Persistent stunning induces myocardial hibernation and protection: flow/function and metabolic mechanisms

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 43+/-2 to 31+/-2 mL/min, and anterior wall thickening (AWT) fell by 54+/-8%, but posterior WT did not change. AWT never recovered fully and remained depressed by 31+/-7% 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 Mo2 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)-3beta 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.