The Dyspnea Dilemma: Immune Checkpoint Inhibitor–Associated Myocarditis Mimicking Overlapping Cardiac Pathologies—A Case Report

Abstract

Background

Immune checkpoint inhibitors (ICIs) such as durvalumab improve survival in solid tumors but can rarely cause fulminant myocarditis (reported in 1% of cases, with 25%–40% mortality). Clinical overlap with coronary artery disease (CAD), chemotherapy‐related cardiomyopathy, or malignancy‐associated complications makes diagnosis challenging.

Case Presentation

A 62‐year‐old woman with gallbladder adenocarcinoma on gemcitabine, cisplatin, and durvalumab presented with 1 week of progressive dyspnea, leg edema, and chest pain. She had a history of portal vein thrombosis on apixaban. On exam, she was tachycardic and hypoxic with signs of volume overload. Labs showed elevated BNP and troponin. EKG revealed lateral T‐wave inversions and chest x‐ray demonstrated pulmonary edema. Echocardiography showed a large fibrinous pericardial effusion without tamponade and reduced LVEF (41%) with apical wall motion abnormalities. Differentials included ischemia, chemotherapy toxicity, ICI myocarditis, or malignant/hemorrhagic effusion. After a multidisciplinary discussion, anticoagulation was held, and the patient was transfused. Serial echocardiography showed a stable effusion but persistent ST‐T changes. Coronary angiography excluded obstructive CAD. Cardiac MRI demonstrated diffuse myocardial edema, most pronounced in apical segments, consistent with myocarditis. Given the temporal relationship to ICI therapy, durvalumab‐associated myocarditis was diagnosed. High‐dose corticosteroids were initiated with symptomatic improvement. She was discharged on gemcitabine–cisplatin, with durvalumab omitted. Anticoagulation was resumed. Discharge echocardiography showed persistent apical wall motion abnormalities with a small effusion.

Conclusion

This case highlights the diagnostic complexity of dyspnea in oncology patients, where multiple cardiac pathologies may coexist. A systematic, multidisciplinary approach—progressing from pericardial evaluation to ischemic work‐up to advanced imaging—was crucial for diagnosis. Clinicians should maintain suspicion for ICI myocarditis when new heart failure or wall motion abnormalities occur without obstructive CAD, as early immunosuppressive therapy is critical.

1. Introduction

Immune checkpoint inhibitor‐induced myocarditis (ICI‐myocarditis) is a rare but potentially fatal immune‐related adverse event occurring in approximately 0.04%–1.14% of patients treated with immune checkpoint inhibitors (ICIs), with mortality rates ranging from 25% to 50% [1, 2]. This complication has emerged as a critical concern in cardio‐oncology since the widespread adoption of ICIs, which include antibodies targeting PD‐1 (programmed cell death protein 1), PD‐L1 (programmed death‐ligand 1), and CTLA‐4 (cytotoxic T‐lymphocyte‐associated antigen 4) [3, 4]. The incidence of ICI‐myocarditis increases substantially with combination ICI therapy, particularly with dual PD‐1 and CTLA‐4 blockade, which carries approximately twice the risk compared to monotherapy [5].

2. Case Presentation

A 62‐year‐old female with medical history of HTN, DM, portal vein thrombosis (On Eliquis), former smoking history (5 pack years), diagnosed with cholangiocarcinoma of gallbladder with ERCP, sphincterotomy, and stent placement 5 months ago, receiving chemotherapy with gemcitabine, cisplatin, and durvalumab (completed eight cycles prior to presentation and was complicated by anemia requiring transfusion) with tentative plans for cholecystectomy, who presented to ED with 1‐day history of worsening dyspnea. She had last received chemotherapy 1 week before presentation. Vitals significant for tachycardia (128 bpm) and hypoxia (92% saturation on 50% FiO₂). Physical exam revealed bilateral crackles. Electrocardiogram was consistent with normal sinus rhythm and T‐wave inversions in leads V3‐6 and II, III, and aVF (Figure 1). Initial labs revealed lactic acidosis (12.6 mEq/L), anemia (hemoglobin 10.1 mg/dl), elevated proBNP (7134 mEq/L), and anion gap metabolic acidosis. High‐sensitivity troponin was elevated to 1138 ng/L and uptrended to 6000 ng/L. She was admitted to CCU for acute hypoxic respiratory failure requiring noninvasive ventilation due to acute decompensated heart failure and started on IV diuresis that improved her lactic acid to 2.6. Transthoracic echocardiogram revealed moderately reduced ejection fraction (41.4%), dilated left atrium, moderate pericardial effusion near the right ventricle without signs of tamponade, and hypokinesis of the apical inferior, apical septal, apical lateral, and apical anterior segments (Figure 2). Therefore, differentials included ischemia, chemotherapy toxicity, ICI myocarditis, or malignant/hemorrhagic effusion. Aspirin and high‐intensity statin were initiated. After a multidisciplinary discussion, anticoagulation was held, and the patient was transfused. Serial echocardiography showed a stable effusion but persistent ST‐T changes. Coronary angiography excluded obstructive CAD. Pericardial effusion was therefore deemed to arise from myocarditis. She was empirically started on pulse‐dose steroids with methylprednisolone 1 g for 3 days. Cardiac MRI revealed akinesis of the true apex as well as the apical anterior, lateral, and septal walls and severe hypokinesis of the midanterior and midanteroseptal walls (Figure 3). On limited T2‐weighted imaging, there is evidence of probable diffuse myocardial edema in the mid to apical segments (Figure 3). The effusion had decreased in size. These findings were suggestive of myocarditis. She was started on GDMT and discharged on peroral steroids with a taper in place as well as Bactrim prophylaxis. On oncology follow‐up outpatient, she completed two more cycles of gemcitabine and cisplatin without any complications. Repeat echocardiography 1 month later showed improvement in EF to 45%.

Figure 1.

Electrocardiogram with nonspecific ST‐T changes (marked in black arrows).

Figure 2.

Echocardiogram with apical four‐chamber view showing mild LV dysfunction with apical hypokinesis (marked by green arrow) and mild pericardial effusion localized around the apex (marked by green arrow).

Figure 3.

Cardiac MRI with subepicardial/midwall late gadolinium enhancement in the lateral and inferolateral LV wall (marked with orange arrows).

3. Discussion

This case represents a classic presentation of durvalumab‐induced myocarditis with acute decompensated heart failure, occurring approximately 1 week after the eighth cycle of combination chemotherapy. This patient developed symptoms 7 days after her last durvalumab dose, which falls within the typical onset window for ICI‐myocarditis, as the median time to onset is 27–34 days after ICI initiation, though cases can occur from days to months after starting therapy [2, 6]. In a case series of durvalumab‐associated myocarditis, the median onset was 42–185 days (median 62 days) after initial ICI exposure [6]. The patient had received eight cycles before presentation, making her cumulative exposure consistent with reported cases.

The patient′s presentation demonstrated several hallmark features of ICI‐myocarditis. The markedly elevated troponin (Initial 1138, Peak 6000) and proBNP (7134) are characteristic, as troponin elevation in ICI‐myocarditis typically shows an evolving plateau pattern rather than the sharp rise‐and‐fall seen in acute coronary syndrome, and peak troponin levels correlate with prognosis [7]. The extreme elevation in this case suggested severe myocardial injury. The T‐wave inversions in V3‐6 and II, III, aVF are nonspecific but consistent with myocardial inflammation. A moderately reduced ejection fraction (41.4%), regional wall motion abnormalities (apical hypokinesis), and moderate pericardial effusion are typical findings; notably, more than 50% of ICI‐myocarditis patients have preserved ejection fraction at presentation yet still carry a significant mortality risk [8]. The presence of reduced LVEF in this case indicated more extensive myocardial involvement.

The cardiac MRI demonstrated akinesis of the true apex and apical segments with severe hypokinesis of midanterior and midanteroseptal walls, along with diffuse myocardial edema on T2‐weighted imaging. These findings are consistent with the modified Lake Louise Criteria for myocarditis, which require evidence of both myocardial injury (T1‐based imaging abnormalities) and myocardial edema (T2 abnormalities) [9, 10]. The apical and septal involvement is particularly noteworthy, as septal late gadolinium enhancement has been identified as a predictor of major adverse cardiovascular events in ICI‐myocarditis [9, 10]. The finding of nonobstructive coronary artery disease helped confirm that the pericardial effusion and myocardial dysfunction were due to myocarditis rather than ischemic injury, though importantly, obstructive CAD can coexist with myocarditis, so the absence of significant stenosis does not exclude the diagnosis but does clarify the primary etiology.

The mechanisms include direct myocardial inflammation and injury, as ICI‐myocarditis results from loss of immune tolerance through PD‐1/PD‐L1 blockade, leading to the expansion of autoreactive CD8+ T cells that infiltrate the myocardium [11]. These T cells, along with inflammatory macrophages (particularly CCR2+ monocyte‐derived macrophages expressing CXCL9 and CXCL10), cause direct myocyte injury and necrosis [11]. The inflammatory cascade involves IFN‐γ signaling and downstream chemokine production, which amplify cardiac damage [11, 12]. The inflammatory infiltrate and myocyte injury lead to reduced contractility and decreased cardiac output, resulting in reduced ejection fraction and regional wall motion abnormalities.

This patient received durvalumab with gemcitabine and cisplatin, and while the literature primarily focuses on dual ICI combinations (PD‐1 + CTLA‐4), combination chemotherapy with ICIs may also increase cardiotoxicity risk. In the PACIFIC trial, durvalumab was associated with 5.5% cardiovascular adverse events compared to 2.5% in placebo, including heart failure, pericardial effusion, and myocardial infarction. Cisplatin induces direct myocardial injury via ROS generation, mitochondrial dysfunction, NF‐κB/NLRP3 inflammasome activation, and cGAS‐STING pathway signaling, causing subclinical cardiomyocyte damage and release of DAMPs (HMGB1, ATP, and mitochondrial DNA) that create a proinflammatory myocardial microenvironment [13]. Simultaneously, cisplatin promotes immunogenic cell death through necroptosis‐dependent RIPK3‐mediated STING activation, upregulating MHC Class I and PD‐L1 expression while enhancing dendritic cell cross‐presentation of cardiac autoantigens such as α‐myosin heavy chain [14]. When checkpoint inhibition removes the PD‐1/PD‐L1 brake, autoreactive CD8+ T cells—driven by TNF‐TNFR2 signaling rather than perforin‐mediated cytotoxicity—mount an unopposed attack on this preinjured myocardium, amplified by M1 macrophage polarization and cytokine cascades [14].

While myocarditis with durvalumab monotherapy is rare (0.06%–1%), it carries high mortality when it occurs [15]. The synergistic effects of chemotherapy‐induced inflammation and ICI‐mediated immune activation could have contributed to this patient′s severe presentation.

Treatment with high‐dose methylprednisolone (1 g daily for 3 days) followed by an oral prednisone taper is usually the mainstay of treatment with discontinuation of the ICI [16].

The management of ICI myocarditis requires immediate ICI discontinuation and initiation of high‐dose intravenous methylprednisolone (500–1000 mg/day for 3–5 days) as first‐line therapy, with transition to oral prednisolone (1 mg/kg, max 80 mg/day) upon clinical improvement, defined as > 50% troponin reduction within 24–72 h and resolution of conduction abnormalities [16]. Up to 50% of patients are steroid‐refractory, necessitating second‐line agents determined by a multidisciplinary team, including mycophenolate mofetil (B and T cell inhibition), IVIG (antibody removal), antithymocyte globulin or alemtuzumab (T cell depletion), abatacept with ruxolitinib (emerging CTLA‐4/JAK inhibition combination associated with improved survival in fulminant cases), tocilizumab (IL‐6 receptor blockade), and infliximab as rescue therapy—though infliximab carries concern given the RENAISSANCE trial showing increased death/hospitalization risk in heart failure patients—along with plasmapheresis to rapidly clear circulating ICIs and cytokines in life‐threatening cases [16]. Notably, after clinical recovery, the patient completed two additional cycles of gemcitabine and cisplatin without durvalumab, consistent with guidelines recommending permanent discontinuation of ICIs after myocarditis, while allowing continuation of non‐ICI chemotherapy [17]. Given that ICI rechallenge carries a substantial risk of recurrence and is reserved for highly selected cases, the ability to proceed with chemotherapy alone supports an ICI‐mediated rather than chemotherapy‐induced myocarditis [17]. ICI rechallenge after myocarditis recovery remains controversial due to the potentially fatal nature of the condition; it may be considered in selected patients following multidisciplinary evaluation per 2022 ESC cardio‐oncology guidelines, weighing irAE recurrence risk against oncological benefit, with the caveat that resuming anti‐PD‐1 therapy after severe irAEs carries relatively high rates of recurrent or new toxicities [16].

4. Conclusion

Despite its low incidence, ICI‐myocarditis carries substantial morbidity and mortality, can occur after cumulative exposure rather than initial dosing, and may mimic acute coronary syndromes or decompensated heart failure. Early recognition, prompt exclusion of obstructive coronary disease, and rapid initiation of high‐dose corticosteroids were critical to this patient′s recovery and stabilization of cardiac function. The favorable outcome, along with the patient′s ability to safely continue non‐ICI chemotherapy after permanent discontinuation of durvalumab, reinforces current guideline recommendations and emphasizes the importance of multidisciplinary collaboration between cardiology and oncology. Ultimately, this case illustrates that timely diagnosis and aggressive immunosuppression can be lifesaving in ICI‐myocarditis, while enabling continued oncologic treatment through alternative, non‐ICI regimens.

Nomenclature

ICIs

immune checkpoint inhibitors

CAD

coronary artery disease

BNP

brain natriuretic peptide

EKG

electrocardiogram

LVEF

left ventricular ejection fraction

MRI

magnetic resonance imaging

PD‐1

programmed cell death protein 1

PD‐L1

programmed death‐ligand 1

CTLA‐4

cytotoxic T‐lymphocyte‐associated antigen 4

HTN

hypertension

DM

diabetes mellitus

CCU

cardiac critical care unit

Author Contributions

N.J. and V.I. wrote the initial version of the manuscript. S.V.V.A. provided data critical to the manuscript. V.I., S.V.V.A., and P.J. retrieved images for the manuscript. S.A. and P.J. performed interventions at key steps of the diagnostic process and reviewed and revised the final draft of the manuscript.

Funding

No funding was received for this manuscript.

Disclosure

All authors read and approved the final manuscript.

Ethics Statement

Our institution does not require IRB approval for individual cases.

Consent

Consent was obtained from the patient before drafting the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Javed, Nismat , Itare, Vikram , Ashraf, Shoaib , Allu, Sai Vishnu Vardhan , Jadhav, Preeti , The Dyspnea Dilemma: Immune Checkpoint Inhibitor–Associated Myocarditis Mimicking Overlapping Cardiac Pathologies—A Case Report, Case Reports in Cardiology, 2026, 9654777, 5 pages, 2026. 10.1155/cric/9654777

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.