Arrhythmias in cancer: rhythm is gonna get you!

This article refers to ‘Ventricular tachycardia, premature ventricular contractions, and mortality in unselected patients with lung, colon, or pancreatic cancer: a prospective study’ by M.S. Anker et al., published in this issue on pages 145–153. Cardiovascular (CV) disease is increasingly being recognized as an important part of the clinical spectrum of patients with cancer, representing the second most common cause of death in these patients.1, 2 Coexisting CV disorders and CV complications of anticancer therapies may thus have an impact on the outcomes of these patients, a fact that gave rise to the concept and new field of Cardio-Oncology.3 Among CV manifestations of patients with malignancies, arrhythmias hold a prominent position. Cancer patients may develop a wide range of rhythm disorders, including either bradycardias and conduction defects or tachyarrhythmias such as atrial fibrillation and monomorphic or polymorphic ventricular tachycardia.1, 4 Arrhythmias in cancer may result from the interaction of three main factors: patient's characteristics, cancer and anticancer therapy (Figure 1). Patient-related factors that may predispose to arrhythmias include: (i) coexisting CV disease; (ii) ageing, a common denominator for both CV disease and cancer further, associated with rhythm disorders such as atrial fibrillation or sick sinus syndrome; (iii) comorbid conditions such as diabetes mellitus or chronic kidney disease; (iv) genetic predisposition. Cancer, on the other hand, may induce arrhythmias by direct invasion of the heart from a primary cardiac neoplasm or, more often, a metastatic tumour or by causing systemic abnormalities, such as autonomic nervous system derangement and inflammation.4 Finally, cancer therapy may induce or contribute to rhythm disorders, including systemic anticancer therapies (e.g. chemotherapy, targeted therapies, immunotherapies), radiotherapy with chest irradiation involving cardiac tissue and supportive medications, such as antiemetics. Certain anticancer agents have been associated with pro-arrhythmic properties, with QT prolongation being the most typical one.5-7 Anticancer drugs may further predispose to arrhythmias by causing other forms of CV disease such as ventricular dysfunction and heart failure or myocardial ischaemia as part of their cardiotoxicity profile or by inducing electrolyte and metabolic disorders due to gastrointestinal and other toxicities. The role of the Cardio-Oncology specialist in the prevention and management of arrhythmias in patients with cancer is multiple and concerns baseline assessment upon cancer diagnosis, monitoring and management during active cancer and long-term surveillance in cancer survivors3, 8 (Figure 2). Baseline evaluation aims at risk stratification of patients, identifying those who would require a close monitoring during and after cancer therapy, and the optimization of CV therapies.9 In this context, identifying patients with pre-existing rhythm disorders such as atrial fibrillation or risk factors for arrhythmias, such as QT prolongation, would inform special precautions during cancer therapy or even proper adaptations of anticancer therapies, in close collaboration with the attending oncologist or haematologist. During anticancer therapy, monitoring of selected high-risk patients would allow the timely diagnosis and management of arrhythmias, among other potential CV complications, although arrhythmias may often be treated in an emergency setting. The management of occurring rhythm disorders follows the general approach as in non-cancer patients but with certain precautions. The handling of medications, such as antiarrhythmics or anticoagulants (in the case of atrial fibrillation), requires careful assessment of potential drug interactions with anticancer agents.10 Decision making for certain interventions, such as device implantation, should also take under consideration the prognosis of the malignancy and the life-expectancy of the patient. Anticoagulation for atrial fibrillation may be challenging in patients with active malignancies in whom thromboembolic or bleeding risk may be quite higher than in non-cancer patients.10 In addition, proper adjustment of ongoing anticancer therapies may also be required after arrhythmia development. Long-term surveillance may be necessary in cancer survivors with coexisting CV disease or those exposed to therapies with significant cardiotoxic properties, as arrhythmias may be part of late cardiotoxicity. For example, chest irradiation may cause degeneration and fibrosis of the conduction system that may in turn lead to atrioventricular block several years after radiotherapy.11 In the present issue of the Journal, Anker and colleagues report the findings of a case-control study comparing ventricular arrhythmias between patients with advanced cancer and healthy age- and sex-matched controls.12 Patients with cancer had a higher incidence of non-sustained ventricular tachycardia (NSVT) during ambulatory electrocardiographic monitoring. The authors proposed a new perspective for the association between cancer and arrhythmias, beyond that related to the prevention and management of rhythm disorders during or after cancer therapy. On one hand, they showed that ventricular arrythmias may bear a prognostic significance in patients with advanced malignancies, as they found that the burden of either NSVT or premature ventricular contractions predicted independently all-cause mortality. Similarly, previous studies have shown that atrial fibrillation, even if related to transient stressors such as surgery, is an independent predictor of worse outcomes in patients with malignancies.4 Beyond the prognostic impact of ventricular arrhythmias, Anker and colleagues make one more step forward, suggesting that rhythm disorders may represent a therapeutic target in cancer and that cardioactive medications may have an impact on mortality by mitigating ventricular arrhythmias. Although this latter concept remains a hypothesis that needs to be investigated by proper clinical studies and should also consider cancer type and stage, it stresses the importance of addressing CV disease in patients with cancer. It has previously been shown that a well-structured baseline CV assessment, risk stratification, monitoring and management of patients with malignancies renders the majority of them fit to receive the best available cancer therapy without interruptions,13 which in turn increases the possibility of a favourable outcome. In addition, the timely diagnosis and treatment of CV toxicity during cancer therapy also improves patients' survival.14 Further improvements are expected to be accomplished if the ongoing research on the primary prevention of cardiotoxicity provides solid evidence and when the long-term CV surveillance of cancer survivors is well established. All these activities constitute the framework of a comprehensive Cardio-Oncology service. Conflict of interest: D.F. has received consultation fees and/or speaker honoraria from Abbott Laboratories, Bayer, Boehringer Ingelheim, Leo, Menarini, Novartis, Orion Pharma and Roche Diagnostics. G.F. has served as member of committees in trials sponsored by Amgen, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier and Vifor.