ArticleCirculation2008
Proarrhythmic defects in Timothy syndrome require calmodulin kinase II.
Article in Circulation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
55 citing papers in PubMed, 87 citations in OpenAlex.
- A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome.Scientific reports · 2024Article
- JOSD2 mediates isoprenaline-induced heart failure by deubiquitinating CaMKIIδ in cardiomyocytes.Cellular and molecular life sciences : CMLS · 2024Article
- Transmural APD heterogeneity determines ventricular arrhythmogenesis in LQT8 syndrome: Insights from Bidomain computational modeling.PloS one · 2024Article
- Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics.Expert reviews in molecular medicine · 2023Review
- CaMKII as a Therapeutic Target in Cardiovascular Disease.Annual review of pharmacology and toxicology · 2023Review
- Unexpected impairment ofNature cardiovascular research · 2023Article
- Inactivation influences the extent of inhibition of voltage-gated CaFrontiers in physiology · 2023Article
- Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome.Nature cardiovascular research · 2022Article
- Calcium Handling Defects and Cardiac Arrhythmia Syndromes.Frontiers in pharmacology · 2020Review
- Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside.Experimental biology and medicine (Maywood, N.J.) · 2019Article
- Computational models in cardiology.Nature reviews. Cardiology · 2019Review
- Methyl-β-Cyclodextrin Impairs the Phosphorylation of the β₂ Subunit of L-Type Calcium Channels and Cytosolic Calcium Homeostasis in Mature Cerebellar Granule Neurons.International journal of molecular sciences · 2018Article
- Calcium Signaling and Cardiac Arrhythmias.Circulation research · 2017Review
- Murine Electrophysiological Models of Cardiac Arrhythmogenesis.Physiological reviews · 2017Review
- Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8:Frontiers in physiology · 2017Article
- Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models.Scientific reports · 2016Article
- Calcium Revisited: New Insights Into the Molecular Basis of Long-QT Syndrome.Circulation. Arrhythmia and electrophysiology · 2016Review
- Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal.Cardiovascular research · 2016Review
- Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation.Nature communications · 2016Article
- Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.Circulation · 2015Article
Corrections and comments
- Commented on by
Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
backgroundTimothy syndrome (TS) is a disease of excessive cellular Ca(2+) entry and life-threatening arrhythmias caused by a mutation in the primary cardiac L-type Ca(2+) channel (Ca(V)1.2). The TS mutation causes loss of normal voltage-dependent inactivation of Ca(V)1.2 current (I(Ca)). During cellular Ca(2+) overload, the calmodulin-dependent protein kinase II (CaMKII) causes arrhythmias. We hypothesized that CaMKII is a part of the proarrhythmic mechanism in TS. METHODS AND
resultsWe developed an adult rat ventricular myocyte model of TS (G406R) by lentivirus-mediated transfer of wild-type and TS Ca(V)1.2. The exogenous Ca(V)1.2 contained a mutation (T1066Y) conferring dihydropyridine resistance, so we could silence endogenous Ca(V)1.2 with nifedipine and maintain peak I(Ca) at control levels in infected cells. TS Ca(V)1.2-infected ventricular myocytes exhibited the signature voltage-dependent inactivation loss under Ca(2+) buffering conditions, not permissive for CaMKII activation. In physiological Ca(2+) solutions, TS Ca(V)1.2-expressing ventricular myocytes exhibited increased CaMKII activity and a proarrhythmic phenotype that included action potential prolongation, increased I(Ca) facilitation, and afterdepolarizations. Intracellular dialysis of a CaMKII inhibitory peptide, but not a control peptide, reversed increases in I(Ca) facilitation, normalized the action potential, and prevented afterdepolarizations. We developed a revised mathematical model that accounts for CaMKII-dependent and CaMKII-independent effects of the TS mutation.
conclusionsIn TS, the loss of voltage-dependent inactivation is an upstream initiating event for arrhythmia phenotypes that are ultimately dependent on CaMKII activation.
Indexed as
Identifiers
What OpenQuestion holds
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.