(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{at}emory.edu
Key Words: Editorials • endothelium • myocardial infarction • heart failure • free radicals
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Introduction |
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 Top Introduction References |
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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, TNF- increases degradation of eNOS
mRNA, most likely via stimulation interaction of RNA-destabilizing
proteins with a specific portion of the 3'-untranslated region of the
eNOS message. Moreover, both the activity and expression of eNOS are
regulated by endothelial shear stress.7
Thus, chronic reductions in blood flow and the resultant decrease in
shear stress may decrease endothelial NO
production and contribute to endothelial
dysfunction in patients with CHF.
A second mechanism responsible for impaired endothelial
function in heart failure is enhanced biodegradation of NO by the
superoxide anion. Both NO and superoxide are radicals and when exposed
to one another undergo a diffusion-limited radical-radical reaction to
form the peroxynitrite anion. The latter is a strong oxidant with only
minimal vasodilator activity. Ultimately, peroxynitrite degrades to
nitrate and nitrite. Recent clinical and experimental studies provide
indirect evidence that in chronic CHF, the production of
oxygen-derived free radicals is increased.8 9 10 Prasad et
al11 showed that polymorphonuclear leukocyte
production of oxygen-derived free radicals is increased 4-fold
in patients with heart failure compared with controls. Dhalla and
Singal12 showed that production of superoxide
in cardiac tissue is increased as a consequence of reduced antioxidant
reserve in heart failure. In patients with CHF, levels of
malondialdehyde are increased, compatible with increased lipid
peroxidation by oxygen-derived free radicals.13
Pericardial levels of 8-iso-PGF2 correlate
with the functional severity of heart failure.14 There is
also a correlation between plasma lipid peroxide and malondialdehyde
levels and the clinical class of heart failure.15 In
addition, there seems to be a close relationship between
exercise-induced malondialdehyde, superoxide dismutase (SOD) activity,
and exercise capacity in heart failure, suggesting that exercise
intolerance may be related to oxidative stress in this
condition.16
Indirect evidence for increased oxidative stress as a determinant of endothelial dysfunction in CHF was provided by Hornig et al.17 In these studies, treatment with vitamin C improved endothelial dysfunction both short- and long-term in patients with CHF. Interestingly, Winlaw et al18 showed that plasma nitrate, the stable metabolite of NO, is paradoxically increased in patients with CHF, suggesting that NO production may be preserved or even increased in a compensatory fashion in heart failure.
In this issue of Circulation, Bauersachs et al19 have added to our understanding of interactions between superoxide and NO in heart failure. These authors induced heart failure in rats by producing myocardial infarction. These animals had a marked degree of endothelial dysfunction despite increased expression of both eNOS and soluble guanylyl cyclase (the downstream target of NO in vascular smooth muscle). Incubation of aortas from these animals with radical scavengers normalized cGMP responses to sodium nitroprusside and improved vascular relaxations. These investigators also identified vascular NADH oxidase as the likely source of vascular superoxide in this model.
The findings of Bauersachs et al are extremely important and provide
further insight into the pathophysiology of heart failure. In
retrospect, one might have predicted that vascular NADH oxidase would
be activated in heart failure. This enzyme system is the major
source of reactive oxygen species in both the
endothelium and vascular smooth muscle. Previous in
vitro and in vivo studies have shown that angiotensin II
and cytokines such as TNF- can stimulate activity and/or
expression of this oxidase. As noted above, circulating levels of
TNF- are increased in heart failure, and activation of the
renin/angiotensin system is a consistent finding in
this condition. It is interesting to speculate that the now
well-established benefit of ACE inhibitors in heart failure
may be in part related to suppression of the activity of this oxidase
and a concomitant decrease in vascular oxidative stress. Indeed, recent
studies have shown that treatment with either ACE
inhibitors or angiotensin-receptor
antagonists decrease vascular superoxide production
in models of angiotensin II–driven
hypertension.20 Finally, hydralazine has been used
for many years as a treatment for heart failure. Interestingly, this
drug is a potent inhibitor of NADH
oxidase.21
It is unclear why some laboratories find that eNOS is reduced but others find that eNOS expression is not altered and in fact may be increased (as shown by Bauersachs et al) in heart failure. One explanation may be related to the type of heart failure examined. Bauersachs et al used a model resembling ischemic cardiomyopathy, whereas investigators studying pacing-induced heart failure have found a decrease in eNOS expression in the aorta and coronary microvessels. The latter model resembles an idiopathic cardiomyopathy in many respects. Vitamin C has not been found to improve endothelium-dependent vasodilation in patients with idiopathic dilated cardiomyopathy,22 which suggests that superoxide may not play a role in this condition. There may also be differences in the effect of heart failure on different vascular beds and perhaps in animal species used in various experiments.
Interestingly, daily exercise has been shown to enhance expression of eNOS in normal animals and to improve endothelium-dependent vasodilation in patients with CHF.23 24 The increase in cardiac output that occurs during exercise increases endothelial shear stress, which, as noted above, stimulates eNOS expression. In addition, shear stress has been shown to augment Cu/Zn SOD expression in human aortic endothelial cells.25 Taken together with the results of Bauersachs et al, these findings suggest that exercise may improve endothelium-dependent vasodilation by reducing local levels of superoxide by increasing endothelial Cu/Zn SOD content.
CHF is generally considered to be caused by myocardial dysfunction. The present study and other recent studies suggest that heart failure also involves perturbations of vascular function and that reactive oxygen species most likely contribute to this process. Under normal circumstances, production of reactive oxygen species by mammalian cells almost certainly has important roles in modulating cell growth and development, gene expression, and inflammation. The acute production of superoxide may limit the biological effect of NO at times when vasoconstriction is needed. An example may be as a "biochemical baroreflex" during prolonged activation of the renin/angiotensin system, for instance, during dehydration or hemorrhage. Unfortunately, in certain disease states, including hypertension, atherosclerosis, and now heart failure, this biochemical baroreflex goes awry, leading to increased vascular oxidant stress. Therapeutic strategies to modulate this maladaptive response should become a target of future research. Finally, studies like those of Bauersachs et al shed light on mechanisms whereby proven therapies benefit heart failure and other vascular diseases.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Zelis R, Flaim S. Alterations in vasomotor tone in congestive heart failure. Prog Cardiovasc Dis. 1982;24:437–459.[Medline] [Order article via Infotrieve]
2. Drexler H, Hayoz D, Munzel T, Hornig B, Just H, Brunner HR, Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol. 1992;69:1596–1601.[Medline] [Order article via Infotrieve]
3.
Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM.
Endothelium dependent vasodilation is attenuated in
patients with heart failure. Circulation. 1991;84:1589–1596.
4.
Wang J, Seyedi N, Xu XB, Wolin MS, Hintze TH.
Defective endothelium-mediated control of coronary circulation in
conscious dogs after heart failure. Am J Physiol.. 1994;266:H670–H680.
5.
Smith CJ, Sun D, Hoegler C, Roth DS, Chang X, Chao G,
Xu XB, Kobari Y, Pritchard K, Sessa WC, Hintze TH. Reduced gene
expression of vascular endothelial NO synthase and
cyclooxygenase I in heart failure. Circ
Res. 1996;78:58–64.
6. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236–241.[Abstract]
7. Nishida K, Harrison DG, Navas JP, Fisher AA, Dockery SP, Uematsu M, Nerem RM, Alexander RW, Murphy TJ. Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest. 1992;90:2092–2096.
8.
Belch JJF, Bridges AB, Scott N, Chopra M. Oxygen free
radicals and congestive heart failure. Br Heart J. 1991;65:245–248.
9. McMurray J, McLay J, Chopra M, Bridges A, Belch JJF. Evidence for enhanced free radical activity in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1990;65:1261–1262.[Medline] [Order article via Infotrieve]
10. Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol. 1996;148:291–300.[Abstract]
11. Prasad K, Gupta JB, Kalra J, Bharadwaj B. Oxygen free radicals in volume overload heart failure. Mol Cell Biochem. 1992;111:55–59.[Medline] [Order article via Infotrieve]
12.
Dhalla AK, Singal PK. Antioxidant changes in
hypertrophied and failing guinea pig hearts. Am J
Physiol. 1994;266:H1280–H1285.
13. Diaz-Velez CR, Garcia-Castineiras S, Mendoza-Ramos E, Hernandez-Lopez E. Increased malondialdehyde peripheral blood of patients with congestive heart failure. Am Heart J. 1996;131:146–152.[Medline] [Order article via Infotrieve]
14.
Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J,
Tedgui A. Elevated levels of 8-iso-prostaglandin
F2 in pericardial fluid of patients with heart
failure: a potential role for in vivo oxidant stress in
ventricular dilatation and progression to heart failure.
Circulation. 1998;97:1536–1539.
15.
Keith M, Geranmayegan A, Sole MJ, Kurian R, Robinson A,
Omran AS, Jeejeebhoy KN. Increased oxidative stress in patients with
congestive heart failure. J Am Coll Cardiol. 1998;31:1352–1356.
16. Nishiyama Y, Ikeda H, Haramaki N, Yoshida N, Imaizumi T. Oxidative stress is related to exercise intolerance in patients with heart failure. Am Heart J. 1998;135:115–120.[Medline] [Order article via Infotrieve]
17.
Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C
improves endothelial function of conduit arteries in patients with
chronic heart failure. Circulation.. 1998;97:363–368.
18. Winlaw DS, Smythe GA, Keogh AM, Schyvens CG, Spratt PM, Macdonald PS. Increased nitric oxide production in heart failure. Lancet. 1994;344:373–374.[Medline] [Order article via Infotrieve]
19.
Bauersachs J, Bouloumié A, Fraccarollo D, Hu K,
Busse R, Ertl G. Endothelial dysfunction in chronic
myocardial infarction despite increased vascular
endothelial nitric oxide synthase and soluble
guanylate cyclase expression: role of enhanced vascular
superoxide production. Circulation. 1999;100:292-298.
20. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–1923.[Medline] [Order article via Infotrieve]
21. Munzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA, Freeman BA, Harrison DG. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase: a new action for an old drug. J Clin Invest. 1996;98:1465–1470.[Medline] [Order article via Infotrieve]
22. Ito K, Akita H, Kanazawa K, Yamada S, Terashima M, Matsuda Y, Yokoyama M. Comparison of effects of ascorbic acid on endothelium-dependent vasodilation in patients with chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy versus patients with effort angina pectoris secondary to coronary artery disease. Am J Cardiol. 1998;82:762–767.[Medline] [Order article via Infotrieve]
23.
Katz SD, Yuen J, Bijou R, LeJemtel TH. Training
improves endothelium-dependent vasodilation in
resistance vessels of patients with heart failure. J Appl
Physiol. 1997;82:1488–1492.
24.
Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C,
Kaiser R, Yu J, Adams V, Niebauer J, Schuler G. Regular physical
exercise corrects endothelial dysfunction and improves
exercise capacity in patients with chronic heart failure.
Circulation. 1998;98:2709–2715.
25.
Inoue N, Ramasamy S, Fukai T, Nerem RM, Harrison DG.
Shear stress modulates expression of Cu/Zn superoxide dismutase in
human aortic endothelial cells. Circ Res. 1996;79:32–37.
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