Aims Cardiac biomarkers are a mainstay in diagnosis of cardiovascular disease but their role in cardio‐oncology has not yet been systematically evaluated. This meta‐analysis aims to determine whether cardiac troponins and (N‐terminal pro) brain natriuretic peptide (BNP/NT‐proBNP) predict cancer therapy‐related left ventricular (LV) dysfunction. Methods and results Scientific databases were searched for studies that assessed troponins or BNP/NT‐proBNP in adult patients undergoing cancer therapy. Data from 61 trials with 5691 patients were included. Cancer therapy was associated with an increase in troponin levels [odds ratio (OR) 14.3, 95% confidence interval (CI) 6.0–34.1; n = 3049]. Patients with elevated troponins receiving chemotherapy or human epidermal growth factor receptor 2 inhibitor therapy were at higher risk for LV dysfunction (OR 11.9, 95% CI 4.4–32.1; n = 2163). Troponin had a negative predictive value of 93%. Mean BNP/NT‐proBNP levels were increased in patients post‐treatment (standardized mean difference 0.6, 95% CI 0.3–0.9; n = 912), but the available evidence did not consistently indicate prediction of LV dysfunction (OR 1.7, 95% CI 0.7–4.2; n = 197). β‐blocker and angiotensin‐converting enzyme inhibitor therapy to mitigate cardiotoxicity during cancer therapy was associated with a decline in serum troponins (OR 4.1, 95% CI 1.7–9.8; n = 466). Conclusion Elevated troponin levels predict LV dysfunction in patients receiving cancer therapy. Assessment of troponin levels may qualify as a screening test to identify patients who require referral to cardio‐oncology units and benefit from preventive strategies. Further evidence is required for both biomarkers.

Key Points Question What is the rate of cardiovascular adverse events among patients with melanoma treated with BRAF and MEK inhibitors compared with patients treated with BRAF inhibitor monotherapy? Findings In this systematic review and meta-analysis of 5 randomized clinical trials including 2317 patients, treatment with BRAF and MEK inhibitors was associated with a higher risk of pulmonary embolism, decrease in left ventricular ejection fraction, and arterial hypertension compared with treatment with BRAF inhibitor monotherapy. The risks of myocardial infarction, atrial fibrillation, and QTc prolongation were similar between groups. Meaning These findings demonstrate an association of cardiovascular adverse events with BRAF and MEK inhibitor therapy, which may guide clinical cardio-oncological management.

Aims Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease. Methods and results We 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-crosstalk. Using a novel melanoma mouse model, we 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, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. Conclusions 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 the manifestation of ICI-related cardiotoxicity.

Cardioprotection by salvage of the infarct-affected myocardium is an unmet yet highly desired therapeutic goal. To develop new dedicated therapies, experimental myocardial ischemia/reperfusion (I/R) injury would require methods to simultaneously characterize extent and localization of the damage and the ensuing inflammatory responses in whole hearts over time. Here we present a three-dimensional (3D), simultaneous quantitative investigation of key I/R injury-components by combining bleaching-augmented solvent-based non-toxic clearing (BALANCE) using ethyl cinnamate (ECi) with light sheet fluorescence microscopy. This allows structural analyses of fluorescence-labeled I/R hearts with exceptional detail. We discover and 3D-quantify distinguishable acute and late vascular I/R damage zones. These contain highly localized and spatially structured neutrophil infiltrates that are modulated upon cardiac healing. Our model demonstrates that these characteristic I/R injury patterns can detect the extent of damage even days after the ischemic index event hence allowing the investigation of long-term recovery and remodeling processes.

Immune checkpoint inhibitor (ICI) therapy has greatly improved treatment of various advanced cancers but increasing use of ICI therapy has exposed the risk of ICI-related cardiovascular side effects.Immune checkpoints are inhibitory regulators of T cell activation and mediate T cell effector functions during physiological responses to shield from autoimmune reactions. ICI therapy for advanced cancers promotes immune activity against tumors and is applied within a broad collective of cancer patients. Widespread use of ICI therapy has revealed the burden of immune related adverse events with various organ manifestations and characteristics. Since immune checkpoints are highly relevant for maintaining myocardial homeostasis as emerging evidence implicates, inhibition of immune checkpoint pathways has been associated with various forms of cardiotoxicity in preclinical models and patients. Although ICI-related cardiotoxicity is rare, it has significant relevance due to high mortality rates.This review focuses on current knowledge about cardiac ICI-related toxicity. We summarize the most common forms and delineate incidence, presentation, and treatment. Clinical characteristics are correlated to potential underlying pathomechanisms. We outline epidemiology, risk factors, and course of disease. Recommendations for monitoring and critical diagnostic measures are specified within the context of different forms of cardiac involvement. Different therapeutic implications for suspected ICI-related cardiotoxicity and their limitations are critically summarized.We highlight current gaps of knowledge concerning the underlying pathomechanisms and clinical characteristics of ICI-related cardiotoxicity. Future challenges are depicted for optimum cardio-oncology care of patients receiving ICI therapy.