Abstract 10858: Post-Ischemic Contractile Dysfunction is Exacerbated in a Porcine Model of Metabolic Syndrome, but Ameliorated by Restricting Fatty Acid Availability
Background: The poor prognosis of acute coronary syndrome (ACS) in patients with metabolic syndrome (Met Syn) is not fully explained by the extent of coronary atherosclerosis, suggesting that myocardial metabolic abnormalities may be culpable. We tested the hypothesis that myocardial contractile and metabolic recovery after regional ischemia are impaired in a porcine model of Met Syn and investigated underlying mechanisms for such responses.
Methods and Reults: Micropigs (n=27) were assigned to control (low-fat, no added sugar) or Met Syn diet (25% coconut oil, 20% high-fructose corn syrup w/w). Because no cholesterol was added to Met Syn diet, no atherosclerosis developed. However, Met Syn diet caused obesity, hypertension, dyslipidemia, insulin resistance without diabetes, and elevated plasma free fatty acids (FFA). After 7 months of diet, anesthetized pigs underwent 45 min low-flow regional ischemia followed by 120 min reperfusion. In 16 pigs, ischemia was imposed at ambient levels of arterial FFA (Control, 0.2 mmol/L; Met Syn 0.5 mmol/L). Contractile function (regional work) was similar in both groups at baseline. There were no differences between groups in PDK2 or PDK4 expression, PDH or AMPK activity, lactate oxidation, or perfusion. However, myocardial FFA utilization was greater in Met Syn than control. At 120 min reperfusion, regional work recovered to 61±13% of baseline in ontrols, but only 16±14% of baseline in Met Syn (p=0.01). In 11 pigs, euglycemic hyperinsulinemia was imposed for 90 min, ending 45 min prior to ischemia. Plasma insulin returned to baseline prior to ischemia and Akt was not persistently activated, but arterial FFA and myocardial FFA utilization remained at negligible levels during ischemia and reperfusion in both groups. Under these conditions, contractile recovery improved in both groups (Control, 73±6% of baseline; Met Syn, 59±14% of baseline) and no longer differed between groups.
Conclusion: Pigs with characteristics of Met Syn exhibit poor contractile recovery after myocardial ischemia that may be attributable to a shift in substrate preference toward FFA. The findings may help explain the poor prognosis of ACS in Met Syn, and suggest a potential role for interventions that acutely lower plasma FFA in that setting.
- © 2011 by American Heart Association, Inc.