The challenge of cancer therapy-related cardiac dysfunction: facts and perspectives

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on cardio-oncology and arrhythmias contains the State of the Art Review article ‘Breast cancer and cardiovascular health’ by Teresa López-Fernández from the La Paz University Hospital in Madrid, Spain, and colleagues.1 The authors note that modern cancer therapies greatly improve clinical outcomes for both early and advanced breast cancer patients. However, these advances have raised concerns about potential short- and long-term toxicities, including cardiovascular toxicities.2–8 Therefore, understanding the common risk factors and underlying pathophysiological mechanisms contributing to cardiovascular toxicity is essential to ensure best breast cancer outcomes. While cardio-oncology has emerged as a subspeciality to address these challenges, it is essential that all cardiologists recognize and understand the cardiovascular consequences of cancer therapy. This review aims to provide a comprehensive overview of the potential adverse cardiovascular effects associated with modern breast cancer therapies. A preventive, diagnostic, and therapeutic workflow to minimize the impact of cardiovascular toxicity on patient outcomes is presented. Key aspects of this workflow include regular monitoring of cardiovascular function, early detection and management of cancer therapy-related cardiovascular toxicities, and optimization of cardiovascular risk factor control. By highlighting the gaps in knowledge in some areas, this review aims to emphasize the critical role of cardio-oncology research in ensuring the holistic well-being of patients with breast cancer. Recent advances in techniques, technologies, and proven superiority over antiarrhythmic drugs have made catheter ablation the cornerstone of management for atrial fibrillation (AF), which has shown a steady increase in prevalence in the ageing population worldwide.9–14 In a State of the Art Review article entitled ‘Catheter ablation for atrial fibrillation: indications and future perspective’, Andrea Natale from the St. David’s Medical Center in Austin, TX, USA, and colleagues note that the aim of therapeutic interventions is to achieve stable sinus rhythm that would improve the quality of life and reduce the risk of AF-associated complications.15 Pulmonary veins (PVs) were first described as the source of initiation of ectopic triggers driving AF, which led to the establishment of PV isolation (PVI) as the most widely practised procedure to treat AF. Antral PVI is still recognized as the stand-alone ablation strategy for newly diagnosed paroxysmal AF (PAF). However, in non-PAF patients, PVI seems to be inadequate, and several adjunctive strategies, including ablation of the left atrial posterior wall and non-PV triggers, AF mapping and ablation of rotors and drivers, ethanol infusion of the vein of Marshall, and renal denervation, have been reported with mixed results. Recent trials have also documented the benefits of early rhythm control in preventing cardiovascular events in addition to slowing the progression of PAF to more persistent forms. Similarly, very late relapse of the arrhythmia after successful PVI has drawn attention to the critical role of non-PV triggers and highlighted their relevance as potential ablation targets during repeat procedures. Ablation technology is also under constant evolution, with the introduction of non-thermal energy sources and new tools to create durable lesions. This review summarizes the indications, advancements, and future perspective of AF ablation. Liver transplant candidates require a detailed cardiovascular assessment, involving a multidisciplinary approach, which incorporates evaluation of traditional and ESLD factors as well as evaluation for cardiac conditions including coronary artery disease, cardiomyopathies, and rhythm disturbances. Liver disease induces systemic haemodynamic changes including portal hypertension, increased cardiac output, and vascular resistance alterations, predisposing candidates to cardiovascular complications. Thorough cardiovascular evaluation may involve non-invasive tests (electrocardiography, echocardiography, cardiac biomarkers, coronary artery calcium score, stress testing) and invasive assessments (coronary angiography) to stratify risk and guide management decisions. Optimal management should involve lifestyle modifications, pharmacotherapy, revascularization for high-risk patients after discussion with a heart team, review of the immunosuppression regimen, and pre-operative optimization. Successful cardiovascular management in liver transplant candidates improves peri-operative outcomes and reduces post-operative complications. CNI, calcineurin inhibitor; CSA, cyclosporine; ECG, electrocardiogram; ESLD, end-stage liver disease; MELD, model for end-stage liver disease; MASH, metabolic dysfunction-associated steatohepatitis; Tac, tacrolimus16 The prevalence and mortality related to end-stage liver disease (ESLD) continue to rise globally. In another State of the Art Review article entitled ‘Cardiovascular disease assessment and management in liver transplantation’, Matthew Harinstein from the University of Pittsburgh Medical Center in Pittsburgh, PA, USA, and colleagues indicate that liver transplant (LT) recipients continue to be older and have inherently more comorbidities.16 Among these, cardiac disease is one of the three main causes of morbidity and mortality after LT. Several reasons exist including the high prevalence of associated risk factors, which can also be attributed to the rise in the proportion of patients undergoing LT for metabolic dysfunction-associated steatohepatitis (MASH). Additionally, as people age, the prevalence of now treatable cardiac conditions, including coronary artery disease (CAD), cardiomyopathies, significant valvular heart disease, pulmonary hypertension, and arrhythmias, rises, making the need to treat these conditions critical to optimize outcomes. There is an emerging body of literature regarding CAD screening in patients with ESLD; however, there is a paucity of strong evidence to support the guidance regarding the management of cardiac conditions in the pre-LT and peri-operative settings. This has resulted in significant variations in assessment strategies and clinical management of cardiac disease in LT candidates between transplant centres, which impacts LT candidacy based on a transplant centre’s risk tolerance and comfort level for caring for patients with concomitant cardiac disease. Performing a comprehensive assessment and understanding the potential approaches to the management of ESLD patients with cardiac conditions may increase the acceptance of patients, who appear too complex, but rather require extra evaluation and may be reasonable candidates for LT. The unique physiology of ESLD can profoundly influence pre-operative assessment, peri-operative management, and outcomes associated with underlying cardiac pathology, and requires a thoughtful multidisciplinary approach. The strategies proposed in this manuscript attempt to review the latest expert experience and opinions and provide guidance to practising clinicians who assess and treat patients being considered for LT. These topics also highlight the gaps that exist in the comprehensive care of LT patients and the need for future investigations in this field (Figure 1). From 355 patients with normal left ventricular function undergoing anthracycline therapy, 333 with additional risk factors for cancer therapy-related cardiac dysfunction (CTRCD) were able to undergo baseline and magnetic resonance imaging and echocardiography. Of these, 105 developed isolated impairment of global longitudinal strain (GLS), and were randomized to cardioprotection with neurohormonal inhibition or usual care. Patients taking cardioprotection experienced a smaller change in left ventricular ejection fraction (LVEF) over 12 months. The baseline-corrected mean difference in LVEF was −3.6%. Normal LVEF and GLS = not meeting an LVEF-CTRCD criterion or a GLS change >12%; GLS only = an isolated >12% relative reduction in GLS; Lost = patients lost to follow-up. EF = patients who met the LVEF-CTRCD criteria17 The detection of cancer therapy-related cardiac dysfunction (CTRCD) by reduction of left ventricular ejection fraction (LVEF) during chemotherapy usually triggers the initiation of cardioprotective therapy. In a Fast Track Clinical Research article entitled ‘Strain surveillance during chemotherapy to improve cardiovascular outcomes: the SUCCOUR-MRI trial’, Thomas Marwick from the Baker Heart and Diabetes Institute in Melbourne, Australia, and colleagues addressed whether the same approach should be applied to patients with worsening of global longitudinal strain (GLS) in the absence of LVEF reduction.17 The strain surveillance during chemotherapy for improving cardiovascular outcomes trial (SUCCOUR-MRI) was a prospective multicentre randomized controlled trial involving 14 sites. Of 355 patients receiving anthracyclines with normal baseline LVEF, 333 patients (mean age 59 years, 79% women) with at least one other CTRCD risk factor, able to undergo magnetic resonance imaging (MRI), GLS, and three-dimensional echocardiography, were tracked over 12 months. A total of 105 patients (69% breast cancer) developing GLS-CTRCD (>12% relative reduction of GLS without a change in LVEF) were randomized to cardioprotection with neurohormonal antagonists vs. usual care. The primary endpoint was 12-month change in MRI-LVEF. During follow-up, two patients died, and two developed heart failure. Due to a smaller LVEF change from baseline with cardioprotection than usual care (−2.5 ± 5.4% vs. −5.6 ± 5.9%, P = .009), follow-up LVEF was higher after cardioprotection (59 ± 5% vs. 55 ± 6%, P < .0001) (Figure 2). GLS improved at 3 months post-randomization in the cardioprotection group, with little change with usual care. Marwick and colleagues conclude that in patients with isolated GLS reduction after anthracyclines, cardioprotection is associated with better preservation of 12-month MRI-LVEF compared with usual care. This manuscript is accompanied by an Editorial by Ana Barac, Lauren Mauro, and Kathleen Harnden from the Inova Schar Heart and Vascular in Fairfax, VA, USA.18 The authors note that in clinical practice, these patients will probably need a cardiology referral, and it is imperative to include oncologists in the creation and implementation of risk stratification/referral pathways. These are likely to be different for breast oncologists as compared with malignant haematologists as treatment regimens and patient characteristics vary widely between cancer types. Cardiac assessment needs to be streamlined and facilitated to reduce patient burden and increase compliance with the treatment regimen. We all share the same goal: to help our patients live longer, healthier, and happier lives. By using strategies such as described in this trial, cardiologists and oncologists can reach towards this goal together. Ventricular arrhythmias (VAs) impact on the outcome in several cardiovascular diseases.19–21 In a Clinical Research article entitled ‘Prognostic value of ventricular arrhythmia in early post-infarction left ventricular dysfunction: the French nationwide WICD-MI study’, Mathieu Echivard from the Université de Lorraine in Nancy, France, and colleagues note that prophylactic implantable cardioverter-defibrillators (ICDs) are not recommended until LVEF has been reassessed 40–90 days after an acute myocardial infarction.22 Data analysis was based on a nationwide registry of 1032 consecutive patients with LVEF ≤35% after acute myocardial infarction who were implanted with an ICD after being prescribed a wearable cardioverter-defibrillator (WCD) for a period of 3 months upon discharge from hospital after the index infarction. ICDs were implanted either because a sustained VA occurred while on WCD (VA+/WCD, n = 72) or because LVEF remained ≤35% at the end of the early post-infarction phase (VA−/WCD, n = 960). The median follow-up was 30.9 months. Sustained VAs occurred within 1 year after ICD implantation in 22% and 3% of VA+/WCD and VA−/WCD patients, respectively (P < .0001). The adjusted multivariable analysis showed that sustained VAs while on WCD independently predicted recurrence of sustained VAs at 1 year (adjusted hazard ratio [HR] 6.91; P < .0001) and at the end of follow-up (adjusted HR 3.86; P < .0001) as well as 1-year mortality (adjusted HR 2.86; 95% confidence intgerval [CI] 1.28–6.39; P = .012). The authors conclude that in patients with LVEF ≤35%, sustained VA during the early post-infarction phase is predictive of recurrent sustained VAs and 1-year mortality. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Haemodynamic changes after interventional closure of the left atrial appendage may facilitate peri-device leaks’, Claudia Stöllberger from Vienna, Austria and colleagues comment on the recent publication ‘Residual leaks following percutaneous left atrial appendage occlusion and outcomes: a meta-analysis’ by Athanasios Samaras from the Aristotle University of Thessaloniki in Greece.23,24 Samaras et al. respond in a separate comment.25 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.