Clinical Expression Of Pathobiological Events

Acute MI

Occurring in upwards of one million individuals yearly in the United States, ST-seg-ment elevation MI represents the most commonly observed arterial thrombotic event in clinical practice. In the vast majority of cases, fissuring or rupture of an atherosclerotic plaque within a major epicardial coronary artery is followed by occlusive thrombosis, typically anchored to the damaged vascular surface and exposed plaque components.

It is of interest and of clinical importance that plaque rupture does not occur randomly throughout the coronary tree. Instead, there are vulnerable sites located in:

• the proximal portion of the left anterior descending coronary artery;

• the right coronary artery near the origin of its marginal branch; and

• the left circumflex coronary artery at the origin of the first obtuse marginal branch.

In general terms, the severity of vessel wall injury determines the extent of thrombosis. Mild injury (type I) is typically associated with the deposition of platelets in a single (nonocclusive) layer. Moderate injury (type II) provokes a loosely adherent platelet mass that can quickly be dispersed by normal blood flow. Severe injury (type III) leads to platelet adherence, activation, and stimulation of the coagulation cascade, producing an occlusive thrombus. Type III injury is present in most of patients with MI.

Unstable Angina/Non-ST-Segment Elevation MI

Angiographic, angioscopic, and pathologic studies have shown that atherosclerotic plaque disruption accompanied by varying degrees of intraluminal thrombosis is the primary pathologic event in unstable angina/non-ST segment elevation MI (non-ST segment elevation acute coronary syndromes). Mounting evidence suggests that chronic recurrent plaque rupture of mild to moderate severity may contribute to plaque development and its natural history. Thrombosis occurs with each episode, but may not be of sufficient mass (clot burden) to compromise coronary arterial blood flow. Over time, however, plaque growth occurs, obstructing the coronary lumen. Thus, the obstructive lesion is a combination of mature plaque and layers of aged thrombus, consisting primarily of platelets in a tightly packed fibrin network.

In some patients, non-ST-segment elevation MI has clinical features reminiscent of ST-segment elevation MI, progressing suddenly, because of plaque rupture and occlusive intracoronary thrombosis. Experience has shown that these patients frequently have multivessel coronary artery disease and, therefore, represent a high-risk group.

Most patients with unstable angina/non-ST-segment elevation MI have advanced underlying atherosclerotic coronary artery disease with nearly uniform distribution of single, double, and triple vessel involvement. The available evidence suggests that the clinical conversion from asymptomatic or stable angina to unstable angina is a direct result of pathologic changes within the atheromatous plaque, specifically plaque fissur-ing, disruption, and intraluminal thrombosis. Angiographic studies have revealed a high prevalence of eccentric irregular narrow-necked stenoses with overhanging edges (type II lesion) and reduced thrombolysis in myocardial infarction (TIMI) flow (83). In contrast, patients with stable angina most often exhibit concentric symmetric stenoses or eccentric broad-necked stenoses (type I lesion).

The presence of intracoronary thrombosis and the overall thrombus burden has varied greatly in studies of patients within unstable angina/non-ST-segment elevation MI. On average, thrombus has been reported in 40-50% of patients. The variability can be traced to differences in clinical presentation (accelerated angina, angina at rest, postinfarction angina), variability in electrocardiographic features (T-wave inversion, ST-segment shifts), the time frame of clinical assessment (early, late), and the method of imaging.

Coronary angioscopy has proved to be a useful tool in the evaluation of coronary arterial morphology. In a landmark study by Forrester and colleagues (84), angioscopy was performed at the time of bypass grafting in 20 patients, 10 with unstable angina and 10 with advanced but clinically stable coronary artery disease. All patients with accelerated angina exhibited complex-appearing plaques (Fig. 9A), and all patients with angina at rest had thrombus (Fig. 9B). In contrast, patients with stable coronary disease had neither of these features. These observations, representing a pathobiology-clinical correlation "snapshot," suggest strongly that plaque morphology, in general, and intracoronary thrombosis, in particular, are major determinants of disease expression.

Unique Characteristics of Acute Coronary Syndromes

Although plaque disruption with thrombus formation has been associated with acute coronary syndromes, including unstable angina and MI, determinants of which particular entity within the spectrum of possibilities a patient will develop have not been fully elucidated. The challenge becomes greater when one considers that plaque disruption is not an uncommon event, yet only certain individuals experience symptoms, as a clinical expression of mechanical and biochemical events, which characterize acute coronary syndromes.

The available evidence suggests that although plaque rupture is a common theme in acute coronary syndromes, the degree and composition of the associated thrombus burden differs. Percutaneous angioscopy performed in patients with unstable angina frequently reveals gray-white nonocclusive thrombi; reddish occlusive thrombi are seen in patients with acute MI. These characteristics suggest that unstable angina is a platelet-mediated phenomenon and, by contrast, acute MI is predominantly fibrin-mediated. Autopsy-based studies have drawn similar conclusions. In a study of 14 patients with unstable angina and 32 patients with a fatal first MI, Kragel et al. (85) observed a predominance of platelets within nonocclusive thrombi in those with a diagnosis of unstable angina, whereas thrombi in patients with acute MI consisted almost entirely of fibrin and were occlusive. The investigators also found that the extent or depth of plaque rupture, approximated by the presence of hemorrhage, was less in patients with unstable angina when compared with those with acute MI.

The question then remains: what are the determinants of disease progression (or suppression) and clinical expression in acute coronary syndromes? Our group has shown that patients with unstable angina and non-ST-segment elevation MI exhibit varying degrees of platelet activation and thrombin generation, suggesting that not only the thrombotic stimulus may differ, but that regulation of thrombus growth may differ as well (Table 3).

Microvascular Disease

The supply-demand paradigm of myocardial ischemia, when considered comprehensively, takes both epicardial and microvascular conditions into consideration. Because tissue perfusion is regulated at the microvascular level and downstream resistance to flow has

Fig. 9. (A) Coronary angioscopy in a patient with unstable angina. An eccentric plaque with disruption is evident (arrow). Reprinted with permission from ref. 84. (B) Coronary angioscopy in a patient with unstable angina at rest. Intraluminal thrombus (nonocclusive) is visualized (arrow). Reprinted with permission from ref. 48.

4 color figure

Fig. 9. (A) Coronary angioscopy in a patient with unstable angina. An eccentric plaque with disruption is evident (arrow). Reprinted with permission from ref. 84. (B) Coronary angioscopy in a patient with unstable angina at rest. Intraluminal thrombus (nonocclusive) is visualized (arrow). Reprinted with permission from ref. 48.

Table 3

Multidimensional Determinants of Clinical Expression and Cardiac Events in Coronary Atherosclerosis

Table 3

Multidimensional Determinants of Clinical Expression and Cardiac Events in Coronary Atherosclerosis











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