ArticleJournal of molecular and cellular cardiology2015
T-tubule disruption promotes calcium alternans in failing ventricular myocytes: mechanistic insights from computational modeling.
Article in Journal of molecular and cellular cardiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 56 citations in OpenAlex.
- Metabolic-Electrophysiological Coupling in Heart Failure: from Bidirectional Decoupling to Therapeutic Recoupling.Current heart failure reports · 2025Review
- Ultrastructure and cardiac impulse propagation: scaling up from microscopic to macroscopic conduction.The Journal of physiology · 2025Review
- Desmosomal Junctions and Connexin-43 Remodeling in High-Pacing-Induced Heart Failure Dogs.Anatolian journal of cardiology · 2023Article
- Diversity of cells and signals in the cardiovascular system.The Journal of physiology · 2023Article
- Mechanisms of spontaneous CaThe Journal of physiology · 2023Article
- Cardiac Alternans: From Bedside to Bench and Back.Circulation research · 2023Review
- Modeling Calcium Cycling in the Heart: Progress, Pitfalls, and Challenges.Biomolecules · 2022Review
- Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives.Frontiers in physiology · 2022Review
- Review
- Role of Reduced Sarco-Endoplasmic Reticulum CaFrontiers in physiology · 2021Article
- Mechanisms of Arrhythmogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (Frontiers in cell and developmental biology · 2021Article
- Spatially Discordant Repolarization Alternans in the Absence of Conduction Velocity Restitution.Biophysical journal · 2020Article
- Studying signal compartmentation in adult cardiomyocytes.Biochemical Society transactions · 2020Review
- Remodeling Promotes Proarrhythmic Disruption of Calcium Homeostasis in Failing Atrial Myocytes.Biophysical journal · 2020Article
- Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes.PloS one · 2020Article
- A Novel Computational Model of the Rabbit Atrial Cardiomyocyte With Spatial Calcium Dynamics.Frontiers in physiology · 2020Article
- Multiscale Modeling of Dyadic Structure-Function Relation in Ventricular Cardiac Myocytes.Biophysical journal · 2019Article
- Quantitative systems models illuminate arrhythmia mechanisms in heart failure: Role of the NaWiley interdisciplinary reviews. Systems biology and medicine · 2019Review
- Reduced myocyte complex N-glycosylation causes dilated cardiomyopathy.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Computational modeling of amylin-induced calcium dysregulation in rat ventricular cardiomyocytes.Cell calcium · 2018Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the effects of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in "orphaned" RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down-regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.