{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T01:38:34Z","timestamp":1790386714549,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["DCVA\u00a0Double\u00a0Dose\u00a02021"],"award-info":[{"award-number":["DCVA\u00a0Double\u00a0Dose\u00a02021"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["91818602"],"award-info":[{"award-number":["91818602"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["20CVD01"],"award-info":[{"award-number":["20CVD01"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"\n Abstract<\/jats:title>\n \n Hypertrophic cardiomyopathy (HCM) caused by heterozygous pathogenic gene variants is characterized by highly variable disease phenotypes. Ageing and systemic metabolic disruption are thought to act as additional \u2018second hits\u2019 that modulate this genotype\u2013phenotype relationship. To define mechanisms through which metabolic and ageing\u2010related stressors may trigger development of HCM, we investigated whether Western diet (WD) feeding or ageing (3, 8.5 and 18\u00a0months) could trigger and\/or aggravate cardiac hypertrophy and dysfunction in targeted knock\u2010in mice harbouring the Dutch heterozygous (HET) c.2373InsG mutation in\n Mybpc3<\/jats:italic>\n encoding cardiac myosin\u2010binding protein C (cMyBP\u2010C). Using cardiac magnetic resonance imaging we revealed impaired relaxation in absence of left ventricular hypertrophy in HET compared to WT mice.\n Mybpc3<\/jats:italic>\n transcript levels were reduced by approximately 50%, but no cMyBP\u2010C haploinsufficiency was observed. Both WD\u2010feeding and ageing did not trigger cardiac hypertrophy or haploinsufficiency in HET\n Mybpc3<\/jats:italic>\n c.2373insG<\/jats:sub>\n mice. Ageing induced cardiac remodelling and peripheral vascular remodelling, which coincided with enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation capacity and increased myocardial perfusion. Noteworthy both mitochondrial function and myocardial perfusion were significantly higher in HET compared to WT mice at a younger age. This study shows that the HET\n Mybpc3<\/jats:italic>\n c.2373insG mice represent a model for early\u2010stage HCM, characterized by impaired relaxation, preserved cMyBP\u2010C protein levels despite reduced\n Mybpc3<\/jats:italic>\n transcripts and early \u2018ageing\u2019\u2010related myocardial changes in energy supply. As WD\u2010feeding and ageing did not trigger hypertrophy or haploinsufficiency, our HET mouse model most likely requires a combination of additional disease stressors to elicit a more severe cardiac phenotype.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Heterozygous (HET)\n Mybpc3<\/jats:italic>\n c.2373insG mice displayed an early\u2010stage HCM phenotype characterized by impaired diastolic function, early mitochondrial alterations and cardiac remodelling, without developing left ventricular hypertrophy; cMyBP\u2010C protein levels were preserved.\n <\/jats:p>\n <\/jats:list-item>\n \n Cardiac magnetic resonance imaging sensitively detected impaired diastolic dysfunction in HET mice.<\/jats:p>\n <\/jats:list-item>\n \n Western diet\u2013induced metabolic stress did not trigger cardiac hypertrophy, worsen dysfunction or impair mitochondrial function in HET mice.<\/jats:p>\n <\/jats:list-item>\n \n Ageing induced systemic, vascular and mitochondrial adaptations, but did not exacerbate cardiac pathology.<\/jats:p>\n <\/jats:list-item>\n \n \n The heterozygous\n Mybpc3<\/jats:italic>\n mutation induced earlier onset of ageing\u2010related myocardial changes in absence of cMyBP\u2010C haploinsufficiency.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp291248","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:22:08Z","timestamp":1788942128000},"page":"7594-7639","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Early\u2010stage myocardial changes are not aggravated by Western diet or ageing in\n Mybpc3<\/i>\n c.2373insG heterozygous mice"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8501-760X","authenticated-orcid":false,"given":"Floor W.","family":"van den Dolder","sequence":"first","affiliation":[{"name":"Department of Physiology Amsterdam UMC, Location VUmc Amsterdam The Netherlands"},{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar E.","family":"Nollet","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, Location VUmc Amsterdam The Netherlands"},{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"},{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3997-241X","authenticated-orcid":false,"given":"Vincent A. J.","family":"Warnaar","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, Location VUmc Amsterdam The Netherlands"},{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentijn J.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, Location VUmc Amsterdam The Netherlands"},{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etto C.","family":"Eringa","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, Location VUmc Amsterdam The Netherlands"},{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3946-653X","authenticated-orcid":false,"given":"Bram F.","family":"Coolen","sequence":"additional","affiliation":[{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"},{"name":"Department of Biomedical Engineering and Physics Amsterdam UMC Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6700-5058","authenticated-orcid":false,"given":"Gustav J.","family":"Strijkers","sequence":"additional","affiliation":[{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"},{"name":"Department of Biomedical Engineering and Physics Amsterdam UMC Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diederik W. D.","family":"Kuster","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, Location VUmc Amsterdam The Netherlands"},{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-5788","authenticated-orcid":false,"given":"Jolanda","family":"van derVelden","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, Location VUmc Amsterdam The Netherlands"},{"name":"Cardiomyopathy and Arrhythmia Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"},{"name":"Netherlands Heart Institute Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2011.01.006"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad194"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.11.018"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00913.2013"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00032"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.114.002411"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.04.009"},{"issue":"1","key":"e_1_2_6_9_1","first-page":"421","article-title":"Cardiac magnetic resonance markers of pre\u2010clinical hypertrophic and dilated cardiomyopathy in genetic variant carriers","volume":"23","author":"Croon P. M.","year":"2025","journal-title":"BioMed Central Medicine"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.3791\/62595"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.03.009"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/procel\/pwae032"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.116.003806"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.116.005604"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000012222.70819.64"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2009.08.658"},{"issue":"2","key":"e_1_2_6_17_1","article-title":"Effects of MYBPC3 loss\u2010of\u2010function mutations preceding hypertrophic cardiomyopathy","volume":"5","author":"Helms A. S.","year":"2020","journal-title":"Journal of Clinical Investigation Insight"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2023.10.008"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv025"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13062-023-00363-z"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.06.011"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119770"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.202440"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00222.2016"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7377"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.88.4.383"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180064"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-2846-8"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.123.016042"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.07.008"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.018641"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmccpl.2023.100050"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad028"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.123.004369"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.20517\/jca.2025.04"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.02.092"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1097\/00019501-199301000-00009"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2021.100069"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.657023"},{"issue":"12","key":"e_1_2_6_40_1","first-page":"2530","article-title":"Comprehensive cardiovascular magnetic resonance diastolic dysfunction grading shows very good agreement compared with echocardiography","volume":"13","author":"Ramos J. G.","year":"2020","journal-title":"Journal of the American College of Cardiology: Cardiovasc Imaging"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.053575"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2021717118"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10974-011-9273-6"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.120.007022"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy531"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24676"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2024.04.010"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00419.2021"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1680-z"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00245"},{"issue":"4","key":"e_1_2_6_51_1","first-page":"511","article-title":"Experimental Models of hypertrophic cardiomyopathy: A systematic review","volume":"10","author":"Dolder F. W.","year":"2025","journal-title":"Journal of the American College of Cardiology Basic Translational Science"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2024.102084"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.727405"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab370"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.838672"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.24424"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa233"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.201251"},{"issue":"11","key":"e_1_2_6_59_1","first-page":"1083","article-title":"Cardiac remodeling in subclinical hypertrophic cardiomyopathy: The VANISH randomized clinical trial","volume":"8","author":"Vissing C. R.","year":"2023","journal-title":"Journal of the American Medical Association Cardiology"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu127"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP291248","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP291248","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP291248","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:07:48Z","timestamp":1789502868000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP291248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":59,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1113\/JP291248"],"URL":"https:\/\/doi.org\/10.1113\/jp291248","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-02-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}