Cardio-oncology: a focus on cardiovascular toxicities of cancer therapies and on atrial fibrillation in cancer

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This issue opens with two Special Articles of the series the Year in Cardiovascular Medicine. The first article is ‘The year in cardiovascular medicine 2021: diabetes and metabolic disorders’ by Francesco Cosentino from the Karolinska University Hospital in Stockholm, Sweden, and colleagues.1 In their contribution, the authors review recently published studies that are helping us to understand how the treatment landscape for glucagon-like peptide-1 receptor agonists (GLP RAs) and sodium–glucose co-transporter-2 (SGLT2) inhibitors is moving forward. They have also included relevant articles related to cardiovascular disease prevention in the setting of diabetes and metabolic disorders, with a specific focus on obesity. The second article from this series is ‘The year in cardiovascular medicine 2021: digital health and innovation’ by Paul Friedman from the Mayo Clinic in Rochester, MN, USA, and colleagues.2 Some of the most important developments in the field of digital medicine that have appeared over the last 12 months and are related to cardiovascular medicine are presented. The article consists of three main sections: (i) artificial intelligence (AI)-enabled cardiovascular diagnostic tools, techniques, and methodologies; (ii) big data and prognostic models for cardiovascular risk protection; and (iii) wearable devices in cardiovascular risk assessment, cardiovascular disease prevention, diagnosis, and management. In their conclusion, the authors present a brief further prospective on this new domain, highlighting existing gaps that are specifically related to AI technologies, such as explainability, cost-effectiveness, and of course the importance of proper regulatory oversight for each clinical implementation. The issue then continues with a focus on cardio-oncology. In a Special Article entitled ‘Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement’ by Joerg Herrmann from the Mayo Clinic in Rochester, MN, USA, and colleagues,3 the authors note that the discipline of cardio-oncology has seen tremendous growth over the past decade.4–9 It is devoted to the cardiovascular care of the cancer patient, especially to the mitigation and management of cardiovascular complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed cardiovascular toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in cardiovascular toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes cardiovascular toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported cardiovascular toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in cardiovascular toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of cardiovascular toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and cardiovascular endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with cardiovascular diseases. In a Fast Track Clinical Research article entitled ‘Incidence, risk factors, and mortality of atrial fibrillation in breast cancer: a SEER-Medicare analysis’, Avirup Guha from Case Western Reserve University in Cleveland, OH, USA, and colleagues indicate that the national incidence, risk factors, and associated mortality of atrial fibrillation (AF) in breast cancer patients are unknown.10 Using the Surveillance, Epidemiology, and End Results-Medicare-linked database, the authors identified females, ≥66 years old, with a new primary diagnosis of breast cancer from 2007 through 2014. These patients were individually matched 1:1 to Medicare enrolees without cancer, and each pair was followed for 1 year to identify a primary outcome of AF. This study included >85 000 breast cancer patients. New-onset AF was diagnosed in 2993 patients in a 1-year period after the breast cancer diagnosis (incidence 3.3%) while the incidence of new-onset AF in matched non-cancer controls was 1.8%. In addition to traditional demographic and cardiovascular risk factors, breast cancer stage was strongly associated with the development of AF [American Joint Committee on Cancer (AJCC) Stage II/III/IV vs. I: adjusted hazard ratio (aHR) 1.51/2.63/4.21, respectively]. New-onset AF after breast cancer diagnosis was associated with increased 1-year cardiovascular mortality (aHR 3.00). The authors conclude that AF incidence is significantly higher in women after a breast cancer diagnosis. Higher breast cancer stages at diagnosis are significantly associated with a higher risk of AF. New-onset AF after new breast cancer diagnosis is associated with 1-year cardiovascular mortality but not with breast cancer-related mortality. The article is accompanied by an Editorial by Jose Merino from the La Paz University Hospital in Madrid, Spain.11 Merino concludes that this study further supports that AF has direct or indirect causal relationships with breast cancer and suggests that the occurrence of this arrhythmia increases cardiovascular mortality, with thrombo-embolic complications being one of the main drivers. The potential benefits of anticoagulation in this setting appear not to be outweighed by the risk of bleeding. Although ideally the net benefit of anticoagulation and the best agent for it would need to be validated by randomized trials in this population, the number of patients needed for such trials makes registries such as the present one valid pieces of evidence until the former are conducted. Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern.12–15 Once cardiac irAEs become clinically manifest, fatality rates are high. In a Translational Research article entitled ‘Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy’, Lars Michel from the University Hospital Essen in Germany, and colleagues aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease.16 The authors investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune cross-talk. Using a novel melanoma mouse model, they assessed that anti-PD1 therapy promoted myocardial infiltration with CD4 + and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure–volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, the authors found that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anticancer efficacy of anti-PD1 therapy. Michel et al. conclude that anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent ICI-related cardiotoxicity. This manuscript is accompanied by an Editorial by Carlo Tocchetti from the Federico II University in Naples, Italy and colleagues.17 The authors conclude that while blocking TNFα in heart failure has been proven to be contraindicated in symptomatic (NYHA III and IV) patients, the experimental data provided here by Lars Michel seem to suggest that such an approach may be promising in the presence of subclinical cardiac involvement, aiming at limiting derangements in cardiac immunity, and hence preventing overt cardiac adverse events. Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). In a Clinical Research article entitled ‘Longitudinal strain is an independent predictor of survival and response to therapy in patients with systemic AL amyloidosis’, Oliver Cohen from the University College London in the UK, and colleagues sought to evaluate the utility of LS% in a prospectively observed series of patients.18 A total of 915 consecutive newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included; 69% had cardiac involvement. The LS% worsened with advancing cardiac stage, with mean −21.1, −17.1, −12.9, and −12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤ −16.2%, 80 months; −16.1% to −12.2%, 36 months; −12.1% to −9.1%, 22 months; and ≥ −9.0%, 5 months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response. Strain improvement was associated with improved OS (P = 0.007). Patients achieving an LS% improvement and a standard N-terminal probrain natriuretic peptide-based cardiac response survived longer than those achieving a biomarker-based cardiac response alone (P < 0.0001). The authors conclude that baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy, respectively, in cardiac AL amyloidosis. The contribution is accompanied by an Editorial by Claudio Rapezzi from the University of Ferrara in Italy, and colleagues.19 The authors conclude that the growing body of evidence about LS in cardiac amyloidosis is transforming a simple echocardiographic functional parameter into a multipurpose biomarker, useful for diagnosis, risk stratification, and decision-making in patients with AL cardiac amyloidosis. The study by Cohen et al. represents a relevant step during this journey. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Iron therapy on quality of life in acute heart failure: alternative approaches’, Konrad Teodor Sawicki and Hossein Ardehali from Northwestern University in Chicago, IL, USA comment on the recent publication ‘The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study’ by Ewa A. Jankowska from Wrocław Medical University in Poland.20,21 Jankowska et al. respond in a separate comment.22 Cumulative incidence function plot for atrial fibrillation in breast cancer patients compared with matched non-cancer patients. The start of follow-up is at breast cancer diagnosis or pseudo-diagnosis date for the non-cancer cohort. Partial forest plot showing risk factor analysis of atrial fibrillation after breast cancer diagnosis. Partial forest plot showing fully adjusted model for all-cause, cardiovascular, and breast cancer-specific mortality in those after new-onset atrial fibrillation after breast cancer diagnosis as well as those with atrial fibrillation prior to breast cancer diagnosis. AF, atrial fibrillation; HR, hazard ratios; ref, reference; AJCC, American Joint Committee on Cancer. The editors hope that readers of this issue of the European Heart Journal will find it of interest.