This chapter discusses the pathophysiological development of atherothrombosis. Atherothrombosis is the chronic, lipid-driven, multifocal inflammatory process of atherosclerotic plaque development (see accompanying Hurst’s Central Illustration) and subsequent thrombosis. Individual susceptibility to well-known risk factors for atherothrombosis varies considerable, and better detection of at-risk individuals may be achieved by visualizing the arterial wall. Plaques are very heterogeneous in size and composition. Many plaques remain asymptomatic, some become obstructive, and a few, if any, become vulnerable to plaque rupture or erosion. The major determinants of plaque vulnerability seem to be the size of the necrotic core and the thickness of the fibrous cap. However, because of the complexity of the processes leading to plaque vulnerability and susceptibility to thrombosis, trying to predict the fate and clinical impact of a particular plaque may be futile. Combining knowledge of risk factors and detection of overall disease burden, and treating patients who are at highest risk, may be the best strategy for this systemic disease. Inflammatory activity is present in most, or all, atherosclerotic lesions within the body and might therefore be a useful marker of systemic disease activity. Additionally, focal calcifications are very common in atherosclerotic plaques, and the total amount of coronary artery calcium correlates strongly with plaque burden and is a strong predictor of coronary events.
Hurst’s Central Illustration: Pathophysiological Development of a Vulnerable Plaque in Atherothrombosis.
Development of an atherosclerotic plaque that becomes vulnerable to plaque rupture or erosion and, therefore, to thrombosis.
Atherosclerosis with thrombosis superimposed, atherothrombosis, is the main cause of coronary heart disease (CHD), peripheral artery disease, and large-artery stroke.1,2,3 The development of thrombosis-prone atherosclerotic plaques, also known as high-risk or vulnerable plaques,4 in the coronaries and other arteries is the leading cause of death and severe disability, not only in affluent countries, but also worldwide.5,6
Causal and modifiable risk factors for atherosclerotic cardiovascular disease are well known (eg, smoking, dyslipidemia, high blood pressure, diabetes) and account for most heart attacks in both sexes.7 However, for unknown reasons, the individual susceptibility to these risk factors varies greatly, and consequently, their predictive value is limited.8,9 Most first heart attacks occur among people with average or only slightly elevated risk factor levels.10,11,12 Recurrent events still occur despite lowering of these levels,13,14 indicating that we need both better detection and better treatment of those who are destined for a heart attack. Better detection of at-risk individuals may be achieved by visualizing the diseased arterial wall rather than just assessing risk factors for getting the disease.15,16,17 The prospect for atherosclerosis-based risk assessment will be discussed in the concluding section of this chapter.
ATHEROGENESIS AND PLAQUE DEVELOPMENT