Coronary artery disease (CAD) continues to be a leading cause of mortality and morbidity, stymieing screening approaches to predict risk for future debilitating events, despite intensive investigation and significant interventional advances. More than 1 million Americans and nearly 20 million people worldwide suffer from acute coronary syndrome (ACS).1 The estimated healthcare cost to manage end-stage cardiovascular disease is in excess of $350 billion, which does not account for the associated cost of loss of productivity.2 Therefore, it is very important to develop effective approaches to identify early CAD.
Rapid progress in cardiac computed tomography (CT) now enables not only the detection and quantification of coronary artery calcification (CAC) but also the grading of coronary stenosis.3"9 The contrast resolution afforded by CT potentially may permit assessment of the blood vessel wall, which would allow physicians to shift the emphasis in CAD from the "end game"�the hemodynamically significant lesion�to a more remedial point earlier in the natural history of the disease. Moreover, since ACS is believed to be caused by atherosclerotic plaque rupture, CT evaluation of coronary artery plaque may yield a more effective approach to risk stratification than with current strategies, which rely more on assessment of clinical risk factors such as age, gender, family history, hypertension, dys-lipidemia, diabetes, and tobacco usage.
The coronary artery plaque that lies at the core of the disease process has been the subject of intensive research, which has led to major inroads into understanding the molecular and cellular underpinnings of atherogenesis and plaque progression.10" Inflammation has a central role, with the macrophage as the key cellular inflammatory mediator of the atheroma, implicated in each phase of atherogenesis, including plaque initiation, progression, and rupture.12 Initially, circulating monocytes adhere to a region of dysfunctional endothelium along the arterial wall, maturing into macrophages that phagocytose lipoproteins, and then morphing into the well-known foam cells that form the early atheroma. Macrophages that die in the atheroma contribute to a paucicellular lipid core. The secretion of proteases by remaining macrophages and other immune cells can cause weakening of connective tissue in the atheroma that could predispose to hemorrhage and even frank disruption of the fibrous cap, eventually leading to plaque erosion and rupture. Recruitment of other cellular mediators can induce neovascularization. The aggregate of these changes ultimately can manifest as dystrophic calcification that can be detected as calcified plaque and luminal narrowing.1011
For decades, the paradigm for pathology in CAD focused on the degree of luminal stenosis, in part because the primary imaging examination for CAD was angiography and also because clinical success was noted following revascularization procedures that targeted critical coronary arterial stenoses. In short, CAD severity was viewed as dependent on the degree of luminal narrowing, and atherosclerosis was primarily thought of as a focal disorder. However, more recent work has triggered a shift in this thinking and has elucidated the importance of arterial remodeling, suggesting a new way to improve patient outcomes. It is now believed that, for much of its life history, the atheroma expands extrinsically from the vessel lumen, rather than inward, an adaptive process called "positive remodeling."10" The implication is that a non-trivial atherosclerotic plaque burden can manifest even in the absence of stenosis. Ergo, substantial disease could exist but remain occult to angiography.