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Clin. Cardiol. Vol. 20 (Suppl. II), (1997)

Endothelial Dysfunction, the Renin-Angiotensin System, and Nitric Oxide: Impact on Coronary Artery Disease and Therapeutic Interventions

Carl J. Pepine, M.D.
Guest Editor

Follow this link to download the entire supplement in PDF form [950k]


The Vascular Biology Working Group was formed under the auspices of the University of Florida College of Medicine to bring together researchers from various fields to explore the clinical implications of recent basic research related to the endothelium. A central focus was work dealing with the pathogenesis of cardiovascular disease. The initial meetings of the Working Group were held in March 1994 (North America) and March 1995 (Europe), and annual meetings have refined our understanding of the complex processes that influence the development of atherosclerosis, hypertension, and other vascular diseases. The primary goal of these meetings is to translate basic and clinical research into a message useful to the practicing physician, with the hope that it could impact on adverse outcomes of patients with cardiovascular disease.

This supplement to Clinical Cardiology is based on the proceedings of Working Group meetings held in the United States and Europe in late 1996 and early 1997. The nine articles by prominent cardiologists review the current understanding of the endothelium as a mediator of cardiovascular tone and structure. They also discuss interventions that are proposed (e.g., estrogen in postmenopausal women, L-arginine supplementation) and proven [e.g., HMG-CoA reductase inhibitors, angiotensin-converting enzyme (ACE) inhibitors, and others] to improve endothelial function in the coronary circulation of patients with atherosclerosis or hypertension.

To begin, Thomas F. Lüscher, M.D., from University Hospital Zürich and the University of Zürich, Switzerland, establishes the basis for the ensuing discussions with an overview of the biology of the endothelium [PDF]. As he explains, the endothelium produces substances that regulate both relaxation and contraction of blood vessels, and it also contributes to the maintenance of vascular structure.

Next, David G. Harrison, M.D., of Emory University School of Medicine, Atlanta, examines oxidant stress and endothelial function [PDF]. We now know that oxidation inactivates nitric oxide and likely contributes to many abnormalities of endothelium that characterize atherosclerosis, hypertension, and other disease processes.

The article onthe homeostatic balance between angiotensin II and nitric oxide [PDF] by Gary H. Gibbons, M.D., from Brigham and Women's Hospital in Boston, provides an excellent overview of the balance between vasoconstrictors and vasodilators as well as between growth promoters and growth inhibitors. In this regard, angiotensin II in particular mediates vascular remodeling. Dr. Gibbons indicates that blocking angiotensin II by ACE inhibition may have profound effects on vascular function and structure.

Although recent research has established that endothelial dysfunction of both large and small blood vessels contributes to hypertension, the exact cause of the pathologic disturbance that causes endothelial dysfunction in patients with hypertension has not been defined. Julio A. Panza, M.D, and colleagues at the National Institutes of Health, Bethesda, have conducted a series of investigations designed to clarify the potential contributions of various endothelium-dependent and -independent factors to abnormal endothelial function. He provides an outstanding overview of the relation between hypertension and endothelial dysfunction [PDF] as well as an update on the results of experiments to identify potential mechanisms.

A primary focus of the Vascular Biology Working Group is the role of the renin-angiotensin system and ACE in endothelial function [PDF]. Douglas E. Vaughan, M.D., of Vanderbilt University Medical Center, Nashville, explores this relationship as it pertains to local fibrinolysis, one of the primary endogenous mechanisms for preventing intravascular thrombosis. He provides results of the newest studies showing that ACE inhibition can interrupt the occurrence of acute ischemic events in some populations.

As the inner lining of blood vessels, the endothelium is involved early in the development of atherosclerotic plaque. Plaque disruption causes coronary thrombosis, which is, in turn, the primary mechanism responsible for acute coronary syndromes such as unstable angina, acute myocardial infarction, and sudden cardiac death. The article by Prediman K. Shah, M.D., of Cedars-Sinai Medical Center, Los Angeles, provides an update on the pathogenesis and prevention of plaque disruption and coronary thrombosis [PDF], including the recent concept of plaque stabilization as a potential clinical intervention.

In his discussion of the endothelium as a target organ [PDF], John P. Cooke, M.D., Ph.D., from Stanford University School of Medicine, Stanford, reviews risk factors known to lead to endothelial dysfunction. These range from well-recognized risk factors for atherosclerosis such as hypertension and increased levels of low-density lipoprotein cholesterol to a recently identified factor, asymmetric dimethylarginine (ADMA), an endogenous antagonist of nitric oxide synthase. A number of potential therapeutic interventions, both pharmacologic (ACE inhibitors, lipid-lowering agents) and nonpharmacologic (e.g., antioxidants), have been shown to improve endothelial function. They accomplish this by modifying or reducing the effects of these factors or by decreasing the vulnerability of the endothelium to damage.

Christophe Bauters, M.D., of the University and Cardiology Hospital of Lille, France, presents results of experimental studies performed at his laboratory on the beneficial effects exerted by several vascular growth factors [PDF], including basic fibroblast growth factor and vascular endothelial growth factor, on endothelial function. These growth factors offer a new avenue for therapy of ischemia in either the limbs or the heart.

The final article by myself examines the potential role of ACE inhibition in clinical myocardial ischemia [PDF]. A number of recently completed or ongoing randomized, clinical trials are reviewed. Results of these trials will provide critical information on the potential benefits of ACE-inhibitor therapy in improving endothelial function.

It is hoped that the publication of this supplement, made possible through an unrestricted grant from Parke-Davis, will further our goal of making the latest research in vascular biology accessible to the practicing physician and provide insights into the basis for clinical interventions to improve outcomes in coronary artery disease.