Endothelial function, inflammation, and prognosis in cardiovascular disease
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
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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.
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Established therapies, such as LDL cholesterol lowering using statins plus TZDs, appear to have a role in improving endothelial dysfunction and decreasing CRP.
References (84)
- et al.
Hsp90 ensures the transition from the early CA2+-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells
J Biol Chem
(2001) - et al.
Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis
J Am Coll Cardiol
(1998) - et al.
Close relation of endothelial function in the human coronary and peripheral circulations
J Am Coll Cardiol
(1995) - et al.
Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis
Lancet
(1992) - et al.
Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease
Am J Cardiol
(1996) - et al.
Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain
Am J Cardiol
(2000) - et al.
Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus
J Diabetes Complications
(1998) Endothelial dysfunctiondoes it matter? Is it reversible?
J Am Coll Cardiol
(1997)- et al.
Prediction of coronary heart disease using risk factor categories
Circulation
(1998) - et al.
Modulation of coronary vasomotor tone in humansprogressive endothelial dysfunction with different early stages of coronary atherosclerosis
Circulation
(1991)
Role of impaired endothelium-dependent vasodilation in ischemic manifestations of coronary artery disease
Circulation
Ischemic heart disease
Atherosclerosis as disease of redox-sensitive genes
Trans Am Clin Climatol Assoc
Endothelial functionfrom vascular biology to clinical applications
Am J Cardiol
Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease
Circulation
Childhood risk factors predict adult risk associated with subclinical cardiovascular diseasethe Bogalusa Heart Study
Am J Cardiol
Integrated approach to evaluating coronary artery disease and ischemic heart disease
Am J Cardiol
Atherosclerosisan inflammatory disease
N Engl J Med
Current concepts of the pathogenesis of the acute coronary syndromes
Circulation
Role of nitric oxide in cardiovascular diseasefocus on the endothelium
Clin Chem
The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine
Nature
Functional reconstitution of endothelial nitric oxide synthase reveals the importance of serine 1179 in endothelium-dependent vasomotion
Circ Res
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation
Nature
Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release
Circ Res
Cellular and molecular mechanisms of endothelial cell dysfunction
J Clin Invest
Inflammation and atherosclerosis
Circulation
LPC in oxidized LDL elicits vasocontraction and inhibits endothelium-dependent relaxation
Am J Physiol
Protein kinase C inhibitors prevent impairment of endothelium-dependent relaxation by oxidatively modified LDL
Arterioscler Thromb
Endothelial regulation of vasomotion in apoE-deficient miceimplications for interactions between peroxynitrite and tetrahydrobiopterin
Circulation
Superoxide generation by endothelial nitric oxide synthasethe influence of cofactors
Proc Natl Acad Sci U S A
Does ADMA cause endothelial dysfunction?
Arterioscler Thromb Vasc Biol
Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries
N Engl J Med
Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans
Circulation
Nitric oxide activity in the human coronary circulationimpact of risk factors for coronary atherosclerosis
J Clin Invest
Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function
Circulation
Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease
Circulation
Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans
Circulation
The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion
N Engl J Med
Cholesterol reduction rapidly improves endothelial function after acute coronary syndromesthe RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial
Circulation
Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month
Circulation
Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease
Circulation
Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test
Circulation
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