Takotsubo Syndrome Triggered by Immune Checkpoint Inhibitor-Induced Pneumonitis: A Multidisciplinary Diagnostic and Therapeutic Challenge

Abstract

Patient: Female, 64-year-old

Final Diagnosis: Immune checkpoint inhibitor-associated pneumonitis • takotsubo cardiomyopathy

Symptoms: Dynpnea • heart failure

Clinical Procedure: —

Specialty: Cardiology

Objective: Unusual clinical course

Background

Immune checkpoint inhibitor (ICI) myocarditis imposes immunotherapy discontinuation due to concerns of poor outcomes. We present a case of ICI cardiomyopathy for which ICI re-challenge was safely performed. According to the World Health Organization (WHO), only 13 cases of takotsubo cardiomyopathy (TTS) have been associated with ICI use. We report a rare case of this.

Case Report

A 64-year-old woman with history of stage IV squamous cell carcinoma of the right lung presented with symptoms of heart failure and worsening dyspnea. Her symptoms started 2 weeks after her first round of chemotherapy with carboplatin, paclitaxel, and pembrolizumab. Electrocardiography (EKG) revealed right bundle branch block with ST elevations, troponin peaked at 424 ng/L, and proBNP 865 pg/mL. A transthoracic echocardiogram (TTE) showed left ventricle ejection fraction (LVEF) of 35% to 39% along with akinesis of all the mid- to apical left ventricle (LV) wall segments.

Conclusions

Not all ICI-related heart failure is myocarditis. This case highlights the utility of CMR and endomyocardial biopsy to aid diagnosis of TTS. TTS and ICI myocarditis may appear similar on CMR, with prominent edema, although the regional distribution may help finalize the diagnosis. Endomyocardial biopsies can be helpful to identify pro-inflammatory macrophages as possible mediators in the association between oncology treatment and development of TTS. This interesting case highlights the utility of further advanced cardiac testing before making the diagnosing of ICI myocarditis and potentially withholding life-saving cancer therapy.

Introduction

The use of immune checkpoint inhibitors (ICIs) in oncology has advanced cancer care, but these drugs can cause immune-related adverse events (irAEs) that include rare cardiovascular complications. Differentiating immune-mediated myocarditis from stress-induced takotsubo cardiomyopathy (TTC) is a critical diagnostic challenge in modern cardio-oncology. Both conditions can present with acute heart failure, biomarker elevation, and EKG changes soon after ICI initiation. This report shows how advanced cardiac magnetic resonance imaging (CMRI) and endomyocardial biopsy (EMB) can resolve such ambiguity and guide safe continuation of life-prolonging immunotherapy.

Case Report

A 64-year-old woman with long-term tobacco use, emphysema, and stage IV squamous cell carcinoma of the lung with liver and brain metastases experienced acute dyspnea, cough, and pleuritic chest pain for 2 days. She started combination therapy with carboplatin, paclitaxel, and pembrolizumab 9 days before presentation.

She presented to the emergency department with hypertension (BP 156/103 mmHg), tachycardia (HR 120 bpm), tachypnea (RR 32/min), and hypoxemia (SpO2 88% on 5 L oxygen). The physical examination revealed a loud P2 heart sound, bilateral expiratory wheezing, and mild lower-extremity edema.

The initial 12-lead EKG (Figure 1) demonstrated sinus tachycardia (HR 124 beats per minute) with right bundle branch block and mild ST-segment elevation in leads V3–V5. No reciprocal ST depression was noted. The laboratory results indicated high-sensitivity troponin-T levels at 424 ng/L, troponin-I level at 31 ng/L, and proBNP levels at 865 pg/ml. Echocardiography revealed LVEF of 35% with severe hypokinesis of mid-apical LV wall segments. Based on TTE, the differential diagnosis included severe coronary artery disease (CAD), myocarditis, and stress-induced cardiomyopathy. She was immediately taken for left heart catheterization, which revealed non-obstructive coronary artery disease with a left ventricular end-diastolic (LVED) pressure of 17 mmHg (Figure 2). Serial measurements of high-sensitivity troponin (hs-T) demonstrated a downward trend (hs-T 429 → 424 → 80 → 52 → 22 ng/L; Tn-I 31 → 18 → 9 ng/L) over the course of 5 days (reference ranges are hs-T <14 ng/L and Tn-I <10 ng/L.) Her follow-up EKG on the follow-up day showed resolution of ST elevations (Figure 3).

Figure 1.

Initial EKG on presentation showing sinus tachycardia with right bundle branch block and mild ST-segment elevation in leads V3-V5.

Figure 2.

Normal coronary angiogram.

Figure 3.

Follow-up EKG showing resolution of ST-segment elevation.

A CMR was performed for further evaluation and concerns for ICI myocarditis. It showed LVEF at 32% with mid-to-apical anterior and anteroseptal akinesis and myocardial edema in affected segments without late gadolinium enhancement (LGE). Findings of the CMR were consistent with TTS. Quantitative parametric mapping values demonstrated T1=1100–1500 ms and T2=59 ms in the apical segments (elevated when compared with basal myocardium, T1=980 ms, T2=50 ms) with extracellular volume (ECV)=35%, which is indicative of myocardial edema (Figures 4, 5). Dynamic CMR cine imaging revealed an apical ballooning pattern with hyperkinesis of basal segments (Videos 1–3). These findings, in combination with the absence of late gadolinium enhancement (LGE) (Figure 6), established the diagnosis of takotsubo syndrome rather than myocarditis.

Figure 4.

CMR T2-weighted imaging showing myocardial edema in apical segments.

Figure 5.

Quantitative parametric mapping values demonstrated elevated T1, T2, and ECV values in the apical myocardial segments compared to basal myocardium.

Video 1.

Steady-state free precession (SSFP) sequence, 2-chamber view, showing mid-apical akinesis and basal hyperkinesis consistent with takotsubo pattern.

Video 2.

SSFP sequence, 4-chamber view, showing apical ballooning and systolic dysfunction during peak contraction.

Video 3.

SSFP sequence, 3-chamber view, showing akinesis of mid-anteroseptal/inferolateral wall and apical septal and lateral segments.

Figure 6.

CMR Inversion recovery sequence showing absence of Late Gadolinium enhancement.

A chest computed tomography (CT) scan was performed, and the distribution of pulmonary infiltrates were predominantly patchy and non-dependent, without evidence of cardiomegaly, septal thickening, or pleural effusions, which are classic features of hydrostatic congestion. CT imaging favored an immune-mediated pneumonitis rather than cardiogenic pulmonary edema (Figure 7).

Figure 7.

CXR (left panel) and CTPE (right panel) suggestive of pneumonitis.

To verify diagnosis of TTS, an EMB was subsequently obtained from the right ventricular septum (4 samples). Histopathology showed interstitial fibrosis without myocyte necrosis. Immunohistochemistry (IHC) was negative for CD3 (T-lymphocytes), CD68 (macrophages), and PD-L1, effectively excluding ICI-induced myocarditis (Figure 8).

Figure 8.

EMB: Cardiac muscle fibers with interstitial fibrosis by H&E stain (right panel) and highlighted blue by trichrome stain (left panel).

After multidisciplinary discussions, she received a diagnosis of ICI-related Grade 2 pneumonitis together with TTC. She received intravenous methylprednisolone (1 mg/kg/day) for 3 days, transitioned to an oral prednisone taper over 4 weeks, consistent with National Comprehensive Cancer Network (NCCN) recommendations for grade 2 pneumonitis. She improved rapidly, allowing discontinuation of supplemental oxygen by day 5. She was also started on guideline-directed medical therapy (GDMT) for TTC, which included metoprolol succinate and sacubitril/valsartan.

Re-initiation of pembrolizumab 2 weeks after discharge was approved by a multidisciplinary team (MDT) comprising oncology, cardiology, and pulmonology specialists. The decision followed comprehensive reassessment of cardiac and pulmonary function, which demonstrated full clinical recovery in 8 weeks: LVEF normalization (60%) as shown in Videos 4 and 5, resolution of pneumonitis on CT imaging, and normalization of troponin-I (<10 ng/L) and beta natriuretic peptide ([BNP] <100 pg/mL). The MDT reached the unanimous consensus that the benefits of continued immunotherapy outweighed the risks of recurrence, with a plan for serial cardiac monitoring during ongoing therapy (Table 1).

Video 4.

Follow-up transthoracic echocardiography (2-chamber view) showing full recovery of LV wall motion and normalization of systolic function.

Video 5.

Follow-up echocardiography (4-chamber view) confirming resolution of apical ballooning and normal LV ejection fraction.

Table 1.

Timeline of key diagnostic and therapeutic events.

Day	Event/findings
−9	Initiated carboplatin + paclitaxel + pembrolizumab
0	Dyspnea, chest pain; ECG = RBBB + ST elevation; hs-T 424 ng/L; CT = bilateral opacities
0	Coronary angiography → normal (Figure 5);
1	CMR → LVEF 32%, apical edema ↑, no LGE (Figures 2–4)
2	EMB 4 samples → fibrosis only (Figure 6)
3	Started corticosteroids + GDMT (metoprolol, sacubitril/valsartan)
5	Troponins decreasing; symptoms improving
14	Discharged; MDT cleared re-challenge with pembrolizumab
56	Follow-up TTE → LVEF 60%, normal wall motion

Discussion

ICIs can lead to a wide range of cardiotoxic effects, including myocarditis, arrhythmias, pericarditis, acute coronary syndromes, heart failure, and TTC [1]. Myocarditis related to ICI is a rare but serious consequence that needs prompt medical treatment. Histological findings of lymphocytic infiltration together with myocyte necrosis characterize this condition [2]. Patients often present with nonspecific symptoms such as chest pain, dyspnea, palpitations, or fatigue, typically within the first 6 to 8 weeks of starting ICI therapy. In many cases, elevated troponin levels and new EKG abnormalities, such as ST-segment changes, conduction disturbances, or arrhythmias, are the earliest diagnostic clues. Cardiac MRI can show myocardial edema, T1 and T2 parametric mapping abnormalities, and late gadolinium enhancement, typically in the inferolateral or septal regions. However, endomyocardial biopsy remains the gold standard for definitive diagnosis, revealing lymphocytic infiltration and myocyte necrosis [2]. The treatment for ICI myocarditis demands both stopping the offending ICI therapy and starting high-dose corticosteroids (1 to 2 mg/kg/day of methylprednisolone). Steroid-resistant patients may benefit from mycophenolate mofetil, infliximab or intravenous immunoglobulin (IVIG) as alternative immunosuppressive therapies [3]. Patients need to undergo continuous cardiac surveillance together with follow-up imaging and biomarker tests for evaluating treatment success.

ICI-induced pneumonitis is one of the most common irAEs, which occurs in 3% to 5% of non-small cell lung cancer patients and up to 10% of patients receiving combination therapies [4]. Patients can develop new or worsening cough, dyspnea, fever, and pleuritic chest pain. CT imaging shows bilateral ground-glass opacities or patchy consolidations as the typical radiographic findings. The standard treatment for symptomatic cases involves starting patients on prednisone 1 to 2 mg/kg/day, which should be tapered over 4 to 6 weeks. Patients with severe cases (Grade 3 to 4) require hospital admission and oxygen therapy and may need second-line immunosuppressive treatment with infliximab or IVIG. The combination of prompt detection with steroid treatment leads to decreased rates of respiratory failure and mortality [4].

In our case, the diagnosis of grade II ICI pneumonitis was based on the clinical, imaging, and hemodynamic findings consistent with a non-cardiogenic process. CT chest demonstrated non-dependent, patchy pulmonary infiltrates without cardiomegaly, septal thickening, or pleural effusions—features that are atypical for cardiogenic pulmonary edema. Additionally, right heart catheterization revealed a left ventricular end-diastolic pressure (EDP) of 17 mmHg, supporting a non-cardiogenic etiology. The patient’s symptomatic dyspnea requiring supplemental oxygen, together with these radiographic findings, met the definition of grade II pneumonitis according to the Common Terminology Criteria for Adverse Events (CTCAE) [5]. The diagnostic and management approaches were consistent with the National Comprehensive Cancer Network (NCCN) Guidelines for Management of Immunotherapy-Related Toxicities [6], emphasizing exclusion of infectious and cardiogenic causes through imaging, biomarkers, and multidisciplinary review.

The coexistence of ICI pneumonitis with TTS in this clinical case is unique. We believe the systemic inflammatory response from an irAE was an acute physical stress for our patient and this created a vulnerable cardiac environment for a condition like TTS to occur. ICI-induced pneumonitis generates an inflammatory cascade, which elevates cytokines such as IL-6, TNF-α, and IFN-γ [7]. The released catecholamines and sympathetic system overactivation result in myocardial stunning together with microvascular dysfunction, which are central mechanisms of TTS. TTS commonly presents with chest pain alongside simulated acute coronary syndrome EKG patterns and short-term left ventricular dysfunction that develops after emotional or physical stress [8]. The disease primarily affects the apical and mid-ventricular segments of the heart through a well-known pattern known as apical ballooning [8,10]. Management of takotsubo syndrome remains predominantly supportive, focusing on hemodynamic stabilization and neurohormonal modulation. Evidence-based long-term pharmacotherapy is lacking, although beta-blockers and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are commonly used during the recovery phase. The addition of sacubitril/valsartan in our case aimed to optimize reverse remodeling and LV function recovery, as suggested by limited observational data [9]. This agent is not a standard component of TTS therapy but was used empirically due to transient LV dysfunction and patient tolerance [10].

In our case, the clinical trigger, which was the presence of apical akinesis, myocardial edema, and the absence of LGE on CMR, along with a confirmatory cardiac biopsy, were critical in confirming TTS over ICI myocarditis. These findings guided the clinical decision to administer temporary immunosuppression and facilitated a safe re-challenge with ICI therapy.

The assessment of troponin assays proved crucial for distinguishing between the conditions because troponin-T shows high cardiac sensitivity but can increase due to muscle or renal dysfunction. Troponin-I demonstrates higher specificity for cardiac tissue [11]. Our patient’s elevated troponin-T combined with lower troponin-I levels pointed towards TTS instead of myocarditis.

Although cardiac MRI and EMB provided decisive evidence in this case, both modalities have recognized limitations. Myocarditis may be patchy or limited to focal regions that escape sampling, and the absence of LGE does not entirely exclude inflammatory injury. However, the agreement between CMR, serial biomarkers, and negative immunohistochemistry strongly supported a diagnosis of takotsubo syndrome.

The decision to reintroduce immune checkpoint inhibitor (ICI) therapy was made 2 weeks after resolution of the grade 2 pneumonitis episode. Re-initiation was based on complete clinical recovery, normalization of cardiac biomarkers, restoration of left ventricular systolic function on echocardiography, and near-complete radiographic resolution of pneumonitis on chest CT. The patient remained asymptomatic with no residual dyspnea or hypoxia at rest or exertion. Re-challenge was undertaken following a unanimous multidisciplinary consensus among cardiology, oncology, and pulmonary teams, in accordance with general principles outlined in the Common Terminology Criteria for Adverse Events (CTCAE v5.0) and NCCN Guidelines for Management of Immunotherapy-Related Toxicities. The patient tolerated ICI re-initiation without recurrence of pneumonitis or cardiac dysfunction during follow-up.

To our knowledge, this case is one of only a few documented instances of ICI-induced pneumonitis precipitating takotsubo syndrome. In addition to the report by Serzan et al [12], a more recent case report described pembrolizumab-induced pneumonitis accompanied by hypophysitis and TTS [13]. Furthermore, a systematic review of 17 ICI-associated TTS cases found that 62% occurred alongside other irAEs, such as pneumonitis or endocrinopathies [14].

Our case remains distinct because the diagnosis was confirmed by both advanced cardiac MRI and EMB, and the patient underwent successful ICI re-challenge under multidisciplinary guidance.

Clinical Implications

Clinicians should maintain a high index of suspicion for takotsubo syndrome in patients presenting with cardiopulmonary symptoms during ICI therapy [15], particularly when concurrent irAEs are identified [16]. Early multidisciplinary collaboration and sequential use of biomarkers, cardiac MRI, and histology can ensure diagnostic accuracy. This case reinforces that prompt recognition and tailored immunosuppression can allow safe continuation of immunotherapy and improve patient outcomes.

Conclusions

We report a rare case of TTS developing from ICI-induced pneumonitis, which presented with myocarditis-like symptoms. To our knowledge, this is the third reported instance of pneumonitis acting as the precipitating irAE for TTS in the context of ICI therapy [12,13]. The combination of early diagnosis through CMR imaging and a personalized steroid treatment plan enabled fast patient recovery while maintaining the essential ICI therapy for survival. Awareness of irAE-triggered TTS presentations can facilitate timely, life-saving interventions.

Abbreviations

ICI

immune checkpoint inhibitor

TTS

takotsubo cardiomyopathy

irAEs

immune-related adverse events

TTE

transthoracic echocardiogram

LV

left ventricle

EF

ejection fraction

CT

computed tomography

LGE

late gadolinium enhancement

EMB

endomyocardial biopsy

CV

cardiovascular

MDT

multidisciplinary teams

CMR

cardiovascular magnetic resonance

NSTEMI

non-ST-elevation myocardial infarction

CHF

congestive heart failure

EKG

electrocardiogram

HST

high-sensitivity troponin-I

ECV

extracellular volume

PD-L1

programmed death ligand 1

GDMT

guideline-directed medical therapy

SSFP

steady-state free precession imaging

ACS

acute coronary syndrome

AV

atrioventricular