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. 2025 Apr;7(3):234-248.
doi: 10.1016/j.jaccao.2025.01.020.

Immune Checkpoint Inhibitor Myocarditis and Left Ventricular Systolic Dysfunction

Yen-Chou Chen  1 , Charles Dolladille  2 , Anjali Rao  3 , Nicolas L Palaskas  4 , Anita Deswal  4 , Lorenz Lehmann  5 , Jennifer Cautela  6 , Pierre-Yves Courand  7 , Salim Hayek  8 , Han Zhu  9 , Richard K Cheng  10 , Joachim Alexandre  11 , Lauren A Baldassarre  12 , François Roubille  13 , Michal Laufer-Perl  14 , Aarti Asnani  15 , Stephane Ederhy  16 , Yuichi Tamura  17 , Sanjeev Francis  18 , Elizabeth M Gaughan  19 , Douglas B Johnson  20 , Danette L Flint  21 , Peter P Rainer  22 , Guillaume Bailly  23 , Steven M Ewer  24 , Mandar A Aras  25 , Dimitri Arangalage  26 , Eve Cariou  27 , Roberta Florido  28 , Giovanni Peretto  29 , Osnat Itzhaki Ben Zadok  30 , Nausheen Akhter  31 , Anna Narezkina  32 , Joshua E Levenson  33 , Yan Liu  34 , Shanthini M Crusz  35 , Nahema Issa  36 , Nicolas Piriou  37 , Darryl Leong  38 , Shahneen Sandhu  39 , Isik Turker  40 , Pedro Moliner  41 , Michel Obeid  42 , Lucie Heinzerling  43 , Wei-Ting Chang  44 , Andrew Stewart  45 , Vishnu Venkatesh  45 , Zoe Du  46 , Anirudh Yadavalli  46 , Dohyeong Kim  46 , Alvin Chandra  45 , Kathleen W Zhang  45 , John R Power  47 , Javid Moslehi  25 , Joe-Elie Salem  48 , Vlad G Zaha  49 ; International ICI Myocarditis Registry
Affiliations

Immune Checkpoint Inhibitor Myocarditis and Left Ventricular Systolic Dysfunction

Yen-Chou Chen et al. JACC CardioOncol. 2025 Apr.

Abstract

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but ICI myocarditis (ICI-M) remains a potentially fatal complication. The clinical implications and predictors of left ventricular ejection fraction (LVEF) <50% in ICI-M are not well understood.

Objectives: The aim of this study was to identify factors associated with LVEF <50% vs ≥50% at the time of hospitalization for ICI-M. A secondary objective was to evaluate the relationship between LVEF and 30-day all-cause mortality.

Methods: The International ICI-Myocarditis Registry, a retrospective, international, multicenter database, included 757 patients hospitalized with ICI-M. Patients were stratified by LVEF as reduced LVEF (<50%) or preserved LVEF (≥50%) on admission. Cox proportional hazards models were used to assess the associations between LVEF and clinical events, and multivariable logistic regression was conducted to examine factors linked to LVEF.

Results: Of 757 patients, 707 had documented LVEFs on admission: 244 (35%) with LVEF <50% and 463 (65%) with LVEF ≥50%. Compared with patients with LVEF ≥50%, those with LVEF <50% were younger (<70 years), had a body mass index of <25 kg/m2, and were more likely to have received chest radiation (24.2% vs 13.5%; P < 0.001). Multivariable analysis identified predictors of LVEF <50%, including exposure to v-raf murine sarcoma viral oncogene homolog B1/mitogen-activated protein kinase inhibitors, pre-existing heart failure, dyspnea at presentation, and at least 40 days from ICI initiation to ICI-M onset. Conversely, myositis symptoms were associated with LVEF ≥50%. LVEF <50% was marginally associated with 30-day all-cause mortality (unadjusted log-rank P = 0.062; adjusted for age, cancer types, and ICI therapy, HR: 1.50; 95% CI: 1.02-2.20).

Conclusions: Dyspnea, time from ICI initiation, a history of heart failure, and prior cardiotoxic therapy may be predictors of an initial LVEF <50% in patients with ICI-M.

Keywords: cardiac magnetic resonance; echocardiography; heart failure; immune checkpoint inhibitor myocarditis; immunotherapy; left ventricular ejection fraction; myocarditis; troponin.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Palaskas is supported by Cancer Prevention and Research Institute of Texas grant RP200670, National Cancer Institute grant 1P01CA261669-01, and the Andrew Sabin Family Foundation; and is a consultant for Replimune and Kiniksa Pharmaceuticals. Dr Deswal is supported in part by the Ting Tsung and Wei Fong Cho Distinguished Chair; and is a consultant to Bayer. Dr Cautela has served as consultant for Janssen, AstraZeneca, Bristol Myers Squibb, and Novartis; and has received grants from Bristol Myers Squibb and Novartis. Dr Zhu has received funding from the National Heart, Lung, and Blood Institute (grant K08-HL153798). Dr Laufer-Perl has served on advisory boards for BI, AstraZeneca, and Bayer; has served as a consultant for Alleviant, AbbVie, and Unipharm; has received research grants from Novartis, BI, AstraZeneca, Pfizer, and Bayer; and has served as a lecturer for BI, AstraZeneca, Bayer, Alleviant, AbbVie, Unipharm, Novartis, Pfizer, Medison, and Novo Nordisk. Dr Gaughan has received research support to her institution from Bristol Myers Squibb, Merck Sharpe & Dohme, Regeneron Pharmaceuticals, and Iovance Biotherapeutics; has been reimbursed for travel expenses by Regeneron Pharmaceuticals and Iovance Biotherapeutics; and has received funding from University of Virginia Cancer Center Support Grant P30CA044579. Dr Johnson has received funding from National Heart, Lung, and Blood Institute grant R01HL155990; has served on advisory boards or consulted for AstraZeneca, Bristol Myers Squibb, Merck, Mosaic, Novartis, Pfizer, and Teiko; and has patents for the use of major histocompatibility complex II as a biomarker for immunotherapy response and abatacept for the treatment of immune-related adverse events. Dr Rainer has received consulting fees and travel support from Novartis, Boehringer Ingelheim, Pfizer, Abbott, Bayer, and AstraZeneca; and has received research funding from the Austrian Science Fund and European Research Area Network ERA-CVD grant AIR-MI (I 4168). Dr Aras has served as a consultant for Bristol Myers Squibb. Dr Arangalage has served as a consultant for Sanofi; and has received speaker fees from Bristol Myers Squibb and Ipsen. Dr Narezkina is a consultant for Pharmacyclics and Janssen; and has conducted clinical trial enrollment for HeartFlow and Ionis. Dr Moliner has received speaker or advisory fees from Eisai, Bayer, Bristol Myers Squibb, Novartis, Vifor, Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Janssen (not related to this work); and has received research funding to his institution from Daiichi-Sankyo. Dr Moslehi is supported by National Institutes of Health grants R01HL141466, R01HL155990, R01HL156021, R01HL160688, and R01HL170038; has served in consulting and advisory roles for Bristol Myers Squibb, Deciphera, Takeda, AstraZeneca, Regeneron, Kiniksa Pharmaceuticals, Daiichi-Sankyo, BeiGene, IQVIA, AskBio, Bitterroot Bio, Repare Therapeutics, and Cytokinetics; and is a coinventor of a patent related to the use of abatacept in the treatment of ICI myocarditis. Dr Salem has served as consultant for Bristol Myers Squibb, AstraZeneca, BeiGene, Ipsen, Eisai, Banook, and Novartis; and has received grants from Bristol Myers Squibb and Novartis. Dr Zaha has received funding from the Cancer Prevention and Research Institute of Texas (RP180404). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Cohort Selection and Myocarditis Definition for the International ICI-Myocarditis Registry (A) Cohort selection for immune checkpoint inhibitor myocarditis study cohort. (B) Intersection of diagnostic features (upset plot). Bar heights indicate the number of patients meeting each specific diagnostic criterion. CK = creatine kinase; ECG = electrocardiography; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging.
Figure 2
Figure 2
Factors Associated With Initial LVEF in ICI Myocarditis ORs with 95% CIs were calculated to assess factors associated with an initial left ventricular ejection fraction (LVEF) <50% vs LVEF ≥50%, measured on echocardiography or cardiac magnetic resonance imaging at admission for immune checkpoint inhibitor (ICI) myocarditis. Univariable and multivariable logistic regression models were conducted. Variables with univariable P ≤ 0.05 were included in the multivariable models. (A) Model including variables with univariable P ≤ 0.05. (B) Model using backward selection with a threshold of P ≤ 0.05. Light gray lines represent associations from univariable logistic regression models. In the multivariable models, red lines indicate significant associations with LVEF <50%, green lines indicate significant associations with LVEF ≥50%, and blue lines indicate no association with LVEF. The reference region is North America. History of v-raf murine sarcoma viral oncogene homolog B1/mitogen-activated protein kinase inhibitors refers to prior or concurrent use of therapies with ICI.
Central Illustration
Central Illustration
Left Ventricular Dysfunction in ICI Myocarditis Previous cardiac conditions, such as history of heart failure or coronary artery disease and exposure to cardiotoxic therapy, including prior chest radiation therapy or v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/mitogen-activated protein kinase (MEK) inhibitors, are associated with left ventricular ejection fraction (LVEF) <50% on admission in immune checkpoint inhibitor (ICI) myocarditis. After adjusting for age, cancer types, and ICI therapy, LVEF <50% was marginally associated with 30-day all-cause mortality. Peripheral symptoms of myositis are associated with preserved LVEF on admission. LVEF on admission may reflect both pre-existing medical history and the severity of myocarditis, so should be interpreted with caution.
Figure 3
Figure 3
Thirty-Day All-Cause Mortality From Immune Checkpoint Inhibitor Myocarditis by Initial LVEF Kaplan-Meier curve showing 30-day survival probability, stratified by initial left ventricular ejection fraction (LVEF) <50% and LVEF ≥50%, measured using echocardiography or cardiac magnetic resonance imaging at admission, whichever was performed first. The green line represents LVEF <50%, and the red line represents LVEF ≥50%. Dashed lines indicate unadjusted survival probabilities, and solid lines represent survival probabilities after adjusting for age, cancer types, and immune checkpoint inhibitor therapy.
Figure 4
Figure 4
Cubic Spline Curve of the Association Between LVEF and 30-Day All-Cause Mortality Hazard The association between left ventricular ejection fraction (LVEF) and 30-day mortality was evaluated using a Cox proportional hazards model with a natural cubic spline (3 degrees of freedom, 2 knots). The red line represents the HR, and the shaded area indicates the 95% CI. The HR decreases as LVEF increases from approximately 30% to 50%.
Figure 5
Figure 5
30-Day Cause-Specific Mortality From ICI Myocarditis by Initial LVEF Cumulative incidence of 30-day cause-specific mortality, accounting for all-cause mortality as a competing risk, stratified by initial LVEF <50% and LVEF ≥50% for cause-specific deaths: myocarditis, myositis or myasthenia gravis–like syndrome, cancer, and sepsis. The green line represents LVEF <50%, and the red line represents LVEF ≥50%. Dashed lines indicate unadjusted cumulative incidence, and solid lines represent cumulative incidence after adjusting for age, cancer types, and ICI therapy. BRAF = v-raf murine sarcoma viral oncogene homolog B1; COPD = chronic obstructive pulmonary disease; MEK = mitogen-activated protein kinase; other abbreviations as in Figures 1 and 2.
See this image and copyright information in PMC

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