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

Jansen, Manon A. A.; Schuldt, Maike; Driel, Beau van; Schmidt, Amand F.; Christiaans, Imke; Crabben, Saskia N. van der; Hoedemaekers, Yvonne M.; Dooijes, Dennis; Jongbloed, Jan D. H.; Boven, Ludolf G.; Deprez, Ronald Lekanne; Wilde, Arthur A.M.; Jans, Judith; Velden, Jolanda van der; Boer, Rudolf A. de; Tintelen, Peter van; Asselbergs, Folkert W.; Baas, Annette F.

doi:10.3390/ijms24044031

Cited by 5 publications

(2 citation statements)

References 52 publications

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“…There appear to be potential biomarkers for severe phenotypes of MYBPC3-associated HCM. Multiple pathways, including acylcarnitine, histidine, lysine, purine, steroid hormone metabolism, and proteolysis are altered in these patients, which could lead to possible risk stratification methods in the future [ 87 ].…”

Section: From Genetics To Clinical Implicationsmentioning

confidence: 99%

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

Tudurachi,

Zăvoi,

Leonte

et al. 2023

IJMS

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Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM’s morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin–proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM.

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Section: From Genetics To Clinical Implicationsmentioning

confidence: 99%

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

Tudurachi,

Zăvoi,

Leonte

et al. 2023

IJMS

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“…Using direct-infusion high-resolution mass spectrometry, the group of Annette F. Baas performed a study to comprehensively compare metabolites among severely and mildly affected carriers of Hypertrophic Cardiomyopathy (HCM)-causing variants. They could associate several metabolic pathways, including histidine, lysine, acylcarnitine, purine and steroid hormone metabolism with cases of severe HCM, which might in the future give additional indications for the pathogenesis, prognostic, and therapeutic care of patients with HCM [16]. Francesca Di Lorenzo and colleagues propose to define variants in the Desmoplakin (DSP) gene as an own clinical entity in the case of arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM).…”

mentioning

confidence: 99%

Molecular Mechanisms of Cardiac Development and Disease

Wagner

2023

IJMS

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Metabolic abnormalities and reprogramming in cats with naturally occurring hypertrophic cardiomyopathy

Li,

Homilius,

Achilles

et al. 2024

ESC Heart Failure

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Background and aimsThe heart is a metabolic organ rich in mitochondria. The failing heart reprograms to utilize different energy substrates, which increase its oxygen consumption. These adaptive changes contribute to increased oxidative stress. Hypertrophic cardiomyopathy (HCM) is a common heart condition, affecting approximately 15% of the general cat population. Feline HCM shares phenotypical and genotypical similarities with human HCM, but the disease mechanisms for both species are incompletely understood. Our goal was to characterize global changes in metabolome between healthy control cats and cats with different stages of HCM.MethodsSerum samples from 83 cats, the majority (70/83) of which were domestic shorthair and included 23 healthy control cats, 31 and 12 preclinical cats with American College of Veterinary Internal Medicine (ACVIM) stages B1 and B2, respectively, and 17 cats with history of clinical heart failure or arterial thromboembolism (ACVIM stage C), were collected for untargeted metabolomic analysis. Multiple linear regression adjusted for age, sex and body weight was applied to compare between control and across HCM groups.ResultsOur study identified 1253 metabolites, of which 983 metabolites had known identities. Statistical analysis identified 167 metabolites that were significantly different among groups (adjusted P < 0.1). About half of the differentially identified metabolites were lipids, including glycerophospholipids, sphingolipids and cholesterol. Serum concentrations of free fatty acids, 3‐hydroxy fatty acids and acylcarnitines were increased in HCM groups compared with control group. The levels of creatine phosphate and multiple Krebs cycle intermediates, including succinate, aconitate and α‐ketoglutarate, also accumulated in the circulation of HCM cats. In addition, serum levels of nicotinamide and tryptophan, precursors for de novo NAD+ biosynthesis, were reduced in HCM groups versus control group. Glutathione metabolism was altered. Serum levels of cystine, the oxidized form of cysteine and cysteine‐glutathione disulfide, were elevated in the HCM groups, indicative of heightened oxidative stress. Further, the level of ophthalmate, an endogenous glutathione analog and competitive inhibitor, was increased by more than twofold in HCM groups versus control group. Finally, several uremic toxins, including guanidino compounds and protein bound putrescine, accumulated in the circulation of HCM cats.ConclusionsOur study provided evidence of deranged energy metabolism, altered glutathione homeostasis and impaired renal uremic toxin excretion. Altered lipid metabolism suggested perturbed structure and function of cardiac sarcolemma membrane and lipid signalling.

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

Cited by 5 publications

References 52 publications

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

Molecular Mechanisms of Cardiac Development and Disease

Metabolic abnormalities and reprogramming in cats with naturally occurring hypertrophic cardiomyopathy

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