Cardiac Toxicities Induced by Immunotherapy: A Brief Review

Abstract

Immunotherapies, particularly immune checkpoint inhibitors (ICIs), have revolutionized the treatment of various malignant tumors by reactivating antitumor immune responses. However, excessive activation of the immune system can trigger immune-mediated adverse events, among which cardiac toxicities are included. Although rare, these complications which encompass myocarditis, pericarditis, arrhythmias, and heart failure carry high morbidity and mortality when not diagnosed and managed promptly. Immune-mediated myocarditis, though reported in less than 1% of patients treated with ICIs, has a mortality rate exceeding 50% in severe cases, underscoring the need for continuous monitoring and multidisciplinary management protocols. Various biomolecular and imaging markers have been evaluated for early diagnosis, including B-type natriuretic peptide (BNP), cardiac troponins, and cardiac magnetic resonance imaging with late gadolinium enhancement. Management is based on temporary or permanent discontinuation of immunotherapy combined with high-dose corticosteroids; additional therapies such as azathioprine and intravenous immunoglobulin may be instituted in refractory cases. Protocols for reintroducing ICIs after severe cardiac toxicity remain controversial and require case-by-case assessment. This review critically examines current evidence on the epidemiology, pathophysiology, diagnosis, and management of immunotherapy-related cardiac toxicities, proposing guidelines for early identification and therapeutic strategies aimed at reducing morbidity and mortality associated with these adverse events.

Keywords: Immunotherapy; Cardiotoxicity; Myocarditis; Checkpoint inhibitors; Cardiac safety

Introduction
The advent of immune checkpoint inhibitors (ICIs) has markedly improved outcomes for patients with advanced malignancies, including melanoma, lung cancer, and renal cell carcinoma^1,2. Agents targeting CTLA-4 (ipilimumab) and PD-1/PD-L1 (pembrolizumab, nivolumab, atezolizumab) reinvigorate anergic T lymphocytes, thereby eliciting robust antitumor responses. Despite these significant clinical benefits, disrupting immune tolerance can lead to immune-mediated toxicities across multiple organ systems, known as immune-related adverse events (irAEs). While dermatologic, gastrointestinal, endocrine, and hepatic irAEs are most common, cardiac toxicities, though less frequent, can be rapidly fatal³. Population-based studies estimate ICI-associated myocarditis incidence at under 1%, yet symptomatic cases may exceed a 50% mortality rate without immediate intervention^4,5. Beyond myocarditis, reported manifestations include pericarditis, brady- and tachyarrhythmias, conduction blocks, and heart failure. The underlying pathophysiology involves lymphocytic infiltration of the myocardium, release of proinflammatory cytokines, and direct myocyte injury⁶. Preclinical murine models lacking PD-1 regulation have demonstrated fulminant myocarditis, confirming the critical role of checkpoint pathways in cardiac immune homeostasis^7,8.