Background: Immune checkpoint inhibitors (ICI) have tremendously improved survival in patients with melanoma. By unbalancing the immune system, ICI also generate immune-related adverse events (IRAEs) that could affect any tissue, including the heart. Early detection of IRAEs under ICI therapy is essential to avoid life-threatening adverse events e.g. myocarditis and to maintain patients under this effective therapy.

Objective: To identify whether patients treated with ICI that develop extra-cardiac IRAEs also show a subclinical impairment of the heart function.

Methods: We have analysed patients with melanoma without established cardiac disease  in our cardio-oncology unit between July 2018 and December 2019. Data was collected at two timepoints: before initiating the ICI therapy (baseline) and one month after ICI treatment (follow-up). Evaluation was performed using clinical and laboratory parameter, electrocardiography, 2D and 3Dechocardiography for the measurement of the left ventricular ejection fraction, tissue Doppler echocardiography for the evaluation of the diastolic function, and speckle tracking echocardiography for the quantification of myocardial strain. 

Results: A total of 69 patients with melanoma (59 ± 12 years old, 63 % males, 93.8 % metastatic disease), without known cardiovascular disease were included.  Patients were divided in two groups: patients with extra-cardiac IRAEs after one month of ICI therapy (Group 1, n = 22) and patients without extra-cardiac IRAEs after one month of ICI therapy (Group 2, n = 46). One patient was diagnosed with immune-related myocarditis at follow-up and was excluded from the analysis. Patients in Group 1 developed the following extra-cardiac IRAEs after ICI therapy: colitis (n=10), thyroiditis/hypophysitis (n=8), hepatitis (n=2), pneumonitis (n=2). There were no differences in age, gender distribution, incidence of cardiovascular risk factors, or proportion of the metastatic disease between the two groups. The proportion of patients treated with combination ICI therapy (nivolumab plus ipilimumab) was significantly higher in Group 1 (72% vs. 33%, p = 0.04). The left ventricular systolic and diastolic function were similar at baseline and after one month of therapy between the two groups, except for global longitudinal strain (GLS), which showed a significant reduction after one month of ICI therapy in patients from Group 1 compared to the patients from Group 2 (-18.8 ± 2.6 % vs. -21 ± 1.2 %, p = 0.03). The radial and circumferential strain were similar between groups. Patients with combination ICI therapy had a 5 times higher risk to develop extra-cardiac IRAEs (OR 5.33, 95% CI (1.07-26.61), p = 0.04). Troponin and NT-proBNP were not significantly different after one month of ICI therapy between the two groups.

Conclusion: The abnormal function of the immune system triggered by ICI therapy in patients with extra-cardiac IRAEs seems to induce a subclinical left ventricular dysfunction, signalized by a reduction of the GLS. However, the diagnosis criteria for myocarditis could be fulfilled in only one patient. The mechanism of these changes should be further investigated and addressed.