Myocardial ischemia has, for many decades, been viewed as an all-or-none process that causes myocardial necrosis when prolonged and severe, but whose effects are transient when it is brief or mild. In view of the evidence that the ischemic process may "hit, run and stun," perhaps our thinking about the consequences of myocardial ischemia should be expanded. According to this formulation, an ischemic insult not of sufficient severity of duration to produce myocardial necrosis may acutely affect myocardial repolarization and cause angina (hit); but these changes wane rapidly (run), when the balance between myocardial oxygen supply and demand has been reestablished. However, the ischemia may interfere with normal myocardial function, biochemical processes and ultrastructure for prolonged periods (stun). The severity and duration of these postischemic changes depend on the length and intensity of the ischemia, as well as on the condition of the myocardium at the onset of the ischemic episode. Furthermore, it is likely that when the myocardium is repeatedly stunned, it may exhibit chronic postischemic left ventricular dysfunction, an ill-defined condition. If prolonged, chronic postischemic left ventricular dysfunction can progress to myocardial scarring and ischemic cardiomyopathy, it may be important to determine how often it can be ameliorated by permanent improvement of myocardial perfusion by surgical treatment.

The stunned myocardium: prolonged, postischemic ventricular dysfunction.

The time relationship for recovery of mechanical function, the intramyocardial electrogram and coronary flow after brief periods of regional myocardial ischemia, was studied in conscious dogs. Total left vemtricular (LV) function was assessed with measurements of LV systolic and diastolic pressures, rate of change of LV pressure (dP/dt), and dP/dt/P. Regional LV function was assessed with measurements of regional segment length and velocity of shortening. An implanted hydraulic occluder on either the left anterior descending or circumflex coronary artery was inflated for 5- and 15-min periods on separate days. A 5-min occlusion depressed overall LV function transiently, but just before release of occlusion overall function had nearly returned to control. At this time regional function in the ischemic zone was still depressed to the point of absent shorteining or paradoxical motion during systole and was associated with marked ST segment elevation (+ 10 +/- 2.2 mV) at the site where function was measured. With release of occlusion and reperfusion the intramyocardial electrogram returned to normal within 1 min, and reactive hyperemia subsided by 5-10 min. In contrast to the rapid return to preocclusion levels for coronary flow and the electrogram, regional mechanical function remained depressed for over 3 h. A 15-min coronary occlusion resulted in an even more prolonged (greater than 6 h) derangement of function in the ischemic zone. Thus, brief periods of coronary occlusion result in prolonged impairement of regional myocardial function which could not have been predicted from the rapid return of the electrogram and coronary flow. These observations indicate that brief interruptions of coronary flow result either in a prolonged period of local ischemia or that alterations of mechanical induced by ischemia far outlast the repayment of the oxygen debt.

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Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs.

We have shown previously that preconditioning myocardium with four 5-minute episodes of ischemia and reperfusion dramatically limited the size of infarcts caused by a subsequent 40-minute episode of sustained ischemia. The current study was undertaken to assess whether the same preconditioning protocol slowed the loss of high energy phosphates, limited catabolite accumulation, and/or delayed ultrastructural damage during a sustained ischemic episode. Myocardial metabolites and ultrastructure in the severely ischemic subendocardial regions were compared between control and preconditioned canine hearts. Hearts (four to 10 per group) were excised after 0, 5, 10, 20, or 40 minutes of sustained ischemia. All groups had comparable collateral blood flow. Preconditioned hearts developed ultrastructural injury more slowly than controls; evidence of irreversible injury was observed after 20 minutes in controls but not until 40 minutes in preconditioned hearts. Furthermore, after 40 minutes of ischemia, irreversible injury was homogeneous in controls but only focal in preconditioned myocardium. Preconditioning reduced starting levels of ATP by 29%. Nevertheless, it also slowed the rate of ATP depletion during the episode of sustained ischemia, so that after 10 minutes of ischemia, preconditioned hearts had more ATP than controls. However, after 40 minutes, ATP contents were not significantly different between groups. Preservation of ATP resulted from reduced ATP utilization and was not due to increased ATP production. Accumulation of purine nucleosides and bases (products of adenine nucleotide degradation) was limited in preconditioned myocardium. Accumulation of glucose-1-phosphate, glucose-6-phosphate, and lactate also was reduced markedly by preconditioning, due to reduced rates of glycogen breakdown and and anaerobic glycolysis. We propose that preconditioning reduces myocardial energy demand during ischemia, which results in a reduced rate of high energy phosphate utilization and a reduced rate of anaerobic glycolysis. Either preservation of ATP or reduction of the cellular load of catabolites may be responsible for delaying ischemic cell death.

Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode.

Myocardial regional function during acute coronary artery occlusion was studied using ultrasonic dimension gauges in open-chest dogs. Three pairs of 2-mm ultrasonic crystals were implanted 1 cm apart near the endocardium in an ischemic segment, a control segment, and a segment at the margin of the ischemic zone. In the ischemic segment, coronary artery occlusion resulted in prompt dyskinesis which progressed to holosystolic expansion; length at enddiastole (diastolic length) increased by 11%, segment stroke work decreased by 91%, and the diastolic pressure-length relationship was displaced and steepened. In the marginal segment, active shortening and stroke work decreased by 37% and diastolic length increased by 4%. In the control segment, an initial increase in active shortening was observed, followed by compensatory operation of the Frank-Starling mechanism. Nitroglycerin administered during coronary artery occlusion decreased diastolic length and increased shortening in all three segments. An early beneficial effect of isoproterenol on all segments was later replaced by deterioration in marginal and ischemic segments. After propranolol administration, the decrease in shortening of the marginal segment was reduced to half of that observed during a control coronary artery occlusion, suggesting a protective effect of this drug. These results indicate the power of this approach, which provides continuous quantification of regional wall function in myocardial ischemia and during therapeutic interventions.

Regional Myocardial Function during Acute Coronary Artery Occlusion and Its Modification by Pharmacologic Agents in the Dog

Coronary arteriography was performed before and after the intracoronary injection of nitroglycerin to determine the presence or absence of spasm in patients within the first 12 hours of acute myocardial infarction. Coronary arterial spasm was demonstrated in six of fifteen (40%) acute myocardial infarctions associated with coronary artery disease. In five of the six instances the interval from the onset of symptoms to arteriography was less than 6 hours. Spasm was superimposed on a high-grade atherosclerotic obstruction and was separated from the catheter tip by a segment of normal vessel in each instance. The coronary artery remained patent (following the initial relief of spasm) in two patients maintained on sublingual nitrates and heparin. Spasm, superimposed on an atherosclerotic obstruction, may be the primary event or a secondary occurrence in the pathophysiology of acute myocardial infarction. Catecholamines could play an important role in the early pathophysiology of acute myocardial infarction by producing spasm and/or platelet aggregation at the site of an atherosclerotic obstruction. A dynamic interaction between spasm, platelet aggregates and the atherosclerotic plaque may precede coronary thrombosis.

Arteriographic evidence of coronary arterial spasm in acute myocardial infarction.

The tissue content of energy-rich phosphates and glycolytic metabolites and the activity of myocardial enzymes were examined in the dog after producing myocardial infarction by ligating branches of the anterior descending and circumflex coronary arteries. The pattern of systolic fiber movement shown by a strain-gauge assembly differentiated ischemic from nonischemic portions of myocardium. In ischemic muscle, 30 minutes after onset of ischemia, creatine phosphate content fell from 8.0 to 1.4 µmoles/g, ATP content fell from 5.8 to 1.5 µmoles/g, lactate content rose tenfold, and α-glycerophosphate content rose fivefold. The content of energy-rich phosphates and glycolytic metabolites did not change much in nonischemic muscle. The activities of myocardial enzymes were assayed in extracts of tissue samples from ischemic and nonischemic muscle 5 to 120 minutes after coronary artery occlusion. The activities of aldolase, lactic dehydrogenase (LDH), glyceraldehydephosphate dehydrogenase, α-glycerophosphate dehydrogenase, malate dehydrogenase (MDH), and 6-phosphogluconate dehydrogenase did not change significantly in ischemic muscle during 2 hours of observation. In nonischemic muscle, phosphofructokinase activity increased 75% 5 minutes after coronary occlusion, followed by an increase in activity of isocitrate dehydrogenase, creatinephosphokinase, MDH, and LDH. The enzymatic changes in nonischemic muscle suggest metabolic changes in nonischemic muscle accompanying compensatory hyperfunction and increased energy requirements of surviving muscle.

Early Changes in Energy Metabolism in the Myocardium Following Acute Coronary Artery Occlusion in Anesthetized Dogs

The action of sublingual nitroglycerin (0.6 mg) and intravenous propranolol (0.1 mg/kg) on shortening of right ventricular fibers was investigated in patients with and without coronary artery disease. This was accomplished with a newly devised strain gauge catheter. Hemodynamic parameters and changes in the oxidation-reduction potential of heart muscle were determined. Nitroglycerin results in decrease in shortening and velocity of shortening of ventricular fibers, heart rate, left ventricular end-diastolic and systemic pressure, dp/dt, tension-time index, stroke index, peripheral resistance, and left ventricular minute work in normal and arteriosclerotic subjects. Intravenous propranolol leads to a fall in velocity of shortening of myocardial fibers, heart rate, dp/dt, stroke index, and left ventricular minute work. However, there is an increase in tension-time index and peripheral resistance with no change in systemic pressure. Left ventricular end-diastolic pressure rises significantly in arteriosclero...

A Comparative Study of Nitroglycerin and Propranolol

The effects of coronary reperfusion on recovery of regional myocardial contractility and high energy phosphate levels were studied In dogs after various periods of coronary occlusion. Segmental changes in myocardial contractility were measured by means of a strain gaugetipped, two-pronged catheter probe that measures myocardial fiber shortening. The curves of contraction are sensitive to the effects of ischemia. Coronary occlusion resulted in a rapid replacement of fiber shortening by passive fiber lengthening. If coronary occlusion was released and blood flow restored within 45 minutes, myocardial contractility returned promptly; adenosine triphosphate and creatine phosphate values were restored to normal. With coronary occlusion of 1 hour or longer, contractility failed to return in the immediate postperfusion period, but delayed return was recorded after 2 weeks of reperfusion. The extent of such recovery varied with the duration of preceding occlusion. Thus, reperfusion after 1 hour of occlusion was followed by return of fiber shortening over the entire reperfused region. With 2 hours of occlusion, recovery occurred over 75 percent of the reperfused myocardium. With 3 hours of occlusion followed by reperfusion, recovery of contractility was only partial, comprising approximately 60 percent of the reperfused region. High energy phosphate content of the reperfused myocardium showed a similar pattern of recovery. With occlusion of longer duration, reperfusion failed to restore contractility to any significant extent. These findings indicate that reperfusion after coronary occlusion of 1 to 3 hours may restore contractility over a period of 2 weeks, but the extent of such recovery diminishes with the increase in the duration of occlusion.

Contractile and biochemical effects of coronary reperfusion after extended periods of coronary occlusion

Biochemical changes in non-infarcted heart muscle following myocardial infarction

Drugs used in cardiogenic shock, namely, norepinephrine, norepinephrine plus phentolamine, metaraminol, isoproterenol and methoxainine, were experimentally evaluated by investigating their effects on myocardial forcevelocity relation in normal closed chest dogs. Further, the differential effects of these drugs on ischemic and nonischemic portions of the myocardium were appraised in open chest experiments in which acute myocardial infarction had been induced. The velocity of shortening of fibers was measured with the newly devised strain-gauge catheter assembly. These studies have shown that the desired increase in myocardial contractility and aortic pressure may best be accomplished by a combination of norepinephrine and phentolamine; the latter, in appropriate amounts, counteracts the excessive increase in peripheral resistance induced by norepinephrine. Isoproterenol, which augments contractility, may prove effective when peripheral resistance is adequate. Methoxamine, on the other hand, is least suited, since it has no effect on the myocardial contractile state and the increase in pressure load leads to a reciprocal decline in velocity of contraction and an increase in left ventricular end-diastolic pressure. Since most of these drugs act by increasing the velocity of contraction or by increasing afterload, or both, the effect of these variables oil myocardial oxygen demand is highly pertinent to the clinical use of these drugs. The action of these drugs in augmenting the magnitude of paradoxic systolic stretching of the fibers of the ischemic myocardium and the resulting increase in dissipation of ventricular pressure expended in producing such distention is regarded as an important factor working against the effectiveness of drug therapy.

Pritpal S. Puri

Papers

Early Changes in Energy Metabolism in the Myocardium Following Acute Coronary Artery Occlusion in Anesthetized Dogs

A Comparative Study of Nitroglycerin and Propranolol

Contractile and biochemical effects of coronary reperfusion after extended periods of coronary occlusion

Biochemical changes in non-infarcted heart muscle following myocardial infarction

Effect of drugs on myocardial contractility in the intact dog and in experimental myocardial infarction