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Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.

ABSTRACT: The 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.To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility.Using 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.Myofilament 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.

SUBMITTER: Huke S

PROVIDER: S-EPMC3850761 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.

Huke Sabine S Venkataraman Raghav R Faggioni Michela M Bennuri Sirish S Hwang Hyun S HS Baudenbacher Franz F Knollmann Björn C BC

Circulation research 20130326 10

<h4>Rationale</h4>The 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.<h4>Objective</h4>To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility.<h4>Methods and results</h4>Using hypertrophic cardio ...[more]

PMID: 23532597

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Project description:Spontaneous sub-cellular calcium release events (SCRE) are conjectured to promote rapid arrhythmias associated with conditions such as heart failure and atrial fibrillation: they can underlie the emergence of spontaneous action potentials in single cells which can lead to arrhythmogenic triggers in tissue. The multi-scale mechanisms of the development of SCRE into arrhythmia triggers, and their dynamic interaction with the tissue substrate, remain elusive; rigorous and simultaneous study of dynamics from the nanometre to the centimetre scale is a major challenge. The aim of this study was to develop a computational approach to overcome this challenge and study potential bi-directional coupling between sub-cellular and tissue-scale arrhythmia phenomena. A framework comprising a hierarchy of computational models was developed, which includes detailed single-cell models describing spatio-temporal calcium dynamics in 3D, efficient non-spatial cell models, and both idealised and realistic tissue models. A phenomenological approach was implemented to reproduce SCRE morphology and variability in the efficient cell models, comprising the definition of analytical Spontaneous Release Functions (SRF) whose parameters may be randomly sampled from appropriate distributions in order to match either the 3D cell models or experimental data. Pro-arrhythmogenic pacing protocols were applied to initiate re-entry and promote calcium overload, leading to the emergence of SCRE. The SRF accurately reproduced the dynamics of SCRE and its dependence on environment variables under multiple different conditions. Sustained re-entrant excitation promoted calcium overload, and led to the emergence of focal excitations after termination. A purely functional mechanism of re-entry and focal activity localisation was demonstrated, related to the unexcited spiral wave core. In conclusion, a novel approach has been developed to dynamically model SCRE at the tissue scale, which facilitates novel, detailed multi-scale mechanistic analysis. It was revealed that complex re-entrant excitation patterns and SCRE may be bi-directionally coupled, promoting novel mechanisms of arrhythmia perpetuation.

Project description:Background Sodium-calcium (Ca2+) exchanger isoform 1 (NCX1) is the dominant Ca2+ efflux mechanism in cardiomyocytes and is critical to maintaining Ca2+ homeostasis during excitation-contraction coupling. NCX1 activity has been implicated in the pathogenesis of cardiovascular diseases, but a lack of specific NCX1 blockers complicates experimental interpretation. Our aim was to develop a tamoxifen-inducible NCX1 knockout (KO) mouse to investigate compensatory adaptations of acute ablation of NCX1 on excitation-contraction coupling and intracellular Ca2+ regulation, and to examine whether acute KO of NCX1 confers resistance to triggered arrhythmia and ischemia/reperfusion injury. Methods and Results We used the α-myosin heavy chain promoter (Myh6)-MerCreMer promoter to create a tamoxifen-inducible cardiac-specific NCX1 KO mouse. Within 1 week of tamoxifen injection, NCX1 protein expression and current were dramatically reduced. Diastolic Ca2+ increased despite adaptive reductions in Ca2+ current and action potential duration and compensatory increases in excitation-contraction coupling gain, sarcoplasmic reticulum Ca2+ ATPase 2 and plasma membrane Ca2+ ATPase. As these adaptations progressed over 4 weeks, diastolic Ca2+ normalized and SR Ca2+ load increased. Left ventricular function remained normal, but mild fibrosis and hypertrophy developed. Transcriptomics revealed modification of cardiovascular-related gene networks including cell growth and fibrosis. NCX1 KO reduced spontaneous action potentials triggered by delayed afterdepolarizations and reduced scar size in response to ischemia/reperfusion. Conclusions Tamoxifen-inducible NCX1 KO mice adapt to acute genetic ablation of NCX1 by reducing Ca2+ influx, increasing alternative Ca2+ efflux pathways, and increasing excitation-contraction coupling gain to maintain contractility at the cost of mild Ca2+-activated hypertrophy and fibrosis and decreased survival. Nevertheless, KO myocytes are protected against spontaneous action potentials and ischemia/reperfusion injury.

Dataset Information

Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.

Publications

Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.

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