Abstract
Congestive heart failure (CHF) is defined by inability of the heart to provide adequate blood flow, oxygen, and nutrients to tissues and organs. There is now overwhelming evidence suggesting that oxygen-derived free radicals are involved in the pathogenesis of CHF. In vitro studies suggest that the highly toxic radical species damage sub-cellular membranes leading to the disruption in excitation-contractile coupling and eventually the dysfunction of the myocardium. In addition, these radicals destroy nitric oxide, a potent signaling molecule responsible for maintaining cardiovascular tone. Antioxidants hold great promise in minimizing the damage occurring as a result of the excessive generation of the free radicals during ischemia/reperfusion injury and CHF.
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Kukreja RC, Janin Y. Reperfusion injury: Basic concepts and protection strategies. J Thrombosis Thrombolysis 1997;4:7–24.
Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol 1996;148:300.
Fridovich I. The biology of oxygen radicals. Science 1978;201:875–880.
McCord JM, Fridovich I. The biology and pathology of oxygen radicals. Ann Int Med 1978;89:122–127.
Chambers DE, Parks DA, Patterson G, et al. Xanthine oxidase as a source of free radical damage in myocardiac ischemia. J Mol Cell Cardiol 1985;17:145–152.
McCord JM. Oxygen-derived free radicals in post-ischemic tissue injury. N Engl J Med 1985;313:159–163.
McCord JM, Roy RS, Schaffer SW. Free radicals and myo-cardial ischemia. The role of xanthine oxidase. Adv Myocardiol 1985;5:183–189.
McCord JM. Oxygen-derived radicals: A link between reperfusion injury and inflammation. Fed Proc 1987;46:2402–2406.
Freeman BA, Crapo JD. Biology of disease. Free radicals and tissue injury. Lab Invest 1982;47:412–426.
Singal PK, Kapur N, Dhillon KS, et al. Role of free radicals in catecholamine-induced cardiomyopathy. Can J Physiol Pharmacol 1982;60:1390–1397.
Kukreja RC, Kontos HA, Hess ML, et al. PGH synthase and lipoxygenase generate superoxide in the presence of NADH or NADPH. Circ Res 1986;59:612–619.
Singal PK, Beamish RE, Dhalla NS. Potential oxidative pathways of catecholamines in the formation of lipid peroxides and genesis of heart disease. Adv Exp Med Biol 1980;191:421–427.
Garlick PB, Davies MJ, Hearse DJ, et al. Direct detection of free radicals in the reperfused rat heart using electron spin resonance spectroscopy. Circ Res 1987;61:757–760.
Sekizuka E, Benoit JN, Grisham MB, et al. Dimethylsulfoxide prevents chemoattractant-induced leukocyte adherence. Heart Circ Physiol 1989;256:H594–H597.
Hess ML, Manson NH. Molecular oxygen: Friend or foe. J Mol Cell Cardiol 1984;16:969–985.
Bolli, R. Oxygen-derived free radicals and myocardial reperfusion injury: An overview. Cardiovasc Drugs Ther 1991;5:249–268.
Tappel AL. Measurement of and protection fromin vivo lipid peroxidation. In: Zimmerman RS, ed. Free Radicals in Biology. Orlando, FL: Academic Press, 1980;1–19.
Kellogg EW. Superoxide, hydrogen peroxide and singlet oxygen in lipid peroxidation by a xanthine oxidase system. J Biol Chem 1975;250:8812–8817.
Mead JF. Free radical mechanisms in lipid peroxidation and prostaglandins. In: Anonymous Free Radicals inMolecular Biology and Disease. New York: Raven Press, 1984;53–65.
Tappel AL. Lipid peroxidation damage to cell components. Fed Proc 1973;32:1870–1874.
Gwathmey JK, Liao R, Helm PA, et al. Is contractility depressed in the failing human heart? Cardiovasc Drugs Ther 1999;4:581–587.
Schmidt U, Hajjar RJ, Helm PA, et al. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J Mol Cell Cardiol 1998;30:1929–1937.
Nascimben L, Ingwall JS, Pauletto P, et al. Creatine kinase system in failing and nonfailing human myocardium. Circulation 1996;94:1901.
Burton KP, McCord JM, Ghai G. Myocardial alterations due to free-radical generation. Am J Physiol 1984;246:H776–H783.
Blaustein AS, Schine L, Brooks WW, et al. Influence of exogenously generated oxdidant species onmyocardial function. Am J Physiol 1986;250:H595–H599.
Schrier GM, Hess ML. Quantitative identification of superoxide anion as a negative inotropic species. Heart Circ Physiol 1988;255:H138–H143.
Shattock MJ, Manning AS, Hearse DJ. Effects of hydrogen peroxide on cardiac function and postischemic functional recovery in the isolated “working” rat heart. Pharmacology 1982;24:118–122.
Ytrehus K, Myklebust R, Mjos OD. Influence of oxygen radicals generated by xanthine oxidase in the isolated perfused rat heart. Cardiovascular Res 1986;20:597–603.
Miki S, Ashraf M, Salka S, et al. Myocardial dysfunction and ultrastructural alterations mediated by oxygen metabolites. J Mol Cell Cardiol 1988;20:1009–1024.
Jackson CV, Mickelson JK, Pope TK, et al. O2 free radicalmediated myocardial and vascular dysfunction. Am J Physiol 1986;251:H1225–H1231
Goldhaber JI, Lamp ST, Weiss JN. Effects of exogenous free radicals on electrochemical function and metabolism in isolated rabbit and guinea pig ventricle. J Clin Inv 1989;83:1800–1809.
Przyklenk K, Whittaker P, Kloner RA. In vivo infusion of oxygen free radical substrates causes myocardial systolic, but not diastolic dysfunction. Am Heart J 1990;119:807–815.
Donck LV, Van Reempts J, Vandeplassche G, et al. A new method to study activated oxygen species induced damage in cardiomyocytes and protection by Ca+ antagonists. J Mol Cellular Cardiology 1988;20:811–823.
Hearse DJ, Kusama Y, Bernier M. Rapid electrophysiological changes leading to arrhythmias in the aerobic rat heart: Photosensitization studies with rose bengal-derived reactive oxygen intermediates. Circ Res 1989;65:146–153.
Kusama Y, Bernier M, Hearse DJ. The exacerbation of reperfusion arrhythmias by sudden oxidant stress. Circ Res 1990;67:481–489.
Yamada M, Hearse DJ, Curtis MJ. Reperfusion and readmission of oxygen. Pathophysiological relevance of oxygen-derived free radicals to arrhythmogenesis. Circ Res 1990;67:1211–1224.
Vandeplassche G, Bernier M, Kusama BM, et al. Singlet oxygen and myocardial injury: Ultrastructural, cytochemical and electrocardiographic consequences of photoactivation of rose bengal. J Mol Cell Cardiol 1990;22(Abstract): 287–301.
Shattock MJ, Matsuura H, Hearse DJ. Functional and electrophysiological effects of oxidant stress on isolated ventricular muscle: A role for oscillatory calcium release from sacroplasmic reticulum in arrhythmogenesis? Cardiovasc Res 1991;25:645–651.
Kazziha SY, Kraus S, Loesser KE, et al. Photosensitizer studies with rose bengal-derived reactive oxygen intermediates on isolated papillary rat heart muscle. Faseb J 1991;5(Abstract):A1282–A1282.
Shattock MJ, Matsuura H, Hearse DJ. Functional and electrophysiological effects of reactive oxygen intermediates on isolated ventricular muscle: A role for oscillatory calcium release from the sarcoplasmic reticulum in arrhythmogenesis? JMol Cell Cardiol 1989;22(Suppl II)(Abstract):129–129.
Tarr M, Valenzeno DP. Modification of cardiac action potential by photosensitizer-generated reactive oxygen. J Mol Cell Cardiol 1989;21:539–543.
Itoh S, Yanagishita M, Tomita M, et al. Detection of free radicals during reperfusion injury in dog heart. J Mol Cell Cardiol 1991;23 (Suppl)(Abstract):S.42–S.42.
Konno N, Yanagishita T, Geshi E, et al. Degradation of the cardiac sarcoplasmic reticulum in acute myocardial ischemia. Japan Circ J 1987;51:411–420.
Kim M-S, Akera T. O2 free radicals: Cause of ischemia-reperfusion injury to cardiac Na+-K+-ATPase. Am J Physiol 1987;252:H252–257
Kukreja RC, Kearns AA, Zweier JL, et al. Singlet oxygen interaction with Ca2+-ATPase of cardiac sarcoplasmic reticulum. Circ Res 1991;69:1003–1014.
Holmberg SRM, Cumming DVE, Kusama Y, et al. Reactive oxygen species modify the structure and function of the cardiac sarcoplasmic reticulum calcium-release channel. Cardioscience 1991;2:19–25.
Knowles RG, Moncada S. Nitric oxide synthases in mammales. Biochem J 1994;298:249–258.
Weiss HR, Rodriguez E, Tse J, et al. Effect of increased myocardial cyclic GMP induced by cyclic GMP-phosphodiesterase inhibition on oxygen consumption and supply of rabbit hearts. Clin Exp Pharmacol Physiol 1994;21:607–614.
Ku DD. Coronary vascular reactivity after acute myocardial ischemia. Science 1982;218:576–578.
Gunsalus IC, Pederson TC, Sligar SG. Oxygenase-catalyzed biological hydroxylations. Ann Rev Biochem 1975;44: 377–407.
Mehta JL, Nichols WW, Donnelly WM, et al. Impaired canine responses to acetylcholine and bradykinin after occlusion-reperfusion. Circ Res 1993;64:43–54.
Armstrong PW, Walker DC, Burton JR, et al. Vasodilator therapy in acute myocardial infarction: A comparison of sodium nitroprusside and nitroglycerin. Circulation 1975;52: 1118–1122.
Bussman WD, Passek D, Seidel W, et al. Reduction of CK and CK-MB indexes of infarct size by intravenous nitroglycerin. Circulation 1981;63:615–622.
Flaherty JT, Becker LC, Bulkly BH, et al. A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1993;68:576–588.
Johnson GI, Tsao PS, Mulloy D, et al. Cardioprotective effects of acidified sodium nitrite in myocardial ischemia with reperfusion. J Pharmacol Exp Therap 1990;252:35–41.
Johnson GI, Tsao PS, Lefer AM. Cardioprotective effects of authentic nitric oxide in myocardial ischemia with reperfusion. Crit Care Med 1991;19:244–252.
Qiu Y, Rizvi A, Tang XL, et al. Nitric oxide triggers late preconditioning against myocardial infarction in conscious rabbits. Am J Physiol 1997;273:H2931–H2936.
Bolli R, Manchikalapudi S, Tang XL, et al. The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning. Circ Res 1997;81:1094–1107.
Cheng W, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death. J Clin Invest 1995;96: 2247–2259.
Zweier JL. Measurement of superoxide-derived free radicals in the reperfused heart. J Biol Chem 1988;263:1353–1357.
Belch JJ, Bridges AB, Scott N, et al. Oxygen free radicals and congestive heart failure. Br Heart J 1991;65:245–248.
Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992;69: 1596–1601.
Hornig B, Arakawa N, Kohler C, et al. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998;97:363–368.
Matheis G, Sherman MP, Buckberg GD, et al. Role of L-arginine-nitric oxide pathway in myocardial reoxygenation injury. Am J Physiol 1992;262:H616–H620
Naseem SA, Kontos MC, Rao PS, et al. Sustained inhibition of nitric oxide by NG-nitro-l-arginine improves myocardial function following ischemia/reperfusion in isolated rat heart. J Mol Cell Cardiol 1995;27:419–426.
Wang P, Zweier JL. Measurement of nitric oxide and peroxynitrite generation in the postischemic heart. Evidence for peroxynitrite-mediated reperfusion injury. J Biol Chem 1996;271:29223–29230.
Habib F, Dutka D, Crossman D, et al. Enhanced basal nitric oxide production in heart failure: Another failed counterregulatory vasodilator mechanism? Lancet 1994;344: 371–373.
Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323:236–241.
Roberts AB, Vodovotz Y, Roche NS, et al. Role of nitric oxide in antagonistic effects of transforming growth factorbeta and interleukin-1 b on the beating rate of cultured cardiac myocytes. Mol Endocrinol 1992;6:1921–1930.
Evans T, Carpenter A, Kinderman H, et al. Evidence of increased nitric oxide production in patients with the sepsis syndrome. Circ Shock 1993;41:77–81.
Winlaw DS, Smythe GA, Keogh Am, et al. Increased nitric oxide production in heart failure. Lancet 1994;344:374.
Myers ML, Bolli R, Lekich RF, et al. N-2-Mercaptopropionylglycine improvers recovery of myocardial function following reversible regional ischemia. J Am Coll Cardiol 1986;8:1161–1168.
Brown JM, Grosso MA, Tarada GJ, et al. Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat heart. Pro Natl Acad Sci USA 1989;86:2516–2520.
Pearson PJ, Lin PJ, Schaff HV. Production of endothelium derived contracting factor is enhanced after coronary reperfusion. Ann Thorac Surg 1991;288:481–487.
Burton GW, Joyce A, Ingold KU. Is vitamin E the only lipid-soluble, chain-breaking antioxidant in human blood plasma and erythrocyte membrane? Arch Biochem Biophys 1983;221:281–290.
McCay PB, Vitamin E: Interactions with free radicals and ascorbate. Ann rev Nutr 1995;5:323–340.
Janero DR, Burghardt B, Oxidative injury to myocardial membrane: Direct modulation by endogenous-tocopherol. J Mol Cell Cardiol 1989;21:1111–1124.
Dhalla AK, Hill MF, Singal PK. Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol 1996;28:506–514.
Keith M, Geranmayegan A, Sole MJ, et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 1998;31:1352–1356.
Sobotka PA, Brottman MD, Weitz Z, et al. Elevated breath pentane in heart failure reduced by free radical scavenger. Free Radic Biol Med 1993;14:643–647.
Singal PK, Gupta M, Randhawa AK. Reduced myocardial injury due to exogenous oxidants in pressure induced heart hypertrophy. Basic Res Cardiol 1991;86:273–282.
Guarnieri C, Ferrari R, Visioli, et al. Effect of tocopherol on hypoxic-perfused and reoxygenated rabbit heart muscle. J Mol Cell Cardiol 1978;10:893–906.
Massey DK, Burton KP. Tocopherol attenuates myocardial membrane related alterations resulting from ischemia and reperfusion. Am J Physiol 1989;25:H1192–H1199.
Klein HH, Pich S, Lindert S, et al. Combined treatment with viamin E and C in myocardial infarction in pigs. Am Heart J 1989;118:667–673.
Grisar JM, Petty MA, Bolkenius FN, et al. A cardioselective, hydrophilic N,N,N-Trimethylethanaminium-tocopherol analogue that reduces myocardial infarct size. J Med Chem 1991;34:260–275.
Petty MA, Dow J, Grisar JM, et al. Effect of a cardioselective-tocopherol analogue on reperfusion injury in rats induced by myocardial ischemia. Eur J Pharmacol 1991;192:383–388.
Zughaib ME, Tang X-L, Schleman M, et al. Beneficial effects of MDL 74,405, a cardioselective water soluble-tocopherol analogue, on the recovery of function of stunned myocardium in intact dogs. Cardiovasc Res 1994;28:235–241.
Tang X-L, McCay PB, Sun J-Z, et al. Inhibitory effect of a hydrophilic-tocopherol analogue, MDL74,405, on generation of free radicals in stunned myocardium in intact dogs. Free Radic Res 1995;22:293–302.
Bellows SD, Hale SL, Simkhovich BZ, et al. Do antioxidant vitamins reduce infarct size following acute myocardial ischemia/ reperfusion. Cardiovasc Drugs Ther 1995;9:117–123.
Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary disease in men. N Engl J Med 1993;328:1450–1456.
Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444–1449.
Singh RB, Niaz MA, Rastogi SS, et al. Usefulness of antioxidant vitamins in suspected acute myocardial infarction (The Indian Experiment of Infarct Survival-3). Am J Cardiol 1996;77:232–236.
Fantone JC, Schrier D, Weingarten B. Inhibition of vascular permeability changes in rats by captopril. J Clin Invest 1982;69:1207–1211.
Martin MF, McKenna F, Bird HA, et al. Captopril: A new treatment for rheumatoid arthritis? Lancet 1984;1325–1327.
Westlin W, Mullane K. Does captopril attenuate reperfusion induced myocardial dysfunction by scavenging free radicals? Circulation 1988;77(Suppl):I30–I39
Weglicki WB, Dickens BF, Pflug BR, et al. Protective effects of sulfhydryl-containing ACE inhibitors against lipid peroxidation in endothelial and smooth muscle cells. Faseb J 1989;3:A593
Mak IT, Freidman AM, Dickens BF, et al. Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells. Biochem Pharmacol 1990;40:2169–2175.
Bagchi D, Prasad R, Das DK. Direct scavenging of free radicals by captopril, an angiotensin converting enzyme inhibitor. Biochem Biophys Res Commun 1989;158:52–57.
Kukreja RC, Kontos HA, Hess ML. Captopril and enalaprilat do not scavenge the superoxide anion. Am J Cardiol 1990;65:24-I–27-I
Ortolani O, Conti A, Imperatore R, et al. Photooxidation of epinephrine sensitized by methylene blue as an assay for the evaluation of alpha-mercaptopropionylglycine as a free radical scavenger. Boll Soc Ital Biol Sper 1982;58:444–449.
Ichida F, Shibasaki K, Takino T, et al. Therapeutic effects of tiopronin on chronic hepatitis: A double-blind clinical study. J Int Med Res 1982;10:325–332.
Marban E, Koretsune Y, Corretti M, et al. Calcium and its role in myocardial cell injury during ischemia reperfusion. Circulation 1989;80:IV:17–22.
Guarnieri C, Flamingni F, Caldarera C. Role of oxygen in the cellular damage induced by re-oxygenation of hypoxic heart. J Mol Cell Cardiol 1980;12:797–808.
Mitsos SE, Askew TE, Fantone JC. Protective effects of N-2 mercaptopropionyl glycine against myocardial reperfusion injury after neutrophil depletion in the dog: Evidence for the role of intracellular-derived free radicals. Circulation 1986;73:1077–1086.
Folkers K. Heart failure is a dominant deficiency of coenzyme Q10 and challenges for future clinical research on CoQ10. Clin Invest 1993;71(8 Suppl):S51–S54
Hofman-Bang C, Rehnqvist N, Swedberg K, et al. Coenzyme Q10 as an adjunctive in the treatment of chronic congestive heart failure. The Q10 Study Group. J Card Fail 1995;1:101–107.
Kukreja RC, Hess ML. Free Radicals, Cardiovascular Dysfunction and Protection Strategies. Austin, TX: R.G. Landes Company, 1994.
Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic hert failure. U.S. Carvedilol Heart Failure Group. N Engl J Med 1996;334:1349–1355.
Ruffolo RR Jr, Feuerstein GJ. Pharmacology of carvedilol: Rational for use in hypertension, coronary artery disease and congestive heart failure. Cardiovasc Drugs Ther 1997;11(Suppl 1):247–256.
Ferrari R, Ceconi C, Curello S, et al. Protective effect of propionyl-L-carnitine against ischaemia and reperfusion damage. Mol Cell Biochem 1989;88:161–168.
Paulson DJ, Traxler J, Schmidt M, et al. Protection of the ischaemic myocardium by L-propionylcarnitine: effects on the recovery of cardiac output after ischaemia and reperfusion, carnitine transport and fatty acid metabolism. Cardiovasc Res 1986;20:536–541.
Serbinova E, Reznick SKAZ, Packer L. Thioctic acid protects against ischemia-reperfusion injury in the isolated perfused langendorff heart. Free Rad Res Commun 1992;17: 49–58.
Reznick AZ, Kagan VE, Ramsey R, et al. Antiradical effects in L-propionyl carnitine protection of the heart against ischemia reperfusion injury—The possible role of iron chelation. Arch Biochem Biophys 1992;296:394–401.
Misra BR, Misra HP. Vasoactive intestinal peptide, a singlet oxygen quencher. J Biol Chem 1990;265:15371–15374.
Kalant N, McCormick S, Parniak MA. Effect of copper and histidine on oxidative modification of low density lipoprotein and its subsequent binding to collagen. Arterioscler Thromb 1991;11:1322–1329.
Chevion M. A site-specific mechanism for free radical induced biological damage: The essential role of redox-active transition metals. Free Rad Biol Med 1988;5:27–37.
Kukreja RC, Loesser KE, Kearns AA, et al. Protective effects of histidine during ischemia/reperfusion in isolated perfused rat hearts. Am J Physiol 1993;264:H1370–H1381
Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488–493
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Kukreja, R.C., Emani, V.R. & Hess, M.L. Activated Oxygen Species in Heart Failure. Heart Fail Rev 4, 1–12 (1999). https://doi.org/10.1023/A:1009816207172
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DOI: https://doi.org/10.1023/A:1009816207172