Inflammation and plaque vulnerability.

Development of a thrombus at the site of an atherosclerotic plaque initiates abrupt arterial occlusion and is the proximate event responsible for the vast majority of acute ischemic syndromes. In nearly 75% of cases thrombus overlies a disrupted or ruptured plaque whereas the remainder of the thrombi overly an intact plaque with superficial endothelial erosion. Over the past several years, it has been recognized that plaque composition rather than plaque size or stenosis severity is important for plaque rupture and subsequent thrombosis.

Exogenous heat shock protein-70 inhibits cigarette smoke-induced intimal thickening.

Cigarette smoke is associated with increased carotid intimal thickening or stroke. Preliminary work showed that exposure to smoke resulted in a 4.5-fold reduction of heat shock protein-70 (HSP70) expression in spleens of mice using gene microarray analysis.

Molecular mechanisms of plaque instability.

Purpose Of Review: Coronary artery thrombosis superimposed on a disrupted atherosclerotic plaque initiates abrupt arterial occlusion and is the proximate event responsible for 60-80% cases of acute coronary syndromes. This article provides a concise update on the evolving concepts in the pathophysiology of plaque rupture and thrombosis.

Recent Findings: Over the past several years, the critical role of plaque composition rather than plaque size or stenosis severity, in plaque rupture and thrombosis have been recognized.

Active and passive immunization for atherosclerosis.

This review summarizes experimental findings that highlight the role of immune mechanisms in atherosclerosis and the potential atheroprotective effects of active or passive immunization strategies. Inmmunomodulation therapy appears to be feasible and effective, suggesting that a vaccine for atherosclerosis can be developed for clinical testing. Given the increasing number of patients with atherosclerotic disease on current therapy, a new therapy is needed and an immunization strategy could provide such a possibility.

Emerging HDL-based therapies for atherothrombotic vascular disease.

Statin therapy has been a significant advance in the management of dyslipidemia and atherothrombotic cardiovascular disease with a resultant 30% to 40% reduction in cardiovascular events; however, a significant number of events continue to occur in statin-treated patients, including in patients treated with high-dose statins targeted to achieve mean low-density lipoprotein cholesterol levels in the range of 60 to 80 mg/dL. Therefore, development and testing of new therapies that exploit the vascular protective effects of high-density lipoprotein (HDL) constitutes a rational and complementary approach. A number of HDL-based therapies are in various stages of development and testing.

Immunomodulation of atherosclerosis with a vaccine.

Experimental observations have established that the innate and adaptive immune mechanisms both have roles in the modulation of atherosclerosis. The complex function that the immune system has in the pathophysiology of atherosclerosis is highlighted by the fact that both proatherogenic and atheroprotective effects of immune activation can be demonstrated. An immune response to the protein and lipid components of oxidized LDL cholesterol has been observed in experimental models, and immunization with these antigens has generally reduced atherosclerosis.

Effect of exposure to cigarette smoke on carotid artery intimal thickening: the role of inducible NO synthase.

Objective: We investigated the role of inducible NO synthase (iNOS) in intimal thickening with exposure to cigarette smoke (CS).

Methods And Results: Intimal thickening in wild-type (WT) and iNOS-deficient (iNOS-/-) mice subjected to CS exposure was induced by placement of a cuff around the carotid artery. CS exposure in WT mice was associated with increased arterial iNOS expression, superoxide production, activator protein-1 (AP-1) activation, and serum NO.

Pathophysiology of plaque rupture and the concept of plaque stabilization.

Atherosclerotic coronary artery disease is the major cause of death, in men and women, in the United States and in much of the Western world. Atherosclerosis is responsible for coronary heart disease, limb ischemia, and most strokes. Although luminal narrowing by an atherosclerotic plaque and exaggerated or anomalous vasoconstriction contribute to some of the clinical manifestations of atherosclerotic arterial disease, it is the superim-position of a thrombus over an underlying ruptured or eroded plaque that results in the acute coronary syndromes (unstable angina, acute myocardial infarction, and sudden death) that are the most serious clinical manifestations of this disease.

Emerging non-statin LDL-lowering therapies for dyslipidemia and atherosclerosis.

Elevated low-density lipoprotein cholesterol is an important risk factor for atherothrombotic arterial disease. HMG-CoA reductase inhibitors, or statins, are very effective in lowering cholesterol levels, and several trials using statins have shown reductions in mortality and cardiovascular events, leading to the recent recommendations that all patients with known vascular disease, or who are at high risk for vascular disease, should be considered candidates for statin therapy. Yet statins reduce cardiovascular events by only about 20%-40%.

Mechanisms of plaque vulnerability and rupture.

Rupture of atherosclerotic plaque has been identified as the proximate event in the majority of cases of acute ischemic syndromes. Plaque rupture exposes thrombogenic components of the plaque, activating the clotting cascade and promoting thrombus formation. Future culprit lesions are difficult to identify, however, and angiographic assessment of stenosis severity is prone to underestimation.

New strategies in managing and preventing atherosclerosis: focus on HDL.

The development of atherosclerosis is a complex process whose central elements include the entrapment of low-density lipoprotein in the vessel wall, its subsequent oxidative modification, and the stimulation of proinflammatory gene expression leading to inflammatory cell recruitment, infiltration, and activation. High-density lipoprotein interacts with this process at multiple points, and these interactions could provide therapeutic targets to prevent, stabilize, or even promote the regression of atherosclerosis. High-density lipoprotein may retard atherosclerotic progression by promoting cholesterol efflux from the arterial wall, thereby reducing plaque lipid content as well as potentially inhibiting nascent fatty streak formation.

Pathophysiology of coronary thrombosis: role of plaque rupture and plaque erosion.

Coronary artery disease is the leading cause of death in much of the western world. Atherosclerotic plaques in the coronary arteries contribute to luminal obstruction leading to myocardial ischemia; however, abrupt coronary artery occlusion most frequently results from superimposition of a thrombus on a disrupted plaque, leading to the most serious clinical manifestations of coronary artery disease, ie, unstable angina, acute myocardial infarction, and sudden death. Plaque that have undergone disruption and, by inference, plaques at risk for disruption (vulnerable plaques), tend to demonstrate outward vessel remodeling, contain a large lipid core, thinned out fibrous cap, reduced collagen content, and increased inflammatory cell infiltration.

Chronic infections and atherosclerosis/thrombosis.

An emerging pathophysiologic paradigm implicates chronic inflammation in the initiation, progression, and destabilization of atherosclerotic vascular disease. Various potential contributors to the inflammatory response in the vessel wall include atherogenic lipids, mechanical stress and injury, hypertension and angiotensin II, cigarette smoking, immune response to neoantigens, and chronic infections with viruses and or bacteria (Table 1). The potential link between chronic infection and atherosclerosis/thrombosis is under extensive investigation in several laboratories around the world.

Focus on HDL: a new treatment paradigm for athero-thrombotic vascular disease.

Atherosclerotic vascular disease is the leading cause of mortality and morbidity in much of the Western world. Although advances in lifestyle and risk factor modification, pharmacotherapy, endovascular interventions and surgery have considerably improved clinical outcome, 40 - 50% of adverse cardiovascular events continue to occur despite current strategies. A number of new targets for therapeutic exploitation are currently being investigated that include, among others, apolipoprotein A-I, the major structural component of high density lipoprotein (HDL) particle.