An In Silico Cardiomyocyte Reveals the Impact of Changes in CaMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The ai...
| Publicado en: | BioMed Research International Vol. 2024; pp. 1 - 15 |
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| Autores principales: | , , |
| Formato: | equations & formulas pictorial research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
3/25/2024
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=176216134&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 176216134 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 23146133 FT2T jtl: BioMed Research International issn: 23146133 maglogo: N pubinfo: dt: 3/25/2024 vid: 2024 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 176216134 176216134 176216134 10.1155/2024/6160554 176216134 ppf: 1 ppct: 14 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: An In Silico Cardiomyocyte Reveals the Impact of Changes in CaMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy. aug: au: Adeniran, Ismail Wadee, Hafsa Degens, Hans affil: Centre for Advanced Computational Science, Manchester Metropolitan University, Manchester M15 6BH, UK sug: subj: Cardiomyopathy, Hypertrophic Physiopathology Myocardial Contraction Kinetics Signal Transduction Myocytes, Cardiac Phosphotransferases Metabolism Electrophysiology Energy Metabolism Human Models, Biological Ion Channels Calcium Binding Proteins Simulations Phosphocreatine Adenosine Triphosphate Descriptive Statistics ab: Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism, and crossbridge cycling in HCM at the single-cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism, and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by (a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways and (b) increased Ca2+ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine-to-ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half-sarcomere model, we also compared the fraction of detached, weakly bound, and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force-producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply and demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM. pubtype: Academic Journal doctype: equations & formulas pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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