Monitoring of the Evolution of Immune Checkpoint Inhibitor Myocarditis With Cardiovascular Magnetic Resonance.

November 2020 1 Toru Sato, MD Shiro Nakamori , MD Susumu Watanabe, MD Kohei Nishikawa, MD Takahiro Inoue, MD Kyoko Imanaka-Yoshida, MD Masaki Ishida, MD Hajime Sakuma, MD Masaaki Ito, MD Kaoru Dohi, MD A 67-year-old man with metastatic clear cell renal cell carcinoma presented with myalgias and a high-grade fever 20 days after his first treatment with a combination of ipilimumab and nivolumab. Laboratory tests were as follows: creatine kinase, 2355 U/L (normal range: 59–248 U/L), creatine kinase-MB, 99.6 U/L (normal range: <12 U/L), and troponin I, 6248 pg/mL (normal range: <34.2 pg/mL). ECG revealed T-wave abnormalities in the precordial leads, while echocardiography showed normal left ventricular systolic function (Figure IA and Movie I in the Data Supplement). Cardiovascular magnetic resonance (CMR) demonstrated severely elevated myocardial native T1 and T2 on multiparametric mapping, with multiple areas of myocardial inflammation as well as scarring/fibrosis on late gadolinium-enhanced CMR (Figure 1A through 1C; also see Movies II through V in the Data Supplement for cine CMR). Coronary angiography revealed normal coronary arteries, and biopsy samples were taken from the mid-right ventricular septum (Figure 2). Histological samples depicted an intense lymphocytic infiltrate, positive interstitial tenascin-C immunoreactivity, and myocyte necrosis consistent with myocarditis (Figure 1D through 1F). Immunohistochemical staining in cardiac tissues is shown in Figure 3. With a confirmed diagnosis of immune checkpoint inhibitors (ICI)-associated myocarditis, the patient was treated with prednisolone of 1 mg/kg per day. The troponin I level remarkably decreased from 33889 to 3050 pg/ mL, followed by an intended prednisolone taper of 10 mg every week. On day 10, the ECG became remarkable for frequent, consecutive ventricular ectopy. Methylprednisolone at 1 g daily and intravenous immunoglobulin were initiated, and the rhythm and conduction disturbances gradually improved without any mechanical support (Figure IB and IC in the Data Supplement). Follow-up echocardiography and CMR at 1 month revealed severe left ventricular systolic dysfunction with inferoseptal aneurysm formation (Movies VI through X in the Data Supplement), continuously high native T1 and T2 and increased myocardial scarring/fibrosis (Figure 4A through 4C); while 1-month follow-up endomyocardial biopsy samples still showed lymphocytic infiltrates and tenascin-C positive areas, they were to a lesser extent (Figure 4D through 4F). Three months later, the patient is asymptomatic without recurrence of myocarditis, but he continues to require immunotherapy interruption secondary to the extensive myocardial damage. ICI-associated myocarditis is rare but potentially life-threatening and leads to devastating clinical sequelae.1 To our knowledge, this is the first comprehensive CMR and histopathologic case study assessing ICI-associated myocarditis with longitudinal follow-up. When clinically suspected, cardiac enzymes, ECG, and echocardiography are the usual testing modalities for initial assessment and therapeutic monitoring of patients with ICI-associated myocarditis. Indeed, some centers stratify management based on magnitude of troponin changes.2 However, this case highlights the necessity of developing more accurate and reliable techniques for monitoring ICI-associated myocarditis. © 2020 American Heart Association, Inc. CARDIOVASCULAR IMAGES