Development of short-term myocardial hibernation. Its limitation by the severity of ischemia and inotropic stimulation.
Authors: Schulz R , Rose J , Martin C , Brodde O E , Heusch G 
Published: June 2012

BACKGROUND
Short-term hibernating myocardium is characterized by a decrease in contractile function in proportion to the reduced myocardial blood flow. Myocardial creatine phosphate content, initially decreased during the first minutes of ischemia, returns to near-control values, the ischemia-induced net lactate production is attenuated, and the myocardium remains viable despite ongoing hypoperfusion and contractile dysfunction. Hibernating myocardium after 85 minutes of ischemia maintains an inotropic reserve and responds to short-term intracoronary dobutamine infusion with increased work; however, this inotropic response is at the expense of metabolic recovery. We therefore hypothesized that the development of myocardial hibernation is a delicate process that is easily disturbed by unfavorable alterations in the oxygen-supply demand balance.

METHODS AND RESULTS
To study the impact of prolonged inotropic stimulation on the development of myocardial hibernation, the left anterior descending coronary artery was cannulated and hypoperfused at constant flow in 12 enflurane-anesthetized swine. The reduction of coronary inflow was followed by a reduction of regional myocardial work (sonomicrometry) from 248 +/- 59 mm Hg.mm to 73 +/- 35 mm Hg.mm (P < .05) at 5 minutes of ischemia. Dobutamine (2.5 +/- 1 micrograms/min) was then infused for an additional 85 minutes. Work was increased at 5 minutes of dobutamine to 139 +/- 34 mm Hg.mm (P < .05 versus 5 minutes of ischemia). However, this increase was only transient, and after 85 minutes of dobutamine, work was decreased below the initial ischemic value (42 +/- 34 mm Hg.mm). At 5 minutes of ischemia, creatine phosphate content was reduced from 8.80 +/- 1.97 to 6.21 +/- 3.87 mumol/g wet wt, and myocardial ATP content was decreased slightly from 4.75 +/- 0.92 to 4.12 +/- 1.29 mumol/g wet wt (both, P = NS). After 5 minutes of dobutamine, further reductions in creatine phosphate content to 3.11 +/- 0.76 mumol/g wet wt and in ATP to 3.14 +/- 0.81 mumol/g wet wt were observed (both, P < .05 versus control). During the remainder of the continuous dobutamine infusion, creatine phosphate content remained unchanged, whereas ATP further decreased significantly to 1.68 +/- 0.96 mumol/g wet wt. The beta-adrenoceptor density of the left anterior descending coronary artery-perfused myocardium was 36.5 +/- 5.8 fmol (-)-[125I]iodocyanopindolol/mg protein under control conditions, and this was unchanged during ischemia and the subsequent dobutamine infusion. Following 90 minutes of ischemia with 85 minutes of dobutamine and 2 hours of reperfusion, infarct size (triphenyl tetrazolium chloride staining) was 26.3 +/- 7.5% of the area at risk. With constant hypoperfusion, dobutamine redistributed blood flow away from the subendocardium (0.20 +/- 0.08 versus 0.11 +/- 0.04 mL.min-1.g-1) toward the subepicardium (0.45 +/- 0.13 versus 0.51 +/- 0.21 mL.min-1.g-1) as well as to the right ventricle (0.26 +/- 0.08 versus 0.32 +/- 0.09 mL.min-1.g-1). Therefore, in two other groups of six and five swine, the severity of ischemia was increased to achieve an 80% or a 90% reduction in regional function, respectively, and the importance of the severity of blood flow reduction per se for the development of myocardial infarction was studied. The infarct size in the animals undergoing 85 minutes of dobutamine (26.3 +/- 7.5%) was increased above the level expected from the blood flow reduction alone (6.3 +/- 6.4%, P < .01).

CONCLUSIONS
Both the increased severity of ischemia and the enhanced energy expenditure induced by dobutamine impair the development of myocardial short-term hibernation and precipitate myocardial infarction.