Cardiac phenotype and tissue sodium content in adolescents with defects in the melanocortin system.

Context Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. Objective We aimed to characterize cardiac morphology and function as well as tissue Na + content in humans with mutations in POMC and MC4R genes. Participants A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause and 12 normal-weight controls) underwent cardiac magnetic resonance (CMR) imaging and 23Na-MRI. Results Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) compared to non-monogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in non-monogenic obese patients. Subcutaneous fat and skin Na + content was significantly higher in POMC- and MC4R-deficient patients compared to non-monogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control-groups. Conclusions Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA and stored more Na + within the subcutaneous fat tissue compared to non-monogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function, tissue Na + storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients.