Identification of EPHB4 variants in dilated cardiomyopathy patients

Guillermo Luxan (Frankfurt am Main)1, M. Muhly-Reinholz (Frankfurt am Main)1, S.-F. Glaser (Frankfurt am Main)2, J. Trebing (Heidelberg)3, C. Reich (Heidelberg)4, J. Haas (Heidelberg)4, F. Sedaghat-Hamedani (Heidelberg)4, B. Meder (Heidelberg)4, S. Dimmeler (Frankfurt am Main)2

1Goethe Universität Frankfurt am Main Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland; 2Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; 3University Hospital Heidelberg Institute for Cardiomyopathies Heidelberg Heidelberg, Deutschland; 4Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland


Cardiovascular disease (CVD) is the leading cause of death in the EU. Among CVD, dilated cardiomyopathy (DCM) is an irreversible type of heart failure and the third most common type of heart disease with an estimated prevalence of 40 in 100.000 people. Cardiac homeostasis relies on the appropriate provision of nutrients and functional specialization of local endothelial cells. Previous murine studies have shown that the endothelial Eph-ephrin signaling is required for the maintenance of vascular integrity and correct fatty acid transport uptake in the heart via regulating the caveolar trafficking of the fatty acid receptor CD36. In the mouse, endothelial specific loss-of-function of the receptor EphB4, or its ligand ephrin-B2, induces DCM like defects.

Now, we analysed the EPHB4 sequences of in total 573 DCM patients, which were either enrolled in the TranslatiOnal Registry for CardiomyopatHies-Plus (TORCH-Plus-DZHK21), or recruited at the Institute for Cardiomyopathies Heidelberg (ICH). In six patients, of which histology was also available, we found six new EPHB4 variants. The Combined Annotation Dependent Depletion (CADD) score of these variants (21,64 [IQR 19,41-23,50]) indicates that the variants have a high potential to be deleterious. The allele frequency of all the variants was significantly increased in the DCM cohort when compared to a control cohort of non-finnish european descent suggesting that these variants are enriched in DCM populations. Histological analysis of cardiac biopsies obtained from these patients compared to biopsies from DCM patients with reference genotype and healthy donors have revealed that, similar to what we found in EphB4 mutant mice, the expression of CD36 and CAV1 is altered in DCM patients. CD36 is strongly expressed in the capillaries and in the membrane of cardiomyocytes of healthy hearts, while CAV1 can be strongly detected in the capillary endothelial cells. In wild type DCM patients, the expression of CD36 is abrogated, while a disorganized expression of CAV1 can be observed in the cardiomyocytes. On the contrary, in the EPHB4 mutant carriers, the expression of CD36 is reduced in the membrane of cardiomyocytes but colocalizes with CAV1 in vesicle structures in the cardiomyocytes, suggesting impaired CD36 caveolar transport. Analysis of available human cardiac single-nuclei-RNA-sequencing revealed that EPHB4 is also expressed in human cardiomyocytes suggesting that EPHB4 may control CD36 localization also in cardiomyocytes.

This study confirms the crucial role of EPHB4 in the heart and corroborates the importance of CD36 and CAV1 for the cardiac health. Furthermore, it has the potential to improve diagnosis and risk stratification tools for DCM. In addition, as other genes crucial for fatty acid transport may be involved in cardiac disease, this study may help identify new diagnostic or therapeutic targets.

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