ACUTE MYOCARDIAL INFARCTION PATHOPHYSIOLOGY

Acute MI is nearly always caused by occlusion of a coronary artery by thrombus overlying a fissured or ruptured atheromatous plaque. The ruptured plaque, by direct release of tissue factor (TF) and exposure of the subintima, is highly thrombogenic. Exposed collagen provokes platelet aggregation. The extrinsic coagulation cascade is activated through the interaction between vascular TF and the circulating blood, causing in vivo generation of thrombin, which converts fibrinogen to fibrin.

Fibrin interacts with activated platelets to form a mesh structure that stabilizes the mural thrombus. Thus, atherothrombosis completes the occlusion of the artery. Lipidrich atheromatous plaques contain TF associated with macrophages within the lesion that may enhance the thrombogenicity of these plaques. In coronary angiography performed during the early hours of ST elevation, MI has confirmed the presence of total occlusion of the infarct-related artery in more than 90% of patients. It is not surprising that aspirin, through inhibition of platelet aggregation, reduces the incidence of coronary thrombosis and is especially useful in prevention of the progression of unstable angina to thrombosis and MI. Chewable aspirin (160 to 320 mg) is particularly useful when given at the onset of chest pain produced by infarction. Patients must be informed that the use of chewable aspirin can prevent fatal and nonfatal infarction but that nitroglycerin does not. This advice should serve to motivate individuals to carry chewable aspirins for emergency use.

However, aspirin does not block all pathways that relate to platelet aggregation and does not nullify the intensely thrombogenic constituents of atheromatous plaques. In addition, aspirin does not decrease the incidence of sudden death in patients with acute MI. Aspirin does however reduce the incidence of MI in patients postinfarction and in those with unstable and stable angina. Thus, chewable aspirin administration plays a key role in the prevention and management of acute MI.

The increased morning incidence of acute MI, documented in several studies of the diurnal variation of infarction, is related to the early-morning catecholamine surges, which induce platelet aggregation, and an increase in blood pressure and hydraulic stress, which may lead to plaque rupture (Fig. 1.1.). β-adrenergic blockers have been shown to decrease the early-morning peak incidence of acute infarction and sudden death. It is important for clinicians to recognize that calcium antagonists and nitrates do not have these lifesaving effects and that these agents are overprescribed and β-adrenergic blocking agents are underused.

Unfortunately, when an atheromatous plaque ruptures, the thrombogenic effect of plaque contents cannot be completely nullified by the inhibition of all aspects of platelet aggregation, and chemical agents that can arrest the effects of these thrombogenic substances deserve intensive study. Preliminary studies in patients suggest that direct thrombin inhibitors such as hirudin, administered with aspirin, are effective in the prevention of coronary thrombosis. These studies may pave the way for further research that may uncover newer types of antithrombotic agents that are superior to available agents in preventing coronary thrombosis.

Coronary artery spasm appears to play a lesser role in the pathogenesis of coronary occlusion leading to infarction. Evidence of coronary vasoconstriction was found when angioscopy was performed shortly after infarction, and intermittent occlusion, presumably on a vasomotor basis, has been apparent in some cases. Vasoconstriction appears to be a secondary factor.

The first gene linked directly to acute MI has been isolated from an extended Iowa family that has been plagued for generations with CAD. The gene, MEF2A, appears to protect the artery walls from building up atheroma. Individuals who have this gene mutation are destined to have the disease.

Vulnerable (High-Risk) Atheromatous Plaques
Plaque disruption is associated with physical forces, and occurs more frequently with the fibrous cap that is weakest, that is, when it is thinnest and most heavily infiltrated by foam cells. For eccentric plaques, this is often the shoulder or between the plaque and adjacent vessel wall. The shoulder regions of plaques often have a thinner fibrous cap that is highly infiltrated with macrophages and is prone to rupture. In sudden coronary death, often only a superficial erosion of a markedly stenotic and fibrotic plaque is observed

Thrombosis occurs over plaques because of the following:
• Denudation and erosion of the endothelial surface.
• Disruption or tear in the cap of a lipid-rich plaque; blood from the lumen enters the lipid core of the plaque, where thrombus is formed. Plaque disruption appears to be three times more common than the more superficial process of endothelial denudation. Sudden death as a result of CAD in relatively young subjects, however, has put the ratio of thrombi owing to plaque rupture compared with endothelial erosion as 1.3:1. In sudden death in younger patients, plaque rupture is more commonly caused by endothelial erosion. Acute MI with thrombosis caused by endothelial erosion is reportedly more common at a younger age and particularly in women.

Three major factors determine the vulnerability of the fibrous cap:
1. Circumferential wall stress or cap fatigue.
2. Location, size, and consistency of atheromatous core.
3. Blood flow characteristics, particularly the impact of flow on the configuration and angulation of the plaque.

Plaque Rupture
Uneven thinning and fracture or fissuring of the plaque’s fibrous cap leads to rupture. The porridge-like substances exposed to the flowing blood is highly thrombogenic and trigger thrombosis that blocks the lumen of the artery. This is the main cause underlying an MI. Fracture of the fibrous cap occurs often at the shoulders of a lipid-rich plaque where macrophages enter. The fibrous cap is believed to become thin because of the depletion of matrix components through the activation of enzymes such as matrixdegrading proteinases and cysteine and aspartate proteases, and through the reduction in the number of smooth muscle cells. Endothelial-cell desquamation through activation of basement membrane degrading metalloproteinases appears to be involved, but the mechanisms are unclear.

Activated T cells may also inhibit matrix synthesis through the production of interferon- γ. Evidence of superficial erosion of the intimal lining has been observed in approximately 25% of patients who had sustained an MI and died within a few hours.
• The provision of durable collagenous tissue processed by smooth muscle cells is important in maintaining the existence of the plaque’s fibrous cap. Collagen provides most of the biomechanical resistance to disruption of the fibrous cap. Substances found in degranulating platelets appear to increase smooth-muscle cell collagen synthesis that may reinforce the strength and viability of the fibrous cap. In addition, in some lesions there is a marked decrease in the presence of smooth muscle cells or increased smoothmuscle cell death within the plaque occurs and reduces collagen production.
• It is possible that the new capillaries and vessels within the plaque may be important for the survival of smooth muscle cells.

Platelets play an important role in initiating clotting in arteries and arterioles. Platelets form an initial plug of clot and are followed by the deposit of a fibrin mesh that forms a firm clot. Platelets are trapped by the material exposed by the fractured plaque, and the first phase of thrombosis is initiated. Aspirin or platelet glycoprotein (GP) IIa/IIIb receptor blockers are used to prevent this deleterious platelet aggregation.

Hemorrhage Into the Plaque
New capillaries and small vessels grow into the plaque and provide a useful function in that they may provide nutrient material for smooth muscle cells that form collagen necessary to strengthen the fibrous cap. However, these new vessels are fragile and may burst, causing a minute hemorrhage within the plaque. The pressure within the plaque may cause disruption of the fibrous cap, and thrombosis completes the occlusion of the artery. In approximately 5% of patients with acute MI, the initiating cause is hemorrhage into a plaque of atheroma rather than erosion–rupture followed by thrombosis. Angiogenesis and gene therapy may promote hemorrhage into plaques, and caution is required.

Myocardial Necrosis
In about 20 minutes, occlusion of a coronary artery leads to death of cells in areas of severely ischemic tissue, which will usually become necrotic over 4 to 6 hours. Because early and late mortality are directly related to the size of the infarct, limitation of infarct size (or even prevention of necrosis) initiated at the earliest possible moment is of the utmost importance. The ischemic zone surrounding the necrotic tissue provides electrophysiologic inhomogeneity that predisposes the occurrence of lethal arrhythmias. These arrhythmias are most common during the early hours after onset and contribute to one of the major mechanisms of sudden death.

Extensive myocardial necrosis is the major determinant of HF; papillary, septal, and freewall rupture; and cardiogenic shock in which more than 35% of the myocardium is usually infarcted. The most effective means of reducing the extent of myocardial necrosis is the administration of chewable aspirin and a β-blocking agent (metoprolol or carvedilol) and establishment of patency of the infarct-related artery by thrombolytic therapy or percutaneous coronary intervention (PCI) within 1 hour of the onset of symptoms of coronary thrombosis.