Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.

BACKGROUND Coronary endothelial dysfunction is characterized by vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. Although endothelial dysfunction is considered an early phase of coronary atherosclerosis, there is a paucity of information regarding the outcome of these patients. Thus, this study was designed to evaluate the outcome of patients with mild coronary artery disease on the basis of their endothelial function. METHODS AND RESULTS Follow-up was obtained in 157 patients with mildly diseased coronary arteries who had undergone coronary vascular reactivity evaluation by graded administration of intracoronary acetylcholine, adenosine, and nitroglycerin and intracoronary ultrasound at the time of diagnostic study. Patients were divided on the basis of their response to acetylcholine into 3 groups: group 1 (n=83), patients with normal endothelial function; group 2 (n=32), patients with mild endothelial dysfunction; and group 3 (n=42), patients with severe endothelial dysfunction. Over an average 28-month follow-up (range, 11 to 52 months), none of the patients from group 1 or 2 had cardiac events. However, 6 (14%) with severe endothelial dysfunction had 10 cardiac events (P<0.05 versus groups 1 and 2). Cardiac events included myocardial infarction, percutaneous or surgical coronary revascularization, and/or cardiac death. CONCLUSIONS Severe endothelial dysfunction in the absence of obstructive coronary artery disease is associated with increased cardiac events. This study supports the concept that coronary endothelial dysfunction may play a role in the progression of coronary atherosclerosis.

[1]  E. Nabel,et al.  Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. , 1989, Circulation.

[2]  A. Becker,et al.  Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. , 1994, Circulation.

[3]  P. Libby,et al.  Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. , 1995, The Journal of clinical investigation.

[4]  F J Pinto,et al.  Nitroglycerin‐Induced Coronary Vasodilation in Cardiac Transplant Recipients: Evaluation With In Vivo Intracoronary Ultrasound , 1992, Circulation.

[5]  A. Tajik,et al.  Epicardial vasomotor responses to acetylcholine are not predicted by coronary atherosclerosis as assessed by intracoronary ultrasound. , 1995, Journal of the American College of Cardiology.

[6]  H. Drexler,et al.  Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. , 1991, Circulation.

[7]  M. Bell,et al.  Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. , 1995, Circulation.

[8]  Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) , 1994, The Lancet.

[9]  P. Ganz,et al.  Hypertension and Left Ventricular Hypertrophy Are Associated With Impaired Endothelium‐Mediated Relaxation in Human Coronary Resistance Vessels , 1993, Circulation.

[10]  M. Sugimachi,et al.  Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. , 1993, The Journal of clinical investigation.

[11]  A. Zeiher,et al.  Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. , 1995, Circulation.

[12]  R. Ross The pathogenesis of atherosclerosis: a perspective for the 1990s , 1993, Nature.

[13]  M. Hori,et al.  Adenosine, the Heart, and Coronary Circulation , 1991, Hypertension.

[14]  J. Stengård,et al.  Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease , 1994, The Lancet.

[15]  J. Hodgson,et al.  Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. , 1994, Journal of the American College of Cardiology.

[16]  S. Higano,et al.  Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. , 1998, Circulation.

[17]  P. Ganz,et al.  Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. , 1986, The New England journal of medicine.

[18]  D. Harrison,et al.  The Nitrovasodilators New Ideas About Old Drugs , 1993, Circulation.

[19]  H. M. Payne,et al.  Validation of A Doppler Guide Wire for Intravascular Measurement of Coronary Artery Flow Velocity , 1992, Circulation.

[20]  A. Tajik,et al.  Erratum: Epicardial vasomotor responses to acetylcholine are not predicted by coronary atherosclerosis as assessed by intracoronary ultrasound (J. Am. Coll. Cardiol. (1995) 26 (41-49)) , 1995 .

[21]  Walter L. Henry,et al.  Intravascular Ultrasound Imaging of Human Coronary Arteries In Vivo: Analysis of Tissue Characterizations With Comparison to In Vitro Histological Specimens , 1991, Circulation.

[22]  R. Gibbons,et al.  Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects. , 1997, Circulation.

[23]  A. Heagerty,et al.  Hyperlipidaemia, hypertension, and coronary heart disease , 1995, The Lancet.

[24]  E. Nabel,et al.  Responses of coronary arteries of cardiac transplant patients to acetylcholine. , 1988, The Journal of clinical investigation.

[25]  D. Celermajer,et al.  Endothelial dysfunction: does it matter? Is it reversible? , 1997, Journal of the American College of Cardiology.

[26]  J. Myers,et al.  Prevention of Coronary Heart Disease With Pravastatin in Men With Hypercholesterolemia , 1996 .

[27]  E Fleck,et al.  Prognostic value of intracoronary flow velocity and diameter stenosis in assessing the short- and long-term outcomes of coronary balloon angioplasty: the DEBATE Study (Doppler Endpoints Balloon Angioplasty Trial Europe). , 1997, Circulation.

[28]  P. Tsao,et al.  Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. , 1998, Circulation.

[29]  A. Yeung,et al.  Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. , 1990, Circulation.

[30]  J. Albers,et al.  Lipid Lowering and Plaque Regression New Insights Into Prevention of Plaque Disruption and Clinical Events in Coronary Disease , 1993, Circulation.

[31]  M. Sugimachi,et al.  Effects of Age on Endothelium‐Dependent Vasodilation of Resistance Coronary Artery by Acetycholine in Humans , 1993, Circulation.

[32]  P. Tsao,et al.  Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. , 1992, The Journal of clinical investigation.