Cardiotoxicity Associated with Immune Checkpoint Inhibitors

This article addresses cardiotoxicity associated with immune checkpoint inhibitors (ICIs), a class of monoclonal antibodies targeting PD-1, PD-L1, and CTLA-4 that have transformed outcomes in multiple cancers. Although cardiotoxicity is relatively infrequent (generally <1%), it can be severe, with myocarditis being among the most serious manifestations. The piece outlines timing of onset across cardiotoxic phenotypes, potential immunologic mechanisms, diagnostic approaches, management considerations, and implications for special populations such as the elderly. It also discusses onco-hypertension, the relationship between ICIs and blood pressure, and long-term cardiovascular risks including atherosclerosis in ICI-treated patients.

Prior systematic reviews indicate that timing and phenotype of ICI-related cardiotoxicity vary by cancer type, ICI regimen, and toxicity subtype, with median onset typically 1–31 weeks after initiation but rare cases occurring as late as 2 years (Shalata et al.). Reported cardiotoxic events include myocarditis, arrhythmias, conduction disease, pericardial disease, and takotsubo cardiomyopathy. Mechanistic insights point to CD4+ T cell–mediated inflammation with cytokines such as TNF-α, granzyme B, and IFN-γ, and a protective role of the PD-1/PD-L1 axis against cardiac autoimmunity, with CTLA-4 being less central. Comparative transcriptomics implicate interferon-γ pathways and inflammasome-regulated proteins (e.g., GBP5) in myocarditis pathophysiology. Real-world data suggest ICI therapy is generally well tolerated in elderly patients with cardiotoxicity rates comparable to the broader population. The onco-hypertension framework emphasizes monitoring and management of blood pressure in cancer patients, including those receiving ICIs. Emerging work proposes PCSK9 as a therapeutic target to mitigate atherosclerotic risk in ICI-treated patients.

The article is a narrative review that synthesizes existing evidence. It also summarizes a previously conducted systematic literature review and meta-analysis assessing hypertension risk at ICI initiation across randomized controlled trials: databases were searched for RCTs; hypertension severity was graded (e.g., grades I–V and III–V) per prespecified criteria; odds ratios for hypertension grades were pooled via meta-analysis. The meta-analysis encompassed 32 RCTs with 19,810 patients and a median follow-up of 36 months. Diagnostic modalities for ICI-related myocarditis discussed include laboratory biomarkers (BNP/NT-proBNP, CRP, hepcidin, troponin, CK-MB), endomyocardial biopsy (invasive, selective use), cardiac magnetic resonance imaging as the gold standard, and PET/CT when CMR is unavailable. Management principles summarized include identification and grading of cardiotoxicity, decisions to withhold ICI therapy, initiation of corticosteroids and other immunosuppression, institution of guideline-directed cardiac care, and consideration of ICI rechallenge.

• Cardiotoxicity from ICIs is uncommon (<1%) but potentially severe; myocarditis is one of the most serious forms. - Onset timing varies by toxicity type, regimen, and cancer, with median onset typically 1–31 weeks post-initiation; rare cases occur up to 2 years after starting therapy. - Proposed mechanisms center on CD4+ T cell–mediated inflammation and the protective role of the PD-1/PD-L1 pathway against myocardial autoimmunity; interferon-γ and inflammasome-related proteins (e.g., GBP5) may contribute to myocarditis. - Biomarkers (BNP/NT-proBNP, CRP, hepcidin, troponin, CK-MB) are often elevated but lack specificity; cardiac MRI is the imaging gold standard; PET/CT is an alternative; biopsy can confirm but is invasive. - Elderly patients appear to tolerate ICIs with cardiotoxicity rates similar to the general population. - A meta-analysis of 32 RCTs (n=19,810) found no significant association between ICI initiation and short-term hypertension risk for grades I–V or III–V; median follow-up was 36 months, and median overall survival in the ICI group was 15 months. - Despite short-term hypertension risk not being elevated, ICI-treated patients may face increased long-term risk of atherosclerosis and cardiometabolic disease; PCSK9 inhibition is proposed as a potential strategy to reduce cardiovascular events in this context. - Management requires early recognition, risk stratification, immunosuppression (e.g., steroids), standard cardiac therapy, and careful consideration of ICI rechallenge.

The synthesis underscores that while the absolute incidence of ICI-related cardiotoxicity is low, its severity necessitates vigilant monitoring, timely diagnosis, and multidisciplinary management. Understanding the variable timing and spectrum of cardiotoxic phenotypes informs surveillance strategies, especially early after therapy initiation but extending long term. Mechanistic insights into PD-1/PD-L1-mediated cardioprotection and inflammatory pathways provide biological plausibility for observed toxicities and suggest avenues for biomarker development and targeted interventions. The lack of increased short-term hypertension risk at ICI initiation supports continued ICI use without additional BP-related contraindications, while the potential for accelerated atherosclerosis highlights the need for aggressive cardiovascular risk assessment and consideration of lipid-lowering strategies such as PCSK9 inhibition. Real-world evidence that elderly patients experience similar cardiotoxicity rates supports ICI use in this population with appropriate monitoring.

ICIs revolutionize cancer therapy but can cause serious, albeit infrequent, cardiotoxicities, notably myocarditis, arrhythmias, and pericardial disease, with variable timing. Cardiac MRI remains central to diagnosis; biomarkers aid detection but are nonspecific. Management hinges on early recognition, immunosuppression, and guideline-directed cardiac care, with individualized decisions about ICI rechallenge. Short-term hypertension risk does not appear to increase with ICI initiation; however, long-term atherosclerotic risk may be elevated, for which PCSK9 inhibition is an emerging consideration. Ongoing basic and clinical research is needed to clarify mechanisms, improve risk prediction, refine diagnostic algorithms, and test preventive and therapeutic strategies for ICI-associated cardiovascular disease.

As a narrative synthesis, conclusions are limited by heterogeneity among studies, potential publication and selection biases, and the absence of uniform diagnostic criteria across reports. Biomarkers for myocarditis lack specificity; endomyocardial biopsy is invasive and not routinely performed. Data on long-term cardiovascular outcomes after ICI therapy remain limited, and real-world evidence, especially for late-onset events, is still evolving.