New Paradigm Of Clinical Syndromes

The extent of local thrombosis at the site of coronary plaque rupture is largely responsible for the severity of the clinical syndrome (Fig. 1). If the thrombosis causes total occlusion of the coronary artery, persistent ischemic pain and STE develop, which usually evolves into a Q-wave MI (11,12). In some patients, the amount of local thrombosis is extensive, but the obstruction is subtotal, resulting in a flow-limiting coronary stenosis and myocardial ischemia (e.g., UA) sometimes associated with myocardial necrosis (NSTEMI) (13,14). Plaque rupture plays a major role even in patients with stable angina: large numbers of plaques are found to have undergone rupture and healing in the past (5,17,61). Indeed, it is estimated that up to 99% of all plaque ruptures are clinically silent events (19). This highlights the importance of continued antithrombotic therapy for all patients with coronary artery disease.

STEMI: THE OPEN ARTERY THEORY

The "open artery theory" explains the beneficial effects of fibrinolytic therapy and catheter-based revascularization in acute STEMI: early achievement of an open infarct-related artery is associated with improved outcome (91). If occlusion persists for more than 30 min, myocardial necrosis develops in the territory at risk (Fig. 5). If the area at risk is large and the artery remains occluded, left ventricular function is impaired. Fib-rinolytic therapy acts to interrupt this cascade of events. By lysing the coronary thrombus, reperfusion of the infarct-related artery is achieved. This leads to a limitation of infarct size and decreases the extent of left ventricular dysfunction (92). The most important result of thrombolysis is improved survival (93,94).

Beginning with animal studies (95), the initial angiographic studies in patients using intracoronary streptokinase (96,97) and numerous other angiographic studies over the subsequent 20 yr have all lent strong support to this theory (91,98). An overview of all the angiographic studies that used the TIMI flow grading system (12), comprising over 4200 patients, found that patients who achieved complete and normal coronary perfusion,

Antithrombotic Therapy

Acute Coronary Occlusion

Thrombolysis Primary PCI

Recurrent infarction

Recurrent infarction

Coronary Repertusion i

Myocardial Necrosis Limitation of infarct size i I

LV Dysfunction Reduction of LV Dysfunction

improved Survival

Death

Fig. 5. The pathophysiology of acute STEMI and the paradigm of thrombolytic therapy.

Fig. 6. The relationship between TIMI flow grade at 90 min following fibrinolytic therapy and subsequent mortality. Adapted with permission from ref. 98.

graded TIMI grade 3 flow, at 90 min had the lowest mortality, 3.6%, compared with 9.5% with patients with TIMI grade 0 or 1 flow (p < 0.00001) (Fig. 6) (98). Patients with slowed or delayed coronary flow in the infarct-related artery compared to the uninvolved artery, graded as TIMI grade 2 flow, had an intermediate mortality of 6.6% and a relative risk of mortality that was significantly better than an occluded artery (98) These findings have also been confirmed in the Global Use of Strategies to Open Occluded Arteries (GUSTO) angiographic substudy, in which the mortality rates of patients with TIMI flow grades 2 and 3 were adjusted for differences in baseline characteristics (99). A direct relationship between full reperfusion and lower mortality also is also seen in an overview of trials of primary angioplasty and fibrinolytic therapy (Fig. 7) (100). When plotting the percentage of patients in various trials vs the corresponding mortality, a strong correlation between increasing rates of early TIMI grade 3 flow and lower mortality is observed (100).

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