Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy

Edgar E. Nollet, Maike Schuldt, Vasco Sequeira, Aleksandra Binek, Thang V. Pham, Stephan A.C. Schoonvelde, Mark Jansen, Bauke V. Schomakers, Michel van Weeghel, Fred M. Vaz, Riekelt H. Houtkooper, Jennifer E. Van Eyk, Connie R. Jimenez, Michelle Michels, Kenneth C. Bedi, Kenneth B. Margulies, Cristobal G. dos Remedios, Diederik W.D. Kuster, Jolanda van der Velden*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: 

Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations (genotype-negative HCM) in the other half of patients. We explored how alterations in the metabolomic and lipidomic landscape are involved in cardiac remodeling in both patient groups. 

METHODS: 

We performed proteomics, metabolomics, and lipidomics on myectomy samples (genotype-positive N=19; genotype-negative N=22; and genotype unknown N=6) from clinically well-phenotyped patients with HCM and on cardiac tissue samples from sex- and age-matched and body mass index-matched nonfailing donors (N=20). These data sets were integrated to comprehensively map changes in lipid-handling and energy metabolism pathways. By linking metabolomic and lipidomic data to variability in clinical data, we explored patient group-specific associations between cardiac and metabolic remodeling. 

RESULTS:

HCM myectomy samples exhibited (1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage. In genotype-negative patients, septal hypertrophy and diastolic dysfunction correlated with lowering of acylcarnitines, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines. In contrast, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines were positively associated with septal hypertrophy and diastolic impairment in genotype-positive patients. 

CONCLUSIONS: 

We provide novel insights into both general and genotype-specific metabolic changes in HCM. Distinct metabolic alterations underlie cardiac disease progression in genotype-negative and genotype-positive patients with HCM.

Original languageEnglish
Pages (from-to)238-253
Number of pages16
JournalCirculation: Genomic and Precision Medicine
Volume17
Issue number3
DOIs
Publication statusPublished - 10 Jun 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc.

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