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The role of oxidative stress in the genesis of heart disease

Pawan K Singal, Neelam Khaper, Vince Palace, Dinender Kumar
DOI: http://dx.doi.org/10.1016/S0008-6363(98)00244-2 426-432 First published online: 1 December 1998


Although researchers in radiation and cancer biology have known about the existence of free radicals and their potential role in pathobiology for several decades, cardiac biologists only began to take notice of these noxious species in the 1970s. Exponential growth of free radical research occurred after the discovery of superoxide dismutase in 1969. This antioxidant enzyme is responsible for the dismutation of superoxide radical — a free radical chain initiator. A fine balance between free radicals and a variety of endogenous antioxidants is believed to exist. Any disturbance in this equilibrium in favour of free radicals causes an increase in oxidative stress and initiates subcellular changes leading to cardiomyopathy and heart failure. Our knowledge about the role of free radicals in the pathogenesis of cardiac dysfunction is fast approaching the point where newer therapies employing antioxidants are in sight.

  • Free radicals
  • Antioxidants
  • Heart failure

Time for primary review 17 days.

1 Introduction

1.1 Our atmosphere: ‘air vital’ and ‘gas azote’

Lavoisier, in 1773 [1], was the first to recognize that Earth's atmosphere was composed of substances (‘air vital’) that supported life. Oxygen, as the key life-supporting element, was independently discovered by Priestly, in 1775 [2], and Scheele, in 1777 [3]. Within a few years of these seminal findings, it was also discovered that oxygen had toxic side effects that did not support life (‘gas azote’). This revelation was also made by Lavoisier in 1785 by a simple (perhaps ingenious at the time) experiment in which guinea pigs exposed to oxygen in a container showed congestion of the right heart as well as lungs and died before the oxygen was fully utilized [4]. Thus, the discoverers of oxygen, more than two centuries ago, already knew about the good and bad facets of oxygen. About two centuries later, the discovery of an important antioxidant enzyme, superoxide dismutase, by McCord and Fridovich [5], renewed interest in oxygen-radical biology.

The life-sustaining role of oxygen is played out by its unique molecular structure. Oxygen is a diradical, having two electrons with parallel spins in its outermost shell. Because of this structural configuration, oxygen can accept four electrons and the resultant one-step tetravalent reduction results in the formation of water, with a concurrent production of ATP, a high energy source needed to perform vital metabolic functions. Ironically, the same diradical configuration is an ideal substratum for the production of free radicals. Thus, if these four electrons are added one at a time, partially reduced forms of oxygen (PRFO) or free radicals are produced [6–8].

2 Oxidative stress and heart disease

2.1 Oxygen radicals

Activated oxygen species, such as singlet oxygen, superoxide radical, hydrogen peroxide and hydroxyl radical, produced by the partial reduction of oxygen, are highly unstable and extremely reactive. Short half-lives for many of these species makes them highly toxic for tissues, including the heart [8]. Studies on isolated perfused hearts have revealed that even brief exposures to oxygen radicals result in a decrease in high energy phosphates, loss of contractile function and cause structural abnormalities [9–11]. Oxygen radicals are capable of reacting with unsaturated lipids and of initiating the self-perpetuating chain reactions of lipid peroxidation in the membranes [12]. Free radicals can also cause oxidation of sulphydryl groups in proteins and strand scission in nucleic acids is also possible [7, 8]. Early in vivo studies examined the role of catecholamines in stress-induced heart disease, and provided evidence that cardiac dysfunction may be mediated by the production of free radicals initiated by autooxidation of catecholamines [12–14]. About the same time, the role of free radicals in ischemia–reperfusion injury was documented and was shown to be mediated by depressed Ca2+ transport in the sarcoplasmic reticulum [15]. These ex vivo and in vivo studies formed the basis for a multitude of studies on the role of free radicals in the pathogenesis of cardiomyopathies and heart failure.

2.2 Antioxidants

Under normal conditions, 3–5% of the oxygen taken up by the cell undergoes univalent reduction leading to the formation of free radicals. However, tissue concentrations of free radicals are limited by a system of enzymatic and non-enzymatic antioxidants and free radical scavengers that have developed and been conserved during the evolution of aerobic life. Three of the most important cellular enzymes are superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase. SOD catalyzes the dismutation of superoxide anion to hydrogen peroxide, whereas catalase and GSHPx catalyze the reduction of hydrogen peroxide to water [7, 8, 16]. GSHPx also removes other hydroperoxides generated by free radical reactions [17]. These protective cellular antioxidants have been reported to change in response to physiological and pathological conditions, including age, exercise and hypertrophy [8, 16, 18, 19]. In pathological or disease conditions, such as diabetes, β-thalassaemia minor, heart failure and others, the production of free radicals may override the scavenging effects of antioxidants leading to a condition known as ‘oxidative stress’ [8]. Many experimental studies have reported that increased oxidative stress and depressed antioxidant status have deleterious effects on both cardiac structure and function [8, 16]. Clinical studies from heart failure patients have also provided support for the role of free radicals in the pathogenesis of heart failure. The usefulness of antioxidant therapy, especially vitamin E, in attenuating the progression of heart failure has also been reported. A brief account of the role of free radicals in the pathogenesis of cardiac dysfunction, as well as the beneficial effects of antioxidants in a variety of animal studies and some clinical conditions, is provided.

3 Animal studies

Studies documenting molecular, cellular and system level effects of oxidative stress are too numerous to be exhaustively discussed. Thus, only a limited number of studies are cited here to touch upon different aspects of oxidative stress and cardiac pathophysiology as well as to direct the reader to more specific information.

3.1 Free radicals in acute conditions

In order to define the role of free radicals in the pathogenesis of cardiac dysfunction, one approach that has been used time and again is to expose isolated cardiac membranes or cardiac tissue preparations to a defined oxidative stress condition and study the effects. These studies have provided copious information regarding the subcellular defects induced by oxidative stress.

3.1.1 In vitro studies

Free radicals affect the activity of Na+–K+ ATPase, the Na+–Ca++ exchanger and Ca++ binding [20–23], which ultimately can affect Ca++ movements across the sarcolemma. The addition of xanthine oxidase, as a source of free radicals, to a sarcolemma preparation resulted in a significant decrease in the binding capacity of the muscarinic receptors. This effect was reversed by the addition of the antioxidant enzymes superoxide dismutase and catalase [24]. Different free radical species have also been reported to alter the coupling of sarcoplasmic reticular Ca++ transport from ATP hydrolysis [15]. Free radicals have been shown to depress mitochondrial respiration, cytochrome oxidase and glucose-6-phosphatase, and increase the levels of malondialdehyde, an indicator of free radical-induced lipid peroxidation [8, 25–27]. Free radicals also reduce the ability of mitochondria to synthesize ATP, while SOD and catalase improve ATP production [28, 29].

3.1.2 Ex vivo studies

Depressed contractile function, impaired energy production, a rise in resting tension and an increase in lipid peroxidation have been reported in various cardiac preparations exposed to free radicals [8, 10, 30, 31]. Free radical-induced reduction of contractile function correlated with a decline in myocardial SOD, glutathione and α-tocopherol content, as well as with an increase in hydrogen peroxide and lipid peroxidation [10, 32]. Antioxidant enzymes are reported to be depressed during ischemia as well as during hypoxia, which have been correlated with poor recovery of function upon reperfusion and reoxygenation [33–36].

3.1.3 In vivo studies

A reduction in infarct size by SOD and catalase infusion in dogs that underwent 90 min of coronary occlusion and 24 h of reperfusion suggested the involvement of free radicals [37]. Oxygen free radicals produced during reperfusion of ischemic hearts have been implicated in ischemia–reperfusion injury [38–40]. Free radical species such as superoxide anion and hydroxyl radicals are formed during reperfusion of the ischemic heart. Recent data also demonstrated that increased production of nitric oxide during reperfusion interacts with superoxide anion to form peroxynitrite (ONOO), which may contribute to the development of cardiac dysfunction [41]. Using spin-trap techniques, the presence as well as the role of oxidative stress in myocardial stunning has also been documented [38]. Antioxidant therapy suppressed the production of free radicals and attenuated myocardial stunning, suggesting a cause and effect relationship [38]. In a conscious dog model, the production of superoxide anion and hydroxyl radicals during ischemia–reperfusion was reported to cause functional and structural alterations in the myocardium and treatment with free radical scavengers partially ameliorated the damage [42].

3.2 Free radicals in chronic conditions

3.2.1 Drug-induced cardiomyopathy

Adriamycin, which is an effective antitumor drug, is known to produce free radicals and deplete myocardial antioxidants [43–47]. Direct evidence for free radical involvement in adriamycin cardiomyopathy was provided by studies which showed that mice treated with vitamin E were less susceptible to adriamycin cardiotoxicity [48]. Moreover, rats maintained on a vitamin E-deficient diet were more susceptible to adriamycin cardiotoxicity [49]. Depressed myocardial antioxidant reserve and increased oxidative stress were correlated with poor hemodynamic function in adriamycin-induced congestive heart failure in rats [44, 45]. Antioxidant treatment with probucol, which is a lipid-lowering drug with antioxidant properties, modulated the pathogenesis of heart failure due to adriamycin [45, 47].

Increased plasma levels of catecholamines occur during many stressful conditions, such as the onset of chest pain and acute myocardial infarction [50, 51]. Plasma levels of catecholamines are also known to be high in heart failure patients [52]. Chronic increases in catecholamines have been shown to cause arrhythmias as well as cardiomyopathy [13]. Excess catecholamines undergo autooxidation leading to the production of free radicals, which play a role in cardiomyopathy [7, 12]. Pretreatment of rats with vitamin E reduced catecholamine-induced arrhythmias as well as other cardiomyopathic changes [12, 53]. Isolated myocytes exposed to oxidative stress showed prolongation of the action potential and inexcitability [54, 55]. Such direct myocytic electrical aberrations due to free radicals can contribute to arrhythmias. In fact, anti-free-radical agents were reported to reduce reperfusion-induced arrhythmias in isolated hearts [56]. Thus, the availability of an adequate myocardial ‘antioxidant reserve’ appears to be the key to modulating oxidative stress changes in the heart [57].

3.3 Hypertrophy and heart failure

An increase in oxidative stress and a decrease in the antioxidant reserve has been reported in a guinea pig model of heart failure subsequent to chronic pressure overload. Banding of the ascending aorta resulted in hypertrophy at ten weeks and heart failure at 20 weeks of post-surgery duration [58]. During the hypertrophy stage, when hemodynamic function was maintained, antioxidant reserve was high and there was low oxidative stress. The heart failure stage was characterized by an increase in left ventricular end diastolic pressure, dyspnea, ascites and lung and liver congestion. At this stage, a significant decline in myocardial SOD and GSHPx activities and a decrease in the redox ratio indicated that there was accompanying oxidative stress [59]. Antioxidant treatment with slow release vitamin E pellets attenuated the heart failure and also decreased oxidative stress. Ultrastructural abnormalities were significantly reduced in the vitamin E-treated hearts compared with the untreated hearts at the failure stage [60].

3.4 Myocardial infarction and heart failure

Heart failure following myocardial infarction (MI) is a common clinical problem with poor prognosis. Despite significant improvement in the management strategy of MI patients, the pathogenesis of congestive heart failure remains poorly understood. Altered energy metabolism and Ca++ homeostasis, and reduced adrenergic support, have been suggested to be the underlying causes of heart failure [16]. More recently, we have demonstrated that free radicals are involved in the pathogenesis of heart failure subsequent to MI. Changes in myocardial antioxidants as well as oxidative stress have been described in the surviving myocardium of rats subjected to MI. These changes correlated with cardiac function at different stages of failure [61]. In this study, maintenance of hemodynamic function in the early stages was accompanied by a significant decrease in oxidative stress and lipid peroxidation, while the antioxidant reserve was maintained. In late stages, where hemodynamic function was depressed, the myocardial antioxidants GSHPx, catalase, SOD and vitamin E were also significantly decreased, while oxidative stress was increased [61].

In a study of differential changes in the two ventricles during the sequelae of heart failure [61], the antioxidant deficit and an increase in oxidative stress occurred first in the left ventricle. In the more chronic stages, these changes also occurred in the right ventricle [62]. Another study, using the same animal model, has reported that improved hemodynamic function after treatment with the afterload reducing drugs captopril or prazosin is related to the improved myocardial antioxidant status and decreased oxidative stress [63].

Antioxidant vitamins, such as vitamin C, carotenoids and vitamin E, have been shown to decrease lipid peroxidation and reduce atherogenesis and the risk of coronary heart disease. Vitamin E is a ‘chain breaking’ antioxidant that acts to protect polyunsaturated fatty acids from oxidation by interrupting the chain reaction of lipid peroxidation in the membrane [64]. Pretreatment with vitamin E limited myocardial necrosis [65–67], while combined pretreatment with vitamins E and C in ischemia–reperfusion settings was found to protect the myocardium and decrease the resultant infarct size in pigs [68].

3.5 Oxidative stress, apoptosis and heart failure

More recently, the loss of myocytes through apoptosis or programmed cell death, has been reported in the infarct regions of myocardium from MI patients [69]as well as from patients with end-stage heart failure [70, 71]. Findings from several in vitro studies and animal models also suggest that apoptosis occurs in response to ischemia–reperfusion, myocardial infarction, and chronic pressure overload [72–74], all of which are conditions that generate oxidative stress [8]. The direct involvement of oxidative stress in apoptosis has been demonstrated in a variety of cell types [75]. Adriamycin, UV radiation and tumor necrosis factor (TNFα) have all been reported to produce free radicals and to cause apoptosis [76, 77]. Furthermore, apoptosis is inhibited by antioxidants such as catalase, SOD, vitamin E and trolox [76–80]. Mechanistic investigations of apoptosis suggest that tumor suppression protein p53 triggers and Bcl2 inhibits the process in cardiomyocytes [81]. The mechanism of action of Bcl2 for the prevention of apoptosis has also been suggested to be mediated by an antioxidant pathway [75]. Although the role of oxidative stress in apoptosis as well as the occurrence of apoptosis in the myocardium of MI- and heart failure patients have been documented, the exact contribution of apoptosis in the loss of myocardial function and heart failure remains to be established.

4 Clinical studies

Studies of patients that support the role of oxidative stress in heart failure have also begun to emerge. Breath pentane content, a measure of lipid peroxidation, was found to be significantly elevated in congestive heart failure patients. Treatment with captopril attenuated this rise in pentane levels and improved the patient's clinical condition [82–84]. Furthermore, it has been demonstrated that the increase in lipid peroxidation is directly proportional to the severity of heart failure [84–86]. Increased malondialdehyde and conjugated diene levels, and low thiol, superoxide dismutase and glutathione levels were reported in congestive heart failure patients [87–89]. Significant increases in blood free radical levels and decreases in vitamin E levels have also been demonstrated in patients undergoing coronary artery bypass graft surgery [90–92]. All of these clinical studies provide support for the concept that increased free radical production and decreased antioxidant reserve may play a role in the pathogenesis of heart failure.

Clinical trials examining the beneficial effects of vitamin E and other antioxidant vitamins in different settings of heart failure have been undertaken. Vitamin E treatment in atherosclerotic patients reduced the rate of nonfatal myocardial infarction [93]. The Health Professional Follow-up Study [94]and the Nurses Health Study [95]found a decrease in the risk of coronary artery disease in men and women supplemented with vitamin E. Combined treatment with vitamins C and E suppressed neutrophil-mediated free radical production and lowered lipid peroxidation in MI patients [96]. A cocktail containing antioxidant vitamins A, C, E and β-carotene resulted in a decrease in oxidative stress as well as the infarct size in MI patients [97]. The Cambridge Heart Antioxidant Study (CHAOS) [77]reported about a 77% decrease in the incidence of non-fatal MI in patients receiving vitamin E versus placebo. Although the available data from epidemiological and clinical studies are promising, it is not clear whether the beneficial effects of vitamin E are due to its antioxidant properties or whether they involve non-antioxidant mechanisms. It should be noted that vitamin E inhibits smooth muscle cell proliferation and growth, and preserves endothelial function [98, 99]. These activities could also account for some of the reduced incidence of cardiac disease reported in vitamin E-supplemented patients.

5 Conclusions

Although there are many gaps in our understanding of the role of free radicals in the pathogenesis of cardiomyopathies and heart failure, based on the available data, some suggestions can be made (Fig. 1). Any acute or chronic cardiac stress conditions, resulting in a relative deficit in the myocardial ‘antioxidant reserve’, are associated with an increase in myocardial ‘oxidative stress’. The latter is capable of causing subcellular abnormalities, through mechanisms that are as yet poorly understood, that may lead to cardiomyopathic changes, depressed contractile function and heart failure. In this regard, the occurrence and importance of free radicals in cardiac pathophysiological conditions is now well established. Furthermore, the available evidence from animal and human studies illustrates that different antioxidants constituting an antioxidant reserve offer protection against oxidative stress-mediated myocardial changes. An understanding of the molecular basis of antioxidant changes will help to develop newer therapies for modulating the pathogenesis of heart failure.

Fig. 1

Proposed scheme for the role of oxidative stress in the development of heart failure.


Dr. Singal is supported by a career award from the Medical Research Council of Canada, Ms. Khaper is supported by a fellowship from the Heart and Stroke Foundation of Canada and Dr. Palace was supported by the Manitoba Health Research Council.


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