Profound bioenergetic abnormalities in peri-infarct myocardial regions

Abstract

Regions of myocardial infarct (MI) are surrounded by a border zone (BZ) of normally perfused but dysfunctional myocardium. Although systolic dysfunction has been attributed to elevated wall stress in this region, there is evidence that intrinsic abnormalities of contractile performance exist in BZ myocardium. This study examined whether decreases of high-energy phosphates (HEP) and mitochondrial F 1F0-ATPase (mtATPase) subunits typical of failing myocardium exist in BZ myocardium of compensated postinfarct remodeled hearts. Eight pigs were studied 6 wk after MI was produced by ligation of the left anterior descending coronary artery (LAD) distal to the second diagonal. Animals developed compensated LV remodeling with a decrease of ejection fraction from 54.6 Ϯ 5.4% to 31 Ϯ 2.1% (MRI) 5 wk after LAD occlusion. The remote zone (RZ) myocardium demonstrated modest decreases of ATP and mtATPase components. In contrast, BZ myocardium demonstrated profound abnormalities with ATP levels decreased to 42% of normal, and phosphocreatine-to-ATP ratio ( 31 Pmagnetic resonance spectroscopy) decreased from 2.06 Ϯ 0.19 in normal hearts to 1.07 Ϯ 0.10, with decreases in ␣-, ␤-, OSCP, and IF 1 subunits of mtATPase, especially in the subendocardium. The reduction of myocardial creatine kinase isoform protein expression was also more severe in the BZ relative to the RZ myocardium. These abnormalities were independent of a change in mitochondrial content because the mitochondrial citrate synthase protein level was not different between the BZ and RZ. This regional heterogeneity of ATP content and expression of key enzymes in ATP production suggests that energetic insufficiency in the peri-infarct region may contribute to the transition from compensated LV remodeling to congestive heart failure. heart failure; metabolism; adenosine 5Ј-triphosphate; hypertrophy; border zone AFTER MYOCARDIAL INFARCTION, a period of compensated left ventricular (LV) remodeling with hemodynamic stability may be followed by the development of congestive heart failure (CHF). The mechanisms that contribute to the transition from compensated remodeling to CHF remain unclear but may be related to progressive contractile dysfunction of the region of viable myocardium that surrounds the infarct (border zone) (13). Tethering to the infarct causes an increase in the radius of curvature of the surrounding viable myocardium, thereby increasing wall stress, and likely energy demands, in this border zone (2,9,35). Using a porcine model of postinfarction LV remodeling, we previously observed modest reductions of ATP and the phosphocreatine (PCr)-to-ATP ratio in the remote noninfarcted myocardium of animals with compensated remodeling but marked abnormalities in animals that developed overt CHF (41). The levels of mitochondrial F 1 F 0 -ATP synthase (mtATPase; the final reaction in the pathway that links carbon substrate utilization to oxidative ATP synthesis) in myocardium remote from the infarct were also decreased in animals that developed overt CHF but not in animal...

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