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Pathophysiology of Myocardial Infarction

Nikolaos G. Frangogiannis

10.1002/cphy.c150006

Source: Volume 5, Issue 4, October 2015

Published online: September 2015

Full Article on Wiley Online Library



ABSTRACT

Myocardial infarction is defined as sudden ischemic death of myocardial tissue. In the clinical context, myocardial infarction is usually due to thrombotic occlusion of a coronary vessel caused by rupture of a vulnerable plaque. Ischemia induces profound metabolic and ionic perturbations in the affected myocardium and causes rapid depression of systolic function. Prolonged myocardial ischemia activates a “wavefront” of cardiomyocyte death that extends from the subendocardium to the subepicardium. Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart. The adult mammalian heart has negligible regenerative capacity, thus the infarcted myocardium heals through formation of a scar. Infarct healing is dependent on an inflammatory cascade, triggered by alarmins released by dying cells. Clearance of dead cells and matrix debris by infiltrating phagocytes activates anti‐inflammatory pathways leading to suppression of cytokine and chemokine signaling. Activation of the renin‐angiotensin‐aldosterone system and release of transforming growth factor‐β induce conversion of fibroblasts into myofibroblasts, promoting deposition of extracellular matrix proteins. Infarct healing is intertwined with geometric remodeling of the chamber, characterized by dilation, hypertrophy of viable segments, and progressive dysfunction. This review manuscript describes the molecular signals and cellular effectors implicated in injury, repair, and remodeling of the infarcted heart, the mechanistic basis of the most common complications associated with myocardial infarction, and the pathophysiologic effects of established treatment strategies. Moreover, we discuss the implications of pathophysiological insights in design and implementation of new promising therapeutic approaches for patients with myocardial infarction. © 2015 American Physiological Society. Compr Physiol 5:1841‐1875, 2015.

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Figure 1. Figure 1. Myocardial infarction is usually caused by rupture of a vulnerable plaque leading to formation of an occlusive thrombus in a coronary artery. A “vulnerable plaque” is often associated with inflammation, activation of macrophages in the fibrous cap, and proteolytic degradation of the matrix.
Figure 2. Figure 2. Pathophysiology of cardiac stunning. A brief (<15‐20 min) ischemic interval is followed by systolic dysfunction that persists for as long as 24 h, despite restoration of blood flow; this pathophysiologic condition is termed “myocardial stunning.” Oxidative stress and calcium overload induce modifications of contractile proteins, resulting in transient systolic dysfunction.
Figure 3. Figure 3. Early evidence of irreversible cardiomyocyte injury in the ischemic myocardium. As ATP levels in the ischemic heart decrease, susceptible cardiomyocytes in the subendocardium can no longer maintain their structural integrity, and exhibit ultrastructural changes suggestive of irreversible injury, such as sarcolemmal disruption and the presence of mitochondrial amorphous densities.
Figure 4. Figure 4. The “wavefront” of ischemic necrosis. In canine models of reperfused infarction, necrosis of cardiomyocytes progresses from the subendocardium to the subepicardium, as the duration of the ischemic event increases.
Figure 5. Figure 5. Mitochondrial dysfunction plays a critical role in cardiomyocyte apoptosis in the ischemic heart. Proapoptotic stimuli permeabilize the outer mitochondrial membrane through actions that involve members of the B‐cell lymphoma 2 (Bcl‐2) family. Subsequent release of mitochondrial apoptogens (such as cytochrome c) into the cytoplasm triggers the apoptotic response. Cyrochrome c binds to the adaptor protein apoptotic protease activating factor 1 (Apaf‐1), causing its oligomerization and mediating recruitment of procaspase‐9. Caspase‐9 induces activation of downstream caspases that cleave many cell proteins causing apoptosis.
Figure 6. Figure 6. The phases of repair following myocardial infarction. Alarmins released by necrotic cardiomyocytes trigger an intense inflammatory reaction that serves to clear the infarct from dead cells and matrix debris. Removal of dead cells induces suppression of proinflammatory signaling, leading to the transition to the proliferative phase. Fibroblasts acquire a synthetic myofibroblast phenotype and deposit extracellular matrix proteins and a rich neovascular network is formed. Finally during the maturation phase, the extracellular matrix is cross‐linked, while infarct fibroblasts become quiescent and may undergo apoptosis.
Figure 7. Figure 7. Alarmins, released by necrotic cells, activate proinflammatory signaling in the infarcted heart. Necrotic cardiomyocytes release Damage associated molecular patterns (DAMPs), including HMGB1, RNA, nucleotides, heat shock proteins (HSP), members of the S100 family and IL‐1a. These mediators activate TLR/IL‐1 and RAGE‐dependent pathways in fibroblasts, vascular cells, leukocytes, and surviving border zone cardiomyocytes triggering an inflammatory reaction. The relative importance of each alarmin remains unknown.
Figure 8. Figure 8. The role of the chemokines in recruitment of leukocyte subpopulations in the infarcted heart. Both CXC and CC chemokines are upregulated in the infarcted heart, bind to glycosaminoglycans on the endothelial surface and interact with chemokine receptors expressed by leukocytes. CCL2/CCR2 interactions are implicated in recruitment of proinflammatory monocytes, whereas CCR5 may be involved in recruitment of regulatory T cells. ELR+ CXC chemokines mediate recruitment of neutrophils.
Figure 9. Figure 9. Deposition and organization of a fibrin‐based provisional matrix in the infarcted heart. Immunohistochemical staining with an antibody to fibrinogen/fibrin in sections from infarcted canine hearts shows extravasation of fibrinogen (A, 1 h ischemia/24 h reperfusion). Fibrin is organized into a network of provisional matrix that serves as a scaffold for migrating cells (B, 1 h ischemia/5 days reperfusion).
Figure 10. Figure 10. Repression of the postinfarction inflammatory reaction. Dual immunohistochemical staining for Mac387 (red), an antibody that labels newly recruited myeloid cells and PM‐2K (black), a macrophage specific antibody illustrates the activation and termination of the inflammatory phase in the infarcted canine myocardium. At the peak of the inflammatory phase (A, 1 h ischemia/24 h reperfusion) abundant newly recruited myeloid cells (arrows) are found in the infarcted canine heart. In contrast, after 7 days of reperfusion, myeloid cells are rare (arrow), reflecting decreased new recruitment of leukocytes.
Figure 11. Figure 11. Myofibroblast activation during the proliferative phase of cardiac repair. Abundant myofibroblasts (stained for α‐smooth muscle actin) are shown in the border zone of a mouse infarct. During the proliferative phase of cardiac repair, cardiac fibroblasts proliferate, transdifferentiate into myofibroblasts, and acquire a matrix‐synthetic phenotype.
Figure 12. Figure 12. The renin‐angiotensin‐aldosterone system (RAAS) critically regulates repair and remodeling of the infarcted heart by modulating the phenotype of cardiomyocytes (CM), fibroblasts (F), leukocytes (L), and endothelial cells (EC).
Figure 13. Figure 13. Deposition of matricellular proteins in the infarcted heart. Thrombospondin (TSP)‐1, a prototypical matricellular protein is deposited in the infarct border zone and regulates cardiac repair and remodeling. (A) Immunohistochemical staining in sections from the infarcted canine heart shows TSP‐1 localization in the infarct border zone (arrows). TSP‐1 activates TGF‐β by binding to the latency‐associated propetide (LAP) (B), inhibits MMP activation (C) and exerts potent angiostatic actions (D).
Figure 14. Figure 14. Angiogenesis in the healing infarct. (A) CD31 immunohistochemistry shows abundant microvessels in the infarcted canine heart (1 h ischemia/7 days reperfusion). (B, C) Dual immunohistochemistry for CD31 (black) and a‐SMA (red) illustrates vascular maturation in the healing infarct. As the infarct heals, microvessels acquire a coat comprised of mural cells (arrows). Irregular and dilated uncoated vessels are also shown (arrowheads). Acquisition of a pericyte coat inhibits inflammatory activation and restrains angiogenesis, stabilizing the scar.
Figure 15. Figure 15. Infarct expansion in the remodeling infarcted heart. The term describes the increased length of the infarcted segment in the absence of additional loss of cardiomyocytes. Cardiomyocyte slippage and matrix degradation due to protease activation have been implicated in the pathogenesis of infarct expansion.
Figure 16. Figure 16. The pathophysiology of cardiogenic shock following myocardial infarction. The size of the infarct, neurohumoral activation, and inflammatory cytokine release contribute to systolic dysfunction. In the clinical setting, the pathophysiology of cardiogenic shock is complex and may involve precipitating factors, such as right ventricular dysfunction, mechanical complications, dysrhythmias, or the inappropriate use of medications that depress contractility or reduce blood pressure.


Figure 1. Myocardial infarction is usually caused by rupture of a vulnerable plaque leading to formation of an occlusive thrombus in a coronary artery. A “vulnerable plaque” is often associated with inflammation, activation of macrophages in the fibrous cap, and proteolytic degradation of the matrix.


Figure 2. Pathophysiology of cardiac stunning. A brief (<15‐20 min) ischemic interval is followed by systolic dysfunction that persists for as long as 24 h, despite restoration of blood flow; this pathophysiologic condition is termed “myocardial stunning.” Oxidative stress and calcium overload induce modifications of contractile proteins, resulting in transient systolic dysfunction.


Figure 3. Early evidence of irreversible cardiomyocyte injury in the ischemic myocardium. As ATP levels in the ischemic heart decrease, susceptible cardiomyocytes in the subendocardium can no longer maintain their structural integrity, and exhibit ultrastructural changes suggestive of irreversible injury, such as sarcolemmal disruption and the presence of mitochondrial amorphous densities.


Figure 4. The “wavefront” of ischemic necrosis. In canine models of reperfused infarction, necrosis of cardiomyocytes progresses from the subendocardium to the subepicardium, as the duration of the ischemic event increases.


Figure 5. Mitochondrial dysfunction plays a critical role in cardiomyocyte apoptosis in the ischemic heart. Proapoptotic stimuli permeabilize the outer mitochondrial membrane through actions that involve members of the B‐cell lymphoma 2 (Bcl‐2) family. Subsequent release of mitochondrial apoptogens (such as cytochrome c) into the cytoplasm triggers the apoptotic response. Cyrochrome c binds to the adaptor protein apoptotic protease activating factor 1 (Apaf‐1), causing its oligomerization and mediating recruitment of procaspase‐9. Caspase‐9 induces activation of downstream caspases that cleave many cell proteins causing apoptosis.


Figure 6. The phases of repair following myocardial infarction. Alarmins released by necrotic cardiomyocytes trigger an intense inflammatory reaction that serves to clear the infarct from dead cells and matrix debris. Removal of dead cells induces suppression of proinflammatory signaling, leading to the transition to the proliferative phase. Fibroblasts acquire a synthetic myofibroblast phenotype and deposit extracellular matrix proteins and a rich neovascular network is formed. Finally during the maturation phase, the extracellular matrix is cross‐linked, while infarct fibroblasts become quiescent and may undergo apoptosis.


Figure 7. Alarmins, released by necrotic cells, activate proinflammatory signaling in the infarcted heart. Necrotic cardiomyocytes release Damage associated molecular patterns (DAMPs), including HMGB1, RNA, nucleotides, heat shock proteins (HSP), members of the S100 family and IL‐1a. These mediators activate TLR/IL‐1 and RAGE‐dependent pathways in fibroblasts, vascular cells, leukocytes, and surviving border zone cardiomyocytes triggering an inflammatory reaction. The relative importance of each alarmin remains unknown.


Figure 8. The role of the chemokines in recruitment of leukocyte subpopulations in the infarcted heart. Both CXC and CC chemokines are upregulated in the infarcted heart, bind to glycosaminoglycans on the endothelial surface and interact with chemokine receptors expressed by leukocytes. CCL2/CCR2 interactions are implicated in recruitment of proinflammatory monocytes, whereas CCR5 may be involved in recruitment of regulatory T cells. ELR+ CXC chemokines mediate recruitment of neutrophils.


Figure 9. Deposition and organization of a fibrin‐based provisional matrix in the infarcted heart. Immunohistochemical staining with an antibody to fibrinogen/fibrin in sections from infarcted canine hearts shows extravasation of fibrinogen (A, 1 h ischemia/24 h reperfusion). Fibrin is organized into a network of provisional matrix that serves as a scaffold for migrating cells (B, 1 h ischemia/5 days reperfusion).


Figure 10. Repression of the postinfarction inflammatory reaction. Dual immunohistochemical staining for Mac387 (red), an antibody that labels newly recruited myeloid cells and PM‐2K (black), a macrophage specific antibody illustrates the activation and termination of the inflammatory phase in the infarcted canine myocardium. At the peak of the inflammatory phase (A, 1 h ischemia/24 h reperfusion) abundant newly recruited myeloid cells (arrows) are found in the infarcted canine heart. In contrast, after 7 days of reperfusion, myeloid cells are rare (arrow), reflecting decreased new recruitment of leukocytes.


Figure 11. Myofibroblast activation during the proliferative phase of cardiac repair. Abundant myofibroblasts (stained for α‐smooth muscle actin) are shown in the border zone of a mouse infarct. During the proliferative phase of cardiac repair, cardiac fibroblasts proliferate, transdifferentiate into myofibroblasts, and acquire a matrix‐synthetic phenotype.


Figure 12. The renin‐angiotensin‐aldosterone system (RAAS) critically regulates repair and remodeling of the infarcted heart by modulating the phenotype of cardiomyocytes (CM), fibroblasts (F), leukocytes (L), and endothelial cells (EC).


Figure 13. Deposition of matricellular proteins in the infarcted heart. Thrombospondin (TSP)‐1, a prototypical matricellular protein is deposited in the infarct border zone and regulates cardiac repair and remodeling. (A) Immunohistochemical staining in sections from the infarcted canine heart shows TSP‐1 localization in the infarct border zone (arrows). TSP‐1 activates TGF‐β by binding to the latency‐associated propetide (LAP) (B), inhibits MMP activation (C) and exerts potent angiostatic actions (D).


Figure 14. Angiogenesis in the healing infarct. (A) CD31 immunohistochemistry shows abundant microvessels in the infarcted canine heart (1 h ischemia/7 days reperfusion). (B, C) Dual immunohistochemistry for CD31 (black) and a‐SMA (red) illustrates vascular maturation in the healing infarct. As the infarct heals, microvessels acquire a coat comprised of mural cells (arrows). Irregular and dilated uncoated vessels are also shown (arrowheads). Acquisition of a pericyte coat inhibits inflammatory activation and restrains angiogenesis, stabilizing the scar.


Figure 15. Infarct expansion in the remodeling infarcted heart. The term describes the increased length of the infarcted segment in the absence of additional loss of cardiomyocytes. Cardiomyocyte slippage and matrix degradation due to protease activation have been implicated in the pathogenesis of infarct expansion.


Figure 16. The pathophysiology of cardiogenic shock following myocardial infarction. The size of the infarct, neurohumoral activation, and inflammatory cytokine release contribute to systolic dysfunction. In the clinical setting, the pathophysiology of cardiogenic shock is complex and may involve precipitating factors, such as right ventricular dysfunction, mechanical complications, dysrhythmias, or the inappropriate use of medications that depress contractility or reduce blood pressure.
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Article Title: Pathophysiology of Myocardial Infarction
 

How to Cite

Nikolaos G. Frangogiannis. Pathophysiology of Myocardial Infarction. Compr Physiol 2015, 5: 1841-1875. doi: 10.1002/cphy.c150006