For several decades, our understanding of the pathogenesis of unstable atherosclerotic lesions has continued to grow. A consistent picture of unstable plaque structure, inflammation, matrix degradation, and prothrombotic activity is emerging. Meanwhile, the mortality rates for coronary artery disease in the United States have steadily declined. 1 Changes in the American life style likely account for much of this decline, 2 and we can expect further improvements through the beneficial use of aspirin and cholesterollowering therapy in subsets of the population. 3-5 Many of these improvements were based on careful epidemiological studies, with fundamental vascular biology serving a largely supportive role.

In light of this major clinical progress, it is reasonable to consider whether further basic understanding of the unstable atherosclerotic lesion will be translated into a clinical benefit beyond these recent advances. 6 We propose that the basic biology of the unstable lesion will now assume even greater importance for two fundamental reasons. First, even with aspirin and cholesterollowering therapy, acute vascular events will continue to be a major cause of morbidity and mortality in developed countries. Performing clinical trials and epidemiological studies in the United States and other developed countries will become more difficult and expensive as the number of patients needed for each study increases. Thus, developing new successful approaches to the prevention of acute vascular syndromes will require a sound understanding of the pathogenesis of lesion destabilization, and proceeding to clinical breakthroughs will require strong justification from vascular biology before clinical trials are undertaken. Second, even as the age-adjusted incidence of ischemic heart disease falls in the United States, the worldwide importance of ischemic heart disease is increasing. In fact, a recent comprehensive survey of the global patterns of disease has projected that by the year 2020, ischemic heart disease (currently the fifth leading cause of global disease burden) will surpass communicable diseases to become the leading cause of disability in the world. 7 This review will discuss our current understanding of the unstable lesion as well as the important gaps in that understanding. The difficult process of filling in these