Repeated short periods of regional myocardial ischemia: effect on local function and high energy phosphate levels

Abstract

The effect of recurrent periods of ischemia on the myocardium was investigated in 15 open-chest dogs. Ischemia was produced by 3 minutes of proximal occlusion of the left anterior descending coronary artery. Each occlusion was followed by reperfusion of 3 minutes duration. Forty occlusions with a total of 120 minutes of ischemia were performed, and regional function (sonomicrometry) as well as high energy phosphates (needle biopsies) were determined at the end of the 5th, 20th, and 40th period of ischemia and reperfusion. The first periods of ischemia had a cumulative effect both on regional postischemic function (44% and 59% respectively of preischemic control after 20 occlusions) and on the ATP content, but with increasing number of occlusions the additive effects became smaller (ATP reduction/mumol/g w w/per occlusion). The ATP breakdown per occlusion was diminished with increasing number of periods of ischemia, and no significant adenosine was measured in the ischemic myocardium. Higher than normal postischemic creatine phosphate levels (9.1 mumol/g w w at the 40th reperfusion vs. 6.7 mumol/g w w control) indicated a functioning oxidative phosphorylation in the presence of an ATP utilization problem at the sarcomere level, because indicators of the cellular energy level (energy charge, free energy change of ATP hydrolysis) quickly normalized during reperfusion. Stunned myocardium is therefore not a problem of energy supply but rather of energy utilization. Reduced ATP utilization and regional dysfunction are the expressions of the same cellular defect which resides either in the ATP-splitting contractile apparatus or in the electromechanical coupling. Contractile dysfunction during reperfusion protects the heart against subsequent periods of ischemia because ATP turnover is reduced.

Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

“…Similar results were obtained by Hoffmeister et al ( 14) in openchest dogs subjected to (18); and in conscious dogs after three episodes of exercise-induced ischemia (17). In one study (19) in conscious dogs subjected to five 5-min LAD occlusions, a cumulative effect was found when the intervening reperfusion period was 5 10 min but not when it was 15 min.…”

“…This issue is important because, if the injury ceases after the first few ischemic episodes, then myocardial stunning would be a self-limiting process; on the other hand, if each subsequent ischemic episode continues to inflict additional injury, then the possibility exists that myocardium subjected to recurrent bouts of ischemia may become chronically stunned. Previous investigations have yielded conflicting results, with some (6-10, [14][15][16][17][18][19][20][21][22] but not all (23)(24)(25) studies reporting a cumulative effect. Even the studies that have observed a cumulative effect, however, have uniformly concluded that the decrement in function resulting from each subsequent occlusion becomes smaller with the number of repetitions and that after the first three to five occlusions, subsequent occlusions have little or no effect on postischemic dysfunction (6)(7)(8)(9)(10)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…One problem with the interpretation of these studies (6)(7)(8)(9)(10)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) is that the presence or absence of a cumulative effect was judged solely from the nadir of function attained immediately or shortly after each ischemia-reperfusion cycle. To our knowledge, no previous study has systematically analyzed the effect of recurrent ischemic episodes on the duration and time course of postischemic abnormalities.…”

“…emic insults may not exacerbate the mechanical dysfunction attained immediately or shortly after each reperfusion, they may increase the overall magnitude of postischemic dysfunction, i.e., the severity of the dysfunction present after the early period of reflow and/or the total duration of the dysfunction. Elucidation of this issue would require a different approach from that used in previous studies (6)(7)(8)(9)(10)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25); namely, different numbers of ischemic episodes would have to be produced in different groups of animals and integrated measurements of postischemic dysfunction would have to be compared.…”

Myocardial protection with preconditioning.

“…There was no reduction of infarct size, however, in preconditioned dogs after 3 hours of sustained ischemia, an observation consistent with the study by Murry et al 9 In a number of studies, the relation between repetitive coronary artery occlusions and myocardial high-energy phosphate stores was examined. [6][7][8]24 The observations from several groups are in agreement and indicate that repetitive occlusion followed by intermittent reperfusion are not associated with a cumulative metabolic deficit. There is no further decrement in high-energy phosphate stores beyond that which is observed to occur with the initial brief occlusion, and there is a decrease in the rate of high-energy phosphate utilization or a "sparing" effect with each subsequent brief ischemic episode.…”