HE FRAMINGHAM RISK SCORE (FRS) is a multivariable statistical model that uses age, sex, smoking history, blood pressure, cholesterol, high-density lipoprotein cholesterol (HDL-C), and blood glucose levels or history of diabetes to estimate coronary event risk among individuals without previously diagnosed coronary heart disease (CHD). 1 Although coronary risk stratification is widely recommended, 2-4 prediction models based on CHD risk factors, such as the FRS, have limitations in their ability to discriminate individuals who will or will not experience CHD. 1,5 Given the uncertainty of current predictive models, 5 the search for new strategies to discriminate patients who would benefit most from intensive primary prevention efforts is a clinically important objective. 3,6 One suggested approach to improve risk prediction over the FRS is the quantification of coronary artery calcium score (CACS), most commonly using computed tomography (CT). 7-13 The objective of this study was to determine whether CACS assessment combined with FRS among asymptomatic adults provides prognostic information superior to either method alone and whether the combined approach can more accurately guide primary preventive strategies for patients with CHD risk factors.

Toll-like receptors (TLRs) and the downstream adaptor molecule myeloid differentiation factor 88 (MyD88) play an essential role in the innate immune responses. Here, we demonstrate that genetic deficiency of TLR4 or MyD88 is associated with a significant reduction of aortic plaque areas in atherosclerosis-prone apolipoprotein E-deficient mice, despite persistent hypercholesterolemia, implying an important role for the innate immune system in atherogenesis. Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. Endothelial-leukocyte adhesion in response to minimally modified low-density lipoprotein was reduced in aortic endothelial cells derived from MyD88-deficient mice. Taken together, our results suggest an important role for TLR4 and MyD88 signaling in atherosclerosis in a hypercholesterolemic mouse model, providing a pathophysiologic link between innate immunity, inflammation, and atherogenesis.

Dystrophic or ectopic mineral deposition occurs in many pathologic conditions, including atherosclerosis. Calcium mineral deposits that frequently accompany atherosclerosis are readily quantifiable radiographically, serve as a surrogate marker for the disease, and predict a higher risk of myocardial infarction and death. Accelerating research interest has been propelled by a clear need to understand how plaque structure, composition, and stability lead to devastating cardiovascular events. In atherosclerotic plaque, accumulating evidence is consistent with the notion that calcification involves the participation of arterial osteoblasts and osteoclasts. Here we summarize current models of intimal arterial plaque calcification and highlight intriguing questions that require further investigation. Because atherosclerosis is a chronic vascular inflammation, we propose that arterial plaque calcification is best conceptualized as a convergence of bone biology with vascular inflammatory pathobiology.P laque structure and composition importantly impact clinical expression of atherosclerosis. Molecular medicine in the 21st century has turned toward a comprehensive understanding of the dynamic processes that influence the composition and stability of atheroma and of how structural plaque components impact clinical outcomes. Recently, increasing interest has focused on understanding how atherosclerotic pathology is related to a common plaque constituent: calcium mineral deposits. Pathologists have long known that calcified atherosclerotic arteries can contain tissue that is histomorphologically indistinguishable from bone (1, 2). Important studies in the last decade have now spawned a model wherein calcification in atherosclerotic plaque is viewed as an active, complex, and therefore presumably regulated process that exhibits intriguing similarities to new bone formation, or remodeling. Ectopic and dystrophic mineral deposition and extracellular matrix calcification can occur in numerous pathologic conditions by passive precipitation. Here we focus on one specific type of mineral deposition with high relevance to cardiac pathology: intimal arterial calcification in the context of atherosclerotic plaque. The emerging view is that plaque calcification represents a meeting of bone biology with chronic plaque inflammation. Remarkable cellular ontogenetic versatility in atherosclerosis appears to effect profound structural alterations, with significant ramifications for plaque stability and clinical outcomes. Clinical SignificanceAtherosclerotic lesions frequently become calcified. The process can begin early and accelerates as the disease progresses and more complex lesions develop. Calcium deposits in coronary arteries indicate the presence of plaque, but the converse statement that an absence of coronary calcium indicates an absence of atheromatous plaque is not true (1). Because calcification is a surrogate measure of coronary atherosclerosis, clinical interest has focused on the usefulness of noninvasive detection of calci...