Author + information
- Published online February 20, 2017.
- aCardio-Oncology Program, University of South Florida Morsani College of Medicine Department of Cardiovascular Sciences and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- bCardiac MR PET CT Program, Department of Radiology, Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- cCardio-Oncology Program, Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Tomas G. Neilan, Cardiac MR PET CT Program, Department of Radiology, Cardio-Oncology Program, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge Street, Boston, Massachusetts 02114.
Dramatic improvements in long-term survival have occurred among patients with cancer; these improvements are driven primarily by improved screening, characterization, and treatments. The improvement in cancer-related outcomes has generated a paradigm shift in our approach to cancer survivors with a renewed focus on maximizing non–cancer-related outcomes. The development or exacerbation of cardiovascular disease is now one of the key determinants of outcomes in patients with cancer (1). Managing cardiovascular disease both during and after cancer therapy has become a high priority for both oncology and cardiology practitioners. As a result, cardio-oncology programs have been established at some academic centers in North America. These programs provide an integrative multidisciplinary approach to the care of cancer patients and survivors.
Cardiotoxicity from chemotherapy can manifest as almost any cardiovascular disease (Figure 1) and multiple chemotherapeutic treatments are associated with cardiotoxicity. The list is extensive, but the cardiotoxicity related to anthracycline-based chemotherapy is best studied. Anthracyclines are a class of chemotherapeutic agents used in many pediatric and adult cancer regimens, with data estimating that up to 50% of patients treated with anthracyclines will demonstrate some form of cardiotoxicity (2). Multiple prior reviews have provided overviews (3) that include all aspects of anthracycline-induced cardiotoxicity (AIC); in brief, AIC can be subdivided into 3 types: acute cardiotoxicity, which occurs immediately after infusion and is typically reversible; early onset chronic progressive cardiotoxicity, which occurs within 1 year of treatment; and late onset chronic progressive cardiotoxicity, which occurs more than 1 year after exposure. Cardiomyopathy is more common in females, in patients who receive high cumulative doses of the medication, in those patients with underlying cardiovascular disease, and in patients at the extremes of age (3). Cardiotoxicity from anthracyclines may not manifest until many years after completion of therapy with heart failure (HF) and asymptomatic left ventricular dysfunction (Figure 1) being the most commonly recognized cardiac complications. Reported rates of HF vary depending on the population and time frame ranging from 5% to almost 26% (4). The limited data on the cardiovascular outcomes among patients who develop clinical HF related to anthracyclines suggest very poor outcomes in comparison with other etiologies of HF (5). Despite significantly improved diagnosis and medical management of cardiomyopathy and HF, there are data indicating that among patients receiving chemotherapy with an asymptomatic decrease in left ventricular ejection fraction, only 31% receive an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 35% receive a beta blocker, and 42% are referred for cardiology consultation (6). The use of HF medications is exceptionally important in this vulnerable population, especially in light of data suggesting that the early use of standard HF medications among patients with an anthracycline-induced decrease in left ventricular ejection fraction to ≤45% resulted in normalization of the left ventricular ejection fraction in almost one-half of patients (7).
There is also increasing recognition that arrhythmias are a frequent toxicity of cancer therapy. Although some therapeutics like ibrutinib, a tyrosine kinase inhibitor used to treat several B-cell malignancies, may be associated intrinsically with the development of rhythm abnormalities (8), most arrhythmias result from some other primary toxicity, such as cardiomyopathy, ischemia, or myocarditis, which in turn creates an arrhythmic substrate. The association with anthracyclines and both atrial and ventricular arrhythmias has been well-established. Atrial arrhythmias occur quite frequently, with more than 10% of patients experiencing atrial fibrillation after the first cycle of therapy (9). Premature ventricular contractions are also commonly identified, with up to 6% of patients developing nonsustained ventricular tachycardia shortly after infusion (10). These arrhythmias are generally reversible, allowing patients to continue receiving this class of therapeutics. More serious ventricular arrhythmias are generally associated with anthracycline-induced cardiomyopathy or with acute cardiotoxicity manifesting as myocarditis, left ventricular dysfunction, and/or HF. The exact mechanism by which anthracyclines induce arrhythmias remains uncertain; however, several hypotheses have been developed, including direct electrophysiologic effects, impaired intracellular signaling, and the accumulation of reactive oxygen species and/or toxic metabolites such as doxorubicinol (11). For example, anthracyclines increase the L-type Ca2+ currents (12) and prolong the action potential duration of cardiac myocytes via inhibition of the transient and delayed outward currents as well as the Na+-Ca2+ exchange complex (13).
It is with all this background that the publication in this issue of JACC: Clinical Electrophysiology is especially important. Mazur et al. (14) report the burden of arrhythmias and associated clinical outcomes in adult cancer survivors with anthracycline-induced cardiomyopathy and an implantable cardiac defibrillator/cardiac resynchronization therapy defibrillator. The investigators found that nonsustained ventricular tachycardia (73.9%) was the most common rhythm abnormality, followed by atrial fibrillation/atrial flutter (56.6%), and sustained ventricular tachycardia or fibrillation (30.4%). These findings were not different from the 2 comparator groups, namely, patients with cancer and a non–anthracycline-mediated cardiomyopathy and patients without cancer with a dilated cardiomyopathy (ischemic or nonischemic). Clinical outcomes, including device therapy, heart transplantation, and overall mortality, did not differ between groups. As such, the authors conclude that anthracycline-induced cardiomyopathy may not represent a substantially higher risk etiology, as had previously been suggested. There are data demonstrating the benefit of cardiac resynchronization therapy defibrillator therapy in patients with AIC, with similarly improved clinical and echocardiographic measures compared to other forms of nonischemic cardiomyopathy (15). Nevertheless, there are few data quantifying the risk of arrhythmias, especially in cancer survivors with late-onset cardiomyopathy. Implantable cardiac electronic devices store arrhythmia data; therefore, patients with devices represent an ideal population to evaluate these issues. This study by Mazur et al. (14) is the first to analyze device recorded data to accurately ascertain arrhythmia burden in anthracycline-induced cardiomyopathy. These data can serve as a foundation for future studies to determine treatment algorithms and long-term prognosis in these patients.
Cardiomyopathy due to anthracyclines has been thought traditionally to portend a worse prognosis compared with other types of cardiomyopathy, especially in the first 5 years of diagnosis (5). The reason for these poor outcomes has not been established definitively; however, the data presented in the current study by Mazur et al. (14) suggests that a diagnosis of AIC and associated HF may not be so dire. Although this is a single-center, retrospective study, these data indicate that patients with anthracycline-induced cardiomyopathy have similar arrhythmic risk and clinical outcomes compared with other forms of cardiomyopathy. These findings, in conjunction with the recently published Danish trial (16), demonstrate the need for prospective studies to determine more accurately the arrhythmia burden and potential mortality benefit of implantable cardiac defibrillators in this population. The MADIT-CHIC trial (Multicenter Automatic Defibrillator Implantation Trial–Chemotherapy-Induced Cardiomyopathy; NCT02164721) is a significant step in this direction and will be the first prospective study evaluating the benefit of a cardiac resynchronization therapy defibrillator in anthracycline-induced cardiomyopathy. The results of this study will be an additional significant step forward in our understanding of the natural history of AIC, allowing for better evaluation and treatment of this population of cancer survivors.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2017 American College of Cardiology Foundation
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