Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease.

Werns, Steven W.; Walton, Joseph A.; Hsia, Henry H.; Nabel, Elizabeth G.; Sanz, M. Eugenia; Pitt, Bertram

doi:10.1161/01.cir.79.2.287

Cited by 290 publications

(86 citation statements)

References 29 publications

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“…Endothelium-derived NO, therefore, is protective for the vasculature and decreased NO bioavailability is often associated with increased risk of cardiovascular disease [62]. As mentioned, endothelial dysfunction is one of the earliest manifestations of atherosclerosis [63].…”

Section: Statins and Vascular Dysfunctionmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

537

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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Section: Statins and Vascular Dysfunctionmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

537

394

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“…[1][2][3][4][5][6][7][8][9] Clinical studies have shown that intracoronary acetylcholine infusion constricts atherosclerotic coronary arteries.9-11 Smooth segments may also constrict in patients with coronary artery disease evident in other vessels, possibly reflecting early atherosclerosis.11 In patients with angiographically "normal" coronary arteries, the vasomotor response to intracoronary acetylcholine is heterogeneous: both dilation and constriction have been reported. [10][11][12][13] This study examines the hypothesis that coronary risk factors disturb endothelial function and may thereby influence the response to intracoronary acetylcholine in patients with angiographically smooth coronary arteries. Methods …”

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confidence: 99%

Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.

et al. 1990

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In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunc- (Circulation 1990;81:491-497) In animals, acetylcholine produces endotheliumdependent dilation of normal arteries and vasoconstriction in pathologic states such as hypersee p 697 cholesterolemia, hypertension, or atherosclerosis.1-9 Clinical studies have shown that intracoronary acetylcholine infusion constricts atherosclerotic coronary arteries.9-11 Smooth segments may also constrict in patients with coronary artery disease evident in

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“…When acetylcholine was infused intravenously, normal controls showed a vasodilatory response, but responses were reduced or vasoconstrictive in patients with hypertension, 13 diabetes, 15 hypercholesterolemia, 14 congestive heart failure 28 or atherosclerosis. 5,21,[23][24][25] Similarly, increases in flow subject the endothelium to increased shear stress, which stimulates the NO-cGMP pathway, so that FMD is also dependent on endothelial cells. Abnormal FMD has been shown in patients with cardiac risk factors and in atherosclerosis.…”

Section: No-dependent Penile Erectionmentioning

confidence: 99%

“…4,[6][7][8][9][10][11] Cardiac risk factors are prevalent in patients with ED 12 and correlate with endothelial dysfunction, including hypertension, 13 hypercholesterolemia, 3,14,15 diabetes, 6,15 smoking 3, [16][17][18] and age, 18 as well as with atherosclerosis. 3,[19][20][21][22][23][24][25] This study reviews normal endothelial function, as well as endothelial dysfunction in general and related specifically to ED. A variety of methods to measure endothelial function and therapies that improve endothelial function are reviewed.…”

Section: Introductionmentioning

confidence: 99%

The endothelial cell in health and disease: its function, dysfunction, measurement and therapy

et al. 2009

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Endothelial cells have numerous endocrine functions and contribute to a variety of processes, including penile erection and vasodilation. Endothelial dysfunction is associated with cardiovascular risk factors and has been implicated in the pathogenesis of atherosclerosis and ED. This study reviews endothelial function, in addition to endothelial dysfunction and its role in atherosclerosis and ED. Measurement of endothelial function is reviewed, including catheter-based methods, venous occlusion plethysmography, high-frequency ultrasound, peripheral arterial tonometry, digital pulse amplitude tonometry, digital thermal monitoring, the L-arginine test and measurement of compounds released by endothelial cells. Therapy and medications that improve endothelial function are reviewed. As the scientific community learns more about the importance of the endothelium, it is increasingly important for the clinician to understand endothelial function, dysfunction, measurement of endothelial function and therapies that affect this remarkable cell type.

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Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease.

Cited by 290 publications

References 29 publications

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.

The endothelial cell in health and disease: its function, dysfunction, measurement and therapy

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