Abstract 516: Pathologic Remodeling of Myocardial Cardiolipin in a Porcine Model of Diet-Induced Obesity and Insulin Resistance

Abstract

Background: Cardiolipin is a dimeric phospholipid required for normal mitochondrial function. The majority of cardiolipin molecules contain four linoleic acid (18:2) residues. Pathologic decrease in (18:2) 4 cardiolipin content has been associated with cardiomyopathy. Patients with obesity and insulin resistance have poorer outcomes after myocardial infarction compared with lean subjects. In the present study, we determined if cardiolipin content and composition are altered in a new porcine model of diet-induced obesity and insulin resistance. Methods: Yucatan micropigs (n=16) were assigned to a control diet (4% w/w fat, 2% simple sugars, quantity fed 30 g/kg/day) or an intervention diet (25% fat from coconut oil, 17% simple sugars, 50 g/kg/day) for 7 months. Pigs were then anesthetized and subjected to 45 min low-flow myocardial ischemia and 120 min reperfusion (I/R, n=11). Regional myocardial external work and O 2 consumption were measured. After euthanasia, neutral lipid content in myocardial samples was assayed by solid phase extraction and gas chromatographic mass spectrometry, and cardiolipin species were quantified by electrospray ionization mass spectrometry. Results: Compared with controls, the intervention diet group recapitulated characteristics of the clinical “metabolic syndrome” with obesity (73 ± 4 vs 40±4 kg), insulin resistance by glucose tolerance testing, hypertension, and hyperlipidemia. There was abnormal substitution of saturated fatty acyl moieties in all myocardial lipid pools. Myocardial content of normal cardiolipin (18:2) 4 was reduced by an average of 13% (p=0.02), while several smaller pools of abnormal cardiolipin species were increased. For example, cardiolipin with one myristic acid residue substituted for a linoleic acid residue was increased by an average of 400% (p=0.001). After I/R, external work was approximately 20% lower (p=0.2) and MVO 2 was 50% lower (p=0.07) in the intervention diet group. Conclusions: Pigs fed a diet high in saturated fat and energy content for 7 months develop a phenotype resembling the clinical metabolic syndrome. This is accompanied by pathologic remodeling of myocardial cardiolipin, which in turn may contribute to decreased contractile and metabolic performance after I/R.