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PROFI5","award":["740264"],"award-info":[{"award-number":["740264"]}]},{"name":"Horizon 2020 Framework Programme of the European Union","award":["321428"],"award-info":[{"award-number":["321428"]}]},{"name":"Horizon 2020 Framework Programme of the European Union","award":["2285733"],"award-info":[{"award-number":["2285733"]}]},{"name":"Horizon 2020 Framework Programme of the European Union","award":["2U01DK062370-15"],"award-info":[{"award-number":["2U01DK062370-15"]}]},{"name":"Horizon 2020 Framework Programme of the European Union","award":["5R01DK093757-10"],"award-info":[{"award-number":["5R01DK093757-10"]}]},{"name":"Horizon 2020 Framework Programme of the European Union","award":["325 022"],"award-info":[{"award-number":["325 022"]}]},{"name":"Horizon 2020 Framework Programme of the European Union","award":["740264"],"award-info":[{"award-number":["740264"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are among the leading causes of sudden cardiac death. We identified 38 pathogenic or likely pathogenic variant carriers for HCM in three sarcomere genes (MYH7, MYBPC3, TPMI) among 9.928 participants of the METSIM Study having whole exome sequencing data available. Eight of them had a clinical diagnosis of HCM. We also identified 20 pathogenic or likely pathogenic variant carriers for DCM in the TTN gene, and six of them had a clinical diagnosis of DCM. The aim of our study was to investigate the metabolite signature in the carriers of the pathogenic or likely pathogenic genetic variants for HCM and DCM, compared to age- and body-mass-index-matched controls. Our novel findings were that the carriers of pathogenic or likely pathogenic variants for HCM had significantly increased concentrations of bradykinin (des-arg 9), vanillactate, and dimethylglycine and decreased concentrations of polysaturated fatty acids (PUFAs) and lysophosphatidylcholines compared with the controls without HCM. Additionally, our novel findings were that the carriers of pathogenic or likely pathogenic variants for DCM had significantly decreased concentrations of 1,5-anhydrogluticol, histidine betaine, N-acetyltryptophan, and methylsuccinate and increased concentrations of trans-4-hydroxyproline compared to the controls without DCM. Our population-based study shows that the metabolite signature of the genetic variants for HCM and DCM includes several novel metabolic pathways not previously described.<\/jats:p>","DOI":"10.3390\/metabo12050437","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T08:37:02Z","timestamp":1652431022000},"page":"437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Metabolite Signature in the Carriers of Pathogenic Genetic Variants for Cardiomyopathy: A Population-Based METSIM Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7994-8547","authenticated-orcid":false,"given":"Rowmika","family":"Ravi","sequence":"first","affiliation":[{"name":"Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0225-842X","authenticated-orcid":false,"given":"Lilian","family":"Fernandes Silva","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagadish","family":"Vangipurapu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maleeha","family":"Maria","sequence":"additional","affiliation":[{"name":"A.I. 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Rev. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.jacc.2015.01.019","article-title":"New perspectives on the prevalence of hypertrophic cardiomyopathy","volume":"65","author":"Semsarian","year":"2015","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1161\/CIRCULATIONAHA.106.174287","article-title":"Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Function","volume":"113","author":"Maron","year":"2006","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/eurheartj\/ehm342","article-title":"Classification of the cardiomyopathies: A position statement from the European Society of Cardiology Working Group on myocardial and pericardial diseases","volume":"29","author":"Elliott","year":"2008","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1111\/joim.12944","article-title":"Dilated cardiomyopathy: From epidemiologic to genetic phenotypes: A translational review of current literature","volume":"286","author":"Reichart","year":"2019","journal-title":"J. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1146\/annurev-genom-083118-015306","article-title":"Advances in the genetic basis and pathogenesis of sarcomere cardiomyopathies","volume":"20","author":"Yotti","year":"2019","journal-title":"Ann. Rev. Genomic. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/ehf2.12420","article-title":"Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy","volume":"6","author":"Vangipurapu","year":"2019","journal-title":"ESC Hearth Fail."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0735-1097(99)00172-2","article-title":"Familial dilated cardiomyopathy: Evidence for genetic and phenotypic heterogeneity","volume":"34","author":"Mestroni","year":"1999","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Stege, N.M., de Boer, R.A., van den Berg, M.P., and Sillj\u00e9, H.H.W. (2021). The time has come to explore plasma biomarkers in genetic cardiomyopathies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062955"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"570421","DOI":"10.3389\/fphys.2020.570421","article-title":"Myocardial energy metabolism in non-ischemic cardiomyopathy","volume":"11","author":"Greenwell","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S388","DOI":"10.21037\/cdt.2019.02.01","article-title":"Hypertrophic cardiomyopathy: Genetics and cellular perspectives","volume":"9","author":"Wolf","year":"2019","journal-title":"Cardiovasc. Diagn. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1161\/CIRCULATIONAHA.121.053575","article-title":"Altered cardiac energetics and mitochondrial dysfunction in hypertrophic cardiomyopathy","volume":"144","author":"Ranjbarvaziri","year":"2021","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-4939-1258-2_1","article-title":"Overview of mass spectrometry-based metabolomics: Opportunities and challenges","volume":"1198","author":"Djukovic","year":"2014","journal-title":"Method Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/ehf2.12133","article-title":"Metabolic profiles in heart failure due to non-ischemic cardiomyopathy at rest and under exercise","volume":"4","author":"Sigl","year":"2017","journal-title":"ESC Heart Fail."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1194\/jlr.O072629","article-title":"The Metabolic Syndrome in Men study: A resource for studies of metabolic and cardiovascular diseases","volume":"58","author":"Laakso","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e002460","DOI":"10.1161\/CIRCGEN.119.002460","article-title":"Evaluating the clinical validity of hypertrophic cardiomyopathy genes","volume":"12","author":"Ingles","year":"2019","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1161\/CIRCULATIONAHA.120.053033","article-title":"Evidence-based assessment of genes in dilated cardiomyopathy","volume":"144","author":"Jordan","year":"2021","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1056\/NEJMoa1110186","article-title":"Truncations of titin causing dilated cardiomyopathy","volume":"366","author":"Herman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/cvr\/cvaa316","article-title":"Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation","volume":"118","author":"Vikhorev","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Deidda, M., Noto, A., Pasqualucci, D., Fattuoni, C., Barberini, L., Piras, C., Bassareo, P.P., Porcu, M., Mercuro, G., and Dessalvi, C.C. (2021). The echocardiographic parameters of systolic function are associated with specific metabolomic fingerprints in obstructive and non-obstructive hypertrophic cardiomyopathy. Metabolites, 11.","DOI":"10.3390\/metabo11110787"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Schuldt, M., van Driel, B., Alg\u00fcl, S., Parbhudayal, R.Y., Barge-Schaapveld, D., G\u00fc\u00e7l\u00fc, A., Jansen, M., Michels, M., Baas, A.F., and van de Wiel, M.A. (2021). Distinct metabolomic signatures in preclinical and obstructive hypertrophic cardiomyopathy. Cells, 10.","DOI":"10.3390\/cells10112950"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"J\u00f8rgenrud, B., Jalanko, M., Heli\u00f6, T., J\u00e4\u00e4skel\u00e4inen, P., Laine, M., Hilvo, M., Nieminen, M.S., Laakso, M., Hy\u00f6tyl\u00e4inen, T., and Ore\u0161i\u010d, M. (2015). The metabolome in Finnish carriers of the MYBPC3-Q1061X mutation for hypertrophic cardiomyopathy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134184"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-2999(00)00046-7","article-title":"Functional characterization of bradykinin analogues on recombinant human bradykinin B(1) and B(2) receptors","volume":"392","author":"Simpson","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/ncpcardio0309","article-title":"Mechanisms of disease: \u03b2-adrenergic receptors\u2014Alterations in signal transduction and pharmacogenomics in heart failure","volume":"2","author":"Feldman","year":"2005","journal-title":"Nat. Clin. Pract. Cardiovasc. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1161\/01.RES.0000102042.83024.CA","article-title":"What is the role of \u03b2-adrenergic signaling in heart failure?","volume":"93","author":"Lohse","year":"2003","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"904","DOI":"10.3389\/fphar.2018.00904","article-title":"New Insights in Cardiac \u03b2-Adrenergic Signaling During Heart Failure and Aging","volume":"9","author":"Eguchi","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s12576-014-0354-3","article-title":"Oscillation of cAMP and Ca2+ in cardiac myocytes: A systems biology approach","volume":"65","author":"Kamide","year":"2015","journal-title":"J. Physiol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1056\/NEJMoa012630","article-title":"Myocardial gene expression in dilated cardiomyopathy treated with \u03b2-blocking agents","volume":"346","author":"Lowes","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1038\/81321","article-title":"Decoding calcium signals involved in cardiac growth and function","volume":"6","author":"Frey","year":"2000","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/BF03402039","article-title":"Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype","volume":"8","author":"Abraham","year":"2002","journal-title":"Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/s41569-020-0381-0","article-title":"Cardiac natriuretic peptides","volume":"17","author":"Goetze","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1161\/HYPERTENSIONAHA.119.12880","article-title":"Sodium reduction, metabolomic profiling, and cardiovascular disease risk in untreated black hypertensives","volume":"74","author":"Chen","year":"2019","journal-title":"Hypertension"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1161\/CIRCRESAHA.112.265819","article-title":"Mitochondria and mitophagy: The yin and yang of cell death control","volume":"111","author":"Kubli","year":"2012","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1146\/annurev.nutr.012809.104810","article-title":"Compartmentalization of mammalian folate-mediated one-carbon metabolism","volume":"30","author":"Tibbetts","year":"2010","journal-title":"Ann. Rev. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"121","DOI":"10.15420\/ecr.2018.13.2.PO2","article-title":"Analysis of the effects of EPA and DHA on cardiomyocyte hypertrophy","volume":"13","author":"Katayama","year":"2018","journal-title":"Eur. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.lfs.2014.04.025","article-title":"Fish oil constituent eicosapentaenoic acid inhibits endothelin-induced cardiomyocyte hypertrophy via PPAR-\u03b1","volume":"118","author":"Shimojo","year":"2014","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D622","DOI":"10.1093\/nar\/gkab1062","article-title":"HMDB 5.0: The Human Metabolome Database for 2022","volume":"50","author":"Wishart","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1161\/01.HYP.0000107779.92645.89","article-title":"Attenuation of lysophosphatidylcholine-induced suppression of ANP release from hypertrophied atria","volume":"43","author":"Han","year":"2004","journal-title":"Hypertension"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1210\/en.2006-1676","article-title":"Calcium-calmodulin kinase II is the common factor in calcium-dependent cardiac expression and secretion of A- and B-type natriuretic peptides","volume":"148","author":"Ronkainen","year":"2007","journal-title":"Endocrinology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1161\/CIRCULATIONAHA.112.134932","article-title":"Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy","volume":"127","author":"Coppini","year":"2013","journal-title":"Circulation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/1475-2840-13-99","article-title":"Low levels of 1,5-anhydro-D-glucitol are associated with vascular endothelial dysfunction in type 2 diabetes","volume":"13","author":"Torimoto","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/nrcardio.2009.130","article-title":"Vascular dysfunction in idiopathic dilated cardiomyopathy","volume":"6","author":"Roura","year":"2009","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1365-2362.2010.02441.x","article-title":"Metabolomic distinction and insights into the pathogenesis of human primary dilated cardiomyopathy","volume":"41","author":"Alexander","year":"2011","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Zhou, T., Chen, X., Li, Z., and Li, L. (2015). Relationship between Serum Bilirubin and Left Ventricular Hypertrophy in Patients with Essential Hypertension. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125275"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/0717-6287-47-7","article-title":"Association of serum total bilirubin levels with diastolic dysfunction in heart failure with preserved ejection fraction","volume":"47","author":"Zheng","year":"2014","journal-title":"Biol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bahls, M., Atzler, D., Markus, M.R.P., Friedrich, N., B\u00f6ger, R.H., V\u00f6lzke, H., Felix, S.B., Schwedhelm, E., and D\u00f6rr, M. (2018). Low-circulating homoarginine is associated with dilatation and decreased function of the left ventricle in the general population. Biomolecules, 8.","DOI":"10.3390\/biom8030063"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1093\/cvr\/cvx242","article-title":"Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine","volume":"114","author":"Faller","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/551037a","article-title":"Biochemistry: The surprising history of an antioxidant","volume":"551","author":"Ruszczycky","year":"2017","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41398-020-0855-1","article-title":"Ergothioneine, a metabolite of the gut bacterium Lactobacillus reuteri, protects against stress-induced sleep disturbances","volume":"10","author":"Matsuda","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41586-019-1457-z","article-title":"Exome sequencing of Finnish isolates enhances rare-variant association power","volume":"572","author":"Locke","year":"2019","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10240","DOI":"10.1038\/s41598-019-46750-3","article-title":"An intronic variant in the GCKR gene is associated with multiple lipids","volume":"9","author":"Vangipurapu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1038\/s41467-022-29143-5","article-title":"Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci","volume":"13","author":"Yin","year":"2022","journal-title":"Nat. Commun."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/5\/437\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:10:09Z","timestamp":1760137809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/5\/437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,13]]},"references-count":53,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["metabo12050437"],"URL":"https:\/\/doi.org\/10.3390\/metabo12050437","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,13]]}}}