**1. Introduction**

Physiopathological mechanisms responsible for myocardial cell death (necrosis, apoptosis, autophagy, etc.) caused by coronary artery disease have been abundantly discussed over the past several decades. Acute myocardial infarction is a leading cause of sudden cardiac death among urban dwellers in North America and Europe. Clinical treatment of patients with coronary artery disease is focused on limiting the deleterious consequences that follow coronary artery occlusion; however, to do so it is fundamental to understand the mechanisms, at the molecular and cellular level, that are involved in cell death and survival. Existing knowledge has progressed massively over the years and useful clinical interventions, both pharmacologic and non-pharmacologic, are currently available to limit, but not abrogate, effects of ischemia. An important question that remains concerns the existence of "reperfusion-induced injury"; many adhere to the notion that significant cellular

death can occur once blood flow is restored to an infarct-related artery. While definitive proof is lacking myocardial stunning, vascular no-reflow (perfusion deficit) and ventricular arrhythmias are often attributed to this form of cardiomyocyte loss after ischemia. The objective of the present chapter is to update current thinking on the question of lethal reperfusion injury and to summarize current treatments used to limit overall effects.

#### **1.1 Acute myocardial infarction**

Myocardial ischemia is defined as *the condition where coronary blood flow across the ventricular wall is insufficient to conserve steady-state metabolism*. Acute disruption of the blood supply to any region of the heart causes cardiomyocyte injury and eventually cellular death depending on the duration of perfusion deficit. Cardiac cell injury is characterized to be either *reversible* (if reperfusion of the infarctrelated artery can be instituted rapidly, ≤15 minutes), or *irreversible* (poor, or no, cellular survival even if blood flow is restored). Cardiomyocyte necrosis progresses as a transmural gradient across the ventricular wall, from endocardium to epicardium, in most animal models studied [1, 2]. Early development of necrosis in the subendocardium is probably related to higher oxygen requirements (due to greater contribution to myocardial contraction) of that layer compared to the subepicardium [3–5]; myocardial perfusion is coupled to myocardial oxygen consumption. Although we agree that progression of coronary heart disease and symptom phenotypes may differ in relation to sex this subject is beyond the scope of this review.

Myocardial ischemia initiates multiple changes in cardiomyocyte structure including marked swelling, development of contraction bands, mitochondrial calcification and membrane disruption; the pathobiology of cellular changes produced by ischemia have been characterized in earlier studies [6–8]. Different modes (apoptosis, autophagy, oncosis, and necrosis) of cellular injury have been described [9] and are discussed elsewhere [10]. The cardiomyocyte cytoskeleton (i.e. structure needed to maintain cellular morphology and physiology) is markedly altered by biochemical changes caused by disruption of oxygen and nutrient supply [11]. Cardiomyocyte death occurs with disruption of the cellular membrane and subsequent leakage of intracellular components into the extracellular fluid [12–14]. Irreversibly injured cardiomyocytes display small breaks in the plasmalemma along with cellular swelling and sarcolemmal blebbing [1]. Necrosis in non-cardiac cells is not well described but it is clear that other cell types within the myocardium (i.e. vascular endothelial and smooth muscle cells, nervous system cells, etc.) are affected by ischemia.

Restoration of blood flow to the perfusion bed of the infarct-related artery can limit damage to cardiomyocyte as long as reperfusion is instituted within a reasonable period. Indeed, this is the basis for widespread use of percutaneous coronary interventions for relief of symptoms in patients with coronary artery disease and is responsible for manifest reduction in mortality. Thousands of studies have examined the physiopathology of ischemia-reperfusion injury over the past half-century with the aim to elucidate pathways leading to cellular necrosis; increased knowledge gained from these studies has led to the realization that this is a complex and multifaceted scenario.

## **1.2 Lethal reperfusion injury**

It is clear that restoration of blood flow to ischemic myocardium is the most effective treatment against myocyte necrosis [15, 16]. Timely opening of an infarctrelated artery is essential as the amount of myocardium salvaged rapidly decreases

**15**

*Acute Myocardial Infarction: Perspectives on Physiopathology of Myocardial Injury…*

when reperfusion interventions are delayed. Furthermore, reperfusion may itself cause further cellular damage; thus it is often viewed in the context of being a "double-edged sword" [17]. Studies have confirmed that reperfusion triggers abrupt metabolic, electrophysiologic, morphologic and functional changes. The term "lethal reperfusion injury" designates damage to viable cardiomyocytes caused after successful restoration of blood flow to the ischemic perfusion bed. Several possible forms of reperfusion injury such as coronary artery no-reflow, myocardial hibernation, myocardial stunning, ventricular arrhythmias, etc. have been advanced [18, 19]; however, definitive proof that reperfusion injury exists remains to be established. With that in mind, we believe that reperfusion might accelerate expression of injury produced by ischemia but does not itself cause *de novo* cardio-

Physiopathological mechanisms that produce reperfusion injury are complex and multifactorial; no specific mechanism has been shown to take precedence over others. In experimental animal models, the release of an acute coronary occlusion produces a prolonged hyperemic response particularly in the deeper myocardial layers (subendocardium > subepicardium); hyperemic responses vary depending on the duration of ischemia [20–22]. Reperfusion of the ischemic myocardium depends on arterial driving pressure and extravascular compressive forces; this is particularly important for the function of coronary collateral vessels that supply much needed oxygen and nutrients to surviving cardiomyocytes post-ischemia. As such, restoration of coronary blood flow in the infarct-related artery does not guarantee homogeneous perfusion of blood across the ventricular wall. Indeed, areas where blood flow is less than normal (i.e. no-reflow) are mostly associated

No-reflow is caused by injury at the structural level (i.e. cell swelling, membrane gaps, etc.) [23, 24]; microvessels might be more resistant to short periods of ischemia compared to cardiomyocytes because their endothelial oxygen requirements are modest and they are in close proximity to oxygen supply. No-reflow does not precede tissue damage but follows it; furthermore, it does not expand myocardial infarct size (role in pathogenesis of tissue damage is considered to be minor) [25, 26]. However, it has been suggested to contribute to infarct expansion, ventricular dilatation and remodeling by limiting access of inflammatory cells to the ischemic zone to initiate cardiac repair [27, 28]. Microvessel damage is also manifest as hemorrhage due to

No-reflow occurs in patients with cardiovascular disease [30, 31]; pharmaco-

Reperfusion injury is associated with depletion of high-energy phosphate stores,

therapy appears to normalize ischemic zone perfusion and reduce mortality.

cellular swelling, increases in capillary permeability and reduced microvessel reactivity [32–34]. Restoration of blood flow to the ischemic myocardium mitigates myocardial injury; however, restoration of contractile function is not necessarily immediate. When blood supply to the heart is limited, myocardial contraction is restricted as described for the "smart heart theory" [35]. In normal myocardium, increases in metabolic demand due to intensification of myocardial work are met by regional increases in blood flow as well as increases in oxygen extraction [36]. Postischemic myocardial stunning and myocardial hibernation have been described in animals [37, 38] and patients [35, 39] and designate viable but chronically

*DOI: http://dx.doi.org/10.5772/intechopen.92838*

with myocardial regions where injury is irreversible.

abnormalities in vessel permeability [29].

*1.2.2 Myocardial stunning and hibernation*

myocyte injury.

*1.2.1 No-reflow*

*Acute Myocardial Infarction: Perspectives on Physiopathology of Myocardial Injury… DOI: http://dx.doi.org/10.5772/intechopen.92838*

when reperfusion interventions are delayed. Furthermore, reperfusion may itself cause further cellular damage; thus it is often viewed in the context of being a "double-edged sword" [17]. Studies have confirmed that reperfusion triggers abrupt metabolic, electrophysiologic, morphologic and functional changes. The term "lethal reperfusion injury" designates damage to viable cardiomyocytes caused after successful restoration of blood flow to the ischemic perfusion bed. Several possible forms of reperfusion injury such as coronary artery no-reflow, myocardial hibernation, myocardial stunning, ventricular arrhythmias, etc. have been advanced [18, 19]; however, definitive proof that reperfusion injury exists remains to be established. With that in mind, we believe that reperfusion might accelerate expression of injury produced by ischemia but does not itself cause *de novo* cardiomyocyte injury.

Physiopathological mechanisms that produce reperfusion injury are complex and multifactorial; no specific mechanism has been shown to take precedence over others. In experimental animal models, the release of an acute coronary occlusion produces a prolonged hyperemic response particularly in the deeper myocardial layers (subendocardium > subepicardium); hyperemic responses vary depending on the duration of ischemia [20–22]. Reperfusion of the ischemic myocardium depends on arterial driving pressure and extravascular compressive forces; this is particularly important for the function of coronary collateral vessels that supply much needed oxygen and nutrients to surviving cardiomyocytes post-ischemia. As such, restoration of coronary blood flow in the infarct-related artery does not guarantee homogeneous perfusion of blood across the ventricular wall. Indeed, areas where blood flow is less than normal (i.e. no-reflow) are mostly associated with myocardial regions where injury is irreversible.

#### *1.2.1 No-reflow*

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

Myocardial ischemia is defined as *the condition where coronary blood flow across the ventricular wall is insufficient to conserve steady-state metabolism*. Acute disruption of the blood supply to any region of the heart causes cardiomyocyte injury and eventually cellular death depending on the duration of perfusion deficit. Cardiac cell injury is characterized to be either *reversible* (if reperfusion of the infarctrelated artery can be instituted rapidly, ≤15 minutes), or *irreversible* (poor, or no, cellular survival even if blood flow is restored). Cardiomyocyte necrosis progresses as a transmural gradient across the ventricular wall, from endocardium to epicardium, in most animal models studied [1, 2]. Early development of necrosis in the subendocardium is probably related to higher oxygen requirements (due to greater contribution to myocardial contraction) of that layer compared to the subepicardium [3–5]; myocardial perfusion is coupled to myocardial oxygen consumption. Although we agree that progression of coronary heart disease and symptom phenotypes may differ in relation to sex this subject is beyond the scope of this review. Myocardial ischemia initiates multiple changes in cardiomyocyte structure including marked swelling, development of contraction bands, mitochondrial calcification and membrane disruption; the pathobiology of cellular changes produced by ischemia have been characterized in earlier studies [6–8]. Different modes (apoptosis, autophagy, oncosis, and necrosis) of cellular injury have been described [9] and are discussed elsewhere [10]. The cardiomyocyte cytoskeleton (i.e. structure needed to maintain cellular morphology and physiology) is markedly altered by biochemical changes caused by disruption of oxygen and nutrient supply [11]. Cardiomyocyte death occurs with disruption of the cellular membrane and subsequent leakage of intracellular components into the extracellular fluid [12–14]. Irreversibly injured cardiomyocytes display small breaks in the plasmalemma along with cellular swelling and sarcolemmal blebbing [1]. Necrosis in non-cardiac cells is not well described but it is clear that other cell types within the myocardium (i.e. vascular endothelial and smooth muscle cells, nervous system cells, etc.) are

Restoration of blood flow to the perfusion bed of the infarct-related artery can limit damage to cardiomyocyte as long as reperfusion is instituted within a reasonable period. Indeed, this is the basis for widespread use of percutaneous coronary interventions for relief of symptoms in patients with coronary artery disease and is responsible for manifest reduction in mortality. Thousands of studies have examined the physiopathology of ischemia-reperfusion injury over the past half-century with the aim to elucidate pathways leading to cellular necrosis; increased knowledge gained from these studies has led to the realization that this is a complex and multi-

It is clear that restoration of blood flow to ischemic myocardium is the most effective treatment against myocyte necrosis [15, 16]. Timely opening of an infarctrelated artery is essential as the amount of myocardium salvaged rapidly decreases

death can occur once blood flow is restored to an infarct-related artery. While definitive proof is lacking myocardial stunning, vascular no-reflow (perfusion deficit) and ventricular arrhythmias are often attributed to this form of cardiomyocyte loss after ischemia. The objective of the present chapter is to update current thinking on the question of lethal reperfusion injury and to summarize current

treatments used to limit overall effects.

**1.1 Acute myocardial infarction**

**14**

affected by ischemia.

faceted scenario.

**1.2 Lethal reperfusion injury**

No-reflow is caused by injury at the structural level (i.e. cell swelling, membrane gaps, etc.) [23, 24]; microvessels might be more resistant to short periods of ischemia compared to cardiomyocytes because their endothelial oxygen requirements are modest and they are in close proximity to oxygen supply. No-reflow does not precede tissue damage but follows it; furthermore, it does not expand myocardial infarct size (role in pathogenesis of tissue damage is considered to be minor) [25, 26]. However, it has been suggested to contribute to infarct expansion, ventricular dilatation and remodeling by limiting access of inflammatory cells to the ischemic zone to initiate cardiac repair [27, 28]. Microvessel damage is also manifest as hemorrhage due to abnormalities in vessel permeability [29].

No-reflow occurs in patients with cardiovascular disease [30, 31]; pharmacotherapy appears to normalize ischemic zone perfusion and reduce mortality.

#### *1.2.2 Myocardial stunning and hibernation*

Reperfusion injury is associated with depletion of high-energy phosphate stores, cellular swelling, increases in capillary permeability and reduced microvessel reactivity [32–34]. Restoration of blood flow to the ischemic myocardium mitigates myocardial injury; however, restoration of contractile function is not necessarily immediate. When blood supply to the heart is limited, myocardial contraction is restricted as described for the "smart heart theory" [35]. In normal myocardium, increases in metabolic demand due to intensification of myocardial work are met by regional increases in blood flow as well as increases in oxygen extraction [36]. Postischemic myocardial stunning and myocardial hibernation have been described in animals [37, 38] and patients [35, 39] and designate viable but chronically

dysfunctional states [40]. Myocardial stunning refers to persistent (but reversible) contractile dysfunction [41, 42] produced by a relatively brief ischemic period [43]. Myocardial hibernation, on the other hand, refers to viable but chronically dysfunctional myocardium that may be related to poor resting perfusion [35], or general absence of perfusion abnormalities [44, 45] but the latter has not been clearly established [46, 47]. Recent findings suggest that repetitive ischemia, chronic stunning and hibernation are linked as a continuum [40]; in other words, stunned myocardium can progressively transform into hibernating myocardium. For both dysfunctional myocardial states, downregulation of contractile function might be a cellular adaptive mechanism to facilitate preservation of myocardial integrity and viability [35]. Perfusion-contraction matching may be key to myocardial hibernation but this may not be so for myocardial stunning; a number of review articles on this subject are available [48–50]. Whether contractile dysfunction can be reversed by improved revascularization in stunned or hibernating myocardium is moot after the formation of scar [40].
