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The major cause of acute myocardial infarction (MI) is coronary atherosclerosis with superimposed luminal thrombus, which accounts for more than 80% of all infarcts. MIs resulting from nonatherosclerotic diseases of the coronary arteries are rare. In past decades, there have been several trends regarding the epidemiology and outcome of patients hospitalized with acute MI. Over the time span from 1975 to 2009, patients became significantly older, were more likely to be women, and were more likely to receive effective cardiac medications. Despite a greater prevalence of comorbidities, hospital survival rates have globally improved over time.1 However, mortality has remained unchanged for patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI,2 mostly because of secular trends as a result of changing population.3 Reperfusion (blood flow restoration into the ischemic territory) is the only available treatment to stop the progression of ischemic damage during an MI, but comes at a price, inducing additional harm to the myocardium.4 Reperfusion injury, which accounts for up to 40% of total infarct size, is thus considered “a necessary evil.”5
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Mechanisms of Myocardial Injury
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The normal function of the heart muscle is supported by high rates of myocardial blood flow, oxygen consumption, and combustion of fat and carbohydrates (glucose and lactate). Under normal aerobic conditions, cardiac energy is derived from fatty acids, supplying 60% to 90% of the energy for adenosine triphosphate (ATP) synthesis (Fig. 37–1). The rest of the energy (10%-40%) comes from oxidation of pyruvate formed from glycolysis and lactate oxidation. Almost all of the ATP formed comes from oxidative phosphorylation in the mitochondria; only a small amount of ATP (< 2%) is synthesized by glycolysis. Approximately two-thirds of the ATP used by the heart goes to contractile shortening, and the remaining third is used by sarcoplasmic reticulum Ca2+ ATPase and other ion pumps.
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Sudden occlusion of a major branch of a coronary artery shifts aerobic or mitochondrial metabolism to anaerobic glycolysis within seconds of reduced arterial flow. Myocardial ischemia primarily affects mitochondrial metabolism, resulting in a decrease in ATP formation by shutting off oxidative phosphorylation. The reduced aerobic ATP formation stimulates glycolysis and an increase in myocardial glucose uptake and glycogen breakdown (Fig. 37–2). Decreased ATP inhibits Na+/K+-ATPase, increasing intracellular Na+ and Cl, leading to cell swelling. Derangements in transport systems in the sarcolemma and sarcoplasmic reticulum increase cytosolic Ca2+, inducing activation of proteases and alterations in contractile proteins. Pyruvate is not readily oxidized in the mitochondria, leading to the production of lactate, a decrease in intracellular pH, and a reduction in contractile function. The decrease in pH also leads to greater ATP requirement to maintain Ca2+ homeostasis.6,7
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Electron microscopic alterations result from reversible and irreversible myocardial ischemic injury and are similar across animal species, with some variation in time course. Reversibly injured myocytes are edematous and swollen from the osmotic overload. The cell size is increased with a decrease in the glycogen content.8,9,10 The myocyte fibrils are relaxed and thinned; I-bands are prominent secondary to noncontracting ischemic myocytes.7 The nuclei show mild condensation of chromatin at the nucleoplasm. The cell membrane (sarcolemma) is intact, and no breaks can be identified. The mitochondria are swollen, with loss of normal dense mitochondrial granules and incomplete clearing of the mitochondrial matrix but without amorphous or granular flocculent densities (Fig. 37–3). Irreversibly injured myocytes contain shrunken nuclei with marked chromatin margination. The two hallmarks of irreversible injury are cell membrane breaks and mitochondrial presence of small osmiophilic amorphous densities.11 The densities are composed of lipid, denatured proteins, and calcium.12 The cell membrane breaks are small and are associated with subsarcolemmal blebs of edema fluid (see Fig. 37–3B).
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Irreversible ischemic injury is characterized by a variety of processes involving the sarcolemmal membrane and eventuating in its disruption and cell death. Increased cytosolic Ca2+ and mitochondrial impairment cause phospholipase activation and release of lysophospholipids and free fatty acids, which are incorporated within the cell and are damaged by peroxidation from free radicals and toxic oxygen species. Cleavage of anchoring cytoskeletal proteins and progressive increases in cell membrane permeability result in physical disruption and cell death.12
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Different Types of Cardiomyocyte Death During Myocardial Infarction: Necrosis, Apoptosis, Autophagy, and Necroptosis
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MI has traditionally been viewed as a manifestation of necrotic cell death, but recently, different forms of cardiomyocyte death have been identified during reperfused MI.4 Necrosis is morphologically characterized by myofibrillar contraction bands, swollen and ruptured mitochondria, destruction of cardiomyocyte membranes, microvascular destruction, hemorrhage, and inflammation. Most of these morphologic features are aggravated and made more manifest by reperfusion.13,14,15,16,17 Necrosis is thought to result from unregulated and uncoordinated pathophysiologic mechanisms. During ischemia, the developing acidosis from anaerobic glycolysis increases the influx of Na+ through the Na+/H+ exchanger, and intracellular Na+ accumulation is increased by the inhibition of Na+/K+-ATPase as a result of the lack of available ATP.18,19 The subsequent exchange of Na+ for Ca2+ by reverse mode operation of the sarcolemmal Na+/Ca2+ exchanger induces intracellular Ca2+ overload. Upon reperfusion, the rapid normalization of pH and re-energization in the context of elevated cytosolic Ca2+ induces oscillatory release and re-uptake of Ca2+ into the sarcoplasmic reticulum, causing uncontrolled excess myofibrillar hypercontraction.19,20,21 The normalization of the acidic pH also activates calpain, which digests the cytoskeleton and the sarcolemma.22 The high cytosolic concentrations of Na+ and Ca2+ result in intracellular edema when extracellular osmolarity is rapidly normalized by reperfusion. Finally, excess formation of reactive oxygen species contributes to sarcolemmal disruption.23 Necrosis is typically followed by an inflammatory response.
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Unlike necrosis, apoptosis, autophagy, and necroptosis are regulated processes with specific underlying signal transduction mechanisms.24,25 Apoptosis is an energy-consuming form of cell death characterized by characteristic DNA strand breaks that are identified by DNA laddering and/or terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining.26 Apoptosis can be initiated extrinsically by activation of sarcolemmal receptors, notably Fas and tumor necrosis factor-α receptors,27 or intrinsically by mitochondrial release of cytochrome C, which initiates a cascade of caspase activation leading to intracellular proteolysis, typically without an inflammatory response.25 A pivotal event in the initiation of apoptotic cell death is the opening of the mitochondrial permeability transition pore (MPTP).28 The MPTP is a large-conductance megachannel that is closed under physiologic conditions but opens in response to increased concentrations of calcium, inorganic phosphate, or reactive oxygen species and to a decreased inner mitochondrial membrane potential, all of which are present in myocardial ischemia/reperfusion.29,30 Formation and opening of the MPTP result in mitochondrial matrix swelling, ultimately leading to rupture of the outer membrane and release of cytochrome C to the cytosol, where it activates the caspase cascade. Pro- and antiapoptotic proteins of the Bcl family interact with the MPTP.31 Recently, the traditional view of the MPTP has been questioned because all of its purported constituents are dispensable under some conditions, and it is possible that the MPTP originates from F-ATP synthase.32 Autophagy is a regulated process of lysosomal degradation and re-cycling of proteins, including mitochondrial proteins (mitophagy).33 Autophagy is characterized by the presence of double-membrane vesicles (autophagosomes) and increased expression of beclin-1, light chain 3, the autophagy-related gene 5-12 complex, p62, and parkin, with the last two being essential for mitophagy.34 Somewhat paradoxically, cell death by autophagy is considered protective rather than detrimental.35 For example, in pigs subjected to 45 minutes of coronary occlusion and reperfusion, the purported autophagy inducer chloramphenicol reduced infarct size.36 However, the role of autophagy in myocardial ischemia/reperfusion injury in humans remains contentious.37,38 Necroptosis shares features with necrosis and apoptosis but is distinctly regulated by activation of receptor-interacting protein kinases 1 and 339 and can be inhibited by substances such as necrostatin.40
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It is currently unclear to what extent necrosis, apoptosis, autophagy, and necroptosis are mutually exclusive processes and to what extent each contributes to infarct size. Typical features of apoptosis (TUNEL staining) and autophagy (characteristic protein expression) are both found in the triphenyltetrazolium chloride staining–defined infarct zone, which has traditionally been considered necrotic. The opening of the MPTP appears to be decisive for necrosis, apoptosis, and necroptosis, and mitochondria are also decisive in mitophagy/autophagy. The importance of regulated forms of cardiomyocyte cell death in ischemia/reperfusion injury is probably related more to their specific signal transduction mechanisms. Recognition of the different modes of cardiomyocyte death during infarction suggests the possibility of identifying therapeutic targets that can modulate these processes. From the clinical perspective, cardiomyocyte death is equally relevant whatever the mechanism.
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Evolution of Myocardial Infarction, Determinants of Infarct Size, and Ventricular Remodeling
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Myocardial ischemia occurs when oxygen and nutrient supply does not meet myocardial demand, and necrosis or infarction occurs when ischemia is severe and prolonged. Although biochemical and functional abnormalities begin almost immediately at onset of ischemia, severe loss of myocardial contractility occurs within 60 seconds, and other changes take a more protracted course; for example, the loss of viability (irreversible injury) takes at least 20 to 40 minutes after total occlusion of blood flow.41
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Two zones of myocardial damage occur: a central zone with no flow or very low flow, and a zone of collateral vessels in a surrounding marginal zone. The survival of the marginal zone depends on the level of ischemia and the duration of ischemia. In autopsy hearts, the size of the ischemic zone surrounding an acute MI is associated with increased apoptosis and degree of occlusion of the infarct-related artery.42 The extent of coronary collateral flow is one of the principal determinants of infarct size. Indeed, at autopsy, it is common to see chronic total coronary occlusion and an absence of MI in the distribution of that artery. Absence of myocardial ischemia (revealed by electrocardiographic changes or angina during transient coronary balloon occlusion) is associated with presence of well-developed collateral vessels, suggesting that patients with well-developed collateral vessels have a low risk of developing acute MI upon abrupt closure of the culprit coronary artery.43 Collaterals are better developed in patients with angina and in younger individuals than in older patients with acute infarcts.44,45 Because infarct size is an important determinant of survival as well as development of congestive heart failure, efforts have been directed to limit infarct size by early reperfusion, reduction of myocardial oxygen demand, and prevention of reperfusion injury.
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Reimer and Jennings, initially in 1979, showed that if a canine coronary artery was occluded for 15 minutes, for 40 minutes, for 3 hours, or permanently for 4 days, myocardial necrosis progressed as a “wave front phenomenon” (Fig. 37–4A).13,46 The extent of myocardial necrosis therefore depended on the duration of coronary occlusion. After only 15 minutes of occlusion, no infarct occurred. At 40 minutes, the infarct was subendocardial, involving only the papillary muscle, resulting in 28% of the myocardium at risk. At 3 hours after coronary artery occlusion and reperfusion, the infarct was significantly smaller compared with nonreperfused permanently occluded infarct (62% of area at risk). The infarct size was the greatest in permanent occlusion, becoming transmural and involving 75% of the area at risk (Fig. 37–4B).13 In the dog model, it is impossible to achieve 100% infarction of the area at risk because of species-related native collaterals. In humans, it has been shown that approximately 40% of patients with acute MI have well-developed collateral circulation.44,45
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Other than the presence of collateral circulation, factors that influence infarct size include preconditioning, which may greatly reduce infarct size, and reperfusion.41 However, there is a balance between benefits of reperfusion in reducing infarct size and reperfusion injury, which is dependent on the time of onset. In general, if ischemic myocardium is reperfused early, the degree of myocardial salvage greatly exceeds damage from free radicals and calcium loading caused by reperfusion. These positive functional consequences of reperfusion are most beneficial within the initial 12 hours after occlusion in humans.
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It was documented in the late 1970s that transmural infarcts may increase in size for weeks after the initial event, and the degree of this expansion is associated with a decrease in survival rate.47 The processes involved in postinfarction ventricular dilatation are known as ventricular remodeling. In general, transmural extent of necrosis is a major determinant of infarct expansion (remodeling) based on large infarct size and the persistence of the occlusion. The preservation of islands of viable myocardium in the subepicardial regions is associated with decreased remodeling or infarct expansion. Other factors that are implicated in reduced ventricular remodeling include microvascular integrity48 and initial ventricular compliance.49 The effect of reperfusion on ventricular remodeling is clear as far as early reperfusion is concerned because there are definite benefits in reducing infarct size and expansion. The benefits of late reperfusion beyond myocardial salvage are unclear. It has been demonstrated that remodeling is affected by the presence of viable zones after successful late PCI.50 In general, the mechanisms of ventricular remodeling are poorly understood because different techniques have been used to assess myocardial viability in human subjects, animal studies, and postmortem specimens. The immune system and the release of matrix metalloproteinases are now being linked to remodeling.51,52,53,54
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The No-Reflow Phenomenon and Reperfusion Injury
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The no-reflow phenomenon (also termed microvascular obstruction) was originally described by Kloner et al55 in 1974 in an experimental canine model of MI. They demonstrated homogenous distribution of thioflavin S dye after 40 minutes of ischemia and reperfusion. However, after 90 minutes of ischemia, areas of no-reflow were identified mainly in the subendocardial regions as zones not staining with thioflavin S. By electron microscopy, they showed swollen endothelial protrusions and membrane-bound intraluminal bodies, which obstructed the capillary lumen and resulted in plugging of the capillaries by red blood cells, neutrophils, platelets, and fibrin thrombi. The areas not stained by thioflavin S were characterized by low regional myocardial blood flow. It is now well-known that angiographic no-reflow is also a strong predictor of major cardiac events, similar to congestive heart failure, malignant arrhythmias, and cardiac death, after acute MI.4
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The process of restoring blood flow to ischemic myocardium has shown utility in limiting cell death in the presence of severe ischemia. Reperfusion, however, has paradoxical effects on myocardium that can result in adverse reactions, thereby reducing its beneficial actions. During reperfusion, the myocardium is subject to abrupt biochemical and metabolic changes governed by several mediators that interact with each other in complex ways.4,56 The term reperfusion injury was coined to describe reperfusion-related expansion or worsening of the ischemic cardiac injury as assessed by contractile performance, the arrhythmogenic threshold, conversion of reversible to irreversible myocyte injury, and microvessel dysfunction.
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The coronary microcirculation, the interface between the epicardial vessel and the cardiomyocytes, plays a critical role in the complex phenomenon of no-reflow and reperfusion injury. No matter how efficiently and rapidly the blood flow is restored to the epicardial artery, if there is a microvascular obstruction, the myocardial tissue will remain without efficient perfusion.4 Potential mediators of reperfusion injury include oxidative stress (oxygen paradox), sudden increases in intracellular Ca2+ (calcium paradox), rapid restoration of physiologic pH (pH paradox), and inflammation.4,56 Neutrophils are activated early during myocardial ischemia and precede the appearance of histologic tissue injury. Reperfusion markedly enhances the infiltration of neutrophils into the ischemic region. The essential initiating step involves interaction of neutrophils with vascular endothelial cells (adhesion). This is followed by activation, diapedesis, and extravascular migration into surrounding myocytes. Production of additional chemoattractants by activated neutrophils amplifies the initial inflammatory response. Neutrophil activation causes a greatly enhanced oxygen uptake by the cell, resulting in the production of large quantities of reactive oxygen species that may lead to disruption of excitation-contraction coupling and inactivate antiproteases present in the plasma.57
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At the time of myocardial reperfusion, there is an abrupt increase in intracellular Ca2+, leading to a disturbance in the normal mechanisms that regulate Ca2+ within the cardiomyocyte, known as the calcium paradox.56 This intracellular Ca2+ overload induces death by causing hypercontracture of myofibrils and MPTP opening.4,56 MPTP is a nonselective channel located on the inner mitochondrial membrane and is a critical determinant of lethal reperfusion injury. Opening the channel, as occurs within the first few minutes after reperfusion, uncouples oxidative phosphorylation, resulting in ATP depletion and cell death.
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In addition, experimental studies have shown that reperfusion of ischemic myocardium generates reactive oxygen species (oxygen paradox). This oxidative stress results in extension of the myocardial injury beyond that induced by ischemia alone. A key mechanism involves the reduction of the bioavailability of the nitric oxide, a cardioprotective signaling molecule. Nitric oxide inhibits neutrophil accumulation, inactivates superoxide radicals, and improves coronary blood flow.56 Further contributing to reperfusion injury is the rapid restoration of physiologic pH that occurs after washout of lactic acid and the activation of the sodium-hydrogen exchanger and the sodium-bicarbonate symporter.6
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The understanding of mechanisms leading to myocardial death during ischemia/reperfusion injury has led to several potential strategies to limit infarct size. These are beyond the scope of this chapter and are described in Chap. 38.
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Acute coronary thrombosis with or without percutaneous intervention results in the embolization of microparticles, including fragments of fibrin-platelet thrombus and necrotic core. Coronary microembolization is associated with arrhythmias, contractile dysfunction, microinfarcts, and reduced coronary reserve.58 Early autopsy studies showed a 30% rate of microembolization in cardiac disease, often associated with focal myocyte necrosis; however, more recent studies show a significantly higher rate of distal embolization 54%.59,60 The rate of coronary microembolization is highest in patients with documented epicardial coronary thrombosis, especially in those with acute MI. Few data are available that compare acute plaque rupture with acute plaque erosion and the rate of embolization, but it has been suggested that distal embolization is more frequent in erosions (70%) than ruptures (42%).60 These emboli and microvessel obstructions have a prominent clinical role because myonecrosis is often associated with these findings.
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Other potential sources of distal embolization include primary PCI, PCI of atherosclerotic plaque in native and saphenous vein grafts, and thrombolysis. Thus, angiographic evidence of distal embolization in patients presenting with acute MI undergoing primary PCI ranges from 15% to 70% (Fig. 37–5).61,62,63 A detailed description of the mechanisms leading to microvascular obstruction during MI (ischemia/reperfusion) can be found in Chap. 38.
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Hibernating Myocardium
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Left ventricular systolic dysfunction caused by ischemia may arise in dead myocardium or from hypocontractile areas of viable myocardium. In the early 1980s, Rahimtoola et al64 found significant improvement in left ventricular function after coronary revascularization in a subset of patients with depressed ventricular performance. They postulated that the mechanism of poor myocardial contractility was chronic ischemia, which could be improved by revascularization. The premise behind this rationale was dependent on the surviving myocardium being in a functional, albeit depressed, state, suggesting that the myocardium may adapt to chronic ischemia by decreasing its contractility but preserving viability.65,66 Reversibly, dysfunctional tissue is commonly referred to as hibernating myocardium. Sheiban et al67 demonstrated that 5 to 7 minutes of angioplasty balloon inflations in the coronary arteries of patients undergoing interventional procedures, followed by tracking of the resolution of the regional wall motion abnormalities over the next 5 days, showed persistence of regional wall motion abnormalities for up to 36 hours. Similarly, return of left ventricular function has been studied after acute MI. Delayed recovery of wall motion was observed in the infarct region, with a positive change in wall motion from 0.2 at 3 days to 1.0 at 6 months in patients with reperfusion but not in those without reperfusion, as measured by the centerline method.68
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The concept of myocardial hibernation was initially based on clinical observation. Subsequently, there have been a number of experimental studies to support the concept that ischemia is not the result of simple inadequacy of blood flow for myocardial contraction but that there is a stepwise decrease in function based on incremental decrease in oxygen-supplying perfusion (so-called perfusion-contraction matching). Evidence suggests that repeated episodes of ischemia-reperfusion may result in a state of chronic hibernation, with alterations in the flow-function relationship and decreased oxygen demand. Chronically hibernating myocardium demonstrates alterations in adrenergic control and calcium responsiveness. Substances that are upregulated in chronic hibernating myocardium include heat shock protein, hypoxia-inducible factor, inducible nitric oxide synthase, cyclooxygenase-2, and monocyte chemotactic protein. Because some of these pathways are involved in preconditioning, a relationship between cardiac hibernation and preconditioning is postulated.
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Morphologically, hibernating myocytes show loss of contractile elements, especially in the perinuclear region and occasionally throughout the cytoplasm. The space left by the dissolution of the myofibrils is occupied by glycogen, as evidenced by the strong positivity for the periodic acid–Schiff reagent. Ultrastructurally, there is depletion of sarcomeres, most pronounced in the perinuclear region, with increased glycogen. The nuclei are enlarged, with a tortuous nuclear membrane and evenly distributed heterochromatin. The mitochondria are elongated, shrunken, and osmiophilic.69 The interstitium shows an increase in connective tissue. Increased numbers of apoptotic myocytes, using the technique of DNA nick-end labeling,70 as well as an increase in autophagic and oncotic cell death, have been demonstrated.71,72
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The composition and distribution of sarcomeric, cytoskeletal, and membrane-associated proteins is significantly altered in chronic myocardial hibernation.73 There is a disorderly increase in cytoskeletal desmin, tubulin, and vinculin, with a decrease in contractile proteins myosin, titin, and actinin. More recently, decreased connexin 43, a membrane transport protein, has been associated with reduced gap junction size and a proposed propensity for arrhythmias in the hibernating state.74
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Advances in noninvasive imaging techniques have helped in the characterization of the hibernated myocardium in patients. Clinical functional techniques such as stress echocardiography and cardiac magnetic resonance are more specific but less sensitive than nuclear modalities, which assess perfusion and metabolic activity, in the detection of hibernating myocardium.65 Radionuclide imaging with positron emission tomography (PET) seems to be especially suitable in assessing cardiac metabolism.75 However, recent advances in magnetic resonance make this method a comprehensive modality that can accurately determine the amount of hibernating myocardium as well as the presence and degree of myocardial ischemia and the extent of the scar.75,76