Persistent Stunning Induces Myocardial Hibernation and Protection

Abstract

Abstract-To test the hypothesis that persistent myocardial stunning can lead to hibernating myocardium, 13 pigs were chronically instrumented, and persistent stunning was induced regionally by 6 repetitive episodes of 90-minute coronary stenosis (CS) (30% reduction in baseline coronary blood flow [CBF]) followed by full reperfusion every 12 hours. During the 1st CS, CBF fell from 43Ϯ2 to 31Ϯ2 mL/min, and anterior wall thickening (AWT) fell by 54Ϯ8%, but posterior WT did not change. AWT never recovered fully and remained depressed by 31Ϯ7% before the 6th CS, reflecting persistent myocardial stunning, but baseline CBF was not changed. Surprisingly, during the 6th CS, AWT did not fall further despite a similar reduction in CBF during CS, as occurred with the 1st episode. Regional MV O 2 fell similarly during the 1st and 6th CS. During the 1st CS, plasma glucose uptake increased, whereas free fatty acid (FFA) uptake was reduced. Before the 6th CS, glucose uptake remained elevated, whereas FFA uptake remained reduced. Histology revealed enhanced glycogen deposition, which could be explained by decreased glycogen synthase kinase (GSK)-3␤ protein levels and activity. These results indicate that persistent stunning, even in the absence of chronic ischemia, can recapitulate the phenotype of myocardial hibernation. This results in a shift in the flow/function relationship where a 30% decrease in CBF is no longer accompanied by a fall in myocardial function, which could be explained, in part, by a shift in substrate utilization. These hemodynamic/metabolic adjustments could facilitate survival of hibernating myocardium. Key Words: hibernating myocardium Ⅲ myocardial stunning Ⅲ metabolism Ⅲ glycogen synthase kinase-3␤ Ⅲ ischemia M yocardial stunning is defined as the impaired but reversible reduction of contractile function after a brief ischemic episode, where the flow/function relationship is altered. 1,2 The related concept of myocardial hibernation is based primarily on clinical observations 3-6 and has been thought to involve a self-protective downregulation in myocardial function and metabolism to match the reduced O 2 supply, rather than a change in the flow/function relationship. Studies in patients with hibernating myocardium where blood flow was measured with positron emission tomography (PET) 7-9 and a study in conscious pigs with progressive coronary stenosis induced by an ameroid constrictor for one month 10 all found maintained myocardial blood flow in the face of chronically and severely reduced regional myocardial function, reminiscent of myocardial stunning. The results from these studies raised the possibility that persistent stunning might be a mechanism involved in mediating hibernating myocardium, alternative to the mechanism of downregulated myocardial blood flow and O 2 consumption. If this is found to be true, then alternative protective mechanisms must be sought to understand how hibernating myocardium can survive in the face of persistent ischemia.In order to examine whether persistent myocardial s...

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