Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder Variants

被引：9

作者：

Jansen, Mark ^{[1
,2
]}

Schuldt, Maike ^{[3
]}

van Driel, Beau O. ^{[3
]}

Schmidt, Amand F. ^{[4
,5
]}

Christiaans, Imke ^{[6
]}

van der Crabben, Saskia N. ^{[7
]}

Hoedemaekers, Yvonne M. ^{[8
]}

Dooijes, Dennis ^{[1
]}

Jongbloed, Jan D. H. ^{[6
]}

Boven, Ludolf G. ^{[6
]}

Deprez, Ronald H. Lekanne ^{[7
]}

Wilde, Arthur A. M. ^{[9
]}

Jans, Judith J. M. ^{[1
]}

van der Velden, Jolanda ^{[3
]}

de Boer, Rudolf A. ^{[10
]}

van Tintelen, J. Peter ^{[1
,2
]}

Asselbergs, Folkert W. ^{[2
,4
,5
,9
,11
]}

Baas, Annette F. ^{[1
]}

机构：

[1] Univ Utrecht, Univ Med Ctr Utrecht, Dept Genet, NL-3584 CX Utrecht, Netherlands

[2] Netherlands Heart Inst, NL-3511 EP Utrecht, Netherlands

[3] Vrije Univ Amsterdam, Dept Physiol, Amsterdam UMC, Amsterdam Cardiovasc Sci, NL-1081 HZ Amsterdam, Netherlands

[4] Univ Utrecht, Univ Med Ctr Utrecht, Dept Cardiol, NL-3584 CX Utrecht, Netherlands

[5] UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London WC1E 6DD, England

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands

[7] Univ Amsterdam, Dept Human Genet, Amsterdam UMC, NL-1105 AZ Amsterdam, Netherlands

[8] Radboud Univ Nijmegen, Med Ctr, Dept Clin Genet, NL-6525 GA Nijmegen, Netherlands

[9] Univ Amsterdam, Heart Ctr, Dept Cardiol, Amsterdam UMC, NL-1081 HZ Amsterdam, Netherlands

[10] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands

[11] UCL, Hlth Data Res UK, London NW1 2DA, England

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2023年 / 24卷 / 04期

关键词：

hypertrophic cardiomyopathy; MYBPC3; biomarkers; metabolomics; SUDDEN CARDIAC DEATH; HEART-FAILURE; RISK; ACID; MUTATIONS; DIAGNOSIS; MANAGEMENT; MORTALITY; MODELS; IMPACT;

D O I：

10.3390/ijms24044031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by pathogenic MYBPC3 variants, and a significant cause of sudden cardiac death. Severity is highly variable, with incomplete penetrance among genotype-positive family members. Previous studies demonstrated metabolic changes in HCM. We aimed to identify metabolite profiles associated with disease severity in carriers of MYBPC3 founder variants using direct-infusion high-resolution mass spectrometry in plasma of 30 carriers with a severe phenotype (maximum wall thickness >= 20 mm, septal reduction therapy, congestive heart failure, left ventricular ejection fraction <50%, or malignant ventricular arrhythmia) and 30 age- and sex-matched carriers with no or a mild phenotype. Of the top 25 mass spectrometry peaks selected by sparse partial least squares discriminant analysis, XGBoost gradient boosted trees, and Lasso logistic regression (42 total), 36 associated with severe HCM at a p < 0.05, 20 at p < 0.01, and 3 at p < 0.001. These peaks could be clustered to several metabolic pathways, including acylcarnitine, histidine, lysine, purine and steroid hormone metabolism, and proteolysis. In conclusion, this exploratory case-control study identified metabolites associated with severe phenotypes in MYBPC3 founder variant carriers. Future studies should assess whether these biomarkers contribute to HCM pathogenesis and evaluate their contribution to risk stratification.

引用

页数：12