ArticleCardiovascular research2007
Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: a simulation study of cellular mechanism.
Article in Cardiovascular research, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 34 citations in OpenAlex.
- An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms ofCirculation · 2020Trial
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- Delayed afterdepolarization-induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves.Physiological reports · 2019Article
- Cardiovascular disease models: A game changing paradigm in drug discovery and screening.Biomaterials · 2019Review
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- The virtual heart as a platform for screening drug cardiotoxicity.British journal of pharmacology · 2015Review
- Ionic mechanisms of arrhythmogenesis.Trends in cardiovascular medicine · 2015Review
- Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition ameliorates arrhythmias elicited by junctin ablation under stress conditions.Heart rhythm · 2015Article
- Na/K pump regulation of cardiac repolarization: insights from a systems biology approach.Pflugers Archiv : European journal of physiology · 2014Review
- Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species.American journal of physiology. Heart and circulatory physiology · 2012Article
- A mathematical model of action potentials of mouse sinoatrial node cells with molecular bases.American journal of physiology. Heart and circulatory physiology · 2011Article
- Local control of β-adrenergic stimulation: Effects on ventricular myocyte electrophysiology and Ca(2+)-transient.Journal of molecular and cellular cardiology · 2011Article
- Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome.American journal of physiology. Heart and circulatory physiology · 2010Article
- Ryanodine receptor-mediated arrhythmias and sudden cardiac death.Pharmacology & therapeutics · 2009Review
- Modeling subunit cooperativity in opening of tetrameric ion channels.Biophysical journal · 2008Article
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2 authors at 1 institution in 1 country.
Funding
Abstract
objectivesPatients with a missense mutation of the calsequestrin 2 gene (CASQ2) are at risk for catecholaminergic polymorphic ventricular tachycardia. This mutation (CASQ2(D307H)) results in decreased ability of CASQ2 to bind Ca2+ in the sarcoplasmic reticulum (SR). In this theoretical study, we investigate a potential mechanism by which CASQ2(D307H) manifests its pro-arrhythmic consequences in patients.
methodsUsing simulations in a model of the guinea pig ventricular myocyte, we investigate the mutation's effect on SR Ca2+ storage, the Ca2+ transient (CaT), and its indirect effect on ionic currents and membrane potential. We model the effects of isoproterenol (ISO) on Ca(V)1.2 (the L-type Ca2+ current, I(Ca(L))) and other targets of beta-adrenergic stimulation.
resultsISO increases I(Ca(L)), prolonging action potential (AP) duration (Control: 172 ms, +ISO: 207 ms, at cycle length of 1500 ms) and increasing CaT (Control: 0.79 microM, +ISO: 1.61 microM). ISO increases I(Ca(L)) by reducing the fraction of channels which undergo voltage-dependent inactivation and increasing transitions from a non-conducting to conducting mode of channel gating. CASQ2(D307H) reduces SR storage capacity, thereby reducing the magnitude of CaT (Control: 0.79 microM, CASQ2(D307H): 0.52 microM, at cycle length of 1500 ms). The combined effect of CASQ2(D307H) and ISO elevates SR free Ca2+ at a rapid rate, leading to store-overload-induced Ca2+ release and delayed afterdepolarization (DAD). If resting membrane potential is sufficiently elevated, the Na+-Ca2+ exchange-driven DAD can trigger I(Na) and I(Ca(L)) activation, generating a triggered arrhythmogenic AP.
conclusionsThe CASQ2(D307H) mutation manifests its pro-arrhythmic consequences due to store-overload-induced Ca2+ release and DAD formation due to excess free SR Ca2+ following rapid pacing and beta-adrenergic stimulation.
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