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Teodora Donisan1, Dinu Valentin Balanescu1, Gloria Iliescu2, Juan Lopez-Mattei1, Nicolas Palaskas1, Peter Y Kim1, Jean-Bernard Durand1, Serban Mihai Balanescu3, Konstantinos Marmagkiolis4, Cezar Iliescu1

1 Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2 Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3 Department of Cardiology, Elias Emergency University Hospital, „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
4 Florida Hospital Pepin Heart Institute, Tampa, Florida, USA
* Dr. Donisan and Dr. Balanescu contributed equally to this work.

Abstract: Acute left ventricular (LV) dysfunction is a common manifestation of cardiotoxicity related to modern cancer treatment, including novel immunotherapies. As immune checkpoint inhibitor (ICI) therapy is increasingly used, different clinical forms of LV dysfunction are observed. Suspicion for ICI-induced cardiotoxicity prompts a complete cardiovascular evaluation, including transthoracic echocardiography and global longitudinal strain. We present 3 cases of ICI-induced car-diotoxicity with a common denominator, an acute drop in LV ejection fraction, but with 3 different etiologies: Takotsubo cardiomyopathy, ischemia, and myocarditis. Clinicians must be aware of the potential risk for immune-related adverse events, including the various forms of cardiotoxicity.

Keywords: Cardio-oncology, cardiotoxicity, immunotherapy, myocarditis, Takotsubo cardiomyopathy.

INTRODUCTION
Left ventricular dysfunction is a common clinical ma-nifestation of cardiotoxicity related to modern cancer therapy1. A precise definition of cardiotoxicity in on-cology is still subject to debate, but experts describe it as a decrease of >10% in left ventricular ejection fraction (LVEF) to values of <53% as measured by two-dimensional echocardiography within a variable time frame following initiation of cancer treatment2. Guidelines recommend the use of transthoracic echo-cardiography (TTE) to screen for cardiotoxicity, as it is the most readily available imaging modality.2 Since measurement of LVEF with TTE is limited by inter-observer variability, global longitudinal strain might be able to provide incremental value3. Novel immunotherapies have led to improvements in cancer survival, even in malignancies previously associated with poor prognoses. Immune checkpoint inhibitors (ICIs) target T cell activation pathways in or-der to increase the host immune response against can-cer cells. These agents can activate both anti-tumor and autoreactive T cells, the latter being responsible for immune-related adverse events involving especi-ally the lungs, gastrointestinal system, liver, endocrine system, and skin4. Initial reports about ICI-associated cardiotoxicity described it as a rare occurrence, with the risk being higher in cases of combination immu-notherapy5. ICIs, however, can cause severe cardiac adverse events, which are refractory to glucocorti-coids. When cardiotoxicity is suspected, a complete cardiovascular workup is required for diagnosis and risk assessment. We present the clinical manifestati-ons and diagnostic workup of 3 patients who suffered from acute drops in ejection fraction of different etio-logies related to ICI therapy for cancer.

CASE SERIES
Patient 1. An 81-year-old woman with a history of myelodysplastic syndrome treated with nivolumab and ipilimumab, presented with dyspnea for 3 days, with onset during her third nivolumab infusion. Subcon-junctival hemorrhage of the right eye and scattered ecchymoses on both arms were seen, in the context of 25.000 platelets/μl. She was admitted for possible pneumonia (Figure 1A) and nonspecifi c T-wave abnor-malities on electrocardiogram (ECG) (Figure 1B). On TTE, an acute drop in LVEF was noticed, with new wall motion abnormalities concerning for ischemic-or stress-induced cardiomyopathy (Figure 1, C1-C2). Coronary angiography revealed normal coronary ar-teries, but ventriculography was suggestive of apical Takotsubo stress cardiomyopathy (Figure 1, D1-D4).
Patient 2. An 82-year-old man with acute myeloge-nous leukemia treated with azacitidine and nivolumab presented for worsening anxiety. His labs were notable for troponin T of 39 ng/ml with rising CK and a plate-let count of 29,000/μL. Chest X-ray revealed bilateral lower lobe linear atelectasis and bibasilar pneumonia (Figure 2A). ECG showed minor ST depressions in the anterior and lateral leads (Figure 2B). Baseline TTE 2 months prior, before chemotherapy, had been normal (Figure 2, C1-C2). At the current presentation, new global left ventricular systolic dysfunction was found, with anteroseptal wall motion abnormalities, and a LVEF of 30-35%. Coronary angiography revealed tri-ple vessel disease (Figure 2, D1-D3), the culprit of his systolic dysfunction.
Patient 3. A 68-year-old man on combination immunotherapy with durvalumab and tremelimumab for 1 month for metastatic pleomorphic gluteal sarcoma presented for weakness and dyspnea. Chest X-ray showed pleural metastatic disease and left lower lobe airspace disease concerning for atelectasis, aspiration, or infection (Figure 3A). ECG was concerning for ventricular tachycardia or supraventricular wide-complex tachycardia with aberrancy (Figure 3B). An acute coronary syndrome treatment protocol was initiated, but after CK increased >24.000 U/L, rhabdomyolysis and myositis were suspected. Myocardial strain measure-ment showed global hypokinesia and LVEF of 30-35%, suggestive of myocarditis (Figure 3, C1-C2). Coronary angiography did not reveal any hemodynamically signi-ficant coronary lesions (Figure 3, D1-D3), but the patient developed a complete heart block, which required the placement of a temporary pacemaker under fluoroscopic guidance (Figure 3, D1).

Figure 1. Takotsubo stress cardiomyopathy during treatment with nivolumab and ipilimumab. Chest X-ray showing possible pneumonia and bilateral pleural effusions (A). Electrocardiogram with nonspecific T-wave abnormalities (B). On transthoracic echocardiogram, new anteroapical and lateral wall motion abnormalities can be seen (ventricular systolic strain 4 chamber view, C1). Myocardial strain imaging revealed a global longitudinal peak strain of -15.9% (C2). Coronary angiography revealed normal coronary arteries (D1-D2) and ventriculography was suggestive of apical Takotsubo stress cardiomyopathy (D3-D4).

Figure 2. Acute coronary syndrome during treatment with nivolumab and azacitidine. Chest X-ray revealed bilateral lower lobe linear atelectasis and bi-basilar pneumonia (A). Electrocardiogram showed minor ST depressions in the anterior and lateral leads (B). Normal transthoracic echocardiogram before chemotherapy (C1-C2). Coronary angiography showed triple vessel disease (D1-D3), with chronic total occlusion of the proximal right coronary artery (D1, arrow), and 70-80% stenoses of the left anterior descending and left circumflex arteries (D2).

DISCUSSION
Immune-related adverse events have been described with various frequencies during treatment with ICIs, from 64-80% with ipilimumab, to 79% with pembro-lizumab4. The highest occurrence was reported when multiple agents were used, 96% with combination ipili-mumab plus nivolumab6. The true incidence of cardiac toxicity with ICIs is thought to be underreported due to the lack of routine cardiac assessment in most clini-cal trials and variable timeframe for the appearance of cardiotoxicity5. Several animal models have highlighted plausible mechanisms for the cardiotoxicity of ICIs. The inhibition of CTLA-4 and PD-1 can lead to dilated cardiomyopathy and autoimmune myocarditis, induce autoantibodies against cardiac troponin and myosin, or potentiate T cells targeting antigens shared by both the heart and the tumor7. It is unclear whether these mechanisms can be extrapolated to humans.
Cardiotoxicity induced by ICI can present in many forms, from asymptomatic cardiac biomarker elevati-ons to cardiogenic shock, but congestive heart failure, arrhythmias, and conduction abnormalities have been more commonly reported5. Myocarditis is a rare side effect of immunotherapy, but it is severe and difficult to manage7. In addition to myocarditis, Takotsubo stress cardiomyopathy has also, albeit rarely, been de-scribed8. ICIs can also trigger cardiac events in patients with pre-existing cardiac disorders9, as was the case of our patient who was diagnosed with triple-vessel coronary artery disease after ICI administration, with prior normal baseline cardiac function. Immunothe-rapy could play a role in the destabilization of athe-rosclerotic lesions7, as reported by Tomita et al in a case of acute coronary syndrome after nivolumab in a previously asymptomatic patient10.
The recommendations for diagnosing ICI-induced cardiotoxicity include a complex array of tests: ECG, cardiac biomarkers (troponin, CK, CK-MB, brain na-triuretic peptide), cardiac imaging (echocardiography, cardiac magnetic resonance), coronary angiography, and endomyocardial biopsy5. Considering the several possible mechanisms underlying cardiotoxicity, diffe-rent markers and diagnostic modalities could provide complementary information, better defining the car-diovascular status and risk for each oncology patient.

Figure 3. Myocarditis during treatment with durvalumab and tremelimumab. Chest X-ray showing right pleural metastatic disease (A, thin arrows), an ap-propriately placed chemotherapy port (A, arrowhead), and left lower lobe airspace disease worrisome for atelectasis, aspiration, or infection. Electrocardio-gram was concerning for ventricular tachycardia or supraventricular wide-complex tachycardia with aberrancy (B). Echocardiographic strain measurement (4 chamber view, C1) showed global longitudinal peak strain of -10.1% (C2), with global hypokinesia and LVEF of 30-35%, suggestive of myocarditis. Coronary angiography did not reveal any significant coronary lesions (D1-D3; D1 arrow pointing at temporary pacemaker lead).

CONCLUSIONS
As novel immunotherapies are increasing in popula-rity, clinicians must be aware of the potential risk for immune-related adverse effects. Although rare, ICI-in-duced cardiotoxicity is severe and may present with a multitude of clinical manifestations. An acute drop in ejection fraction may signal cardiotoxicity, posing for a complete cardiovascular workup. A collaboration between the oncologist and the cardiologist is essen-tial for acute and long-term management of patients with ICI-induced cardiotoxicity.
Conflicts of interest: none declared.

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