Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

Karen R Gaar-Humphreys; Alyssa van den Brink; Mark Wekking; Folkert W Asselbergs; Frank G van Steenbeek; Magdalena Harakalova; Jiayi Pei

doi:10.3389/fcvm.2023.1114459

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

Front Cardiovasc Med. 2023 Jan 19:10:1114459. doi: 10.3389/fcvm.2023.1114459. eCollection 2023.

Authors

Karen R Gaar-Humphreys^{1

2}, Alyssa van den Brink^{1

2}, Mark Wekking^{1

2}, Folkert W Asselbergs^{3

4}, Frank G van Steenbeek^{1

2

5}, Magdalena Harakalova^{1

2

6}, Jiayi Pei^{1

2

6}

Affiliations

¹ Division Heart and Lungs, Department of Cardiology, Circulatory Health Research Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
² Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, Netherlands.
³ Department of Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
⁴ Health Data Research United Kingdom and Institute of Health Informatics, University College London, London, United Kingdom.
⁵ Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
⁶ Netherlands Heart Institute, Utrecht, Netherlands.

Abstract

Inherited cardiomyopathies caused by pathological genetic variants include multiple subtypes of heart disease. Advances in next-generation sequencing (NGS) techniques have allowed for the identification of numerous genetic variants as pathological variants. However, the disease penetrance varies among mutated genes. Some can be associated with more than one disease subtype, leading to a complex genotype-phenotype relationship in inherited cardiomyopathies. Previous studies have demonstrated disrupted metabolism in inherited cardiomyopathies and the importance of metabolic adaptations in disease onset and progression. In addition, genotype- and phenotype-specific metabolic alterations, especially in lipid metabolism, have been revealed. In this mini-review, we describe the metabolic changes that are associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which account for the largest proportion of inherited cardiomyopathies. We also summarize the affected expression of genes involved in fatty acid oxidation (FAO) in DCM and HCM, highlighting the potential of PPARA-targeting drugs as FAO modulators in treating patients with inherited cardiomyopathies.

Keywords: dilated cardiomyopathy; fatty acid oxidation; genetic variants; hypertrophic cardiomyopathy; lipid metabolism; transcription factor PPARA.

Publication types

Review

Grants and funding

This work was supported by the Leducq grant (CURE-PLaN no. 18CVD01 to JP, MH, and FWA), ZonMW Open Competition grant (CONTRACT no. 09120012010018 to KG-H, FWA, and MH), Dutch Cardiovascular Alliance (DCVA) grant (DOUBLE-DOSE no. 2020B005 to MH, FvS, and FWA), and ERA-CVD grant (SCALE no. 2019T109 to JP, FvS, and MH). FWA is supported by UCL Hospitals NIHR Biomedical Research Centre.