Abstract
BackgroundCardiomyopathy is a common side effect of doxorubicin (DOX) chemotherapy. Despite intensive research efforts in the field, there is still no evidence available for routine cardioprotective prophylaxis to prevent cardiotoxicity in the majority of oncological patients at low risk of cardiovascular disease. We have recently demonstrated the advantages of a prophylactic, combined heart failure therapy in an experimental model of DOX-induced cardiomyopathy. In the current work, we focus on individually applied prophylactic medications studied in the same translational environment to clarify their distinct roles in the prevention of DOX cardiotoxicity.MethodsTwelve-week-old male Wistar rats were divided into 5 subgroups. Prophylactic β-blocker (BB, bisoprolol), angiotensin-converting enzyme inhibitor (ACEI, perindopril) or aldosterone antagonist (AA, eplerenone) treatments were applied 1 week before DOX administration, then 6 cycles of intravenous DOX chemotherapy were administered. Rats receiving only intravenous DOX or saline served as positive and negative controls. Blood pressure, heart rate, body weight, and echocardiographic parameters were monitored in vivo. Two months after the last DOX administration, the animals were sacrificed, and their heart and serum samples were frozen in liquid nitrogen for histological, mechanical, and biochemical measurements.ResultsAll prophylactic treatments increased the survival of DOX-receiving animals. The lowest mortality rates were seen in the BB and ACEI groups. The left ventricular ejection fraction was only preserved in the BB group. The DOX-induced increase in the isovolumetric relaxation time could not be prevented by any prophylactic treatment. A decreased number of apoptotic nuclei and a preserved myocardial ultrastructure were found in all groups receiving prophylactic cardioprotection, while the DOX-induced fibrotic remodelling and the increase in caspase-3 levels could only be substantially prevented by the BB and ACEI treatments.ConclusionPrimary prophylaxis with cardioprotective agents like BB or ACEI has a key role in the prevention of DOX-induced cardiotoxicity in healthy rats. Future human studies are necessary to implement this finding in the clinical management of oncological patients free of cardiovascular risk factors.
Highlights
Cancer is the second leading cause of death globally with alarmingly increasing incidence [1]
We focus on the effects of prophylactic, individually applied drug treatments using the same heart failure (HF) medications as in our previous model [β-blocker, angiotensin-converting enzyme inhibitor, and aldosterone antagonist] in order to clarify their distinct roles in the prevention of DOX cardiotoxicity
The survival rates of the D-Negative control group (CON) animals were significantly lower compared to CON (p = 0.0205), while both the β-blocker/bisoprolol-receiving group (BB) and Angiotensin-converting enzyme inhibitor/perindopril-receiving group (ACEI) treatments resulted in an apparent survival benefit compared to Positive control group (D-CON), which was statistically non-significant with this number of study animals [p = 0.0683 (BB vs. D-CON), p = 0.0691 (ACEI vs. D-CON)] (Fig. 2a)
Summary
Cancer is the second leading cause of death globally with alarmingly increasing incidence [1]. Various side effects, such as acute or chronic cardiotoxicity may limit the use of DOX in a dose-dependent manner [2, 3]. The administration of 500–550 mg/m2 intravenous DOX may cause myocardial dysfunction in approximately 4–26% of patients, while a dose increase to 551–600 mg/m2 may lead to a prevalence of 18–26%. When the dose of DOX exceeds 600 mg/m2, the risk of cardiotoxicity can be as high as 36–48% [4,5,6]. Cardiomyopathy is a common side effect of doxorubicin (DOX) chemotherapy. We have recently demonstrated the advantages of a prophylactic, combined heart failure therapy in an experimental model of DOX-induced cardiomyopathy. We focus on individually applied prophylactic medications studied in the same translational environment to clarify their distinct roles in the prevention of DOX cardiotoxicity
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