Evolution of Acute Myocardial Injury

The temporal evolution and extent of irreversible myocardial injury after coronary occlusion is quite variable and strongly dependent on the magnitude of residual coronary flow, the hemodynamic determinants of oxygen consumption, and any endogenous protection afforded by preconditioning.^1,2 Reimer and Jennings demonstrated that in the absence of significant collaterals, irreversible injury begins approximately 20 minutes after coronary occlusion³ and progresses in a wavefront from the subendocardium to the subepicardium (Fig. 36-1).⁴ This susceptibility of the subendocardium to injury reflects its higher oxygen consumption and the redistribution of collateral flow to the outer layers of the heart by the compressive determinants of flow at reduced coronary pressure.⁵ In experimental infarction, the entire subendocardium is irreversibly injured within 1 hour of occlusion, and the transmural progression of infarction is largely complete within 4 to 6 hours. Factors that increase myocardial oxygen consumption (e.g., tachycardia, hypertension) or reduce oxygen delivery (e.g., anemia, hypotension) accelerate the progression to irreversible injury. In contrast, repetitive reversible ischemia prior to occlusion can limit irreversible injury through a preconditioning effect.¹

Figure 36-1 Wavefront of necrosis in infarction. Total coronary occlusions of less than 20 minutes do not cause irreversible injury but can cause myocardial stunning, as well as precondition the heart and protect against recurrent ischemic injury. Irreversible myocyte injury begins after 20 minutes and progresses as a wavefront from subendocardium to subepicardium. After 60 minutes, the inner third of the LV wall is irreversibly injured. After 3 hours, there is a subepicardial rim of tissue remaining, with the transmural extent of infarction completed between 3 to 6 hours after occlusion. The most important factor delaying the progression of irreversible injury is the magnitude of collateral flow, which is primarily directed to the outer layers of the heart.

(Modified from Kloner RA, Jennings RB: Consequences of brief ischemia: Stunning, preconditioning, and their clinical implications: Part 1, Circulation 104:2981–2989, 2001, Reprinted with permission.)

Residual Coronary Flow Limits Infarction

The magnitude of residual coronary flow, either due to subtotal coronary occlusion or the presence of intercoronary collaterals, is the most important determinant of the actual time course of irreversible injury. Ultimate infarct size as a percent of the area at risk of ischemia during a total occlusion is inversely related to collateral flow.⁶ Subendocardial flow of as little as 30% of resting values can prevent infarction during ischemic periods exceeding an hour. More moderate subendocardial ischemia (e.g., flow reduced by 50%) can persist for hours without resulting in significant irreversible injury.⁷ This phenomenon explains how the signs and symptoms of ischemia can be present for prolonged periods without producing significant myocardial necrosis. It also accounts for the observation that late coronary reperfusion can salvage myocardium beyond the 6-hour limit predicted from experimental models.

Mechanisms of Myocyte Death

During prolonged ischemia with myocardial infarction, cell death arises from two distinct mechanisms. Oxidative stress associated with reperfusion immediately causes myocyte necrosis, characterized by sarcolemmal disruption with the leakage of cell contents into the extracellular space. The associated damage is further amplified by leukocyte-mediated injury arising from reperfusion that can variably produce intravascular occlusion and the “no-reflow phenomenon.” After initial survival from ischemia and reperfusion, there is a second wave of myocyte loss due to programmed cell death or apoptosis. This is an energy-dependent and coordinated involution of critically damaged cells that circumvents the inflammation associated with necrotic cell death. The relative importance of each mechanism of cell death in myocardial infarction continues to be controversial.

Stunned Myocardium

There is a temporal delay in the recovery of function after single episodes of ischemia lasting more than 2 minutes. This regional dysfunction occurs despite the restoration of perfusion, with the time course of recovery determined by the duration and severity of the antecedent ischemia. Heyndrickx et al. were the first to demonstrate that regional dysfunction could persist for hours following a 15-minute occlusion, despite complete reperfusion (Fig. 36-3),⁸ a phenomenon that Kloner and Braunwald subsequently called stunned myocardium.⁹ The physiologic hallmark of stunned myocardium is a dissociation of the usual close relation between subendocardial flow and function, where regional dysfunction is present despite normal levels of resting perfusion. Stunned myocardium can also occur after demand-induced ischemia. For example, in the presence of a coronary stenosis, exercise can result in depressed regional function that persists for hours after perfusion is restored, and repetitive ischemia can lead to cumulative stunning.¹⁰ From a clinical perspective, the identification of stunned myocardium is important, since unlike other dysfunctional states, regional function will spontaneously normalize in the absence of recurrent ischemia. Furthermore, contractile reserve is invariably present with inotropic stimulation (e.g., dobutamine infusion), usually normalizing regional function (see Table 36-1). In contrast to animal models, acutely stunned myocardium in patients is not always a “pure entity” and frequently coexists with irreversibly injured and viable, chronically dysfunctional myocardium (i.e., chronically stunned and hibernating myocardium, vide infra).

Figure 36-3 Experimental findings in stunned myocardium. A, Myocardial stunning following a brief total occlusion. During a 15-minute total occlusion (OCCL), wall thickening measured by ultrasonic crystals (WT) is dyskinetic, with systolic thinning. After reperfusion (R), function is initially depressed but normalizes after 24 hours. B, Myocardial stunning following a prolonged partial occlusion. During acute ischemia (red circles), there was perfusion-contraction matching or “short-term hibernation.” With reperfusion (blue squares), wall thickening remains depressed and only returns to normal after several days.

(A, Modified from Heyndrickx et al.⁸⁴ and republished with permission from the American Physiological Society. B, From Matsuzaki M, Gallagher KP, Kemper WS, et al: Sustained regional dysfunction produced by prolonged coronary stenosis: Gradual recovery after reperfusion, Circulation 68:170–182, 1983. Reprinted with permission.)

Short-Term Hibernation During Prolonged Moderate Ischemia

When coronary pressure distal to a stenosis falls below the lower limit of autoregulation, flow reserve is exhausted, resulting in subendocardial ischemia during which reductions in subendocardial flow are closely coupled to reductions in regional contractile function.¹¹ When moderate ischemia persists, the close matching between perfusion and contraction results in a new steady-state with reduced regional oxygen consumption and energy utilization, a phenomenon termed short-term hibernation.^7,11 Despite persistent hypoperfusion, the balance between oxygen supply and demand is reestablished, as reflected by regeneration of creatine phosphate and ATP as well as the resolution of lactate production (Fig. 36-4).¹² Importantly, this ability to restore an energetic balance allows myocyte viability to be maintained for a much longer period of time than when flow is absent. Reperfusion of short-term hibernation also leads to stunning, which may take up to a week to resolve (see Fig. 36-3).¹³

Figure 36-4 Metabolic matching during short-term hibernation. During moderate ischemia, contractile function falls to a new steady state and is accompanied by adaptations in myocardial energy metabolism. These are characterized by an initial fall in creatine phosphate (PCr) and adenosine triphosphate (ATP). The transmural metabolite changes are greatest in the subendocardium (red squares), reflecting the transmural variations in flow. With persistent ischemia, metabolism stabilizes with a regeneration of PCr that prevents further ATP depletion. Although not shown, tissue lactate is transiently increased but normalizes with persistent ischemia.

(Adapted from Pantely GA, Malone SA, Rhen WS, et al: Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia, Circ Res 67:1481–1493, 1990.)

While short-term hibernation was originally hypothesized to be the mechanism of chronic hibernating myocardium, it is now clear that short-term hibernation is an extremely tenuous condition, with small increases in myocardial oxygen demand precipitating recurrent ischemia and a rapid deterioration in function and metabolism.⁶ Thus, the reversible nature of short-term hibernation is limited by the severity and duration of ischemia, with irreversible injury frequently occurring after more than 12 to 24 hours.¹⁴

Chronically Stunned Myocardium

Basic studies have clearly shown that repetitive episodes of myocardial ischemia with^17–19 and without a residual stenosis^20,21 can result in chronic regional dysfunction with normal resting perfusion. In experimental animal models with a progressive stenosis, chronically stunned myocardium precedes the development of hibernating myocardium.^18,22 Although resting flow is normal in chronically stunned myocardium, the regional uptake of the glucose analog, fluorine-18 2-fluorodeoxyglucose (FDG), is variably increased and appears to be related to the physiologic severity of a coronary stenosis. For example, pigs chronically instrumented with a fixed-diameter left anterior descending (LAD) coronary artery stenosis have regional dysfunction with normal resting perfusion at both 1 and 2 months after initial instrumentation (Fig. 36-6).¹⁸ Regional FDG uptake is initially normal, but it becomes increased as the reduction in flow reserve progresses, and this persists with the transition to hibernating myocardium.

Figure 36-6 Physiologic progression from chronically stunned to hibernating myocardium. Transmural microsphere flow measurements from pigs instrumented with a progressive LAD stenosis at rest and during adenosine vasodilation are shown, along with transmural variations in FDG uptake (fasting conditions) obtained by ex vivo counting. Angiographic stenosis severity and anterior wall motion score (3 normal, 2 mild hypokinesis, 1 severe hypokinesis) at each time point are summarized below the graphs. As stenosis severity increases over time, there is a reduction in vasodilated flow (adenosine) to the LAD region, reflecting a functionally significant coronary lesion. Initially (1 and 2 months after instrumentation), anterior hypokinesis develops, with normal resting flow consistent with chronically stunned myocardium. After 3 months, the stenosis frequently progresses to total occlusion with collateral-dependent myocardium and a critical impairment in coronary flow reserve. At this time, resting flow to the inner two-thirds of the LAD myocardium becomes reduced, compared to normally perfused remote myocardium. The latter findings are consistent with hibernating myocardium and develop without evidence of infarction in this animal model. The temporal progression of abnormalities demonstrates that chronic stunning precedes the development of hibernating myocardium. In contrast to short-term hibernation resulting from acute ischemia, the reduction in resting flow is a consequence rather than cause of the contractile dysfunction. FDG, fluorine-18 2-fluorodeoxyglucose; LAD, left anterior descending coronary artery.

(Modified from Fallavollita JA, Canty JM Jr: Differential 18F-2-deoxyglucose uptake in viable dysfunctional myocardium with normal resting perfusion: Evidence for chronic stunning in pigs, Circulation 99:2798–2805, 1999.)

From a clinical perspective, it is important to recognize that viable, chronically dysfunctional myocardium with normal resting perfusion is much more common than hibernating myocardium,^23,24 and it can develop independently of ischemia. For example, in patients with ischemic cardiomyopathy, regional dysfunction with normal resting perfusion may occur distant from a large dysfunctional region (viable or infarcted) as a result of pathologic remodeling. Dysfunction in this remodeled myocardium will not improve with regional revascularization, since it is not a direct result of ischemia. Thus, normal resting perfusion does not necessarily translate into reversible dyssynergy, and it is not surprising that noninfarcted but remodeled segments sometimes have persistent dysfunction after coronary revascularization.²⁵

Chronic Hibernating Myocardium

Hibernating myocardium is characterized by contractile dysfunction with reduced resting flow, in the absence of acute ischemia or significant necrosis. It is common in patients with ischemic cardiomyopathy,²⁶ where it frequently coexists with nontransmural infarction and can also occur in the absence of heart failure or global LV dysfunction. The best clinical example of isolated hibernating myocardium is in patients with chronic coronary occlusions and collateral-dependent myocardium (Fig. 36-7).^27,28 A similar constellation of findings has been reproduced in pigs in the absence of infarction or heart failure, which has facilitated the investigation of the underlying adaptations to ischemia that result in hibernating myocardium.²² Studies examining these key physiologic adaptations are summarized later.

Figure 36-7 Clinical imaging of chronic LAD occlusion and collateral-dependent hibernating myocardium. The RAO tracings of the left ventriculogram show anterior akinesis (upper left). Transaxial PET scans illustrate ¹³NH₃ flow measurements at rest (lower left) and following pharmacologic vasodilation with dipyridamole (lower right). Resting flow is reduced compared to normal regions in the same heart. The perfusion deficit during vasodilation is even more severe, and quantitative analysis demonstrates that LAD flow reserve is critically impaired. Viability is identified by increased FDG uptake (following an oral glucose load) in the anterior wall (upper right). FDG, fluorine-18 2-fluorodeoxyglucose; LAD, left anterior descending coronary artery.

(Modified from Vanoverschelde J-LJ, Wijns W, Depre C, et al: Mechanisms of chronic regional postischemic dysfunction in humans: New insights from the study of noninfarcted collateral-dependent myocardium, Circulation 87:1513–1523, 1993.)

The unpredictable progression of clinical coronary disease precludes defining the temporal evolution of hibernating myocardium in patients, and it was originally thought that hibernating myocardium arose from a primary reduction in flow in a fashion similar to experimental models of prolonged moderate ischemia and short-term hibernation.⁷ While this is a plausible mechanism for the development of hibernating myocardium in association with an acute coronary syndrome, more recent studies have highlighted the role of the physiologic severity of a coronary stenosis and repetitive ischemia as the major determinants of the progression from stunned to hibernating myocardium. This paradigm developed from animal studies with a slowly progressive stenosis that clearly demonstrated that regional dysfunction with normal resting flow (chronically stunned myocardium) preceded the development of hibernating myocardium, with the down-regulation in resting flow associated with a critical impairment in subendocardial flow reserve (see Fig. 36-6).^15,18,22,29 This progression is not merely a function of time, since the transition from chronically stunned to hibernating myocardium can be experimentally produced in as little as 1 week after placement of a critical stenosis which exhausts coronary flow reserve.¹⁹ A common conclusion of all serial studies is that reduced resting flow in hibernating myocardium is a result rather than a cause of the contractile dysfunction. As will be discussed, the down-regulation of resting flow in hibernating myocardium appears to be a physiologic marker reflecting numerous intrinsic metabolic adaptations of the heart to repetitive episodes of ischemia.

Metabolic and Energetic Adaptations to Chronic Ischemia