Case Presentation: A 76-year-old male with metastatic renal cell carcinoma presented to the hospital due to multiple syncopal episodes. The patient was prescribed pembrolizumab by infusion every 3 weeks (last dose was a week and a half prior). His presenting vitals were significant for a heart rate of 30 beats per minute and systolic blood pressure of 80 mmHg. Cardiac exam was notable for normal heart sounds with no murmurs, gallops, or rubs. An electrocardiogram (EKG) demonstrated complete heart block with ventricular escape. Lab work revealed a high sensitivity troponin T level of 1019 ng/L (normal range 0-51 ng/L), creatine kinase of 2021 U/L (30-200 U/L), creatine kinase-muscle brain of 109.0 ng/mL (0.0-6.7 ng/mL), and pro-brain natriuretic peptide of 425 pg/m (0-450 pg/mL). Otherwise, no electrolyte or metabolic abnormalities were identified. A transthoracic echocardiogram (TTE) revealed a left ventricular ejection fraction (LVEF) of 45 percent with mild global left ventricular systolic dysfunction in the setting of complete heart block. The patient received atropine and was started on a dopamine drip prior to placement of a transvenous pacemaker (TVP) for slow ventricular escape and intermittent asystole. The patient was then emergently transferred to the cardiac intensive care unit and implanted with a dual chamber pacemaker. Repeat TTE after pacemaker implantation showed improvement in the LVEF and left ventricular systolic function.
Discussion: Pembrolizumab is an immune checkpoint inhibitor (ICI), a humanized monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor on T lymphocytes, thereby blocking PD-1 ligands on tumor cells from binding. This process reactivates cytotoxic T-cells and induces the anti-tumor response. While it has been shown to improve survival outcomes in certain malignancies, the medication has been associated with numerous immune-related adverse events (irAEs) affecting multiple organ systems. Specifically, pembrolizumab has been associated with myocarditis and cardiac arrhythmias.In one safety database analysis of over 20,000 patients, myocarditis was noted to affect 0.09% of patients on a single ICI. Median onset of ICI-related myocarditis has been reported to be between 30 and 65 days from ICI initiation. Patients often present with troponin elevations and an abnormal EKG, as direct inflammation of the cardiac conduction system may lead to conduction abnormalities. Diagnosis of ICI-related myocarditis can be difficult to make, due to its rarity, variations in symptomology, and lack of formal screening recommendations. Formal diagnosis can be made with cardiac MRI, with endomyocardial biopsy considered the gold standard test. First-line treatment for ICI-related toxicities encompasses high-dose corticosteroids, which should be started pending diagnostic evaluation. One common practice is to initiate methylprednisolone 1 g/day for 3 days, followed by prednisone 1 mg/kg, and then a 4-6 week taper.
Conclusions: Myocarditis is an extremely rare adverse event of immune checkpoint inhibitor use. Providers should maintain a high index of suspicion for its development in asymptomatic patients. Patients being initiated on ICIs may benefit from cardiac screening with surveillance EKGs and cardiac troponin I measurements at baseline and with each cycle of therapy. Any abnormalities should prompt consideration for myocarditis evaluation.