(Circulation. 1999;100:216-218.)
© 1999 American Heart Association, Inc.
Editorial |
Increased Superoxide in Heart Failure
A Biochemical Baroreflex Gone Awry
From the Department of Medicine, Emory University School of Medicine, Atlanta, Ga (D.G.H.), and Eppendorf University, Hamburg, Germany (T.M.).
Correspondence to David G. Harrison, MD, Department of Medicine, Cardiology Division, Emory University School of Medicine, Woodruff Memorial Research Building, Suite 319, 1639 Pierce Dr, Atlanta, GA 30322. E-mail dharr02@emory.edu
Key Words: Editorials • endothelium • myocardial infarction • heart failure • free radicals
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Introduction |
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Increased peripheral vascular resistance is a hallmark of advanced chronic congestive heart failure (CHF) and contributes to the phenomenon of "increased afterload" that complicates this condition. Multiple factors probably underlie this phenomenon, including increased water and sodium content of the vasculature, increased neurohormonal activation, and intrinsic abnormalities of the vasculature.1 During the past decade, it has also been shown that endothelium-dependent vasodilation is strikingly abnormal in both experimental animals and humans with compromised cardiac function.2 3 Given that endothelial regulation of vasomotion plays a major role in the control of systemic hemodynamics, this phenomenon is probably a major cause of increased systemic vascular resistance and afterload in heart failure. Because endothelial regulation of vascular tone is mediated predominantly by endothelium-derived nitric oxide (NO), numerous studies have examined abnormalities of the L-arginine/NO pathway in heart failure. Two major abnormalities have surfaced as important.
Several studies have suggested that CHF leads to a decline in
expression of endothelial cell NO synthase
(eNOS), which is ultimately responsible for
endothelial production of NO. Wang et
al4 produced heart failure in dogs by cardiac pacing
at a rapid rate for 4 weeks. Microvascular endothelial
cells released markedly less nitrite (the stable degradation
product of NO) than cells from hearts of normal animals. Using the
same heart failure model, Smith and colleagues5 observed a
decrease in the expression of both eNOS and
cyclooxygenase 1, the enzyme responsible for
production of prostacyclin. CHF is also associated with
increased circulating levels of the cytokine
TNF-
.6 In vitro,
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