Copyright © 2006, European Society of Cardiology
Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart
aUniversity Laboratory of Physiology, University of Oxford, Parks Rd., Oxford, OX1 3PT, England, UK
bDepartment of Cardiovascular Medicine, Henry Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, England, UK
* Corresponding author. Tel.: +44 1865 272560; fax: +44 870 135 7474. Email address: andrew.murray{at}physiol.ox.ac.uk
Objective Many patients with heart failure have whole-body insulin resistance and reduced cardiac fluorodeoxyglucose uptake, but whether these metabolic changes have detrimental effects on the heart is unknown. Here, we tested whether there is a link between insulin resistance and ischemic damage in the chronically infarcted Wistar rat heart, postulating that the heart would have decreased insulin sensitivity, with lower GLUT4 glucose transporter protein levels due to high circulating free fatty acid (FFA) concentrations. A decreased capacity for glucose uptake would lower glycolytic adenosine triphosphate (ATP) production and thereby increase ischemic injury in the infarcted heart.
Methods and results In vivo left ventricular ejection fractions, measured using echocardiography, were 40% lower in rats 10weeks after coronary artery ligation than in sham-operated control rats. Insulin-stimulated D[2-3H]glucose uptake was 42% lower in isolated, perfused, infarcted hearts. Myocardial GLUT4 glucose transporter protein levels were 28% lower in the infarcted hearts and correlated negatively with ejection fractions and with fasting plasma FFA concentrations. Compared with controls, chronically infarcted hearts had 46% lower total glucose uptake and three-fold faster ATP hydrolysis rates, measured using phosphorus-31 nuclear magnetic resonance spectroscopy, during 32-min ischemia at 0.4ml/min/gww. During reperfusion, recovery of left ventricular developed pressure in infarcted hearts was 42% lower than in control hearts.
Conclusions Glucose uptake, in response to insulin or ischemia, was lower in the chronically infarcted rat heart and associated with increased circulating FFA concentrations and decreased GLUT4 levels. Thus, infarcted hearts had greater ATP depletion, and consequently incurred greater damage, during ischemia.
KEYWORDS Infarction; Heart failure; Ischemia; Insulin resistance; Energy metabolism
Abbreviations: FFA, free fatty acid • ATP, adenosine triphosphate • gww, grams wet weight • PCr, phosphocreatine • 31P NMR, phosphorus-31 nuclear magnetic resonance • RPP, rate–pressure product
Time for primary review 24 days
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