Antioxidative and antisenescent effects of cardiac rehabilitation in heart failure patients

Exercise-based cardiac rehabilitation (CR) is effectively used as an adjuvant therapy in a number of cardiovascular diseases (CVDs), including chronic heart failure (CHF), and it is recommended by the American and European Society of Cardiology guidelines. Exercise training (ET) increases physical and functional capacity, ameliorates quality of life, decreases symptoms (fatigue and dyspnoea) and, more importantly, reduces the incidence of acute cardiac events, mortality and hospitalization rates. Recently, it has been shown that a moderate exercise is able to induce the recovery of antioxidant defences, whose expression changes with aging and during CVDs. Despite the number of evidences underling the CR-associated cardiovascular protection, CR itself is still an underused medical resource and the mechanisms accounting for such benefits are not completely elucidated yet. The present study aimed at investigating whether a well-structured rehabilitation program of 4 weeks was able to modify systemic antioxidant potential in HF patients, and at examining the mechanisms by which exercise improves cardiovascular function. For this purpose, 50 subjects with diagnosis of CHF (NYHA class II and III) were recruited from the Cardiac Rehabilitation Unit of “San Gennaro dei Poveri” Hospital in Naples. On admission, patients underwent case history recording, clinical examination, electrocardiogram, chest X-Ray, echocardiogram, cardiopulmonary stress test and a 6-minute walking test, blood sample collection for routinary and experimental analysis. The CR program consisted in ET of 30' on cycloergometer, respiratory gymnastic along with educational meetings, for a meantime of 4 weeks. Blood samples were collected at baseline and at the end of CR, and oxidants (TBARS and 8-hydroxy-2-deoxyguanosine), antioxidants (catalase, Cat, and superoxide dismutase, SOD), and bioavailability of nitric oxide (NO) were measured in patients’ sera, whereas Sirtuin 1 (Sirt1) activity was quantified in patients’ lymphocytes. Human endothelial cells (ECs), exposed or not to H2O2-oxidative stress, were conditioned with patients’ sera, and cellular redox state and senescence were evaluated. A similar approach in an animal model of post-ischemic HF was used to confirm and assess the effect of exercise on senescence. Finally, inhibitors of Sirt1 (EX-527) and Cat (ATZ) activities were used to investigate the roles of these proteins in modulating endothelial cell senescence. The results demonstrated that CR stimulated an increase of oxidants with concomitant rise of Sirt1 activity, antioxidants and NO bioavailability. Moreover, CR prevented the ECs senescence via Sirt1 and Cat activation while the inhibition of these enzymes eliminated such effect, both in humans and in the animal model. Lastly, Sirt1 and Cat activities were, respectively, inversely and directly associated with cardiopulmonary stress test duration. Taken together, these findings suggest that CR triggers cellular adaptations leading to enhance systemic antioxidant effectiveness. Circulating levels of Sirt1 and Cat activity are suggested to be promising markers for assessing the efficacy of CR program. [edited by author]