Endothelial function, inflammation, and prognosis in cardiovascular disease

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Abstract

The vascular endothelium is an active, dynamic tissue that controls many important functions, including regulation of vascular tone and maintenance of blood circulation, fluidity, coagulation, and inflammatory responses. Cardiovascular risk factors affect many of the normal functions of the endothelium. In particular, oxidized low-density lipoprotein cholesterol initiates a series of events that begin with cell activation, endothelial dysfunction, local inflammation, and a procoagulant vascular surface. These conspire to result in plaque formation and ultimately plaque rupture and cardiovascular events.

Endothelial dysfunction may be evaluated by means of invasive techniques, such as coronary artery reactivity to acetylcholine, or noninvasive techniques, such as brachial artery ultrasonography. Loss of endothelium-dependent vasodilation is a characteristic feature throughout the development of atherosclerosis, and it is independently related to future adverse cardiovascular risk. Therefore, measurement of endothelial function can possibly be used to determine risk, to triage management, and to improve outcomes. At the same time, inflammation is a crucial factor in the atherosclerotic disease process. To identify and monitor the ongoing inflammatory process, markers of inflammation such as C-reactive protein (CRP) have been studied. Scientific evidence shows that elevated plasma CRP values add to the predictive ability of other established risk factors; moreover, elevated values appear to augment the Framingham Coronary Risk Score in identifying individuals who should be considered for cardioprotective treatment programs.

Interestingly, thiazolidinediones (TZDs), peroxisome proliferator-activated receptor–γ agonists that are effective in the treatment of type 2 diabetes mellitus, not only increase insulin sensitivity but can benefit endothelial function because they exhibit anti-inflammatory effects. For many individuals, including those with the metabolic syndrome and/or type 2 diabetes, endothelial dysfunction and elevated plasma CRP levels indicate increased risk of cardiovascular disease. Notably, the TZDs have been shown to reduce CRP levels and may improve endothelial function.

Section snippets

The endothelium in health

The endothelium is a continuous layer of cells that separates blood from the vessel wall; it manifests a variety of phenotypes that vary between vascular beds. An active, dynamic tissue, the endothelium controls many important functions, including maintenance of blood circulation and fluidity as well as regulation of vascular tone, coagulation, and inflammatory responses.6, 12, 13 The arterial endothelium responds to flow and shear forces via a pathway that leads to phosphorylation of

Endothelial dysfunction in atherosclerosis

Cardiovascular risk factors profoundly affect many of the healthy functions of the endothelium. Low-density lipoprotein (LDL), and oxidized LDL in particular, initiate a series of events that occur early during plaque formation.19, 20 In brief, these responses begin with the activation of protein kinase C21 and the transcriptional messenger nuclear factor–κB (NF-κB). This leads to upregulation of genes that code for and induce angiotensin-converting enzyme activity, local production of

Inflammation in atherosclerosis

Inflammation begins with secretion of chemoattractants such as monocyte chemoattractant protein–1 and macrophage colony-stimulating factor, chemokines such as the interleukins (ILs), growth factors, and cell surface adhesion molecules that bind monocytes. In the intimal space, monocytes and T lymphocytes modulate this inflammatory response and eventually form foam cells with intimal thickening, plaque formation, and vessel narrowing. This local macrophage-mediated inflammatory response includes

Clinical manifestations and consequences of endothelial dysfunction and inflammation

Endothelial dysfunction may be evaluated using invasive techniques, such as coronary artery reactivity to acetylcholine, or using noninvasive techniques such as brachial artery ultrasonography. Clinical studies have examined receptor-mediated and flow-mediated vasodilation in coronary and peripheral arteries. These studies have demonstrated that production of NO by the endothelium is important in mediating vasodilation in health. The presence of risk factors and/or atherosclerosis will result

Endothelial dysfunction, inflammation, and prognosis

Evidence suggests that loss of endothelium-dependent vasodilation by NO is characteristic throughout the development of atherosclerosis and has adverse consequences, specifically vasoconstriction. Thus, it would seem reasonable to monitor endothelial function to measure risk, to triage management, and to improve outcomes. In fact, numerous studies have shown that endothelial dysfunction is independently related to future cardiovascular events (e.g., myocardial infarction, stroke, transient

Markers of inflammation, the metabolic syndrome, and cardiovascular disease

Measures of endothelial function have been, and remain, invaluable for research into disease mechanism and response to new therapies. To identify and monitor the ongoing inflammatory process, various proinflammatory cytokines (e.g., IL-1, tumor necrosis factor–α), inflammatory stimuli (e.g., IL-6), adhesion molecules, and markers of inflammation (e.g., CRP) have been studied (Figure 1).62, 63 Scientific evidence shows that assay of CRP adds to the predictive ability of other established risk

Endothelial function and risks in coronary disease: strengths and weaknesses

Clearly, the loss of endothelium-dependent vasomotor function is a characteristic feature of atherosclerosis and its causative risk factors. Clinical measures can be recorded noninvasively; they worsen with advancement of the disease and improve with selected proven therapies. In fact, many (but not all) therapies that improve endothelial function also improve clinical outcomes. However, larger clinical studies with longer follow-up are required to determine whether measures of endothelial

Now and in the future

Measures of endothelial function have been, and remain, invaluable for research into mechanisms and response to new therapies. Before widespread use of such measures for assessment of risk, prognosis, and therapies can be recommended, their sensitivity, specificity, cost, and feasibility must be considered. At present, the Framingham Coronary Risk Score is used to assess risk. It remains to be determined whether measures of endothelial function and surrogate markers of inflammation will provide

Summary statements

  • Endothelial dysfunction and inflammation (increased CRP) are important signs of vascular risk and indicators of a worsened prognosis in patients with the metabolic syndrome or type 2 diabetes.

  • Established therapies, such as LDL cholesterol lowering using statins plus TZDs, appear to have a role in improving endothelial dysfunction and decreasing CRP.

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