Anthracycline-Induced Cardiomyopathy: Secrets and Lies

This article refers to ‘Comparison of long-term outcome in anthracycline-related versus idiopathic dilated cardiomyopathy: a single centre experience’ by A. Fornaro et al., published in this issue on pages 898–906. A growing number of cancer patients survive of cancer and one third of them will eventually die of heart disease that is at least partly related to cancer and its therapy.1, 2 The recognition of this association has recently given rise to a new field in cardiovascular medicine, that of cardio-oncology. In fact, over the previous few years, the number of publications on cardiovascular complications of cancer patients increased impressively, dedicated cardio-oncology clinics begun to arise in heart centres throughout the US and Europe, and the European Society of Cardiology published a position paper on the cardiotoxicity of cancer therapy.3 Cardiac disease in cancer results from the interaction of three main factors: (i) the underlying cardiovascular status of the patient, including pre-existing heart disease and cardiovascular risk factors, (ii) cancer itself that may affect directly and mostly indirectly the cardiovascular system, and (iii) cancer therapy, including classical chemotherapy, targeted agents and radiotherapy, that may damage the heart and vessels through several mechanisms4 (Figure 1). Among cancer therapies, anthracyclines constitute traditionally the typical model of chemotherapy-induced cardiotoxicity. The classical knowledge dictates that anthracyclines represent the main class of anticancer drugs causing cardiomyopathy in a dose-dependent manner, resulting from irreversible oxidative cardiomyocyte damage, usually manifested as ventricular dysfunction and heart failure a long time after patient's exposure.5 However, recent advances in our understanding of cardiomyopathy caused by cancer therapies have challenged the above long-standing statements. First, although anthracyclines are top in the list of anticancer agents causing cardiomyopathy, with an incidence ranging between 3% and 48% depending on anthracycline type and total dose, other drugs, including both classical chemotherapeutics and targeted therapies, also pose a considerable risk of myocardial dysfunction and heart failure3 (Table 1). Among them, the recently introduced proteasome inhibitor carfilzomib, used as second-line therapy for resistant or relapsed multiple myeloma, exhibited an alarming occurrence of left ventricular dysfunction of up to 15%.3 Therefore, the risk of cardiomyopathy related to other anticancer drugs should not be overlooked. Second, although the cumulative dose of anthracyclines is a major determinant of the risk for cardiomyopathy, this risk may be modified by additional factors, such as aging.3 In other words, a certain cumulative dose is associated with higher risk of cardiotoxicity in patients older than 65 years compared to younger adults.6 The same applies to children, who are also more susceptible than young or middle-aged adults. In addition, the widely known indicated maximum cumulative doses have been defined taking under consideration heart failure as an endpoint. Instead, if cardiotoxicity is defined by left ventricular systolic dysfunction, the risk increases at much lower doses. In the case of doxorubicin, for example, the risk of heart failure starts to increase considerably at a total dose of 400 mg/m2, but the risk of left ventricular systolic dysfunction increases already after a total dose of 150 mg/m2.7 Third, the pathophysiology of anthracycline-induced cardiotoxicity, traditionally considered to result from oxidative tissue injury, has further been elucidated. Among the pathogenetic mechanisms that have lately been suggested, the role of topoisomerase-2β, an enzyme required for DNA transcription, replication and recombination, seems to be crucial. When bound to anthracyclines, topoisomerase-2β leads to breaks of double-stranded DNA that in turn result in p53 activation, mitochondrial dysfunction, generation of reactive oxygen species, cell dysfunction and death.6, 8 Interestingly, topoisomerase-2β also seems to mediate the cardioprotective effects of the chelating agent dexrazoxane, once believed to act simply by eliminating iron, the substrate for the production of oxygen free radicals.6 Additional potential mechanisms include the reduction in cardiac mesenchymal and circulating progenitor cells as well as the implication of cardiomyocyte membrane transport systems that regulate anthracycline cellular efflux, such as the multidrug resistance proteins.8 Fourth, it has long been believed that cardiomyopathy may be manifested several years after the exposure of the patient to anthracyclines.5 However, in a recently published study on 2625 patients having received anthracycline-based chemotherapy for breast cancer or non-Hodgkin lymphoma, cardiomyopathy, defined as a left ventricular ejection fraction (LVEF) decline of >10% to values 50%.9 The mean time to LVEF recovery was 8 months. The crucial determinant of LVEF response seems to be the time of onset of cardioactive therapies, with high response rates when therapy is started during the first 1–2 months after chemotherapy and practically lack of response when it is started later than 4–6 months.10 This finding also stresses the need of close monitoring for the early detection and treatment of cardiotoxicity in high-risk patients receiving anthracycline-based chemotherapy. Risk factors include advanced age, coexisting cardiovascular disease, previous exposure to anthracyclines or other cardiotoxic agents, combination of classical chemotherapy with potential cardiotoxic targeted agents and mediastinal irradiation.3 In the current issue of the Journal, Fornaro and colleagues provide some additional new insights into our knowledge and understanding of anthracycline-induced cardiotoxicity.11 The authors show that patients with anthracycline-induced cardiomyopathy treated with optimized heart failure therapy have comparable overall survival rates with idiopathic dilated cardiomyopathy at 5 (86% and 88%, respectively) and 10 years (61% and 75%, respectively), despite cancer-related morbidity and mortality. The same is also true for cardiovascular mortality. These findings contradict an earlier study showing a considerably worse survival rate in doxorubicin-induced cardiomyopathy of <50% at 5 years,12 which probably reflects the effect of optimized heart failure therapy that patients in the Fornaro study received.11 Taking also under consideration the aforementioned findings of LVEF recovery by early initiation of angiotensin-converting enzyme inhibitors and beta-blockers, it becomes clear that cancer patients experiencing anthracycline-induced cardiotoxicity should be offered regular cardiac management and follow-up. The cardiovascular community currently experiences the beginning of the cardio-oncology era. As the population of cancer survivors will keep growing, cardiologists will inevitably have to face new challenges in clinical practice, but, at the same time, this very field offers enormous possibilities for professional development and research exploitation. Conflict of interest: none to declare.