Immune checkpoint inhibitors (ICIs) have significantly impacted treatment options for a wide range of cancers given their efficacy, especially among cancer types that are considered immunologically “hot.” With this broad benefit across many tumor types, researchers continue to look for ways to further improve outcomes with immunotherapy and reduce immune checkpoint inhibitor–related adverse events for better quality of life for patients.
Immune checkpoint inhibitor–related myocarditis is a rare but potentially life-threatening adverse event that typically develops within the first 3 months of treatment but can be challenging to diagnose. Additionally, some patients may develop this type of myocarditis with concomitant immune-related myopathy, which can lead to mortality in more than 50% of patients.1
Two studies published recently in the journal JACC: CardioOncology further explore the characteristics of patients with immune-related myocarditis, with or without myopathy, from immune checkpoint inhibitor therapy to potentially help guide future management strategies for these patients.2,3
Left Ventricular Systolic Dysfunction in ICI-Related Myocarditis
Yen-Chou Chen, MD, MBA, PhD Candidate, of the Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan, and colleagues conducted a study to identify clinical predictors of initial left ventricular systolic dysfunction in patients with immune checkpoint inhibitor–related myocarditis and the prognostic impact of reduced function on overall mortality. They collected data from the International ICI-Myocarditis Registry totaling 707 patients with at least one left ventricular ejection fraction measurement. Reduced left ventricular systolic dysfunction was defined as left ventricular ejection fraction below 50%, in accordance with the 2022 European Society of Cardiology Cardio-Oncology Guidelines.4
Of these patients, 34.5% presented with a left ventricular ejection fraction below 50% (median, 35%). These patients were typically younger (67 vs 71 years; P < .001) and had a lower median body mass index (24.7 kg/m2 vs 26.1 kg/m2; P = .001); many had lung cancer (32.4% vs 19.9%; P < .001), preexisting comorbidities, a longer interval from the start of immune checkpoint inhibition to myocarditis presentation (median, 50 vs 36 days; P < .001), and were more likely to reside in Asia (10.7% vs 6.3%; P = .038) than patients with higher left ventricular ejection fraction. Additionally, these patients were more likely to present with dyspnea and chest pain as well as higher natriuretic peptide levels than those with higher left ventricular ejection fraction levels. They were also more likely to have received prior chest irradiation than those with higher left ventricular ejection fraction levels (24.2% vs 13.5%; P < .001).
In contrast, patients with a left ventricular ejection fraction above 50% were more likely to show symptoms of myositis (38% vs 25%; P = .001) and ocular conditions (18.4% vs 11.1%; P = .016) as well as higher normalized initial creatine kinase levels (median, 5.0 U/L vs 1.2 U/L; P < .001). These patients were also more likely than those with lower levels to have received combination immunotherapy (26.2% vs 18.0%; P = .014).
“Our study demonstrates that dyspnea, a longer interval from immune checkpoint inhibitor initiation to myocarditis onset, and preexisting cardiac and oncologic conditions...may predict reduced left ventricular ejection fraction at admission in patients with immune checkpoint inhibitor–related myocarditis.”— YEN-CHOU CHEN, MD, AND COLLEAGUES
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“Our study demonstrates that dyspnea, a longer interval from immune checkpoint inhibitor initiation to myocarditis onset, and preexisting cardiac and oncologic conditions—such as a history of heart failure and prior exposure to cardiotoxic therapies, including BRAF/MEK inhibitors—may predict reduced left ventricular ejection fraction at admission in patients with immune checkpoint inhibitor–related myocarditis,” the study authors concluded.
Definite or probable myocarditis was more common among patients with left ventricular ejection fraction below 50% than in those with levels above 50% (91.8% vs 70.6%; P < .001). However, concurrent myositis or a myasthenia gravis–like syndrome was found to be more common among patients with left ventricular ejection fraction levels above 50% (P < .001).
Patients with reduced left ventricular ejection fraction were more likely to require use of vasopressors, inotropes, or mechanical circulatory support (29.2% vs 11.5%; P < .001). During hospitalization, these patients also showed higher rates of respiratory failure (29.3% vs 7.8%; P = .006), sepsis (16.4% vs 7.8%; P = .001), and ventricular tachyarrhythmia (19.3% vs 10.8%; P = .003).
No significant difference was observed in 30-day all-cause mortality rates between the two groups of patients (19.7% vs 14.4%; log-rank P = .062). Adjusted analysis did show a greater risk for 30-day all-cause mortality (adjusted hazard ratio [HR] = 1.50; 95% confidence interval [CI] = 1.02–2.20; P = .040) as well as for death from myocarditis (adjusted HR = 2.36; 95% CI = 1.42–3.91; P = .001) for patients with a reduced left ventricular ejection fraction.
Concomitant ICI-Related Myocarditis and Myopathy
Researchers from Brigham and Women’s Hospital in Boston conducted a retrospective cohort study of 101 patients with immune-related myocarditis, 32 of whom (31.7%) also had immune-related myopathy, following treatment with at least one immune checkpoint inhibitor between 2015 and 2023.
Osnat Itzhaki Ben Zadok, MD, MSc, Clinical Fellow in Cardio-Oncology, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, and colleagues defined immune checkpoint inhibitor–related myocarditis according to the 2022 International Cardio-Oncology Society consensus criteria.5 Immune-related myopathy was defined by the 2021 consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors and included both inflammatory myositis and immune-mediated necrotizing myopathy.6
The study investigators analyzed patients’ clinical, laboratory, and imaging characteristics. They then compared cardiovascular outcomes, looking at the cumulative incidence of cardiovascular adverse events as the primary endpoint as well as the all-cause and cardiovascular mortality rates during the index admission and at 1 year.
Among all patients, those with concomitant immune checkpoint inhibitor–related myocarditis and myopathy tended to be older than those with isolated myocarditis (79 vs 72 years; P < .001). The most common underlying cancers were malignant melanoma in 30.7% and lung cancer in 26.7%; a total of 24.8% of patients received combination immune checkpoint inhibitor therapy.
“Specific and nonoverlapping biomarkers are needed to monitor and guide therapy for immune-related myocarditis in the presence of myopathy.”— OSNAT ITZHAKI BEN ZADOK, MD, MSc, AND COLLEAGUES
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At admission, among patients with concomitant immune-related myocarditis and myopathy, 71.9% had oculomotor weakness with concomitant immune-related myocarditis and myopathy, 50% had proximal limb girdle weakness, and 34.4% had dysphagia. The majority of patients (58.1%) were classified with myopathy severity grade of at least 2.
At presentation, patients with concomitant immune checkpoint inhibitor–related myocarditis and myopathy had higher high-sensitivity troponin T levels than those with isolated myocarditis (median, 716 ng/L vs 75 ng/L; P < .001) as well as higher creatine kinase levels (median, 3,441 U/L vs 232 U/L; P < .001). Hepatocellular enzyme levels were also higher in patients with concomitant immune-related myocarditis and myopathy (P < .001). These patients were twice as likely to experience clinically significant arrhythmia than were those with myocarditis alone (HR = 2.12; 95% CI = 1.13–3.97; P = .019).
In contrast, in patients with isolated immune checkpoint inhibitor–related myocarditis, there was evidence of higher N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels than in patients with concomitant myocarditis and myopathy (median, 2,043 pg/mL vs 606 pg/mL; P = .007) and higher alkaline phosphatase levels (median, 98 U/L vs 72 U/L; P = .001).
Left ventricular systolic function, assessed by left ventricular ejection fraction, was lower in patients with isolated immune checkpoint inhibitor–related myocarditis (56% vs 65%; P = .008). These patients were more likely to experience acute decompensated heart failure (HR = 5.88; 95% CI = 1.45–25; P = .013).
No statistically significant differences between the two groups were reported in terms of the rate of cardiovascular deaths (HR = 1.01; 95% CI = 0.23–4.49; P = .99) or all-cause deaths (HR = 0.88; 95% CI = 0.33–2.32; P = .79) during admission. The most common cause of death in the index admission period was cardiogenic shock or pulmonary edema.
During follow-up, median left ventricular ejection fractions were again lower in patients with isolated immune checkpoint inhibitor–related myocarditis (55% vs 64%; P = .035). Moreover, there were no statistically significant differences between the two groups of patients in terms of 1-year cardiovascular readmissions (HR = 0.79; 95% CI = 0.29–2.18; P = 0.65), 1-year cardiovascular mortality (HR = 0.80; 95% CI = 0.21–3.04; P = 0.75), or 1-year all-cause death rates (HR = 0.87; 95% CI = 0.49–1.57; P = 0.65).
The study authors suggested that regarding differences in phenotype between the two groups of patients, “patients with concomitant myocarditis and myopathy may be at increased risk for significant arrhythmias despite preserved left ventricular function. These findings suggest that patients should be monitored with telemetry in the hospital and potentially after discharge. In contrast, patients with isolated myocarditis may warrant close monitoring for volume overload and serial echocardiographic surveillance to enable prompt initiation of heart failure medications.”
“Currently available biomarkers, such as troponin T, do not allow one to distinguish between steroid-refractory immune-related myocarditis and concomitant immune-related myocarditis and immune-related myopathy. Specific and nonoverlapping biomarkers are needed to monitor and guide therapy for immune-related myocarditis in the presence of myopathy,” the study authors concluded.
DISCLOSURE: Dr Chen reported no conflicts of interest. Dr. Itzhaki Ben Zadok has received advisory board honoraria from Pfizer. For full disclosures of the other study authors, visit jacc.org.
REFERENCES
- Anquetil C, Salem JE, Lebrun-Vignes B, et al: Immune checkpoint inhibitor–associated myositis: Expanding the spectrum of cardiac complications of the immunotherapy revolution. Circulation 138:743-745, 2018.
- Itzhaki Ben Zadok O, O’Hare MJ, Nohria A: Immune checkpoint inhibitor–related myocarditis with or without concomitant myopathy: Clinical findings and cardiovascular outcomes. JACC CardioOncol 7:252-264, 2025.
- Chen YC, Dolladille C, Rao A, et al: Immune checkpoint inhibitor myocarditis and left ventricular systolic dysfunction. JACC CardioOncol 7:234-248, 2025.
- Lyon AR, López-Fernández T, Couch LS, et al: 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J Cardiovasc Imaging 23:e333-e465, 2022.
- Herrmann J, Lenihan D, Armenian S, et al: Defining cardiovascular toxicities of cancer therapies: An International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J 43:280-299, 2022.
- Guidon AC, Burton LB, Chwalisz BK, et al: Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors. J Immunother Cancer 9:e002890, 2021
