Doxorubicin is an antibiotic of the anthracycline class used to treat neoplasms. However, the clinical use of this drug may be limited by the development of dose-dependent cardiotoxicity.¹ Among the interventions to minimize doxorubicin-induced cardiotoxicity, physical exercise initiated before chemotherapy has been recommended as part of a comprehensive multidisciplinary therapeutic program. This non-pharmacological strategy can improve tolerance to chemotherapy, protect the heart, and mitigate potential toxic effects.²

The mechanisms by which exercise protects the heart are not yet fully understood. However, it is known that exercise can positively and interactively modulate cardiac defense and adaptation, which seem to antagonize the toxic effects of doxorubicin.³ Physical exercise performed before doxorubicin administration improves mitochondrial function, decreases the production of reactive oxygen species, oxidative damage and apoptosis, preserves alpha-myosin heavy chain, decreases left ventricular end-systolic pressure, and improves the time derivative of ventricular pressure (dP/dt).^4-6

However, despite the recommendation of physical exercise to treat heart failure by the Brazilian Cardio-Oncology Guidelines of the Brazilian Society of Cardiology⁷ and the American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure in adults,⁸ few studies^6,9 have evaluated the effects of physical training performed after doxorubicin administration on cardiotoxicity.

Among these studies, Lee et al.⁹ suggest that the exercise-mediated effects against doxorubicin-induced cardiotoxicity is associated with improved basal autophagy/mitophagy and antioxidative capacity via NADPH oxidase 2 downregulation.⁹

This study aimed to assess the effects of physical training on myocardial structure, cardiac function, and exercise tolerance of Wistar rats, when exercise was performed after the time needed for the development of doxorubicin-induced cardiotoxicity.

Our study showed that physical training initiated after the onset of doxorubicin-induced cardiotoxicity, improved cardiac function and exercise tolerance in rats.

Cardiotoxicity caused by doxorubicin is cumulative and dose-dependent,^17-19 and can progress to heart failure of variable severity.²⁰ Macroscopic and functional cardiac changes, caused by chemotherapy and found in the present study have been described in other animal experimental models^21,22 and are similar to those reported in humans.²³These changes indicate that the treatment intervention triggered cardiac toxicity, and can be used as an experimental evaluation of various therapies.

Systemic reactions reflect the toxicity induced by doxorubicin. In our experiments, we observed lower weight gain, reduced physical activity, and exudation around the eyes and nostrils. These reactions may interfere with organic metabolic processes and are more intense when higher doses of chemotherapy are administered.²²

Physical training is part of the non-pharmacological treatment of acute and chronic heart failure,²⁴ and is recommended by the Brazilian Cardio-Oncology Guidelines. Current evidence indicates that physical training plays both preventive and therapeutic roles for heart disease in patients who will receive chemotherapy.⁷

Two questions motivated this study. The first one is when to start physical training, and the second one is whether exercise can reverse the cardiotoxic effects.

To answer these questions, first we need to validate the methodology used, since the clinical identification of cardiac dysfunction in animals is not always easy. One of the difficulties of interpreting results of models of doxorubicin-induced cardiomyopathy is to quantify the intensity of cardiac dysfunction in relation to the dose of chemotherapy administered in the experiment. Identifying heart failure and its clinical manifestations in animal experiments is a challenge in this context. However, based on the echocardiographic findings, we can affirm that cardiotoxicity did occur in our experiment.

The reduced left ventricular systolic function found in our study was associated with the intensity of cardiotoxicity. Changes in the diameter of cardiac chambers, observed in the DX group, may arise in response to interacting factors, such as inflammation, apoptosis of cardiomyocytes, compensatory cell hypertrophy, fibrosis, and damage caused to the complex mechanism of activation and coupling/uncoupling of contractile filaments.²⁵

The echocardiographic findings answer the question regarding the potential of physical exercise to reverse cardiotoxic effects, and point out two aspects. One of them concerns the hemodynamic repercussion and its potential consequences in cardiac remodeling processes. In experimental models, the simplest way to identify remodeling is to measure the heart weight and calculate the ratio between heart weight and animal weight. These two variables were greater in the EX group compared to C, which corroborates the occurrence of cardiac hypertrophy in response to regular physical training.²⁶ However, when rats trained in the presence of doxorubicin (DXEX group), these variables did not increase, showing that chemotherapy in some way interrupted the hypertrophic signaling triggered by physical exercise. The echocardiographic measurements of the left ventricular diameters (LVESD and LVEDD) confirmed this finding, since they did not change in the DXEX group compared to C.

Physical exercise acts in cardiac remodeling and thereby plays role in preventing and treating heart failure in patients with preserved, partially preserved or reduced LVEF.²⁷ Cardiovascular changes induced by physical activity include blood pressure reduction, improvement of autonomic modulation, enlargement of ventricular cavity dimensions, and increase in stroke volume, contributing to physiological cardiomyocyte hypertrophy with reduced cardiac fibrosis.²⁸ Additional beneficial effects of exercise include increased antioxidant activity, decrease in the release of reactive oxygen species and pro-apoptotic signaling, and a reduction in myocyte turnover (by suppressing pro-apoptotic protein synthesis), leading to favorable changes in energy metabolism.²⁹

These mechanisms may have improved exercise tolerance in the DXEX group when compared to the DX group in our study. The importance of these effects derives from the fact that doxorubicin-induced cardiotoxicity and cardiac dysfunction reduce exercise tolerance, worsen the prognosis, and increase morbidity and mortality.³⁰

In addition to central cardiovascular factors, improved skeletal muscle metabolism in response to physical training may increase exercise tolerance during cancer treatment.³¹ An improved skeletal muscle metabolism improves endothelial function, and increases muscles’ oxidative capacity, the percentage of type I skeletal muscle fibers (oxidative), the recruitment of motor units, and capillary density.

Short and long-term exposure to antineoplastic agents may also cause autonomic dysfunction with direct effects on the cardiovascular system, such as increased cardiac chronotropism and impaired conduction through the atrioventricular node.³²

The present study showed that four weeks of aerobic training initiated after the development of doxorubicin-induced cardiotoxicity preserved systolic function, increased their exercise tolerance, and effectively adapted resting heart rates in rats. The maximum heart rate achieved during an exercise test with the same workload is lower in individuals who had undergone physical training.³³ This reduction has been shown in both animals and humans and been attributed to greater vagal stimulation and lower sympathetic activity.^34-36 This neurohumoral modulation of physical training has a favorable impact on functional capacity.³⁴ However, we need to be careful in interpreting these data. Although the standard deviation found in the C was very high, it is unlikely that it could have been influenced by this random response.

The mechanisms involved in the improvement of cardiotoxic effects by exercise are complex and multifactorial, so an early detection of cardiotoxicity is important to develop strategies to prevent or minimize its deleterious effects.

Physical training initiated after the onset of doxorubicin-induced cardiotoxicity improved left ventricular function and exercise tolerance in Wistar rats.