ISSN ONLINE: 2558-815X
ISSN PRINT: 1584-9244
ISSN-L: 1584-9244

Oxidative stress and heart failure


Oxidative stress is involved in the pathophysiology of many chronic diseases, including heart failure. Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense. The overproduction of ROS can lead to cellular damage and eventually cellular death. This applies also in patients with chronic heart failure, who present a dramatic increase of oxidative stress associated with a pronounced decrease of the antioxidant defense mechanisms.
The components of the antioxidant defense mechanism of myocardial cells are superoxide dismutase (SOD), catalase, nicotinamide adenine dinucleotide (NAD+), glutathione peroxidase (GPx), and glutathione (GSH). Experimental animal studies have demonstrated the decrease of the activity of SOD, catalase and GPx in animal models with heart failure1,2. Furthermore, excessive ROS induce myocardial fibroblasts proliferation with cardiac remodeling. The promising results of experimental studies in animals with heart failure led to the hypothesis that oxidative stress may be a therapeutic target in patients with heart failure. Clinical trials have studied the effects of antioxidant treatments in humans with heart failure. Treatment of oxidative stress can have different approaches: inhibition of oxidative stress producers, increase of endogenous antioxidant capacity, and increase of antioxidant capacity by administration of exogenous antioxidants, such as vitamin C, vitamin A, vitamin E, folic acid. Inhibition of xanthine oxidase by the administration of allopurinol or oxypurinol in patients with chronic heart failure is the most studied treatment 3,4.
Different trials have demonstrated that treatment with allopurinol or oxypurinol (inhibitors of oxidative stress) had beneficial effects on myocardial function, endothelial dysfunction, and led to the decreased levels of serum natriuretic peptides and improved left ventricle ejection fraction3,4. Other trials failed to demonstrate the beneficial effects of oxypurinol5. Other clinical studies focused on the effects of increasing the antioxidant capacity in patients with heart failure, by administration of vitamin A, vitamin C, vitamin E or folic acid. Despite the initial enthusiasm regarding the effects of these antioxidants, a recent meta-analysis of 50 randomized trials on their cardiovascular effects, including almost 300,000 patients, has demonstrated that supplementation with vitamins and other antioxidants failed to demonstrate a decrease of the cardiovascular risk.
The third therapeutic approach, increase of endogenous antioxidant capacity, may be achieved by supplementation of cellular antioxidants GSH and NAD+6. This strategy has been studied only in a few trials, but their results until now seem to be promising. Supplementation with NAC, which is a precursor of GSH, in patients with chronic heart failure can be a potential approach in order to decrease the oxidative stress secondary to myocardial injury6. The improvement of the expression and activity of the gamma-glutamyl cycle and NAD+ producers is another option to increase the endogenous production of antioxidants in heart failure.  Some studies have demonstrated that a few components of the gamma-glutamyl cycle (gamma-glutamyl-cysteine synthetase, GPx, OPLAH) are correlated with the risk of heart failure and its progression7. Therefore, the overexpression of these enzymes may have cardioprotective effects. OPLAH is a cytoplasmic enzyme of the GSH cycle, with a central function in the gamma-glutamyl cycle and also with an important antioxidant function; its expression is decreased in heart failure. Therefore, the stimulation of the expression and activity of OPLAH in patients with heart failure may play an important role for their prognosis. In conclusion, oxidative stress may play an important role in patients with chronic heart failure. Experimental studies have demonstrated the beneficial effects of therapies addressing the oxidative stress in animals. However, until now, these effects have not been fully demonstrated by clinical trials in humans. Further antioxidant strategies must be studied.


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International Secretary General of the Balkan Medical Union
President of the Romanian National Section


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Diaconu C. Oxidative stress and heart failure. Arch Balk Med Union 2019;54(2):219-221.