Cardiac Phenotype and Tissue Sodium Content in Adolescents With Defects in the Melanocortin System

Lia Puder; Sophie Roth; Philipp Krabusch; Susanna Wiegand; Robert Opitz; Martin Bald; Christa Flück; Esther Schulz; Egbert Voss; Lajos Markó; Peter Linz; Felix Berger; Dominik N Müller; Titus Kuehne; Michael J Litt; Roger D Cone; Peter Kühnen; Marcus Kelm

doi:10.1210/clinem/dgab368

Cardiac Phenotype and Tissue Sodium Content in Adolescents With Defects in the Melanocortin System

J Clin Endocrinol Metab. 2021 Aug 18;106(9):2606-2616. doi: 10.1210/clinem/dgab368.

Authors

Lia Puder^{1

2}, Sophie Roth³, Philipp Krabusch^{1

2}, Susanna Wiegand⁴, Robert Opitz¹, Martin Bald⁵, Christa Flück⁶, Esther Schulz⁷, Egbert Voss⁸, Lajos Markó^{9

10

11

12}, Peter Linz¹³, Felix Berger^{14

9}, Dominik N Müller^{9

10

11

12}, Titus Kuehne^{14

3

9}, Michael J Litt¹⁵, Roger D Cone¹⁶, Peter Kühnen¹, Marcus Kelm^{14

3

12}

Affiliations

¹ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Institute for Experimental Pediatric Endocrinology, Berlin 13353, Germany.
² Department for Pediatric Endocrinology and Diabetology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Berlin 13353, Germany.
³ Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin 13353, Germany.
⁴ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Center for Social-Pediatric Care/Pediatric Endocrinology and Diabetology, Berlin 13353, Germany.
⁵ Pediatric Endocrinology, Olgahospital, Klinikum Stuttgart, Stuttgart 70174, Germany.
⁶ Department of Paediatrics and Department of BioMedical Research, Pediatric Endocrinology, Diabetology and Metabolism, Bern University Hospital Inselspital and University of Bern, Bern 3010, Switzerland.
⁷ Pediatric Endocrinology, AKK Altonaer Kinderkrankenhaus GmbH, Hamburg 22763, Germany.
⁸ Cnopfsche Kinderklinik, Nürnberg 90419, Germany.
⁹ DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin 13353, Germany.
¹⁰ Experimental and Clinical Research Center, a cooperation of Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Berlin 13125, Germany.
¹¹ Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany.
¹² Berlin Institute of Health (BIH), Berlin 10178, Germany.
¹³ Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
¹⁴ Department of Congenital Heart Disease, Deutsches Herzzentrum Berlin, Berlin 13353, Germany.
¹⁵ Brigham and Women's Hospital, Harvard University, Boston, MA 02115, USA.
¹⁶ Life Sciences Institute, and Department of Molecular and Integrative Physiology, School of Medicine, University of Michigan, Ann Arbor, MI 48109-5624, USA.

Abstract

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.

Methods: 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) than nonmonogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. Subcutaneous fat and skin Na+ content was significantly higher in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control groups.

Conclusion: 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 than nonmonogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function and tissue Na+ storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients.

Keywords: MC4R; Monogenic obesity; POMC; cardiac function; left ventricular function; melanocortin pathway; tissue sodium content; tissue water content.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Body Water / metabolism
Female
Humans
Hypertrophy, Left Ventricular / etiology*
Hypertrophy, Left Ventricular / genetics
Magnetic Resonance Imaging
Male
Mutation*
Obesity / complications
Phenotype
Pro-Opiomelanocortin / genetics*
Pro-Opiomelanocortin / physiology
Receptor, Melanocortin, Type 4 / genetics*
Receptor, Melanocortin, Type 4 / physiology
Sodium / metabolism*
Ventricular Function, Left / physiology*

Substances

MC4R protein, human
Receptor, Melanocortin, Type 4
Pro-Opiomelanocortin
Sodium

Abstract

Publication types

MeSH terms

Substances

Grants and funding