Impaired contractile recovery after low-flow myocardial ischemia in a porcine model of metabolic syndrome

Am J Physiol Heart Circ Physiol. 2013 Mar 15;304(6):H861-73. doi: 10.1152/ajpheart.00535.2012. Epub 2013 Jan 18.

Abstract

Clinical metabolic syndrome conveys a poor prognosis in patients with acute coronary syndrome, not fully accounted for by the extent of coronary atherosclerosis. To explain this observation, we determined whether postischemic myocardial contractile and metabolic function are impaired in a porcine dietary model of metabolic syndrome without atherosclerosis. Micropigs (n = 28) were assigned to a control diet (low fat, no added sugars) or an intervention diet (high saturated fat and simple sugars, no added cholesterol) for 7 mo. The intervention diet produced obesity, hypertension, dyslipidemia, and impaired glucose tolerance, but not atherosclerosis. Under open-chest, anesthetized conditions, pigs underwent 45 min of low-flow myocardial ischemia and 120 min of reperfusion. In both diet groups, contractile function was similar at baseline and declined similarly during ischemia. However, after 120 min of reperfusion, regional work recovered to 21 ± 12% of baseline in metabolic syndrome pigs compared with 61 ± 13% in control pigs (P = 0.01). Ischemia-reperfusion caused a progressive decline in mechanical/metabolic efficiency (regional work/O2 consumption) in metabolic syndrome hearts, but not in control hearts. Metabolic syndrome hearts demonstrated altered fatty acyl composition of cardiolipin and increased Akt phosphorylation in both ischemic and nonischemic regions, suggesting tonic activation. Metabolic syndrome hearts used more fatty acid than control hearts (P = 0.03). When fatty acid availability was restricted by prior insulin exposure, differences between groups in postischemic contractile recovery and mechanical/metabolic efficiency were eliminated. In conclusion, pigs with characteristics of metabolic syndrome demonstrate impaired contractile and metabolic recovery after low-flow myocardial ischemia. Contributory mechanisms may include remodeling of cardiolipin, abnormal activation of Akt, and excessive utilization of fatty acid substrates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Animals
  • Blood Glucose
  • Cardiolipins / metabolism
  • Cholesterol / metabolism
  • Diet
  • Dietary Fats / adverse effects
  • Dietary Fats / metabolism
  • Disease Models, Animal
  • Glucose / metabolism
  • Heart Function Tests
  • Insulin / blood
  • MAP Kinase Signaling System
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / physiopathology*
  • Myocardial Contraction*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / physiopathology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Swine
  • Swine, Miniature

Substances

  • Acyl Coenzyme A
  • Blood Glucose
  • Cardiolipins
  • Dietary Fats
  • Insulin
  • Cholesterol
  • Proto-Oncogene Proteins c-akt
  • Glucose