Navigating Cardiotoxicity in Immune Checkpoint Inhibitors: From Diagnosis to Long-Term Management

Abstract

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, significantly improving patient outcomes across multiple malignancies. Nonetheless, these therapies are associated with immune-related adverse effects, including cardiotoxicity, which remains a critical concern. This review provides a comprehensive analysis of ICI-related cardiotoxicity, encompassing its pathophysiological mechanisms, risk factors, diagnostic modalities, and management strategies. The onset of cardiotoxicity varies widely, ranging from acute myocarditis to long-term cardiovascular complications. Early identification through clinical assessment, biomarkers, and advanced imaging techniques is crucial for timely intervention. Management strategies include high-dose corticosteroids, other immunosuppressive agents, and supportive therapies, with a focus on balancing oncologic efficacy and cardiovascular safety. Additionally, rechallenging patients with ICIs following cardiotoxic events remains a complex clinical decision requiring multidisciplinary evaluation. As immunotherapy indications expand to include high-risk populations in a curative setting too, optimizing screening, prevention, and treatment strategies is essential to mitigate cardiovascular risks. A deep understanding of the molecular and clinical aspects of ICI-related cardiotoxicity will enhance patient safety and therapeutic decision-making, underscoring the need for ongoing research in this rapidly evolving field.

Keywords: cardiovascular toxicity; diagnosis; immune checkpoint inhibitors; myocarditis; treatment.

Figure 1

Immune checkpoint inhibitors. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals for immune checkpoint inhibitors. * only approved by FDA; ^§ only approved by EMA. NSCLC = non-small cell lung cancer; HCC = hepatocellular carcinoma; MSI-H = microsatellite instability-high; dMMR = mismatch repair deficient; SCLC = small cell lung cancer. Created with BioRender.com.

Figure 2

Immune checkpoint inhibitors’ targets. The figure shows the main targets of immune checkpoint inhibitors available. CTLA4 = cytotoxic T-lymphocyte antigen 4; MHC-TCR = major histocompatibility complex—T-cell receptor; PD-1 = programmed death-1; PD-L1 = programmed death-ligand-1. Created with BioRender.com.

Figure 3

Bonaca’s criteria. The figure reports the criteria for the diagnosis of myocarditis in patients on therapeutics for cancer suggested by Bonaca et al. [67]. CMR = cardiac magnetic resonance; ECG = electrocardiogram; PET = positron emission tomography; WMA = wall motion abnormality.

Figure 4

IC-OS criteria. The diagram shows the criteria for the diagnosis of myocarditis in patients on therapeutics for cancer proposed by the International Cardio-Oncology Society (IC-OS) [69]. * Clinical diagnosis should be confirmed with CMR or endomyocardial biopsy if possible and without causing delays in treatment. CMR = cardiac magnetic resonance; WMA = wall motion abnormalities.

Figure 5

Cardiac magnetic resonance of an ICI-related acute myocarditis. The figure shows myocardial involvement. In particular, the short tau inversion recovery (STIR) image (A) reveals mesocardial hyperintensity in the basal inferior and inferolateral walls. Correspondingly, late gadolinium enhancement (LGE) images in the short-axis (B) and 2-chamber (C) views demonstrate subepicardial involvement of the same regions. Additionally, patchy subepicardial enhancement is observed in the mid-ventricular and apical anterior wall, as well as the mid-ventricular inferior wall. The radiological findings are consistent with myocarditis. ICI = immune checkpoint inhibitor.

Figure 6

Diagnostic-therapeutic algorithm for immune checkpoint inhibitor-related myocarditis. The algorithm integrates the indications for the diagnosis and treatment of immune checkpoint inhibitors-related myocarditis suggested by the European Society of Cardiology (ESC) and the European Society of Medical Oncology (ESMO). * including T1 and T2 mapping, T2-weighted short tau inversion recovery (STIR), and late gadolinium enhancement. ^§ using either [18F]-fluorodeoxyglucose (18FDG) or [68Ga]-DOTAT-octreotide. ^# hemodynamic instability includes acute decompensated heart failure, cardiogenic shock, non-invasive or invasive ventilation, complete heart block, and/or ventricular arrhythmia. CMR = cardiac magnetic resonance; CT = computed tomography; CV = cardiovascular; ECG = electrocardiogram; ECMO = extracorporeal membrane oxygenation; EMB = endomyocardial biopsy; HF = heart failure; ICI = immune checkpoint inhibitor; ICU = intensive care unit; IV = intravenous; LVAD = left ventricular assist device; PET = positron emission tomography.