ArticleCirculation research2013
Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.
Article in Circulation research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals.Clinical research in cardiology : official journal of the German Cardiac Society · 2018Pooled it
- Immature and mature myocardium in the pathophysiology of hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2026Review
- Atrial electrophysiology in hypertrophic cardiomyopathy: current insights and knowledge gaps.Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing · 2026Review
- The Metabolic-Inflammatory Axis in Hypertrophic Cardiomyopathy.JACC. Basic to translational science · 2026Article
- MYOM1 deficiency leads to dilated cardiomyopathy by disrupting the homeostasis of sarcoplasmic reticulum.Redox biology · 2026Article
- Hypercontractility and Oxidative Stress Drive Creatine Kinase Dysfunction in Hypertrophic Cardiomyopathy.Circulation · 2025Article
- Mechano-energetic uncoupling in heart failure.Nature reviews. Cardiology · 2025Review
- Article
- Definitional Challenges in Understanding Hypertrophic Cardiomyopathy.Diagnostics (Basel, Switzerland) · 2024Review
- Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2024Article
- Acute Adenoviral Infection Elicits an Arrhythmogenic Substrate Prior to Myocarditis.Circulation research · 2024Article
- New drug discovery of cardiac anti-arrhythmic drugs: insights in animal models.Scientific reports · 2023Article
- Sarcospan Deficiency Increases Oxidative Stress and Arrhythmias in Hearts after Acute Ischemia-Reperfusion Injury.International journal of molecular sciences · 2023Article
- Mechano-energetic uncoupling in hypertrophic cardiomyopathy: Pathophysiological mechanisms and therapeutic opportunities.Journal of molecular and cellular cardiology plus · 2023Review
- Animal Models to Study Cardiac Arrhythmias.Circulation research · 2022Review
- Translational investigation of electrophysiology in hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology · 2021Article
- Hypertrophic Cardiomyopathy: From Phenotype and Pathogenesis to Treatment.Frontiers in cardiovascular medicine · 2021Review
- Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity-Related Cardiac Defects as a Major Disease Modifier.Journal of the American Heart Association · 2020Review
- Hypertrophic Cardiomyopathy: A Vicious Cycle Triggered by Sarcomere Mutations and Secondary Disease Hits.Antioxidants & redox signaling · 2019Review
- Pathogenic troponin T mutants with opposing effects on myofilament CaArchives of biochemistry and biophysics · 2019Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
rationaleThe Ca(2+) sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca(2+) sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown.
objectiveTo investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility. METHODS AND
resultsUsing hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca(2+) sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca(2+) sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca(2+)-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca(2+) desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias.
conclusionsMyofilament Ca(2+) sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca(2+) sensitivity.
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