk blood was collected for plasma determinations and hearts were removed, rinsed in saline, weighted, snap-frozen in liquid nitrogen and stored at -80°C until further analysis. The second part of the study included 30 male Wistar rats (baseline body weight: 262±6 g; Charles River Laboratories, France) that were either exposed to the control diet (CD, n=10), western diet in combination with sucrose water (20%) (WD, n=10) or the western diet with reversal to control diet (REV, n=10) as described above. After 8 weeks, rats were exposed to sevoflurane (AbbVie, the Netherlands). Rats were sacrificed by decapitation without fasting, trunk blood was collected for plasma determinations and hearts were removed, rinsed in saline, weighted, snap-frozen in liquid nitrogen and stored at -80°C until further analysis. Diets Control diet (CD; Teklad 2016, Harlan, Horst, the Netherlands) consisted of 20 %kcal protein, 9 %kcal fat and 74 %kcal carbohydrates (1804 kcal/kg starch, 200 kcal/kg sugars), whereas western diet (WD; D12451, Research Diets, New Brunswick, NJ) consisted of 20 %kcal protein, 45 %kcal fat and 35 %kcal carbohydrates (291 kcal/kg starch, 691 kcal/kg sugars) with 20% sucrose water (800 kcal/kg), totally containing 3300 kcal/kg and 4857 kcal/kg for CD and WD with sucrose water, respectively.

Chapter 5

Oral glucose tolerance test Awake rats fasted overnight received an oral glucose load (2 g/kg of body weight). Blood glucose was measured from tail bleeds with a Precision Xceed Blood Glucose monitoring system (MediSense, UK) before and 15, 30, 60, 90 and 120 min after glucose ingestion. At similar time points, plasma insulin (LINCO research, St. Charles, Missouri) levels were measured as described previously.18;19 Echocardiography Echocardiography (ALOKA ProSound SSD 4000, Aloka, Tokyo, Japan) using a 13-MHz linear interfaced array transducer was performed after 4 and 8 weeks as described previously.18-21 Briefly, rats received S-Ketamine (Ketanest®, 75 mg/kg, Pfizer, the Netherlands) and diazepam (4 mg/kg, Centrafarm, the Netherlands) anesthesia intraperitoneally, allowed spontaneous respiration and placed on a underbody heating pad. Left ventricular (LV) dimensions during end-systole (ES) and enddiastole (ED) were determined in the M- (motion) mode of the parasternal short-axis view at the level of the papillary muscles. LV systolic function is represented by fractional shortening (FS) and fractional area change (FAC), which were calculated by the equations: FS = (EDD-(6' (''Ɗ DQG )$& (''2-ESD2)/EDD2Ɗ100). Diastolic function was measured in the apical four-chamber view and shown as E flow, E deceleration time and isovolumic relaxation time (IVRT; except 8 weeks data). LV mass was calculated as described previously.18 All parameters were averaged over at least three cardiac cycles. Analyses were performed off-line (Image-Arena

2.9.1,

TomTec

Imaging

Systems,

Unterschleissheim/Munich,

Germany). Sevoflurane intervention The second group of rats was anesthetized with 125 mg/kg S-ketamine (Ketanest®, Pfizer, the Netherlands) and 4 mg/kg diazepam (Centrafarm, the Netherlands) intraperitoneally and maintenance was performed with 40 mg/kg/h S-ketamine and 1 mg/kg/h diazepam intravenously in the tail vein and allowed spontaneous UHVSLUDWLRQ 5DWV Q SHU JURXS ZHUH H[SRVHG WR [ ¶ VHYRIOXUDQH (AbbVie, the Netherlands) in 40% O2/60% N2, whereas control rats received only 40% O2/60% N2 for the same time period (baseline, n=4). Measurement of systolic IXQFWLRQ GXULQJ VHYRIOXUDQH H[SRVXUH ZDV VWDUWHG DIWHU ¶ RI VHYRIOXUDQH DQG performed as described above.

Dietary effects on the heart during sevoflurane

Blood and plasma measurements Plasma hematocrit levels were determined using microcentrifugation. Plasma glucose levels (Abcam, Cambridge, MA), plasma insulin (LINCO research, St. Charles, Missouri), plasma free fatty acids (WAKO NEFA-HR, Wako Pure Chemical Industries, Osaka, Japan), plasma triglyceride (Sigma, Saint Louis, Missouri), and plasma HDL and LDL/VLDL cholesterol (Abcam, Cambridge, MA) levels were measured from trunk blood as described previously.18-21 Protein analysis LV tissues were homogenized to obtain cytoplasmic protein fractions for western blot analysis as previously described.18;20;21 Phosphorylation and/or expression of signaling intermediates were analyzed using the following primary antibodies: Akt, phospho-Akt-6HU JO\FRJHQ V\QWKDVH NLQDVH Ç&#x192; *6. Ç&#x192; SKRVSKR-*6. Ç&#x192;-Ser9, $03 DFWLYDWHG SURWHLQ NLQDVH ÄŽ $03.ÄŽ SKRVSKR-$03.ÄŽ-Thr172 (all Cell signaling Technology, Beverly, MA), pyruvate dehydrogenase kinase 4 (PDK4, Santa Cruz Biotechnology, Santa Cruz, CA), glucose transporter 4 (GLUT4; Abcam, Cambridge, MA), phospholamban (PLB), phospho-PLB-Ser16, (Upstate, Lake Placid, NY), sarcoplasmic reticulum calcium ATPase 2a (SERCA2a)21 and fatty acid transporter (FAT)/CD36 (MO25).18;21 All signals were normalized to total protein expression or actin (Sigma, Saint Louis, Missouri). Myofilament

protein phosphorylation was determined using Pro-Q Diamond

Phosphoprotein Stain as described previously.22 LV tissues were separated on gradient gels (Criterion tris-HCl 4-15% gel, BioRad) and proteins were stained with Pro-Q Diamond Phosphoprotein Stain. Subsequently gels were stained overnight with SYPRO Ruby stain (Molecular Probes). Phosphorylation status of myosin binding protein-C (MyBP-C), troponin T (TnT) and cardiac troponin I (cTnI) were expressed relative to SYPRO-stained protein bands to correct for differences in sample loading. Staining was visualized using the LAS-3000 Image Reader (FUJI; 460 nm/605 nm Ex/Em) and immunoblots were quantified by densitometric analysis of films (AIDA, 4.21.033, Raytest, Strau-benhardt Germany). Histology Sections (4 Îźm) of left ventricular tissue from the free wall at the level of the papillary muscles were cut in the direction of the fibers and mounted on 3aminopropyltriethoxisilane-coated slides (SuperfrostÂŽ Plus, Menzal, Darmstadt, Germany). After deparaffinization and rehydration, cardiomyocyte cross-sectional area was determined in randomly chosen fields of hematoxylin-eosin stained sections for 20-30 cells per heart and normalized to sarcomere length.18;20;21

Chapter 5

Statistical analysis Data were analyzed using Graphpad Prism 5.0 (La Jolla, USA) and are presented as meanÂąSD. Statistical analyses were performed using a student t-test after 4 weeks, one-way ANOVA with Bonferroni post-hoc analysis after 8 weeks, two-way ANOVA with repeated measures and Bonferroni post-hoc analysis for the oral glucose tolerance test and two-way ANOVA with Bonferroni post-hoc analysis for data after 8 weeks with sevoflurane intervention. p<0.05 was considered as statistically significant.

Dietary effects on the heart during sevoflurane

Results Animal model characteristics Western diet (WD) feeding resulted in a prediabetic phenotype with obesity, mild hyperglycemia, hyperinsulinemia, hyperlipidemia and glucose intolerance at 4 and 8 weeks after initiation of the diet (Table 5.1 and Figure 5.1 A-F). Reversion to a control diet (REV) after 4 weeks of western diet feeding resulted in normalization of caloric intake and body weight, and reversed the prediabetic phenotype in western diet-fed rats. Heart weight and the cross sectional area of individual cardiomyocytes were significantly increased in WD-fed rats compared to controls, and these values normalized after diet reversal. Additionally, diet reversion following western diet feeding resulted in a decrease in liver weight and epididymal and perirenal fat pads (Table 5.1). At 4 and 8 weeks, western diet feeding decreased myocardial lumen diameter and increased wall thickness during diastole when compared to control rats (Table 5.2). Moreover, end-systolic lumen diameter was increased at 4 and 8 weeks of western diet feeding, while systolic wall thickness was slightly reduced after 4 weeks of diet exposure. Reversal from western to control diet resulted in normalization of systolic lumen diameter and myocardial diastolic and systolic wall thickness, while the diastolic lumen diameter was not affected by lowering caloric intake (Table 5.2). Western diet feeding induced a reduction in myocardial fractional shortening (Figure 5.2A) and fractional area change (Figure 5.2B), which could be restored by diet reversal. While E flow was unchanged by WD-feeding, the deceleration time of the E peak and isovolumic relaxation time at 4 weeks were prolonged in rats fed a WD when compared to control rats (Table 5.2). After 8 weeks of diet exposure, there was a trend towards impaired left ventricular relaxation in WD-fed rats. Diet reversal improved diastolic function as shown by a shortening of the E deceleration time when compared to WD-fed rats (Table 5.2).

411±135 0.82±0.20 0.92±0.21 71.0±3.0 12.4±2.7 48.3±2.8

6h fasting plasma insulin (pmol/L)

6h fasting plasma free fatty acids (mmol/L)

6h fasting plasma triglycerides (mmol/L)

6h fasting plasma HDL cholesterol (mg/dL)

6h fasting plasma LDL/VLDL cholesterol (mg/dL)

Hematocrit (%)

n.d.

372±54

42.0±0.5

8.0±1.5

6.0±0.8

10.7±1.0

1.19±0.06

410±27

50.7±3.0

15.6±2.2

112.3±11.8

625±105 *

41.8±1.0

16.7±3.8 *

11.4±2.1 *

14.2±1.0 *

1.34±0.15 *

478±25 *

47.9±2.2 *

27.3±7.0 *

61.9±6.7 *

3.33±1.19 *

0.46±0.24 *

0.68±0.18

1524±353 *

0.26±0.10

10.7±1.1 *

129±7

Western diet

933±383

8.8±0.7

124±6

# #

17.8±2.7

389±53

41.4±1.0

9.5±1.8

7.3±1.5

11.3±2.0

1.28±0.06

432±30

49.0±1.3

108.9±11.6

0.78±0.27

0.26±0.11

813±369

8.2±1.2

Reversion 114±6

control diet,

p<0.05 vs. western diet. n.d., non determined.

Data are mean±SD, n=8-16, 4 weeks: student t-test, * p<0.05 vs. control diet, 8 weeks: one-way ANOVA with Bonferroni post-hoc test, * p<0.05 vs.

Cross sectional area (ǋP2) n.d.

n.d.

Tibia length (mm)

Heart composition

n.d.

Perirenal fat weight (g)

n.d.

n.d. n.d.

Liver weight (g)

Epidydimal fat weight (g)

n.d.

362±23 n.d.

Heart weight (g)

397±16 *

47.4±2.5

10.2±3.9

39.8±8.3 *

2.04±0.72 *

0.96±0.20

726±214 *

7.8±1.3

Bodyweight (g)

Body composition

7.1±0.6

155±17 *

Control diet

138±8

6h fasting plasma glucose (mmol/L)

Blood/plasma characteristics

Caloric intake (kcal/100gBW)

8 weeks Western diet

4 weeks Control diet

Table 5.1: Characteristics after 4 and 8 weeks of diet intervention without sevoflurane exposure

94 Chapter 5

Dietary effects on the heart during sevoflurane

Figure 5.1: Oral glucose tolerance test after 8 weeks of diet feeding without sevoflurane exposure Blood glucose (A, C), plasma insulin (B, D) and area under the curve (AUC; E, F) during an oral glucose tolerance test in rats after 4 and 8 weeks of control diet (CD), western diet (WD) or diet reversion (REV) feeding. Data are meanÂąSD, n=6, t-test, one- and two-way ANOVA with repeated measures and Bonferroni post-hoc analyses, * p<0.05 vs. CD, # p<0.05 vs. WD.

6.6±0.4 1.7±0.2 1.7±0.1 3.7±0.2

Diastolic lumen diameter (mm)

Systolic lumen diameter (mm)

Diastolic wall thickness (mm)

Systolic wall thickness (mm)

13.8±2.3

Isovolumic relaxation time (ms)

20.3±4.2 *

31.1±4.2 *

109.3±17.0

3.4±0.2 *

2.0±0.2 *

2.7±0.4 *

5.9±0.5 *

820±57

n.d.

24.5±2.4

98.3±17.3

3.7±0.1

1.7±0.1

2.0±0.3

6.7±0.4

868±118

443±31

Western diet

n.d.

29.1±5.1

110.9±10.9

3.6±0.1

2.3±0.2 *

2.6±0.4 *

6.0±0.5 *

955±87

491±16 *

n.d.

23.4±6.3

115.0±9.5

3.8±0.2

1.9±0.2

1.7±0.3

6.1±0.5

805±62

Reversion 474±16

vs. control diet,

p<0.05 vs. western diet. LV, left ventricular.

Data are mean±SD, n=6-10, 4 weeks: student t-test, * p<0.05 vs. control diet, 8 weeks: one-way ANOVA with Bonferroni post-hoc analyses, * p<0.05

99.8±15.5 23.9±7.4

E flow (cm/s)

E deceleration time (ms)

LV diastolic function

LV dimensions

786±95

LV mass (mg)

488±23

Control diet

465±36

Heart rate (bpm)

8 weeks Western diet

4 weeks Control diet

Table 5.2: Myocardial function after 4 and 8 weeks of diet intervention without sevoflurane exposure

96 Chapter 5

Dietary effects on the heart during sevoflurane

Sevoflurane-induced cardiodepression is only present in western diet-fed rats Exposure to sevoflurane did not alter plasma levels of glucose, insulin, free fatty acids, triglycerides, LDL/VLDL cholesterol and HDL cholesterol in all 3 diet groups (Figure

5.3A-F).

After

weeks

diet

exposure,

sevoflurane

exerted

cardiodepressive effects in control rats as indicated by maintained factional shortening and fractional area change. However, in rats fed a western diet, sevoflurane induced an additional reduction in myocardial contractility, and reducing caloric intake could restore this (Figure 5.2C and D). These findings suggest that diet composition and/or the cardiometabolic phenotype of the rat modulate the interaction of sevoflurane with myocardial function.

Figure 5.2: Systolic function after diet feeding with and without sevoflurane exposure Fractional shortening (A) and fractional area change (B) in rats after 4 and 8 weeks of control diet (CD), western diet (WD) or diet reversion (REV) feeding. Fractional shortening (C) and fractional area change (D) during baseline and sevoflurane in rats after 8 weeks of control diet (CD), western diet (WD) or diet reversion (REV) feeding. Data are meanÂąSD, n=4-6, two-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 vs. CD,

p<0.05 vs. WD,

p<0.05 vs. baseline.

Chapter 5

Figure 5.3: Plasma levels after sevoflurane exposure Plasma glucose (A), insulin (B), free fatty acid (C), triglyceride (D), LDL/VLDL cholesterol (E) and HDL cholesterol (F) levels during baseline and sevoflurane in rats after 8 weeks of control diet (CD), western diet (WD) or diet reversion (REV) feeding. Data are meanÂąSD, n=4-6, two-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 vs. CD, # p<0.05 vs. WD.

Dietary effects on the heart during sevoflurane

Sevoflurane induced molecular alterations Figure 5.4 shows the effects of sevoflurane and type of diet on phosphorylation OHYHOV RI SURWHLQV DVVRFLDWHG ZLWK LQVXOLQ VLJQDOLQJ $NW SDQHO $ *6. Ç&#x192; SDQHO % $03.ÄŽ SDQHO &

SURWHLQ H[SUHVVLRQ OHYHOV RI WKH JOXFRVH WUDQVSRUWHU */87 SDQHO D) and the phosphorylation of two proteins involved in myocardial calcium handling (PLB (panel E) and cTnI (panel F)). The absent effect of sevoflurane exposure on myocardial function in control animals ZDV DVVRFLDWHG ZLWK PDLQWDLQHG OHYHOV RI SKRVSKRU\ODWHG *6. Ç&#x192; ZKLOH $NW DQG $03.ÄŽ SKRVSKRU\ODWLRQ WHQGHG WR LQFUHDVH E\ VHYRIOXUDQH 6HYRIOXUDQH GLG QRW DOWHU protein expression of GLUT4, phospholamban or cTnI. Sevoflurane did not alter SERCA2a protein expression or phosphorylation of myosin binding protein-C and troponin T (data not shown). &RPSDUHG WR FRQWURO DQLPDOV ZHVWHUQ GLHW LQFUHDVHG *6. Ç&#x192; SKRVSKRU\ODWLRQ (p=0.05), which tended to reduce towards control levels after diet reversion. Akt and $03.ÄŽ SKRVSKRU\ODWLRQ DQG */87 SURWHLQ H[SUHVVLRQ UHPDLQHG XQFKDQJHG GXULQJ western

diet-IHHGLQJ

6HYRIOXUDQH

WHQGHG

LQFUHDVH

$NW

DQG

$03.ÄŽ

phosphorylation in control rats compared to baseline, which was blunted in western diet-fed rats and restored after diet reversal, however, these alterations failed to reach statistical significance (Figure 5.4A and 4C). Sevoflurane induced a nonVLJQLILFDQW UHGXFWLRQ LQ *6. Ç&#x192; SKRVSKRU\ODWLon in western diet-fed rats only. WD-feeding significantly increased phosphorylation of phospholamban (PLB) and increased phosphorylation of cardiac troponin I (cTnI). PLB phosphorylation was normalized after diet reversal, while cTnI phosphorylation was still high in the diet reversal group. Compared to baseline, sevoflurane significantly reduced PLB phosphorylation in WD-fed rats, which was restored after diet reversal. Sevoflurane also significantly reduced phosphorylation of cTnI in WD-fed rats (p=0.05), and a similar pattern was observed in the diet reversion group (Figure 5.4F). Diet or sevoflurane did not alter SERCA2a protein expression or phosphorylation of myosin binding protein-C and troponin T after western diet exposure (data not shown).

100

Chapter 5

R EV

Akt-Ser473p

R EV

G SK3Č&#x2022;-Ser9p

Akt

G SK3Č&#x2022; b

R EV

G LU T4

AM PKÄŽ-Thr172p

Actin

AM PKÄŽ b

R EV

PLB-Ser16p

R EV

cTnI-p

PLB

cTnI b

Figure 5.4: Molecular alterations in substrate metabolism and calcium handling after sevoflurane exposure Phosphorylation of Akt (A), glycogen synthase kinase 3Ç&#x192; *6. Ç&#x192; B), AMP activated protein kinase ÄŽ $03.ÄŽ C), protein expression of glucose transporter 4 (GLUT4, D), phosphorylation of phospholamban (PLB, E) and Pro-Q Diamond Phosphoprotein Stain determined cardiac troponin I (cTnI, F) during baseline and sevoflurane in rats after 8 weeks of control diet (CD), western diet (WD) or diet reversion (REV) feeding. Data are meanÂąSD, n=4-6, two-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 vs. CD,

p<0.05 vs. WD, $ p<0.05 vs. baseline.

Dietary effects on the heart during sevoflurane

101

Discussion Sevoflurane exerts cardiodepressive properties in healthy subjects, therefore its perioperative use may lead to hemodynamic alterations. Although it has been suggested that the interaction of sevoflurane with the heart is additionally altered by cardiometabolic

diseases,

most

available

studies

are

restricted

vitro

observations and experimental models for type I diabetes mellitus. With the growing epidemic of obesity and type 2 diabetes mellitus it might be interesting to understand the influence of this condition on the interaction of sevoflurane with myocardial function. Unexpectedly, in an experimental rat model we could not show a direct effect of sevoflurane on myocardial contractility. However, in western diet-induced obesity, which was accompanied by glucose intolerance, hyperglycemia, hyperinsulinemia, dyslipidemia and myocardial dysfunction, sevoflurane exerted cardiodepressive effects. Interestingly, lowering caloric intake following western diet exposure could reverse these effects of sevoflurane on myocardial function. These results suggest that

sevoflurane

has

negative

inotropic

effects

myocardial

function

metabolically altered hearts, and that a reduction of caloric intake may improve the effects of sevoflurane on myocardial function. Our results therefore implicate that diet modification may be explored as an intervention to preserve perioperative myocardial function in subjects with cardiometabolic disease. The present study showed that western diet feeding resulted in a prediabetic phenotype accompanied by myocardial dysfunction. Our results confirm previous findings showing impaired systolic function after 8 weeks of diet feeding.18 Interestingly, the present study showed that lowering caloric intake completely normalized diet-induced T2DM. In small rodents, reducing dietary intake has been shown to reverse diet-induced obesity8-11 and T2DM.12;13 However, it is also shown that diet-induced obesity was not reversed by withdrawal of an energy dense diet.23;24 Importantly, our study showed that lowering caloric intake also improved diet-induced systolic as well as diastolic dysfunction, which is in agreement with the clinical observation that in obese and T2DM patients a low caloric diet decreased myocardial fatty acid uptake14 and improved diastolic function,15 respectively. Taken together, lowering caloric intake normalized the prediabetic phenotype induced by short-term western diet feeding and improved myocardial function. Exposure

sevoflurane

further

impaired

systolic

function

diet-induced

prediabetes, but not in healthy rats. In contrast, sevoflurane caused a reduction in left ventricular systolic function at concentrations of 2% and higher compared to isoflurane in healthy mice.25 An important difference with previous findings is that in the present study all rats were primary sedated with S-ketamine and diazepam. As S-ketamine and diazepam may have intrinsic cardiodepressive effects,26;27 this might

102

Chapter 5

have blurred the additional effect of sevoflurane on the heart in control animals. Limited data are available on the effects of sevoflurane in metabolic altered hearts. In papillary muscles from type 1 diabetic rats, decreased sensitivity to the negative inotropic interaction of halothane, enflurane and isoflurane was found,5 whereas sevoflurane resulted in greater negative inotropic effects compared to controls.4 In contrast, it has been shown that in single ventricular myocytes from type 1 diabetic rats the inotropic effects of halothane, isoflurane, desflurane and sevoflurane were not altered compared to controls.6 As far as we know we are the first to show the negative inotropic effects of sevoflurane on hearts of diet-induced prediabetic rats. A suggested underlying mechanism in the effect of sevoflurane on myocardial function is substrate availability and metabolism,28 which is known to be altered by T2DM.18;20;21 Unexpectedly, sevoflurane did not affect plasma glucose, insulin and lipid levels. In humans, there is indirect evidence that volatile anesthesia increases blood glucose; however, these observations may be biased by confounding factors such as surgical stress.29 Compared to non-anesthetized rats without surgical stress, sevoflurane increased plasma glucose levels, but not plasma insulin levels.30 It is possible that glucose levels did not increase in the present study due to short duration and low concentration of sevoflurane used, but also differences in nutritional status may exist. Moreover, in the present study rats were sedated with S-ketamine and diazepam. Ketamine31 and diazepam32 are known to increase blood glucose levels, which could have abolished the additional effect of sevoflurane on blood glucose levels. Sevoflurane may also affect proteins related to myocardial substrate metabolism. Akt, which regulates translocation of glucose transporter 4 (GLUT4) to the sarcolemma for glucose uptake, is increased during sevoflurane in the isolated ischemic rat heart.33 Moreover, sevoflurane enhances GLUT4 expression in lipid rafts, increases glucose oxidation and decreases fatty acid oxidation after ischemia and reperfusion injury in isolated working rat hearts.34 Although not in ischemic and reperfused hearts, the present study showed no significant differences in proteins related to myocardial substrate metabolism. Another possible mechanism is altered calcium handling, which also seems a common target in T2DM and sevoflurane. Sevoflurane reduces myocardial calcium availability, but increases sarcoplasmic reticulum calcium content.35 In contrast, sevoflurane decreased fractional calcium release, but maintained sarcoplasmic reticulum calcium content.36 In papillary muscles of type 1 diabetic rats, sevoflurane decreased myofilament calcium sensitivity to a greater extent than control rats.4 In the present study, western diet feeding blunted phosphorylation of phospholamban and cardiac troponin I during sevoflurane, but not SERCA2a protein expression. In preconditioned hearts, phosphorylation of phospholamban and SERCA2a protein expression were unaltered after ischemia and reperfusion injury;37 however, no data were reported for non-ischemic hearts. Our data indicate that phospholamban and

Dietary effects on the heart during sevoflurane

103

cardiac troponin I might play a role in impaired systolic function in prediabetic rats during sevoflurane. In conclusion, sevoflurane induced cardiodepression in prediabetic rats, whereas lowering caloric intake restored myocardial function during sevoflurane. These results suggest that a change in dietary intake could be a potential intervention to support the preservation of myocardial function during sevoflurane in subjects with obesity and type 2 diabetes mellitus.

104

Chapter 5

References 1. Harkin CP, Pagel PS, Kersten JR, Hettrick DA, Warltier DC: Direct negative inotropic and lusitropic effects of sevoflurane. Anesthesiology 1994, 81:156-167. 2. Pagel PS, Kampine JP, Schmeling WT, Warltier DC: Influence of volatile anesthetics on myocardial contractility in vivo: desflurane versus isoflurane. Anesthesiology 1991, 74:900-907. 3. Malan TP, Jr., DiNardo JA, Isner RJ, Frink EJ, Jr., Goldberg M, Fenster PE, Brown EA, Depa R, Hammond LC, Mata H: Cardiovascular effects of sevoflurane compared with those of isoflurane in volunteers. Anesthesiology 1995, 83:918-928. 4. David JS, Tavernier B, Amour J, Vivien B, Coriat P, Riou B: Myocardial effects of halothane and sevoflurane in diabetic rats. Anesthesiology 2004, 100:1179-1187. 5. Hattori Y, Azuma M, Gotoh Y, Kanno M: Negative inotropic effects of halothane, enflurane, and isoflurane in papillary muscles from diabetic rats. Anesth Analg 1987, 66:23-28. 6. Graham M, Qureshi A, Noueihed R, Harrison S, Howarth FC: Effects of halothane, isoflurane, sevoflurane and desflurane on contraction of ventricular myocytes from streptozotocin-induced diabetic rats. Mol Cell Biochem 2004, 261:209-215. 7. Mitchell JR, Beckman JA, Nguyen LL, Ozaki CK: Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery 2013, 153:594-598. 8. Hill JO, Dorton J, Sykes MN, DiGirolamo M: Reversal of dietary obesity is influenced by its duration and severity. Int J Obes 1989, 13:711-722. 9. Rogers PJ: Returning 'cafeteria-fed' rats to a chow diet: negative contrast and effects of obesity on feeding behaviour. Physiol Behav 1985, 35:493-499. 10.Bartness TJ, Polk DR, McGriff WR, Youngstrom TG, DiGirolamo M: Reversal of high-fat dietinduced obesity in female rats. Am J Physiol 1992, 263:R790-R797. 11.Walks D, Lavau M, Presta E, Yang MU, Bjorntorp P: Refeeding after fasting in the rat: effects of dietary-induced obesity on energy balance regulation. Am J Clin Nutr 1983, 37:387-395. 12.Parekh PI, Petro AE, Tiller JM, Feinglos MN, Surwit RS: Reversal of diet-induced obesity and diabetes in C57BL/6J mice. Metabolism 1998, 47:1089-1096. 13.Harris RB, Martin RJ: Changes in lipogenesis and lipolysis associated with recovery from reversible obesity in mature female rats. Proc Soc Exp Biol Med 1989, 191:82-89. 14.Viljanen AP, Karmi A, Borra R, Parkka JP, Lepomaki V, Parkkola R, Lautamaki R, Jarvisalo M, Taittonen M, Ronnemaa T, Iozzo P, Knuuti J, Nuutila P, Raitakari OT: Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults. Am J Cardiol 2009, 103:1721-1726. 15.Hammer S, Snel M, Lamb HJ, Jazet IM, van der Meer RW, Pijl H, Meinders EA, Romijn JA, de Roos A, Smit JW: Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. J Am Coll Cardiol 2008, 52:1006-1012. 16.Mitchell JR, Verweij M, Brand K, van d, V, Goemaere N, van den Engel S, Chu T, Forrer F, Muller C, de JM, van IW, IJzermans JN, Hoeijmakers JH, de Bruin RW: Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell 2010, 9:40-53. 17.Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010, 8:e1000412. 18.Ouwens DM, Diamant M, Fodor M, Habets DD, Pelsers MM, El Hasnaoui M, Dang ZC, van den Brom CE, Vlasblom R, Rietdijk A, Boer C, Coort SL, Glatz JF, Luiken JJ: Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36mediated fatty acid uptake and esterification. Diabetologia 2007, 50:1938-1948.

Dietary effects on the heart during sevoflurane

105

19.van den Brom CE, Bulte CS, Kloeze BM, Loer SA, Boer C, Bouwman RA: High fat diet-induced glucose

intolerance

impairs

myocardial

function,

but

not

myocardial

perfusion

during

hyperaemia: a pilot study. Cardiovasc Diabetol 2012, 11:74. 20.van den Brom CE, Bosmans JW, Vlasblom R, Handoko ML, Huisman MC, Lubberink M, Molthoff CF, Lammertsma AA, Ouwens DM, Diamant M, Boer C: Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle. Cardiovasc Diabetol 2010, 9:25. 21.van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, Van der Velden J, Boer C, Ouwens DM, Diamant M: Altered myocardial substrate

metabolism

associated

with

myocardial

dysfunction

early

diabetic

cardiomyopathy in rats: studies using positron emission tomography. Cardiovasc Diabetol 2009, 8:39. 22.Zaremba R, Merkus D, Hamdani N, Lamers JML, Paulus WJ, Remedios C, Duncker DJ, Stienen GJM, Van der Velden J: Quantitative analysis of myofilament protein phosphorylation in small cardiac biopsies. proteomics Clin Appl 2007, 1:1285-1290. 23.Llado I, Proenza AM, Serra F, Palou A, Pons A: Dietary-induced permanent changes in brown and white adipose tissue composition in rats. Int J Obes 1991, 15:415-419. 24.Rolls BJ, Rowe EA, Turner RC: Persistent obesity in rats following a period of consumption of a mixed, high energy diet. J Physiol 1980, 298:415-427. 25.Gentry-Smetana S, Redford D, Moore D, Larson DF: Direct effects of volatile anesthetics on cardiac function. Perfusion 2008, 23:43-47. 26.Plante E, Lachance D, Roussel E, Drolet MC, Arsenault M, Couet J: Impact of anesthesia on echocardiographic evaluation of systolic and diastolic function in rats. J Am Soc Echocardiogr 2006, 19:1520-1525. 27.Stein AB, Tiwari S, Thomas P, Hunt G, Levent C, Stoddard MF, Tang XL, Bolli R, Dawn B: Effects of anesthesia on echocardiographic assessment of left ventricular structure and function in rats. Basic Res Cardiol 2007, 102:28-41. 28.van den Brom CE, Bulte CSE, Loer SA, Bouwman RA, Boer C: Diabetes, perioperative ischaemia and volatile anaesthetics: Consequences of derangements in myocardial substrate metabolism. Cardiovasc Diabetol 2013, In press. 29.Lattermann R, Schricker T, Wachter U, Georgieff M, Goertz A: Understanding the mechanisms by which isoflurane modifies the hyperglycemic response to surgery. Anesth Analg 2001, 93:121-127. 30.Zuurbier CJ, Keijzers PJ, Koeman A, Van Wezel HB, Hollmann MW: Anesthesia's effects on plasma glucose and insulin and cardiac hexokinase at similar hemodynamics and without major surgical stress in fed rats. Anesth Analg 2008, 106:135-42. 31.Saha JK, Xia J, Grondin JM, Engle SK, Jakubowski JA: Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models. Exp Biol Med (Maywood ) 2005, 230:777-784. 32.Yamada J, Sugimoto Y, Noma T: Involvement of adrenaline in diazepam-induced hyperglycemia in mice. Life Sci 2000, 66:1213-1221. 33.Yao Y, Li L, Li L, Gao C, Shi C: Sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by activation of pro-survival kinases and inhibition of mitochondrial permeability transition pore opening upon reperfusion. Biol Pharm Bull 2009, 32:1854-1861. 34.Lucchinetti E, Wang L, Ko KW, Troxler H, Hersberger M, Zhang L, Omar MA, Lopaschuk GD, Clanachan AS, Zaugg M: Enhanced glucose uptake via GLUT4 fuels recovery from calcium overload after ischaemia-reperfusion injury in sevoflurane- but not propofol-treated hearts. Br J Anaesth 2011, 106:792-800.

106

Chapter 5

35.Hannon JD, Cody MJ: Effects of volatile anesthetics on sarcolemmal calcium transport and sarcoplasmic reticulum calcium content in isolated myocytes. Anesthesiology 2002, 96:14571464. 36.Davies LA, Gibson CN, Boyett MR, Hopkins PM, Harrison SM: Effects of isoflurane, sevoflurane, and halothane on myofilament Ca2+ sensitivity and sarcoplasmic reticulum Ca2+ release in rat ventricular myocytes. Anesthesiology 2000, 93:1034-1044. 37.An J, Rhodes SS, Jiang MT, Bosnjak ZJ, Tian M, Stowe DF: Anesthetic preconditioning enhances Ca2+ handling and mechanical and metabolic function elicited by Na+-Ca2+ exchange inhibition in isolated hearts. Anesthesiology 2006, 105:541-549.

6 Western diet modulates the susceptibility of the heart to ischemic injury and sevoflurane-induced cardioprotection in rats CE van den Brom, C Boer, RPF van den Akker, SA Loer, RA Bouwman

Effect of diet and sevoflurane on ischemic injury

111

Abstract Introduction Sevoflurane is known for its cardioprotective effects during myocardial ischemia and reperfusion, which however seems blunted in the presence of type 2 diabetes mellitus. In this study we investigated whether a reduction in caloric intake reverses the impact of western diet on the cardioprotective potency of sevoflurane in rats subjected to ischemic injury. Methods Male Wistar rats were exposed to a western diet (WD) or control diet (CD). A third group of WD fed rats reversed after four weeks to CD for 4 consecutive weeks. After 8 weeks, rats underwent 40 minutes of coronary occlusion followed by 120 minutes of reperfusion with or without 3x 5 min sevoflurane (2 vol%) preconditioning. An extra group of CD-fed rats underwent myocardial infarction during hyperinsulinemic euglycemic clamping. Results WD feeding resulted in a prediabetic phenotype with obesity and hyperinsulinemia. Sevoflurane exerted cardioprotective effects in control rats, resulting in a reduction of infarct size by 59% (p<0.001). Unexpectedly, WD feeding itself reduced infarct size by 43% (p<0.05) compared to control rats, while sevoflurane even enlarged infarct size in WD fed rats (31%, p<0.05). Reversion of WD to CD resulted in normalization of obesity and hyperinsulinemia, but did not affect infarct size and the protective effect of sevoflurane when compared to WD-fed rats. Interestingly, sevoflurane prior to myocardial infarction tended to increase insulin levels in control rats, while sevoflurane exposure in WD-fed rats undergoing myocardial infarction resulted in a decrease of plasma insulin levels. Our data suggested that the protective effects of diet feeding may be mediated by insulin. Indeed, exposure of rats to a hyperinsulinemic intervention also reduced infarct size after myocardial ischemia. Conclusion Unexpectedly, western diet itself had a protective effect against ischemic injury, and lowering caloric intake did not alter this effect. Sevoflurane anesthesia exerted cardioprotective effects in control rats, but this effect was blunted in prediabetic rats. Our data further suggest that the protective effects of sevoflurane in control rats or western diet are mediated by insulin.

112

Chapter 6

Introduction Cardiometabolic alterations due to excessive dietary intake, insulin resistance and type 2 diabetes mellitus (T2DM) increase the risk for perioperative myocardial ischemia.1 In particular, patients with T2DM are more likely to develop coronary artery disease and myocardial ischemia2 and have an increased cardiovascular complication rate after major non-cardiac surgery.3 The

volatile

anesthetic

sevoflurane

perioperative preservation of the heart.

exerts 4;5

protective

effects

that

enhance

We previously showed that sevoflurane

reduced the impact of ischemic myocardial injury.6;7 However, there is growing evidence that these cardioprotective properties are blunted in case of obesity and/or T2DM. Sevoflurane-induced postconditioning was blocked in hyperglycemic8 and obese/insulin resistant Zucker rats9 after myocardial ischemia and reperfusion. Moreover,

obesity

suppressed

sevoflurane

preconditioning-induced

cardioprotection.10 Preoperative lifestyle interventions such as lowering caloric intake to induce weight loss and improve insulin sensitivity may be an attractive approach to improve perioperative myocardial function in obese or diabetic subjects. We previously showed that lowering caloric intake restored the cardiodepressive effects of sevoflurane in western diet-induced prediabetic rats (van den Brom et al., unpublished results). This suggests that the myocardial response to sevoflurane depends on the cardiometabolic state that may be altered by changes in dietary intake. It remains unknown whether these beneficial effects of caloric restriction also affect the cardioprotective effect of sevoflurane in the cardiometabolic altered heart. In this study we investigated whether reversal of western diet-induced prediabetes by caloric restriction restores the cardioprotective potency of sevoflurane in rats subjected to ischemic injury.

Effect of diet and sevoflurane on ischemic injury

113

Material and methods Animals and experimental set-up All animal experiments were approved by the Institutional Animal Care and Use Committee of the VU University, and were conducted following the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes, and the guide for the Care and Use of Laboratory Animals. The first part of the study was performed in male Wistar rats (n=144, baseline body weight: 263±1 g; Charles River). Rats were exposed to a western diet in combination with sucrose water (20%) (WD, n=98) or control diet (CD, n=46) for a period of 8 weeks. Four weeks after the start of diet exposure, 48 WD-fed rats reversed to CD for 4 weeks (Figure 6.1A). Rats were housed in a temperature-controlled room (20-23°C; 40-60% humidity) under a 12/12h light/dark cycle starting at 6.00 am. Body weight was determined on a weekly basis. After 8 weeks of diet exposure, rats underwent myocardial infarction. The second part of the study included 14 male Wistar rats (263±3 g) that were exposed to control diet. After 8 weeks, these rats underwent a myocardial infarction during hyperinsulinemia. After sacrifice, arterial blood was collected for plasma determinations and hearts were removed and stored at -20°C until further analysis. Diets Control diet (Teklad 2016, Harlan, Horst, the Netherlands) consisted of 20 %kcal protein, 9 %kcal fat and 74 %kcal carbohydrates (1804 kcal/kg starch, 200 kcal/kg sugars), whereas western diet (D12451, Research Diets, New Brunswick, NJ) consisted of 20 %kcal protein, 45 %kcal fat and 35 %kcal carbohydrates (291 kcal/kg starch, 691 kcal/kg sugars) with 20% sucrose water (800 kcal/kg), totally containing 3300 kcal/kg and 4857 kcal/kg for CD and WD with sucrose water, respectively. Surgery After 8 weeks of diet exposure, rats were anesthetized with 125 mg/kg S-ketamine (Ketanest®, Pfizer, the Netherlands) and 4 mg/kg diazepam (Centrafarm, the Netherlands) intraperitoneally and were intubated and mechanically ventilated (UNO, the Netherlands; positive end-expiratory pressure, 1-2 cm H2O; respiratory rate, ~65 breaths/min; tidal volume, ~10 ml/kg) with oxygen-enriched air (40% O2/60% N2). Anesthesia was maintained by continuous infusion of 40 mg/kg/h S-ketamine and 1 mg/kg/h diazepam intravenously via the tail vein or the right jugular vein. The respiratory rate was adjusted to maintain pH and carbon dioxide within physiological limits. Body temperature was maintained stabile (37.1±0.05°C) by using a warm water underbody heating pad.

114

Chapter 6

The left carotid artery was cannulated for blood sampling for blood gas analyses (ABL50, radiometer, Copenhagen, Denmark) and for measurements of arterial blood pressure (Safedraw Transducer Blood Sampling Set, Argon Medical Devices, Texas, USA). Arterial blood pressure, ECG and heart rate were continuously recorded using PowerLab software (PowerLab 8/35, Chart 7.0; ADInstruments Pty, Ltd., Castle Hill, Australia). Mean arterial blood pressure was calculated according the following formula: 2/3*diastolic blood pressure + 1/3* systolic blood pressure. Myocardial infarction Left thoracotomy was performed between the fourth and fifth rib. A ligature (Prolene® 6-0; Ethicon LLC, San Lorenzo, Puerto Rico) was placed around the left anterior descending coronary artery (LAD) with a special ligation device that allowed to pull the suture in one simple movement in order to reduce the chance of preconditioning.11 Successful coronary occlusion was verified by ECG changes and ischemia was maintained for 40 min and followed by 120 min of reperfusion (MI) (Figure 6.1B). Rats in the control (CON) group received a sham surgery were the LAD was not occluded. Sevoflurane (AbbVie, the Netherlands) intervention was induced before ischemia and reperfusion by three periods of 5 minutes exposure to 2% (v/v) sevoflurane, interspersed with washout periods of 5 minutes (MI+SEVO). In total, n=144 rats were included, from which n=122 rats survived the surgery (84.7 %). Per diet group the survival rate was 87.0 %, 80.0 % and 85.4 % for CD-, WD- and REV-fed rats, respectively. Hyperinsulinemic euglycemic clamp Rats in the second part of the study were subjected to the same ischemia and reperfusion protocol during a hyperinsulinemic euglycemic clamp. In total, n=14 rats were included, from which n=11 rats survived the surgery (78.6 %). Surgery was performed similarly as described above; only anesthesia was infused intravenously via the femoral vein due to blood glucose measurements via the tail vein. The hyperinsulinemic euglycemic clamp was initiated by 3 minutes insulin priming at an infusion rate of 120 mU/kg/min (Novorapid®, Novo Nordisk, Denmark), followed by constant infusion of insulin at a rate of 12 mU/kg/min via the jugular vein as described before.12 Blood glucose was measured every 5 minutes from tail bleeds with a Precision Xceed Blood Glucose monitoring system (MediSense, UK). Simultaneously, a 20% glucose solution was infused at a variable rate to maintain euglycemia. After ± 90 minutes, glucose disposal rate (M-value, mg/kg/min) was calculated as the average glucose infusion rate during 30 minutes. To prove hyperinsulinemia, plasma insulin levels were determined during the steady state, ischemia and reperfusion phase. The M/I index, which is a measure for insulin sensitivity, was calculated by the amount of glucose metabolized per unit of plasma insulin.

Effect of diet and sevoflurane on ischemic injury

115

6 Figure 6.1: Experimental protocol A) Rats were fed a control diet (CD) or western diet with sucrose water (WD) for 8 weeks. A third group of WD fed rats reversed after 4 weeks to CD for 4 consecutive weeks (REV). B) After 8 weeks of diet exposure, animals underwent left coronary artery occlusion for 40 min followed by 120 min of reperfusion without (MI) or with 3x 5 min sevoflurane (s) exposure (MI+SEVO). C) After 8 weeks of exposure to CD, animals underwent left coronary artery occlusion for 40 min followed by 120 min of reperfusion during hyperinsulinemia (MI+INS).

116

Chapter 6

Evans blue and TTC staining After 120 min of reperfusion, the hearts were excised and the aorta was cannulated. The LAD was re-occluded and 0.2 % Evans Blue (Sigma, St. louis, MO) was infused to stain the non-ischemic myocardium and leaving the area at risk unstained. After rinsing with 0.9% NaCl, hearts were stored at -20°C. For determination of infarct size, frozen hearts were cut in slices of 1 mm, incubated for 15 min in 2,3,5-triphenyl tetrazolium chloride (TTC; Sigma, St. Louis, MO) solution at 37°C, followed by fixation in 4% formaldehyde (Klinipath, Duiven, the Netherlands). Slices were scanned and the area at risk and infarct size were determined in each slice using ImageJ (1.42q, National Institue of Health). The infarct size is presented as the percentage of the area at risk. Plasma measurements Plasma glucose (Abcam, Cambridge, MA), insulin (Millipore, St. Charles, MO), free fatty acid (WAKO NEFA-HR, Wako Pure Chemical Industries, Osaka, Japan), triglyceride (TG; Sigma, St. Louis, MO) and HDL and LDL/VLDL cholesterol (Abcam, Cambridge, MA) levels were measured from arterial blood as described previously.1215

Statistical analysis Data were analyzed using Graphpad Prism 5.0 (La Jolla, USA) and presented as mean±SD. Statistical analyses

were performed

using

one-way

ANOVA with

Bonferroni post-hoc analysis and two-way ANOVA with Bonferroni post-hoc analysis (with repeated measurements) for additional interventions, where p<0.05 was considered as statistically significant.

Effect of diet and sevoflurane on ischemic injury

117

Results Lowering caloric intake normalized obesity and hyperinsulinemia After 8 weeks of western diet (WD) feeding, bodyweight and plasma insulin were significantly increased compared to control diet (CD)-fed rats (Table 6.1). Plasma glucose, triglycerides and free fatty acids tended to increase, whereas HDL cholesterol tended to decrease in WD- compared to CD-fed rats (Table 6.1). LDL/VLDL cholesterol remained unchanged (Table 6.1). Diastolic blood pressure, systolic blood pressure, mean arterial pressure and heart rate were similar among groups (Table 6.1). Reversion to control diet resulted in normalized bodyweight and plasma levels of insulin, triglycerides and HDL cholesterol when compared to WD-fed rats (Table 6.1). Table 6.1: Characteristics of rats after 8 weeks of diet feeding Control diet

Western diet

Reversion

Bodyweight (g)

421±22

450±27 *

431±26

Plasma insulin (pmol/L)

1274±621

2165±856 *

1006±559

Plasma glucose (mmol/L)

12.9±5.7

16.9±9.9

11.0±3.5

Plasma free fatty acids (mmol/L)

0.19±0.09

0.24±0.19

0.18±0.10

Plasma triglycerides (mmol/L)

1.76±0.66

2.23±0.70

1.46±0.44

Plasma HDL cholesterol (mg/dL)

49.4±18.2

38.5±10.5

63.5±7.7

Plasma LDL/VLDL cholesterol (mg/dL)

29.7±5.6

28.0±3.9

25.5±4.4

Systolic blood pressure (mmHg)

152±44

150±22

172±27

Diastolic blood pressure (mmHg)

110±39

111±23

130±18

Mean arterial pressure (mmHg)

124±40

124±22

144±21

Heart rate (bpm)

414±32

381±29

397±39

Data are mean±SD, n=5-11, two-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 vs. control diet,

p<0.05 vs. western diet.

Western diet feeding reduces myocardial ischemic injury The area at risk after ischemia and reperfusion did not differ between groups (Figure 6.2A). Unexpectedly, WD-feeding reduced infarct size compared to control rats (Figure 6.2B). Interestingly, these protective effects of western diet feeding on ischemic injury persisted after lowering caloric intake following 4 weeks of WDfeeding (REV group) (Figure 6.2B). Myocardial ischemia did not affect blood pressure and heart rate in all diet groups (Figure 6.3A, C, E, G). During the reperfusion phase, diastolic blood pressure and mean arterial pressure were only significantly reduced in rats that underwent diet reversal (Figure 6.3B, D, F, H).

118

Chapter 6

Figure 6.2: Myocardial ischemia and reperfusion injury Area at risk (A), infarct size (B) and plasma insulin levels (C) after sham (CON), myocardial infarction (MI) and myocardial infarction with sevoflurane (MI+SEVO) in rats after 8 weeks of control diet (CD), western diet (WD) or reversion diet (REV) feeding. Data are meanÂąSD, n=5-11, two-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 diet effect, HIIHFW S GLHW DQG VHYRIOXUDQH HIIHFW Ă S 0, HIIHFW

p<0.05 sevoflurane

Effect of diet and sevoflurane on ischemic injury

119

Figure 6.3: Hemodynamics during myocardial ischemia and reperfusion Systolic blood pressure (A,B), diastolic blood pressure (C, D), mean arterial pressure (E, F) and heart rate (G, H) after 40 minutes of ischemia (A, C, E, G) or 120 minutes of reperfusion (B, D, F, H) in rats fed a control diet (CD), western diet (WD) or reversion diet (REV) for 8 weeks. Data are meanÂąSD, one-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 MI effect. CON, sham; MI, myocardial infarction.

120

Chapter 6

Sevoflurane reduces ischemic injury in control rats Sevoflurane-induced preconditioning reduced infarct size in CD-fed rats, but offered no additional protection in WD- and REV-fed rats (Figure 6.2B). In particular, infarct size was even higher in WD-fed rats compared to control rats after sevoflurane exposure. Blood pressure and heart rate decreased during sevoflurane exposure, but were partly restored during the washout periods without differences among groups (Figure 6.4A-D).

Figure 6.4: Blood pressure and heart rate during sevoflurane exposure Systolic blood pressure (B), diastolic blood pressure (B), mean arterial pressure (C) and heart rate (D) in rats after 8 weeks of control diet (CD), western diet (WD) or reversion diet (REV) feeding. Data are meanÂąSD, n=5-11.

Effect of diet and sevoflurane on ischemic injury

121

Plasma insulin levels after surgery Western diet feeding increased plasma insulin levels when compared to control rats, while this hyperinsulinemic effect was absent in rats subjected to diet reversal. While myocardial infarction had no effect on insulin levels in control rats, WD-fed rats showed a hyperinsulinemic response upon cardiac ischemia and reperfusion. This effect remained present in the diet reversal group, although to a lesser extent. Sevoflurane prior to myocardial infarction tended to increase insulin levels in control rats, while sevoflurane exposure in WD-fed rats undergoing myocardial infarction decreased plasma insulin levels. In rats exposed to diet reversal the rise in insulin levels during myocardial infarction was abolished after sevoflurane exposure (Figure 6.2C). Myocardial infarction, but not MI+SEVO, significantly increased HDL cholesterol in CD-fed rats, which was absent in WD- and REV-fed rats. MI and MI+SEVO had no effect on plasma glucose, free fatty acids, triglycerides and LDL/VLDL cholesterol (data not shown). Hyperinsulinemia protects against ischemic injury in healthy rats From the findings as shown in figure 6.2C it was hypothesized that the protective effects of western diet feeding against myocardial ischemia may be the result of increases in plasma insulin levels. In order to study the direct effects of hyperinsulinemia on the cardioprotective effects of western diet, control diet-fed rats were subjected to a hyperinsulinemic euglycemic clamp. Steady-state blood glucose levels during hyperinsulinemic euglycemic clamping were 5.43±0.05 mmol/L, whereas the glucose disposal rate (M-value) was 9.83±1.34 mg/kg/min in healthy CD-fed rats. Plasma insulin levels were 9027±679 pmol/L and the insulin sensitivity (M/I-index) was 1.19±0.22 in CD-fed rats during the steady state of the clamp. Hyperinsulinemia combined with euglycemia resulted in a similar area at risk when compared to control rats, but itself protected the heart against myocardial ischemia (Figure 6.5A and B).

122

Chapter 6

Figure 6.5: Myocardial ischemia and reperfusion injury during hyperinsulinemia Area at risk (A) and infarct size (B) after sham (CON), myocardial infarction (MI) and myocardial infarction during hyperinsulinemia (MI+INS) in rats after 8 weeks of control diet (CD) feeding. Data are meanÂąSD, n=5-11, one-way ANOVA with Bonferroni post-hoc analyses, * p<0.05 vs. CON, p<0.05 vs. MI.

Effect of diet and sevoflurane on ischemic injury

123

Discussion The present study showed that short-term western diet feeding in rats resulted in a prediabetic phenotype, and exerted an unexpected cardioprotective effect during myocardial

infarction,

which

was

not

abolished

lowering

caloric

intake.

Sevoflurane preconditioning protected the heart against myocardial ischemia in healthy control rats. However, in diet-induced prediabetic rats, sevoflurane exposure paradoxically increased infarct size. Sevoflurane prior to myocardial infarction tended to increase insulin levels in control rats, while sevoflurane exposure in western dietfed rats undergoing myocardial infarction decreased plasma insulin levels. By mimicking this hyperinsulinemic cardioprotective response using a hyperinsulinemic, euglycemic clamp in control rats, we suspect a pivotal role for insulin underlying the protective effects of sevoflurane or western diet against myocardial ischemia. The present study demonstrated a protective effect of western diet feeding during myocardial ischemia and reperfusion. We are not unique with respect to this unexpected finding, as other groups also showed that high caloric diet feeding may exert cardioprotective properties during ischemia and reperfusion.16-18 In contrast, there are also reports available that show no effect10;19;20 or aggravation of ischemic injury after diet feeding in rats.21-24 These conflicting findings may be due to the type and severity of metabolic disease,25 the used ischemia and reperfusion protocol, the duration of diet feeding and the composition of the diet. Several mechanisms may explain diet-mediated cardioprotection, such as the presence of a high percentage of carbohydrates.16-18 The present diet consisted mainly of saturated fatty acids and a high percentage of sucrose. Jordan et al. showed that 3 days or 4 weeks of fructose diet feeding both reduced infarct size, while only the 4-week fructose intervention was associated with insulin resistance. These findings suggest a protective effect of fructose.17 It is suggested that carbohydrates, such as fructose or sucrose, may protect the heart against ischemia and reperfusion injury via antioxidant mechanisms26,27 or via the response of the heart to injury by increasing myocardial glucose metabolism to improve its energetic efficiency.28,29 Glycolysis becomes an important source of energy due to its ATPgenerating ability in the absence of oxygen and is reported to be cardioprotective during ischemia and reperfusion.30 Sucrose feeding may further stimulate myocardial substrate metabolism. On the other hand, the high fat content of diets may also be cardioprotective.31 Another explanatory mechanism is the presence of metabolic alterations, such as hyperinsulinemia, during ischemic stress. Several studies showed a cardioprotective effect of insulin in healthy rats during myocardial ischemia and reperfusion32-35 and positive effects glucose, insulin and potassium (GIK) treatment in patients with myocardial infarction.36;37 Moreover, infarct size was decreased in diet-induced obese

124

Chapter 6

compared to healthy rat hearts in absence of insulin, whereas the presence of insulin in the coronary perfusate was cardioprotective in healthy and obese hearts, suggesting the importance of insulin.22 In accordance with the literature, we showed a cardioprotective effect of insulin during myocardial ischemia and reperfusion using a hyperinsulinemic euglycemic clamp. Moreover, two independent observations in our study provide further support for the protective role of insulin. First, sevoflurane exposure of control rats tended to increase insulin levels, while this was associated with myocardial protection against ischemic injury. Secondly, while western dietassociated

cardioprotection

was

paralleled

hyperinsulinemia,

the

absent

cardioprotective effect of sevoflurane exposure in western diet fed rats undergoing myocardial infarction resulted in a decrease of plasma insulin levels. However, further

research

needed

discriminate

the

underlying

cardioprotective

mechanism in our diet-induced prediabetic rat model. Beside the unexpected cardioprotective effect of western diet, the present study also demonstrated that sevoflurane preconditioning reduced infarct size in healthy rats, but did had no additive cardioprotective effect in western diet-induced prediabetic rats nor was affected by lowering caloric intake. Previously, it is shown that hyperglycemia8 and obesity/insulin resistance9 abolished the cardioprotective effect of sevoflurane. However, the generalizability of the prediabetic phenotype in these rat models was limited.8;9 Moreover, Song et al. demonstrated in high fat dietinduced obese rats that sevoflurane preconditioning-induced cardioprotection is suppressed.10 Interestingly, our study shows that sevoflurane even increases infarct size in prediabetic rats when compared to control rats, suggesting that western diet feeding has negative effects on sevoflurane preconditioning. In conclusion, western diet feeding resulted in an unexpected cardioprotective effect during myocardial infarction, which was not affected by lowering caloric intake. Sevoflurane preconditioning had no additive cardioprotective effect in prediabetic rats nor was affected by lowering caloric intake. However, the combination of diet and

sevoflurane

was

less

cardioprotective.

Moreover,

hyperinsulinemia

was

cardioprotective in healthy rats, which might be an explanatory mechanism of the cardioprotective effect of the diet. Future studies will discriminate between the possible cardioprotective mechanisms of the diet and sevoflurane anesthesia.

Effect of diet and sevoflurane on ischemic injury

125

and

care

for

noncardiac

surgery:

report

the

American

College

Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation 2007, 116:e418-e499. 2. Preis SR, Pencina MJ, Hwang SJ, D'Agostino RB, Sr., Savage PJ, Levy D, Fox CS: Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation 2009, 120:212-220. 3. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999, 100:1043-1049. 4. Frassdorf J, De HS, Schlack W: Anaesthesia and myocardial ischaemia/reperfusion injury. Br J Anaesth 2009, 103:89-98. 5. De Hert SG, Preckel B, Hollmann MW, Schlack WS: Drugs mediating myocardial protection. Eur J Anaesthesiol 2009, 26:985-995. 6. Bouwman RA, Vreden MJ, Hamdani N, Wassenaar LE, Smeding L, Loer SA, Stienen GJ, Lamberts RR: Effect of bupivacaine on sevoflurane-induced preconditioning in isolated rat hearts. Eur J Pharmacol 2010, 647:132-138. 7. Lamberts RR, Onderwater G, Hamdani N, Vreden MJ, Steenhuisen J, Eringa EC, Loer SA, Stienen GJ, Bouwman RA: Reactive oxygen species-induced stimulation of 5'AMP-activated protein kinase mediates sevoflurane-induced cardioprotection. Circulation 2009, 120:S10-S15. 8. Huhn R, Heinen A, Weber NC, Hollmann MW, Schlack W, Preckel B: Hyperglycaemia blocks sevoflurane-induced postconditioning in the rat heart in vivo: cardioprotection can be restored by blocking the mitochondrial permeability transition pore. Br J Anaesth 2008, 100:465-471. 9. Huhn R, Heinen A, Hollmann MW, Schlack W, Preckel B, Weber NC: Cyclosporine A administered during reperfusion fails to restore cardioprotection in prediabetic Zucker obese rats in vivo. Nutr Metab Cardiovasc Dis 2010, 20:706-712. 10.Song T, Lv LY, Xu J, Tian ZY, Cui WY, Wang QS, Qu G, Shi XM: Diet-induced obesity suppresses sevoflurane preconditioning against myocardial ischemia-reperfusion injury: role of AMPactivated protein kinase pathway. Exp Biol Med (Maywood ) 2011, 236:1427-1436. 11.van Dijk A, Krijnen PA, Vermond RA, Pronk A, Spreeuwenberg M, Visser FC, Berney R, Paulus WJ, Hack CE, van Milligen FJ, Niessen HW: Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction. Apoptosis 2009, 14:753-763. 12.van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, Van der Velden J, Boer C, Ouwens DM, Diamant M: Altered myocardial substrate

metabolism

associated

with

myocardial

dysfunction

early

diabetic

cardiomyopathy in rats: studies using positron emission tomography. Cardiovasc Diabetol 2009, 8:39.

126

Chapter 6

13.Ouwens DM, Diamant M, Fodor M, Habets DD, Pelsers MM, El Hasnaoui M, Dang ZC, van den Brom CE, Vlasblom R, Rietdijk A, Boer C, Coort SL, Glatz JF, Luiken JJ: Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36mediated fatty acid uptake and esterification. Diabetologia 2007, 50:1938-1948. 14.van den Brom CE, Bosmans JW, Vlasblom R, Handoko ML, Huisman MC, Lubberink M, Molthoff CF, Lammertsma AA, Ouwens DM, Diamant M, Boer C: Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle. Cardiovasc Diabetol 2010, 9:25. 15.van den Brom CE, Bulte CS, Kloeze BM, Loer SA, Boer C, Bouwman RA: High fat diet-induced glucose

intolerance

impairs

myocardial

function,

but

not

myocardial

perfusion

during

hyperaemia: a pilot study. Cardiovasc Diabetol 2012, 11:74. 16.Ivanova M, Janega P, Matejikova J, Simoncikova P, Pancza D, Ravingerova T, Barancik M: Activation of Akt kinase accompanies increased cardiac resistance to ischemia/reperfusion in rats after short-term feeding with lard-based high-fat diet and increased sucrose intake. Nutr Res 2011, 31:631-643. 17.Jordan JE, Simandle SA, Tulbert CD, Busija DW, Miller AW: Fructose-fed rats are protected against ischemia/reperfusion injury. J Pharmacol Exp Ther 2003, 307:1007-1011. 18.Joyeux-Faure M, Rossini E, Ribuot C, Faure P: Fructose-fed rat hearts are protected against ischemia-reperfusion injury. Exp Biol Med (Maywood ) 2006, 231:456-462. 19.Mozaffari MS, Schaffer SW: Myocardial ischemic-reperfusion injury in a rat model of metabolic syndrome. Obesity (Silver Spring) 2008, 16:2253-2258. 20.Thim T, Bentzon JF, Kristiansen SB, Simonsen U, Andersen HL, Wassermann K, Falk E: Size of myocardial infarction induced by ischaemia/reperfusion is unaltered in rats with metabolic syndrome. Clin Sci (Lond) 2006, 110:665-671. 21.Axelsen LN, Lademann JB, Petersen JS, Holstein-Rathlou NH, Ploug T, Prats C, Pedersen HD, Kjolbye AL: Cardiac and metabolic changes in long-term high fructose-fat fed rats with severe obesity and extensive intramyocardial lipid accumulation. Am J Physiol Regul Integr Comp Physiol 2010, 298:R1560-R1570. 22.du Toit EF, Smith W, Muller C, Strijdom H, Stouthammer B, Woodiwiss AJ, Norton GR, Lochner A: Myocardial susceptibility to ischemic-reperfusion injury in a prediabetic model of dietaryinduced obesity. Am J Physiol Heart Circ Physiol 2008, 294:H2336-H2343. 23.Morel S, Berthonneche C, Tanguy S, Toufektsian MC, Foulon T, de LM, de LJ, Boucher F: Insulin resistance modifies plasma fatty acid distribution and decreases cardiac tolerance to in vivo ischaemia/reperfusion in rats. Clin Exp Pharmacol Physiol 2003, 30:446-451. 24.Gonsolin D, Couturier K, Garait B, Rondel S, Novel-Chate V, Peltier S, Faure P, Gachon P, Boirie Y, Keriel C, Favier R, Pepe S, DeMaison L, Leverve X: High dietary sucrose triggers hyperinsulinemia, increases myocardial beta-oxidation, reduces glycolytic flux and delays postischemic contractile recovery. Mol Cell Biochem 2007, 295:217-228. 25.van den Brom CE, Bulte CSE, Loer SA, Bouwman RA, Boer C: Diabetes, perioperative ischaemia and volatile anaesthetics: Consequences of derangements in myocardial substrate metabolism. Cardiovasc Diabetol 2013, In press. 26.Yoshida T, Watanabe M, Engelman DT, Engelman RM, Schley JA, Maulik N, Ho YS, Oberley TD, Das DK: Transgenic mice overexpressing glutathione peroxidase are resistant to myocardial ischemia reperfusion injury. J Mol Cell Cardiol 1996, 28:1759-1767. 27.Dhalla NS, Elmoselhi AB, Hata T, Makino N: Status of myocardial antioxidants in ischemiareperfusion injury. Cardiovasc Res 2000, 47:446-456. 28.Stanley WC, Recchia FA, Lopaschuk GD: Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005, 85:1093-1129. 29.Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC: Myocardial fatty acid metabolism

Effect of diet and sevoflurane on ischemic injury

127

in health and disease. Physiol Rev 2010, 90:207-258. 30.Vanoverschelde JL, Janier MF, Bakke JE, Marshall DR, Bergmann SR: Rate of glycolysis during ischemia determines extent of ischemic injury and functional recovery after reperfusion. Am J Physiol 1994, 267:H1785-H1794. 31.Knapp M: Cardioprotective role of sphingosine-1-phosphate. J Physiol Pharmacol 2011, 62:601607. 32.Gao F, Gao E, Yue TL, Ohlstein EH, Lopez BL, Christopher TA, Ma XL: Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 2002, 105:1497-1502. 33.Jonassen AK, Sack MN, Mjos OD, Yellon DM: Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 2001, 89:1191-1198. 34.Jonassen AK, Aasum E, Riemersma RA, Mjos OD, Larsen TS: Glucose-insulin-potassium reduces infarct size when administered during reperfusion. Cardiovasc Drugs Ther 2000, 14:615-623. 35.Doenst T, Richwine RT, Bray MS, Goodwin GW, Frazier OH, Taegtmeyer H: Insulin improves functional and metabolic recovery of reperfused working rat heart. Ann Thorac Surg 1999, 67:1682-1688. 36.Di MS, Boldrini B, Conti U, Marcucci G, Morgantini C, Ferrannini E, Natali A: Effects of GIK (glucose-insulin-potassium) on stress-induced myocardial ischaemia. Clin Sci (Lond) 2010, 119:37-44. 37.Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G: Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation 1998, 98:2227-2234.

7 Conclusions & General discussion

Conclusions & General discussion

131

Patients undergoing surgery and anesthesia are at risk for perioperative cardiac complications, especially in the presence of comorbidities like obesity and type 2 diabetes mellitus. The inhalational anesthetic sevoflurane has been shown to have cardioprotective as well as cardiodepressive properties, which might be affected by metabolic alterations in the heart. While the cardioprotective effects are reduction of ischemia and reperfusion injury, the cardiodepressive effects are negative inotropic and lusitropic effects. In the present thesis we investigated the impact of dietary intake on perioperative myocardial perfusion, function and ischemia and reperfusion injury, thereby focusing on the interaction of dietary intake and sevoflurane anesthesia. We specifically hypothesized that anesthesia-induced changes in perioperative myocardial function are influenced by preoperative dietary alterations.

Critique of methods We tested our hypotheses in instrumented, anesthetized rats. These rats received a standardized diet with a high concentration of saturated fatty acids and different percentages of simple carbohydrates to induce an obese/type 2 diabetic phenotype as a surrogate model for the human setting. This standardized diet improved the comparability of diet interventions within our studies. Overall, 4 weeks of high fat diet (HFD) feeding resulted in glucose intolerance with decreased HDL cholesterol (chapter 3), while 4 weeks of western diet feeding, a diet consisting of HFD with additional sucrose, resulted in

obesity, hyperglycemia, hyperinsulinemia and

hyperlipidemia, going from a glucose intolerant to a prediabetic rat model (chapter 5). Furthermore, these characteristics were extravagated when the duration of feeding was doubled from 4 to 8 weeks (chapter 4, 5 and 6). From these data we can conclude that western diet feeding simulates the human phenotype better than high fat diet feeding in rats. Diet-induced models of obesity and diabetes are more human-like than other models, because obesity is based on excessive caloric intake.1-3 Models such as the genetic Zucker or Zucker Diabetic Fatty rat are not representative for the human pathogenesis of obesity and type 2 diabetes mellitus due to a deficient leptin system, which is uncommon in humans.4 Besides, it is important to realize that untreated type 2 diabetic patients are rare, and that most patients receive medication leading to mild or absence of hyperglycemia. The translational character of diet feeding in rats to humans is still under discussion. There is a large variation in content of the diet, time of feeding and strain used. Diets can vary in the source and percentages of fat and carbohydrates. However, in the present thesis western diet feeding represents a prediabetic phenotype in rats and closely mimics the human diet. Our studies were performed in instrumented rats. Rats were anesthetized, endotracheally intubated and mechanically ventilated. During the experiments, ECG was recorded and arterial blood pressure was measured invasively. Moreover,

132

Chapter 7

interventional techniques such as an oral glucose tolerance test to determine glucose tolerance,

hyperinsulinemic

euglycemic

clamping

induce

hyperinsulinemia,

coronary occlusion to induce ischemia and reperfusion injury, and (contrast) echocardiography to determine myocardial perfusion and diastolic and systolic function have been performed. These techniques allowed standardized study conditions such as preservation of hypoglycemia during hyperinsulinemia. All our results were obtained under strictly standardized conditions with respect to timing and composition of diet feeding. Nevertheless, as with all animal experiments extrapolation to the human setting has to be done with caution.

Major findings Sevoflurane induces cardiodepression without altering myocardial perfusion Under physiological conditions, myocardial blood flow and systolic function are in balance.5 The supply of oxygen to the heart depends on the oxygen content in the blood and coronary blood flow. While oxygen content remains mostly constant, regulation of coronary blood flow is responsible for matching oxygen supply with metabolic demands. Major determinants of myocardial blood flow are perfusion pressure and coronary vascular resistance. Under pathophysiological conditions, such as obesity and type 2 diabetes mellitus, the balance between energy supply and demand could be altered. The present thesis focused on the evaluation of dietary alterations on myocardial systolic function and blood flow. In high fat diet-induced glucose intolerant rats, myocardial perfusion and systolic function are not affected (chapter 3), whereas in western diet-induced prediabetic rats, myocardial perfusion and function are both declined when compared to control animals (chapter 4). This clearly suggests that the stage of diabetes plays a role in the development of cardiovascular alterations and that a reduction in myocardial contractility coincides with a reduction in coronary blood flow. In the context of these findings the question remains whether these myocardial alterations in prediabetic rats are additionally associated with changes in myocardial oxygen demand and supply. It is known that substrate metabolism of diabetic hearts shifts toward fatty acid utilization, which is paralleled by a decrease in glucose metabolism.6 However, the consequence of increased use of fatty acids is a higher demand of ATP which requires more oxygen. In addition to possible alterations in oxygen supply and demand in the heart of prediabetic rats there are other pathophysiological mechanisms that may underlie the reduction in myocardial perfusion and function in our animal model. At first, cardiometabolic alterations may affect myocardial calcium handling.7-10 The consequent reduction in contractility of the heart may also lead to alterations in myocardial blood flow. Secondly, myocardial relaxation is impaired in prediabetic rats, which might result in impairment of coronary perfusion. As shown in patients undergoing biventricular pacing, coronary

Conclusions & General discussion

133

perfusion is dependent on a suction like effect during diastole, the so-called backward-traveling decompression effect.11 The present thesis showed that sevoflurane did not affect myocardial perfusion, while systolic function was decreased in healthy and prediabetic animals (chapter 4). This suggests that sevoflurane uncouples myocardial perfusion and function irrespective of the metabolic state of the heart. The uncoupling of perfusion and function is also observed after prolonged ischemia, which has been describes as a perfusion-contraction

mismatch.5

Moreover,

sevoflurane

exerts

vasodilating

properties, and is known to reduce coronary vascular resistance and perfusion pressure in addition to myocardial depression.12-14 In addition, the vasodilating properties of sevoflurane are influenced by vasoactive mediators, such as nitric oxide.15 Sevoflurane activates nitric oxide; however, altered nitric oxide availability can

significantly

impair

myocardial

perfusion-contraction

matching.16

Thus,

sevoflurane seems to uncouple myocardial perfusion and contraction, however, up to now the mechanisms are unclear. The cardiodepressive effects of sevoflurane are modulated by dietary composition Sevoflurane exerts cardiodepressive properties in healthy subjects, therefore its perioperative use may cause hemodynamic alterations. It has been suggested that the

interaction

sevoflurane

with

the

heart

additionally

altered

cardiometabolic diseases. With the growing epidemic of obesity and type 2 diabetes mellitus it is important to understand the influence of this condition on the interaction of sevoflurane with myocardial function. We found that high fat dietinduced glucose intolerance did not affect myocardial function during baseline conditions,

whereas

myocardial

function

was

impaired

during

conditions

hyperemia (chapter 3). When prediabetes was induced in rats exposed to a diet high in saturated fatty acids and simple carbohydrates, a so-called western diet, we observed impairment of myocardial systolic and diastolic function (Chapter 4 and 5). Moreover, we found that sevoflurane is a stronger cardiodepressant in prediabetic rats than in control rats (chapter 4 and 5), which could be restored by lowering caloric intake (chapter 5). Suggested mechanisms are myocardial substrate metabolism

and

calcium

handling.

Proteins

myocardial

substrate

metabolism, such as the protein kinase Akt17 and glucose transporter 418 are increased by sevoflurane after ischemia and reperfusion, resulting in increased glucose and decreased fatty acid oxidation.18 Moreover, sevoflurane reduces myocardial content.

7;19

calcium

availability7

and

affects

sarcoplasmic

reticulum

calcium

These results suggest that normalization of the cardiometabolic profile

by dietary changes are of direct influence on the myocardial response to sevoflurane in rats.

134

Chapter 7

The cardioprotective effects of sevoflurane during myocardial ischemia are altered by dietary intake Western diet, in combination with a sedentary lifestyle, is an important cause for overweight, obesity and type 2 diabetes mellitus.1 Interestingly, while the overall negative

consequences

western

diet

feeding

for

the

development

cardiometabolic diseases are well acknowledged, there is increasing evidence that diets containing a high percentage of saturated fatty acids and simple carbohydrates may also be protective during stressful conditions, like surgery and anesthesia.20 In the present thesis we observed that western diet feeding itself exerted cardioprotective effects in the ischemic heart (Chapter 6). In animals, feeding a diet high in saturated fatty acids after myocardial ischemia showed preserved myocardial function even in the presence of insulin resistance, suggesting a possible protective effect of high fat diet feeding.21;22 Interestingly, it has been suggested that overweight and obese patients exert a more appropriate inflammatory and immune response to stress, and have a better outcome that their lean or morbid obese counterparts.20 However, it should be kept in mind that, despite macronutrient excess, obese patients remain at risk for perioperative nutritional deficits, such as iron deficiency, and the development of cardiovascular diseases.20 Moreover, we showed that sevoflurane exerted cardioprotective effects during myocardial ischemia and reperfusion in healthy rats. In agreement with our expectations, western diet feeding blunted the protective effects of sevoflurane during ischemia and reperfusion (Chapter 6). Western diet-induced cardioprotection was associated with a rise in plasma insulin levels, suggesting that insulin levels may be involved in the protective response of this diet (chapter 6). Besides a more appropriate inflammatory and immune response to stress, a possible mechanism might be hyperinsulinemia. Hyperinsulinemia is cardioprotective during ischemic stress.23-28

Moreover,

high

fat

diet

feeding

induces

hyperinsulinemia

compensatory mechanism. This hyperinsulinemia in the early phase of diabetes may therefore be a protective mechanisms during conditions of stress. Our experiments showed that hyperinsulinemia induced by a hyperinsulinemic euglycemic clamp mimicked the cardioprotective response as observed after western diet feeding (Chapter 6). These exciting and potentially also clinically relevant findings warrant future studies in humans. Normalizing the caloric intake reverses the cardiodepressive effects, but not the protective characteristics of sevoflurane Perioperative cardiac complications are an economical, medical and social burden that warrants optimization of perioperative health and cardiovascular care to improve patient outcome and reduce health care costs. Preoperative treatment of obesity and type 2 diabetes mellitus may reduce perioperative cardiac complications. Current therapies directed at reducing these risk factors focus on weight loss. Weight

Conclusions & General discussion

135

loss is induced by a negative energy balance, such as dietary interventions, physical activity, pharmacotherapy and surgery.29 Lifestyle interventions, such as changing dietary intake and increasing physical activity to improve insulin sensitivity and glucose control in obese and type 2 diabetic patients is an important part of these treatments.30;31 The evidence for their benefits is nowadays growing and might reduce perioperative complications and improve short and long-term outcome. Hyperglycemia, which may be triggered by the stress condition of anesthesia and surgery, is a strong predictor for morbidity and mortality after non-cardiac procedures, while high perioperative glucose variability enhances this risk even further.32-34 Lowering of the incidence of perioperative hyperglycemia in obese and type 2 diabetic patients may therefore contribute to improved patient outcome and reduced health care costs after surgery.35 Although the benefits of lifestyle interventions

improve

the

incidence

intraoperative

hyperglycemia

are

increasingly acknowledged, it may be expected that these interventions also modulate anesthesia-related physiological alterations. The present thesis showed that lowering caloric intake improved myocardial systolic and diastolic function (chapter 5 and 6) and that the cardioprotective effect of western diet feeding during ischemia and reperfusion is sustained (chapter 6). Further, sevoflurane induced cardiodepression was normalized (chapter 5), whereas sevoflurane had no additional cardioprotective effect on ischemia and reperfusion injury (chapter 6). Although studies focusing on preoperative dietary changes in humans are limited,36 the overall idea is that weight loss reduces risk factors such as diabetes and cardiovascular disease and extends lifespan and reduces mortality. Besides the possibility of the sustained cardioprotective effect of western diet feeding, it is also known that caloric restriction protects against ischemia and reperfusion injury.36 Mitchell et al. reviewed the feasibility and benefits of caloric restriction and concluded that caloric restriction has a wide range of benefits against surgical stress in the experimental setting, which might also account in the human setting.36 One of the suggested underlying mechanisms is reduced insulin signaling. Improvement of insulin signaling by caloric restriction results in improved insulin sensitivity. This might also be an underlying mechanism in improved cardiometabolic state of western diet-induced prediabetic rats. Overall, dietary modulation by lowering caloric intake may have a wide range of benefits including improved insulin sensitivity, altered cardiometabolic state and reduced injury during stress.

136

Chapter 7

Future directions Laboratory investigations already studied the cardioprotective properties of volatile anesthesia for many years.37 However, the clinical applicability in modulating the risk of perioperative cardiovascular complications by volatile anesthetics is still an ongoing debate.38 Several experimental studies showed the protective effects of volatile anesthetics in human heart tissue. However, recent clinical studies suggest that propofol and volatile anesthetics are associated with a comparable incidence of cardiac events. Therefore further research based on large clinical trials is necessary to conclude on the possible beneficial effects of volatile anesthesia on the heart and outcome. Moreover, clinical studies need to be performed to investigate the effects of volatile anesthetics during myocardial infarction in obese and/or type 2 diabetic patients. Secondly, drugs might modulate the sensitivity of the heart for ischemic injury, such as drugs for improvement of insulin sensitivity by glucagon-like peptide 1 (GLP1) or metformin. GLP1 is a gut incretin hormone that is released in response to nutrient

intake,

insulinomimetic

stimulates properties.

insulin

secretion

Metformin

and

exerts

biguanide

with

insulinotropic

and

antihyperglycemic

properties and exerts its actions by enhancing insulin sensitivity. Improvement of the diabetic phenotype might improve the cardioprotective effects of volatile anesthesia during ischemia and reperfusion. Thirdly, we found the protective effects of western diet feeding on ischemia and reperfusion injury. One of the suggested mechanisms is the presence of metabolic alterations, such as hyperinsulinemia, during ischemic stress. Several studies showed a cardioprotective effect of insulin in healthy animals and patients with myocardial infarction. However, the question remains if insulin administration has protective effects in the diabetic heart, due to the presence of insulin resistance. Future studies using insulin blockers need to be performed to prove the beneficial effects of hyperinsulinemia during ischemia and reperfusion in the prediabetic heart.

Conclusions & General discussion

137

Conclusions Patients with obesity and/or diabetes are at increased risk for perioperative cardiovascular complications. Moreover, the choice of anesthetic may modulate the risk of these perioperative cardiovascular complications. In the present thesis we focused on the modulation of dietary intake on sevoflurane-induced alterations in myocardial perfusion and function in rats. Moreover, we investigated whether the cardioprotective effect of sevoflurane is altered by diet composition, and whether changing the dietary balance by lowering fat and sucrose intake could be useful as an intervention to influence the effects of sevoflurane on the heart. Sevoflurane induces cardiodepression without altering myocardial perfusion In healthy control rats, sevoflurane resulted in reduced systolic function without altering myocardial blood flow, leading to uncoupling of cardiac systolic function and perfusion (Chapter 4). The cardioprotective effects of sevoflurane are modulated by dietary composition Rats exposed to a diet high in saturated fatty acids (HFD) developed glucose intolerance, however this phenotype was not associated with alterations in myocardial perfusion and function (Chapter 3). Though, after induction of hyperemia, we observed a reduction in myocardial systolic function in rats fed a high fat diet (HFD) without alterations in myocardial perfusion when compared to control animals (Chapter 3). When rats were exposed to a diet high in saturated fatty acids and simple carbohydrates, a so-called western diet (WD), we observed glucose intolerance and impairment of myocardial perfusion and function at baseline when compared to control animals (Chapter 4 and 5). In the presence of sevoflurane, the reduction in myocardial systolic function in rats fed a western diet (WD) was even more pronounced, while sevoflurane did not alter myocardial perfusion (Chapter 4 and 5). The cardioprotective effects of sevoflurane during myocardial ischemia are altered by dietary intake Sevoflurane exerted cardioprotective effects during myocardial infarction and reperfusion in healthy rats. In agreement with our expectations, western diet feeding blunted the protective effects of sevoflurane during ischemia and reperfusion (Chapter 6). More interestingly, western diet feeding itself exerted cardioprotective effects in the ischemic heart (Chapter 6). Western diet-induced cardioprotection was associated with a rise in plasma insulin levels, suggesting that insulin levels may be involved in the protective response of this diet. Separate experiments showed that hyperinsulinemia induced by a hyperinsulinemic euglycemic clamp mimicked the cardioprotective response as observed after western diet feeding (Chapter 6).

138

Chapter 7

Normalizing the caloric intake reverses the cardiodepressive effects, but not the protective characteristics of sevoflurane Rats subjected to diet reversal, which comprised a period of normal healthy diet following western diet feeding, showed normalization of their prediabetic phenotype. (Chapter 5) This was associated with improvement of cardiac systolic as well as diastolic function (Chapter 5) and a reduction in the cardiodepressive effects of sevoflurane (Chapter 5). While western diet had a protective effect against ischemia and reperfusion injury, lowering caloric intake did not alter the cardioprotective effect of western diet feeding during ischemia and reperfusion (Chapter 6). Moreover, the absence of sevoflurane-induced cardioprotection during myocardial infarction in western diet fed rats could not be restored by diet reversal (Chapter 6).

Conclusions & General discussion

139

References 1. Panchal SK, Brown L: Rodent models for metabolic syndrome research. J Biomed Biotechnol 2011, 2011:351982. 2. Kanasaki K, Koya D: Biology of obesity: lessons from animal models of obesity. J Biomed Biotechnol 2011, 2011:197636. 3. Nilsson C, Raun K, Yan FF, Larsen MO, Tang-Christensen M: Laboratory animals as surrogate models of human obesity. Acta Pharmacol Sin 2012, 33:173-181. 4. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999, 341:879-884. 5. Heusch G, Schulz R: The relation of contractile function to myocardial perfusion. Perfusioncontraction match and mismatch. Herz 1999, 24:509-514. 6. van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, Van der Velden J, Boer C, Ouwens DM, Diamant M: Altered myocardial substrate

metabolism

associated

with

myocardial

dysfunction

early

diabetic

cardiomyopathy in rats: studies using positron emission tomography. Cardiovasc Diabetol 2009, 8:39. 7. Hannon JD, Cody MJ: Effects of volatile anesthetics on sarcolemmal calcium transport and sarcoplasmic reticulum calcium content in isolated myocytes. Anesthesiology 2002, 96:14571464. 8. Fassl J, Halaszovich CR, Huneke R, Jungling E, Rossaint R, Luckhoff A: Effects of inhalational anesthetics on L-type Ca2+ currents in human atrial cardiomyocytes during beta-adrenergic stimulation. Anesthesiology 2003, 99:90-96. 9. Hanley PJ, ter Keurs HE, Cannell MB: Excitation-contraction coupling in the heart and the negative inotropic action of volatile anesthetics. Anesthesiology 2004, 101:999-1014. 10.Bouwman RA, Salic K, Padding FG, Eringa EC, van Beek-Harmsen BJ, Matsuda T, Baba A, Musters RJ, Paulus WJ, de Lange JJ, Boer C: Cardioprotection via activation of protein kinase Cdelta depends on modulation of the reverse mode of the Na+/Ca2+ exchanger. Circulation 2006, 114:I226-I232. 11.Kyriacou A, Whinnett ZI, Sen S, Pabari PA, Wright I, Cornelussen R, Lefroy D, Davies DW, Peters NS, Kanagaratnam P, Mayet J, Hughes AD, Francis DP, Davies JE: Improvement in coronary blood flow velocity with acute biventricular pacing is predominantly due to an increase in a diastolic backward-travelling decompression (suction) wave. Circulation 2012, 126:13341344. 12.Malan TP, Jr., DiNardo JA, Isner RJ, Frink EJ, Jr., Goldberg M, Fenster PE, Brown EA, Depa R, Hammond LC, Mata H: Cardiovascular effects of sevoflurane compared with those of isoflurane in volunteers. Anesthesiology 1995, 83:918-928. 13.Park KW: Cardiovascular effects of inhalational anesthetics. Int Anesthesiol Clin 2002, 40:1-14. 14.Larach DR, Schuler HG: Direct vasodilation by sevoflurane, isoflurane, and halothane alters coronary flow reserve in the isolated rat heart. Anesthesiology 1991, 75:268-278. 15.Nakamura K, Terasako K, Toda H, Miyawaki I, Kakuyama M, Nishiwada M, Hatano Y, Mori K: Mechanisms of inhibition of endothelium-dependent relaxation by halothane, isoflurane, and sevoflurane. Can J Anaesth 1994, 41:340-346. 16.Kingma JG, Jr., Simard D, Rouleau JR: Modulation of nitric oxide affects myocardial perfusioncontraction matching in anaesthetized dogs with recurrent no-flow ischaemia. Exp Physiol 2011, 96:1293-1301.

140

Chapter 7

17.Yao Y, Li L, Li L, Gao C, Shi C: Sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by activation of pro-survival kinases and inhibition of mitochondrial permeability transition pore opening upon reperfusion. Biol Pharm Bull 2009, 32:1854-1861. 18.Lucchinetti E, Wang L, Ko KW, Troxler H, Hersberger M, Zhang L, Omar MA, Lopaschuk GD, Clanachan AS, Zaugg M: Enhanced glucose uptake via GLUT4 fuels recovery from calcium overload after ischaemia-reperfusion injury in sevoflurane- but not propofol-treated hearts. Br J Anaesth 2011, 106:792-800. 19.Davies LA, Gibson CN, Boyett MR, Hopkins PM, Harrison SM: Effects of isoflurane, sevoflurane, and halothane on myofilament Ca2+ sensitivity and sarcoplasmic reticulum Ca2+ release in rat ventricular myocytes. Anesthesiology 2000, 93:1034-1044. 20.Valentijn TM, Galal W, Tjeertes EK, Hoeks SE, Verhagen HJ, Stolker RJ: The obesity paradox in the surgical population. Surgeon 2013, 11:169-176. 21.Rennison JH, McElfresh TA, Okere IC, Vazquez EJ, Patel HV, Foster AB, Patel KK, Chen Q, Hoit BD, Tserng KY, Hassan MO, Hoppel CL, Chandler MP: High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction. Am J Physiol Heart Circ Physiol 2007, 292:H1498-H1506. 22.Rennison JH, McElfresh TA, Chen X, Anand VR, Hoit BD, Hoppel CL, Chandler MP: Prolonged exposure to high dietary lipids is not associated with lipotoxicity in heart failure. J Mol Cell Cardiol 2009, 46:883-890. 23.Gao F, Gao E, Yue TL, Ohlstein EH, Lopez BL, Christopher TA, Ma XL: Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 2002, 105:1497-1502. 24.Jonassen AK, Sack MN, Mjos OD, Yellon DM: Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 2001, 89:1191-1198. 25.Jonassen AK, Aasum E, Riemersma RA, Mjos OD, Larsen TS: Glucose-insulin-potassium reduces infarct size when administered during reperfusion. Cardiovasc Drugs Ther 2000, 14:615-623. 26.Doenst T, Richwine RT, Bray MS, Goodwin GW, Frazier OH, Taegtmeyer H: Insulin improves functional and metabolic recovery of reperfused working rat heart. Ann Thorac Surg 1999, 67:1682-1688. 27.Di MS, Boldrini B, Conti U, Marcucci G, Morgantini C, Ferrannini E, Natali A: Effects of GIK (glucose-insulin-potassium) on stress-induced myocardial ischaemia. Clin Sci (Lond) 2010, 119:37-44. 28.Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G: Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation 1998, 98:2227-2234. 29.Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH: Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Arterioscler Thromb Vasc Biol 2006, 26:968-976. 30.Viljanen AP, Karmi A, Borra R, Parkka JP, Lepomaki V, Parkkola R, Lautamaki R, Jarvisalo M, Taittonen M, Ronnemaa T, Iozzo P, Knuuti J, Nuutila P, Raitakari OT: Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults. Am J Cardiol 2009, 103:1721-1726. 31.Hammer S, Snel M, Lamb HJ, Jazet IM, van der Meer RW, Pijl H, Meinders EA, Romijn JA, de Roos A, Smit JW: Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. J Am Coll Cardiol 2008, 52:1006-1012.

Conclusions & General discussion

141

32.Noordzij PG, Boersma E, Schreiner F, Kertai MD, Feringa HH, Dunkelgrun M, Bax JJ, Klein J, Poldermans D: Increased preoperative glucose levels are associated with perioperative mortality in patients undergoing noncardiac, nonvascular surgery. Eur J Endocrinol 2007, 156:137-142. 33.Akhtar S, Barash PG, Inzucchi SE: Scientific principles and clinical implications of perioperative glucose regulation and control. Anesth Analg 2010, 110:478-497. 34.Tung A: Anaesthetic considerations with the metabolic syndrome. Br J Anaesth 2010, 105 Suppl 1:i24-i33. 35.Lipshutz

AK,

Gropper MA:

Perioperative

glycemic

control:

evidence-based

review.

Anesthesiology 2009, 110:408-421. 36.Mitchell JR, Beckman JA, Nguyen LL, Ozaki CK: Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery 2013, 153:594-598. 37.Frassdorf J, De Hert S, Schlack W: Anaesthesia and myocardial ischaemia/reperfusion injury. Br J Anaesth 2009, 103:89-98. 38.Pagel PS: Myocardial Protection by Volatile Anesthetics in Patients Undergoing Cardiac Surgery: A Critical Review of the Laboratory and Clinical Evidence. J Cardiothorac Vasc Anesth 2013.

8 Summary

Summary

145

In the present thesis we investigated the impact of preoperative dietary composition on sevoflurane anesthesia-induced changes in myocardial perfusion and function. Moreover, we studied the effects of high intake of saturated fatty acids in combination with simple carbohydrates on the cardioprotective effects of sevoflurane in case of myocardial ischemia. We hypothesized that preoperative dietary intake influence sevoflurane-induced changes in perioperative myocardial function. To investigate this we studied myocardial perfusion, function and ischemic injury in dietinduced glucose intolerant or prediabetic rats. Patients undergoing anesthesia and surgery are at risk of perioperative cardiac complications, especially in the presence of comorbidities like obesity and type 2 diabetes mellitus. A general introduction is given in Chapter 1 on perioperative complications, myocardial performance and ischemia during anesthesia and the combination with dietary interventions and lifestyle changes. A broader introduction on diabetes, perioperative ischemia and volatile anesthetics is given in Chapter 2. Several mechanisms involved in anesthesia-induced cardioprotection have been evaluated in the experimental setting. However, the existing evidence suggests that the obese and type 2 diabetic heart is less adaptable to cardioprotective interventions and that anesthesia-induced cardioprotection is just D ÂłKHDOWK\ KHDUW SKHQRPHQRQÂ´ $GGLWLRQDOO\ LW LV VXJJHVWHG WKDW P\RFDUGLDO substrate metabolism is one of the underlying protective mechanisms; therefore we focused on the consequences of derangements in myocardial substrate metabolism. This overview of recent literature reveals the importance of interventional options focusing on recovery of the metabolic flexibility of the heart, especially by improving insulin sensitivity. Myocardial perfusion during diet exposure and sevoflurane anesthesia This thesis focused on the effect of diet-induced glucose intolerance and prediabetes on myocardial perfusion. Chapter 3 describes the effect of high fat diet-induced glucose intolerance on myocardial perfusion and function during baseline and hyperemic conditions. High fat diet-induced glucose intolerance did not affect myocardial perfusion and function during baseline conditions. During hyperemia, we found that diet-induced glucose intolerance is associated with impaired myocardial function, but myocardial perfusion is maintained. These findings result in new insights into the effect of glucose intolerance on myocardial function and perfusion during hyperemia. Sevoflurane is associated with myocardial depression and these effects seem more abundant during obesity and type 2 diabetes mellitus. Chapter 4 focused on the impact of a more severe western, or cafeteria, diet on myocardial perfusion and function and the interaction with sevoflurane exposure. Western diet-induced prediabetes impaired myocardial perfusion and function. Exposure to sevoflurane did

146

Chapter 8

not affect myocardial perfusion, but impaired systolic function in healthy and prediabetic conditions. Our findings therefore suggest that sevoflurane leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state. Effect of changing the dietary balance Furthermore, this thesis investigated the effect of altering the dietary balance on myocardial function and ischemic injury by lowering the caloric intake. In Chapter 5 we investigated whether lowering the caloric intake can restore the effects of sevoflurane on myocardial performance in prediabetes. Western diet-induced prediabetes impaired myocardial systolic and diastolic function, whereas sevoflurane even further impaired systolic function in prediabetes. Lowering caloric intake normalized the prediabetic phenotype, improved myocardial function and restored systolic function during sevoflurane exposure. Therefore, sevoflurane is a stronger cardiodepressant in prediabetes than in healthy conditions, which could be restored by lowering caloric intake. These results suggest that dietary changes-related normalization of the cardiometabolic profile is of direct influence on the myocardial response to sevoflurane. Sevoflurane is known for its cardioprotective effects during myocardial ischemia and reperfusion, which seems blunted in the presence of obesity or type 2 diabetes mellitus. In Chapter 6 we investigated whether a reduction in caloric intake reverses the deteriorating impact of western diet feeding on the cardioprotective potency of sevoflurane during ischemia and reperfusion. In contrast to our hypothesis, western diet itself protected the heart against ischemic injury, and this effect was maintained even after lowering caloric intake. Exposure to sevoflurane exerted cardioprotective effects in healthy conditions, but this effect was blunted in prediabetes. Plasma insulin levels suggested that the protective effects of diet feeding may be induced by insulin. Hyperinsulinemia was cardioprotective in healthy conditions, suggesting that the protective effects of western diet feeding or sevoflurane are mediated by insulin. The main conclusions of this thesis are 1) sevoflurane induces cardiodepression without altering myocardial perfusion, 2) the cardiodepressive effects of sevoflurane are modulated by dietary composition, 3) the cardioprotective effects of sevoflurane during myocardial ischemia are altered by dietary intake, and 4) normalizing caloric intake reverses the cardiodepressive effects, but not the protective characteristics of sevoflurane. In Chapter 7, the conclusions are discussed and this chapter ends with future directions.

9 Samenvatting

Samenvatting

151

Dit proefschrift beschrijft de invloed van dieetsamenstelling op de effecten van het dampvormige anestheticum sevofluraan op de doorbloeding en pompfunctie van het hart,

beschermende

werking

van

sevofluraan

het

hart

tijdens

zuurstoftekort. Om dit te onderzoeken is de doorbloeding, functie en schade ten gevolge van zuurstoftekort in het hart bestudeerd in ratten. Deze ratten hebben door blootstelling aan een vetrijk dieet met of zonder toegevoegde suikers glucose intolerantie of prediabetes ontwikkeld. Het is een bekend gegeven dat patiënten die een operatie onder anesthesie ondergaan een verhoogd risico hebben op het ontwikkelen van complicaties aan het hart. Aandoeningen zoals ernstig overgewicht (obesitas) en type 2 diabetes mellitus vergroten dit risico op complicaties. Hoofdstuk 1 geeft een algemene introductie over deze complicaties, het functioneren van het hart en de schade ten gevolge van zuurstoftekort tijdens anesthesie in combinatie met dieet-interventies en levensstijl veranderingen. Dampvormige anesthetica hebben een beschermend effect op het hart tijdens zuurstoftekort. Recente literatuur toont aan dat deze beschermende effecten verminderd zijn in het obese en/of type 2 diabetische hart. Het lijkt er daarbij op dat deze beschermende effecten alleen worden waargenomen in het gezonde hart. Eén van de verklaringen hiervoor is dat de beschermende effecten van dampvormige anesthetica worden beïnvloed door het glucose en vetzuur metabolisme in het hart, en hier wordt uitgebreid op ingegaan in Hoofdstuk 2. Daarnaast wordt ook het belang van interventiemogelijkheden beschreven, waarbij de focus ligt op het herstel van de metabole flexibiliteit van het hart door het verbeteren van de insuline gevoeligheid. Dit kan bijdragen aan het verminderen van het perioperatieve risico op de complicaties van zuurstoftekort. Doorbloeding

van

het

hart

tijdens

dieetblootstelling

sevofluraan

anesthesie Dit proefschrift richt zich onder andere op het effect van glucose intolerantie en prediabetes op de doorbloeding van het hart. Hoofdstuk 3 beschrijft het effect van een hoog vet dieet op de doorbloeding van het hart in rust en tijdens maximale vaatverwijding. Inname van een hoog vet dieet resulteerde in glucose intolerantie, maar had geen effect op de doorbloeding en pompfunctie van het hart. Tijdens maximale vaatverwijding tonen wij aan dat glucose intolerantie geassocieerd is met een verstoorde hartfunctie, maar dat de doorbloeding van het hart behouden blijft. Deze resultaten geven nieuwe inzichten in het effect van glucose intolerantie op de doorbloeding en functie van het hart tijdens maximale vaatverwijding. Sevofluraan wordt geassocieerd met een verslechterde functie van het hart en deze effecten lijken versterkt aanwezig te zijn in obese en type 2 diabetische harten. Hoofdstuk 4 focust op de invloed van een vet- HQ VXLNHUULMN µFDIHWDULD¶ GLHHW

152

Chapter 9

(westers dieet) op de doorbloeding en functie van het hart in combinatie met blootstelling aan sevofluraan. Inname van een westers dieet resulteerde in prediabetes en verslechterde de doorbloeding en functie van het hart. Blootstelling aan sevofluraan had geen effect op de doorbloeding, maar verslechterde wel de functie in gezonde en prediabetische harten. Deze bevindingen suggereren dat sevofluraan de doorbloeding en functie in het hart ontkoppelt, onafhankelijk van de metabole staat van het hart. Effect van veranderingen in dieetsamenstelling Dit proefschrift beschrijft het effect van dieetsamenstelling op de functie en op de schade ten gevolge van zuurstoftekort in het hart. De resultaten van Hoofdstuk 5 tonen aan dat een westers dieet resulteerde in een prediabetisch fenotype en verslechtering van de hartfunctie. Daarnaast bleken de ongunstige effecten van sevofluraan op de functie van het hart versterkt te worden door prediabetes. Het verlagen van de calorie-inname verbeterde het prediabetische fenotype, de functie van het hart en verminderde de ongunstige effecten van sevofluraan op het hart. Hieruit concluderen we dat de negatieve effecten van sevofluraan op het hart versterkt worden in prediabetische harten. Verlaging van de calorie inname kunnen deze negatieve effecten herstellen. Deze resultaten suggereren dat veranderingen in dieet samenstelling van invloed is op de respons van het hart op sevofluraan. Sevofluraan staat bekend om de beschermende werking op het hart tijdens zuurstoftekort. Obesitas en type 2 diabetes mellitus lijken deze beschermende effecten te verstoren. Hoofdstuk 6 beschrijft of een verlaging van de calorie inname de effecten van sevofluraan op de schade van het prediabetische hart ten gevolge van

zuurstoftekort

be誰nvloedt.

Het

hoog

vet-

suikerrijke

westers

dieet

beschermde het hart tegen de schade ten gevolge van zuurstoftekort en dit beschermende

effect

bleef

behouden

verlaging

van

calorie

inname.

Blootstelling aan sevofluraan resulteerde in bescherming van het gezonde hart tijdens zuurstoftekort, maar dit effect was verminderd in prediabetische harten. Insuline levels in het plasma suggereerden dat de beschermende effecten van het westers dieet en sevofluraan ge誰nduceerd worden door insuline. Hoge concentraties van insuline werkten beschermend op het gezonde hart tijdens zuurstoftekort. Dit suggereert dat insuline mogelijke een rol speelt bij de beschermende effecten van het westers dieet en sevofluraan. De belangrijkste conclusies in dit proefschrift zijn 1) het dampvormige anestheticum sevofluraan verslechtert de functie, maar niet de doorbloeding van het hart; 2) de samenstelling van het dieet be誰nvloedt de effecten van sevofluraan op de doorbloeding en functie van het hart; 3) een hoog vet- en suikerrijk dieet heeft een ongunstige

invloed

beschermende

effecten

van

sevofluraan

tijdens

zuurstoftekort in het hart en 4) verlaging van de calorie inname herstelt de

Samenvatting

153

verminderde functie van het prediabetische hart, maar niet de beschermende kenmerken van sevofluraan. In Hoofdstuk 7 worden deze conclusies bediscussieerd en staat de toekomstige richting van dit onderzoek beschreven.

List of abbreviations

157

A A

microvascular blood volume

AMPK

AMP-activated protein kinase

ATP

adenosine triphosphate

AUC

area under the curve

B ǃ

microvascular filling velocity

C Ca2+

calcium

CABG

coronary artery bypass grafting

control diet

CON

control

CPT-1

carnitine palmitoyl transferase 1

cTnI

cardiac troponin I

D DCA

dichloroacetate

DPP4

dipeptidyl peptidase IV

DSPC

1,2-distearoyl-sn-glycero-3-phosphocholine

E echo

echocardiography

eNOS

endothelial nitric oxide synthase

end-diastole

end-systole

F FABPpm

plasma membrane fatty acid binding protein

FAC

fractional area change

FAT/CD36

fatty acid translocase / CD36

FATP

fatty acid transport protein

fractional shortening

G GIK

glucose-insulin-potassium

GLP1

glucagon-like peptide 1

GLUT

glucose transporter

GSK3ǃ

glycogen synthase kinase ǃ

158

List of abbreviations

H HDL

high-density lipoprotein

HFD

high fat diet

I INS

hyperinsulinemia

IVRT

isovolumic relaxation time

L LAD

left anterior descending coronary artery

LDL

low-density lipoprotein

left ventricle / left ventricular

M MI

mechanical index

MI mito

myocardial infarction K+ATP

MyBP-C

mitochondrial ATP-activated potassium channel myosin binding protein-C

P PDK4

pyruvate dehydrogenase kinase 4

PEG

polyoxyethylene stearate

PLB

phospholamban

PPAR

peroxisome proliferator-activated receptor

R REV

reversion

RPP

rate pressure product

S SEVO

sevoflurane

SERCA2a

sarcoplasmic reticulum calcium ATPase 2a

T T2DM

type 2 diabetes mellitus

TCA

tricarboxylic acid

TnT

troponin T

TTC

2,3,5-triphenyl tetrazolium chloride

List of abbreviations

159

V VLDL

very-low-density lipoprotein

W WD

western diet

wall thickness

Y Y0

signal intensity of first frame after microbubble destruction

Dankwoord

163

Men zegt dat de laatste loodjes het zwaarst zijn. Maar waar komt dit spreekwoord eigenlijk vandaan? Er zijn verschilende µtheorieëQ¶ over de herkomst. De meest plausible verklaring: het is ontleend aan het traditionele wegen waarbij de laatste gewichtjes µde lRRGMHV¶) de doorslag geven om de weegschaal in balans te krijgen. Bij mij heeft de weegschaal halverwege al flink geschommeld en alle gewichten eraf halen en opnieuw plaatsen was op een gegeven moment de enige optie. Om door deze fase heen te komen en mijn proefschrift af te ronden zijn er vele personen belangrijk geweest, maar een aantal personen in het bijzonder en deze wil ik graag bedanken. Lieve Rob, meestal wordt het dankwoord geëindigd met de partner, maar ik wil heel graag met jou beginnen, want zonder jouw onvoorwaardelijke steun was dit proefschrift er nooit geweest. Jij bent mijn alles; mijn man, mijn beste vriend en een fantastische vader! Op de momenten dat ik ³WH´ druk was regelde je naast je eigen drukke werk alles; het huishouden, het eten, de zorg voor Thijs en daarnaast was je er ook nog eens altijd voor mij. Eigenlijk onbeschrijfOLMN KRH GDQNEDDU LN MRX EHQ« Prof.dr. Loer, bedankt dat u mij de mogelijkheid heeft gegeven om bij u dit proefschrift te maken tot wat het geworden is en daarnaast het onderzoek nog veel verder uit te breiden. Ik kijk uit naar onze verdere samenwerking! Dr. Boer, lieve Chris. Jij hebt mij mijn verloren passie voor de wetenschap helpen terug te vinden. Jij gaf mij de zelfverzekerheid en het enthousiasme om opnieuw aan een proefschrift te beginnen. Zonder jouw passie voor onderzoek en altijd maar weer motiverende woorden was dit proefschrift er nooit geweest. Zelfs van de kleinste resultaten word je nog steeds enthousiast. Ik ben erg blij dat we ons onderzoek en het delen van enthousiasme over nieuwe data blijven voortzetten! Dr. Bouwman, beste Arthur. Dit project is ooit begonnen als een zijtakje van beide promotie projecten en uiteindelijk gecombineerd en geëindigd in dit proefschrift. Wie had dat ooit kunnen denken. Veel succes in Eindhoven! Prof.dr. Westerhof, beste Nico. Heel erg bedankt voor uw ondersteuning bij mijn ³GRRUVWDUW´. Prof.dr. Tangelder, beste Geert Jan. Hartelijk dank voor uw gastvrijheid op de afdeling fysiologie. Ik heb het er erg naar mijn zin gehad en me altijd thuis gevoeld. Ik ben dan ook erg blij dat ik nog blijf. Geniet van uw pensioen en alle reizen die u nog gaat maken!

164

Dankwoord

Graag wil ik mijn promotiecommissie, Prof.dr. Preckel, Prof.dr. van Royen, Prof.dr. Glatz, Prof.dr. den Heijer, Prof.dr. Scheeren, Prof.dr. van der Velden en Prof.dr. SernĂŠ bedanken voor het lezen van mijn proefschrift en het deelnemen aan mijn verdediging. Mijn paranimfen, Ester en Marianne. Lieve Ester, bijna gelijk zijn we bij de fysiologie EHJRQQHQ HQ ZH ]LMQ GDQ QX RRN DO ]RÂśQ acht MDDU FROOHJDÂśV HQ RQGHUWXVVHQ vriendinnen. Ik vind het fijn dDW LN ]RÂśQ SRVLWLHYH SHUVRRQOLMkheid naast me mag hebben staan! Lieve Marianne, lief schoonzusje, al 23 jaar ben je in de familie en je bent dan ook echt mijn grote zus. Jij bent niet alleen mijn voorbeeld van hoe ik als moeder wil zijn, maar je hebt ook de bijzondere eigenschap om oprecht blij voor me te zijn zonder altijd exact te weten waarom. Ik ben er trots op dat je naast me wilt staan! Ik ben van mening dat twee paranimfen te weinig zijn. Ondertussen zijn collegaÂśV vriendinnen geworden en hebben een belangrijke plek in mijn leven gekregen. Carolien, drie jaar hebben we niet alleen een kamer gedeeld, maar ook de nodige frustaties, irritaties, blijheden, borrels en nog veel meer. Succes met de laatste loodjes, je bent er echt bijna en je hebt een prachtig proefschrift waar je trots op mag zijn! Lonneke, jij was de nieuwe generatie, maar ondertussen ben je eerder gepromoveerd dan ik ;-). Ik vond het geweldig dat ik jouw paranimf mocht zijn en ben blij dat je nu een nieuw plekje hebt gevonden. Frances, ook bij jou mocht ik je als paranimf ondersteunen en ik vond het erg bijzonder om dit moment met je te mogen delen. Ik vind het super dat jij ook nog onderzoek blijft doen bij de fysiologie en we weer roomies zijn. Sylvia, bedankt voor alle bakkies en onvoorwaardelijke steun. Ik heb ongelooflijk veel respect voor jouw doorzettingsvermogen en positivitieit! In al die jaren heb ik toch heel wat roomies gehad. Louis, Melanie, Frances, Coen, Carolien, Hein, Karolina, Floor, Bas, Noor, Chantal en Yoni. Bedankt voor de gezelligheid, mentale steun, alle klaaguurtjes ;- HQ QLHW WH YHUJHWHQÂŤ DOOH ERUUHOV met bitterballen en natuurlijk de frikandellenlunch. Na acht jaar werken RS GH DIGHOLQJ I\VLRORJLH ]LMQ FROOHJDÂśV YULHQGLQQHQ JHZRUGHQ Hoe bijzonder is dat! 2PDÂśV &DUR-Lynn, Christine, Ester, Frances, Gerrina, Ingrid, Lonneke, Nicky, Sylvia, en surrogaat oma Lynda, bedankt voor alle opaÂśV 2QGDQNV dat we ons uitspreiden over de hele wereld (NY, Zanzibar, AMC), hoop ik dat we onze opaÂśV HQ jaarlijkse oma-de-luxe weekenden blijven voortzetten!

Dankwoord

165

Verder heb ik een mooi onderzoekteam om me heen. Rob, bedankt voor het uit handen nemen van heel veel dierexperimenteel werk. Chantal, Nick, Rob en Carolien, samen gaan we het ELVIS lab op de kaart zetten. $OOH DQGHUH FROOHJDÂśV en studenten (te veel om op te noemen) op de afdelingen anesthesiologie, fysiologie, secretariaat, werkplaats, electronica, interne, en UPC: bedankt voor de ondersteuning op alle vlakken en gezelligheid! 9RRUDO GH 732ÂśV SURPRÂśV VLQWHUNODDV NHUVW HQ ODEXLWMHV ZDUHQ (zijn) super! Verder wil ik ook graag mijn familie, vrienden en iedereen die mij dierbaar is bedanken. Ieder heeft op zijn eigen wijze interesse getoond of een bijdrage geleverd (in de vorm van een wijntje of welke andere vorm van ondersteuning dan ook -): Michael, Anja, Xander & Justin, Gaby, Marianne Ilse & Maud, Wim, Ton & Lia, Mark, Lianne, Tim, Chris & Julia, Ronald Vlasblom, Klaas Kramer, Robert-Jan, Silvia, Xander & Timon, Andu, Maurice & Benji, Kees, Mariska, Lianne & Feline, Jennie, Ivo & Feline, Diederik, Rik, Connie & Edwin, Tilly & Chelso en nog vele anderen -. Lieve mama en papa. Eindelijk ga ik dan ÂľDIVWXGHUHQÂś 2QGDQNV GDW ik niet van jullie kon verwachten helemaal te begrijpen wat promoveren precies inhoudt, hebben jullie altijd 200% achter mij gestaan! Papa, jouw doorzettingsvermogen is onbeschrijfbaar en voor mij een belangrijk voorbeeld. Daarom is mijn proefschrift voor jou. Lieve Rob, Thijs en onze nieuwe aanwinst, het werk zal er niet minder op worden nu ik klaar ben -, maar zal er wel altijd voor jullie zijn. Jullie maken het leven bijzonder en promoveren relatief. Ik hou van jullie. Liefs Charissa

List of publications

169

Full papers van den Brom CE, Boly CA, Bulte CSE, Boer C. Perioperative organ perfusion in obesity and diabetes. Submitted van den Brom CE, Boly CA, Bulte CSE, van den Akker RFP, Kwekkeboom RFJ, Loer SA, Boer C, Bouwman RA. Sevoflurane impairs myocardial systolic function, but not myocardial perfusion in diet-induced prediabetic rats. Submitted van den Brom CE, Boer C, van den Akker RFP, van der Velden J, Loer SA, Bouwman RA. Diet composition modulates sevoflurane-induced myocardial depression in rats. Submitted Bulte CSE, van den Brom CE, SA Loer, Boer C, Bouwman RA. Myocardial blood flow under sevoflurane anaesthesia in type 2 diabetic patients: a pilot study. Submitted Dekker SE, Viersen VA, Duvekot A, de Jong M, van den Brom CE, Schober P, Boer C. Lysis Onset Time as Diagnostic Rotational Thromboelastometry Parameter for Fast Detection of Hyperfibrinolysis. Submitted Vonk ABA, Veerhoek D, van den Brom CE, van Barneveld LJM, Boer C. Individualized

heparin

and

protamine

management

improves

rotational

thromboelastometric parameters and postoperative hemostasis in valve surgery. Accepted at Journal of Cardiothoracic and Vascular Anesthesia van den Brom CE, Bulte CSE, Loer SA, Bouwman RA, Boer C. Diabetes, perioperative ischaemia and volatile anaesthetics: Consequences of derangements in myocardial substrate metabolism. Cardiovascular Diabetology (2013), 12:42 Koning NJ, Vonk AB, Verkaik M, van Barneveld LJ, Beishuizen A, Atasever B, Baufreton C, van den Brom CE, Boer C. Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics. Journal of Applied Physiology (2012), 112(10): 1727-1734

170

List of publications

van den Brom CE, Bulte CSE, Kloeze BM, Loer SA, Boer C, Bouwman RA. High-fat diet-induced glucose intolerance impairs myocardial function, but not myocardial perfusion during hyperaemia: a pilot study. Cardiovascular Diabetology (2012), 11:74 van den Brom CE, Bosmans JWAM, Vlasblom R, Huisman MC, Lubberink M, Molthoff CFM, Lammertsma AA, Boer C, Ouwens DM, Diamant M. Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle. Cardiovascular Diabetology (2010), 9:25 van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CFM, Lammertsma AA, van der Velden J, Boer C, Ouwens DM, Diamant M. Altered myocardial substrate metabolism is associated with myocardial dysfunction in

early

diabetic

cardiomyopathy

in rats: studies

using

positron

emission

tomography. Cardiovascular diabetology (2009), 8(1):39 de Snoo MW, van den Brom CE, Jeneson JAL, Everts ME. The effect of wheel running exercise on plasma IL-6 and muscle IL-6 mRNA levels in mice. ,Q 続5HVSRQVHV RI PRXVH VNHOHWDO PXVFOH WR HQGXUDQFH H[HUFLVH続 7KHVLV GU 0: GH Snoo (2009) chapter 6 Ouwens DM, Diamant M, Fodor M, Habets DDJ, Pelsers MMAL, El Hasnaoui M, Dang ZC, van den Brom CE, Vlasblom R, Rietdijk A, Boer C, Coort SLM, Glatz JCF, Luiken LLFP. Cardiac contractile dysfunction in insulin resistant high-fat diet fed rats associates with elevated CD36-mediated fatty acid uptake and esterification. Diabetologia (2007), 50: 1938-1948 Van Schothorst EM, Keijer J, Pennings JL, Opperhuizen A, van den Brom CE, Kohl T, Franssen-van Hal NL, Hoebee B. Adipose gene expression response of lean and obese mice to short-term dietary restriction. Obesity (2006), 14(6): 974-979

List of publications

171

Papers in preparation Koning NJ, de Lange F, van den Brom CE, Shelep I, Bogaards SJ, Niessen HW, Baufreton C, Boer C. Hemodilution and extracorporeal circulation induce distinct alterations in microcirculatory perfusion and heterogeneity in a rat model of cardiopulmonary bypass. Duvekot A, Viersen VA, Dekker SE, van den Brom CE, Geeraedts jr. LMG, Loer SA, Schober P, de Waard MC, Spoelstra A, Boer C. Hyperfibrinolysis in out-of-hospital cardiopulmonary arrest is more prevalent in patients with low cerebral tissue oxygenation during cardiopulmonary resuscitation. van den Brom CE, Boer C, van den Akker RFP, Loer SA, Bouwman RA. Western diet modulates the susceptibility of the heart to ischemic injury and sevoflurane-induced cardioprotection in rats. Lamberts RR*, van den Brom CE*, Vlasblom R, Duijst S, Loer SA, Boer C, Diamant M, Bouwman RA. Diet composition modulates resistance to ischemia and sevoflurane induced preconditioning in the rat heart. Overmars MAH, Koning NJ, van den Brom CE, van Bezu J, Vonk ABA, van Nieuw Amerongen GP, Boer C. In vitro endothelial cell barrier function decreases after exposure to plasma from patients subjected to cardiopulmonary bypass.

172

List of publications

Published abstracts van den Brom CE, Boer C, van den Akker RFP, Loer SA, Bouwman RA. Western diet modulates the susceptibility of the heart to ischemic injury and sevoflurane-induced cardioprotection in rats. Nederlands tijdschrift voor Anesthesiologie (2013) van den Brom CE, Boly CA, Bulte CSE, van den Akker RFP, Loer SA, Boer C, Bouwman RA. Sevoflurane additionally impairs myocardial function, but not myocardial perfusion in diet-induced prediabetic rats. Nederlands tijdschrift voor Anesthesiologie (2013) van den Brom CE, Boer C, van den Akker RFP, Loer SA, Bouwman RA. Western diet feeding protects against myocardial ischaemic injury, but abolishes sevofluraneinduced cardioprotection in rats. European Journal of Anaesthesia (2013) van den Brom CE, Boer C, van den Akker RFP, Loer SA, Bouwman RA. Changing diet composition normalizes sevoflurane-induced impaired cardiac function in diabetic rats. Nederlands tijdschrift voor Anesthesiologie (2012) van den Brom CE, Bulte CSE, Voogdt C, Kloeze BM, Loer SA, Boer C, Bouwman RA. Short-term

reduction

saturated

fatty acids

improves

glucose

tolerance,

myocardial structure and function in western diet-induced obesity. Anesthesiology (2011) Bouwman RA, Bulte CSE, Loer SA, Boer C, van den Brom CE. High fat diet feeding impairs myocardial function during stress, but not during sevoflurane anesthesia. Anesthesiology (2011) van den Brom CE, Bulte CSE, Loer SA, Boer C, Bouwman RA. Western diet feeding impairs myocardial function during stress, but not during sevoflurane anesthesia. Nederlands tijdschrift voor Anesthesiologie (2011) van den Brom CE, Bouwman RA, Gr채ler MH, Ouwens DM, Diamant M, Boer C. Reversion of high-fat diet normalizes myocardial function and sphingolipid levels. Nederlands tijdschrift voor Anesthesiologie (2010)

List of publications

173

Bouwman RA, van den Brom CE, Loer SA, Boer C, Lamberts RR. Diet composition modulates sevoflurane induced cardioprotection in the rat heart. Anesthesiology (2009) Huisman MC, van den Brom CE, Buijs FL, Molthoff CFM, Boellaard R, Lammertsma AA. Implementation of Physiological Gating on the High Resolution Research Tomograph. Nuclear Science Symposium Conference Record (2008): 4767-4769 Bouwman RA, van den Brom CE, Loer SA, Boer C, Lamberts RR. Sevofluraneinduced cardioprotection in a rat model of high-fat diet-induced type 2 diabetes mellitus. European Journal of Anaesthesia (2008); 25 [Supl 44]: 4AP6-3 Bouwman RA, van den Brom CE, Vlasblom R, Loer SA, Boer C, Diamant M, Lamberts RR. Cardioprotection and dietary intake in a rat model of diet-induced type 2 diabetes mellitus. Nederlands tijdschrift voor Anesthesiologie (2008) Ouwens DM, van den Brom CE, Kriek J, Schaart G, Hesselink MK, Schrauwen P, Vlasblom R, Diamant M. Dietary fish-oil preserves cardiac contractile function by upregulation of UCP3 in a rat model of high-fat diet-induced glucose tolerance and cardiomyopathy. Diabetologia (2007); 50 [Suppl1]: S90 (P-0206) van den Brom CE, Vlasblom R, Kriek J, Rietdijk A, Duijst S, Salic K, Ouwens DM, Diamant M. High fat diet-induced relocation of CD36 to the sarcolemma precedes cardiac dysfunction and associates with activated PKB/AKT. Nederlands tijdschrift voor diabetes (2007) Vlasblom R, van den Brom CE, Salic K, Kriek J, Boer C, Ouwens DM, Diamant M. Western-type diet-induced cardiac contractile dysfunction is associated with nutrient-specific cardiomyocyte remodeling and activation of the Akt-regulated transcription factor GATA-4 in mice. Nederlands tijdschrift voor diabetes (2007) Salic K, van den Brom CE, Vlasblom R, Kriek J, Schaart G, Hesselink MK, Schrauwen P,Ouwens DM, Diamant M. Myocardial contractile function is preserved by dietary fish-oil supplementation through upregulation of UCP3 in a rat model of high-fat diet-induced impaired glucose tolerance and cardiomyopathy. Nederlands tijdschrift voor diabetes (2007)

174

List of publications

van den Brom CE, Vlasblom R, Fodor M, Boer C, Ouwens DM, Diamant M. Shortterm exposure to polyunsaturated high fat diet preserves cardiac contractile function in rats. Diabetologia (2006) 49: [Suppl1] 326(P-0534) Vlasblom R, Ouwens DM, van den Brom CE, Boer C, Diamant M. In wild type mice long-term exposure to high-fat diet induces systemic insulin resistance without affecting cardiac function. Diabetologia (2006) 49: [Suppl1] 327 Vlasblom R, Ouwens DM, van den Brom CE, Boer C, Diamant M. Long-Term Exposure to High-Fat Diet Induces Systemic Insulin Resistance without Affecting Cardiac Function in Wild Type Mice. Diabetes (2006) 55: [Suppl 1] A338 Vlasblom R, Ouwens DM, van den Brom CE, Fodor M, Boer C, Diamant M. Short Term Exposure to a High-Fat Diet Results in Impaired Glucose Tolerance, Cardiac Dysfunction and Epicardial Fat Accumulation in Rats. Diabetes (2006) 55: [Suppl 1] A338 van den Brom CE, Vlasblom R, Ouwens DM, Fodor M, Boer C, Diamant M. Short Term Exposure to a High-Fat Diet Results in Impaired Glucose Tolerance, Cardiac Dysfunction and Epicardial Fat Accumulation in Rats. Nederlands tijdschrift voor diabetes (2006)

Curriculum Vitae

179

Charissa Esmé van den Brom was born on July 8th 1982 in Nijkerk, the Netherlands. After graduating from secondary school (havo, Amersfoort) in 1999 she started the study Biochemistry at the University of Applied Sciences in Utrecht. She did a research apprenticeship at the Department of Toxicology, Pathology and *HQHWLFV DW WKH 5,90 LQ %LOWKRYHQ $IWHU UHFHLYLQJ KHU EDFKHORU¶V GHJUHH LQ VKH started her master Medical Biology at the VU University in Amsterdam. During her master she did a research apprenticeship at the Institute of Food Research in Norwich, England and a research apprenticeship within the Department of Anatomy and Physiology at Utrecht University. She obtained her Master degree in August 2005 and subsequently started as PhD student at the Department of Internal Medicine and Laboratory for Physiology at the VU University Medical Center in Amsterdam. In July 2010 she started her PhD-research at the Department of Anesthesiology and Laboratory for Physiology at the VU University Medical Center in Amsterdam. The results of this research are presented in this dissertation. She is two-time runner-up and in 2011 winner of the best presentation at the Dutch Society of

Anesthesiologists

conference.

She

co-founder

and

coordinator

the

Experimental Laboratory for VItal Signs (ELVIS). From January 2013 she is employed as a postdoctoral researcher at the Department of Anesthesiology of the VU University Medical Center in Amsterdam. Charissa is married to Rob Morren. They are the proud parents of Thijs (2012). In May 2014 they are expecting their second child. Charissa Esmé van den Brom werd geboren op 8 juli 1982 te Nijkerk. Na het behalen van haar havo diploma startte zij in 1999 met de studie Biochemie aan de hogeschool van Utrecht. Haar afstudeerstage heeft zij gelopen op de afdeling Toxicologie, Pathologie en Genetica van het RIVM te Bilthoven. Na het behalen van haar ingenieurs titel begon zij in 2003 met de master Medische Biologie aan de Vrije Universiteit te Amsterdam. Tijdens deze studie verbleef ze voor een half jaar in Norwich (Verenigd Koninkrijk) voor een onderzoeksstage bij het Institute for Food Research. Haar afstudeerstage volbracht zij op de afdeling Anatomie en Fysiologie aan de faculteit Diergeneeskunde van de Universiteit van Utrecht. In augustus 2005 behaalde zij haar doctoraalexamen. In januari 2006 startte zij als promovenda aan de afdelingen Interne Geneeskunde en Fysiologie van het VU medisch centrum. In juli 2010 begon zij als promovenda aan de afdelingen Anesthesiologie en Fysiologie aan het VU medisch centrum te Amsterdam. De resultaten van dit onderzoek staan in dit proefschrift beschreven. Ze is tweevoudig runner-up en de 2011 winnaar van de beste presentatie op het congres van de Nederlandse Vereniging voor Anesthesiologie. Ze is mede oprichtster en coördinator van het Experimental Laboratory for VItal Signs (ELVIS). Per januari 2013 is zij werkzaam als postdoctorale onderzoeker op de afdeling Anesthesiologie aan het VU medisch centrum

180

Curriculum Vitae

te Amsterdam. Charissa is getrouwd met Rob Morren. Samen zijn ze de trotse ouders van hun zoon Thijs (2012). In mei 2014 verwachten ze hun tweede kindje.

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury in rats

UITNODIGING voor het bijwonen van de openbare verdediging van het proefschrift

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury

Dietary modulation of the effects of sevoflurane on myocardial perfusion, function and ischemic injury in rats door Charissa van den Brom

in rats

Donderdag 30 januari 2014 om 15.45 uur In de aula van het Hoofdgebouw Vrije Universiteit De Boelelaan 1105 te Amsterdam Receptie na afloop van de promotie

Charissa EsmĂŠ van den Brom

Paranimfen Ester Weijers e.weijers@vumc.nl Marianne de Gruil-van Eldik eldik400@hotmail.com

Charissa EsmĂŠ van den Brom