ArticleAmerican journal of physiology. Heart and circulatory physiology2012
Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/ΔKPQ hearts suggest an overlap syndrome.
Article in American journal of physiology. Heart and circulatory physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 27 citations in OpenAlex.
- A novel gain-of-function mutationAmerican journal of cardiovascular disease · 2025Article
- Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias.Journal of personalized medicine · 2021Article
- Chenodeoxycholic and deoxycholic acids induced positive inotropic and negative chronotropic effects on rat heart.Naunyn-Schmiedeberg's archives of pharmacology · 2021Article
- Cardiomyocyte Deletion ofFrontiers in physiology · 2021Article
- Cardiac Pacemaker Activity and Aging.Annual review of physiology · 2020Review
- The Genetic Puzzle of Familial Atrial Fibrillation.Frontiers in cardiovascular medicine · 2020Review
- Transverse cardiac slicing and optical imaging for analysis of transmural gradients in membrane potential and CaThe Journal of physiology · 2018Article
- Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1βMechanisms of ageing and development · 2018Article
- Multiple targets for flecainide action: implications for cardiac arrhythmogenesis.British journal of pharmacology · 2018Review
- Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations.International journal of molecular sciences · 2018Article
- Age-dependent electrocardiographic changes in Pgc-1β deficient murine hearts.Clinical and experimental pharmacology & physiology · 2018Article
- Ion channels, long QT syndrome and arrhythmogenesis in ageing.Clinical and experimental pharmacology & physiology · 2017Review
- The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3.Scientific reports · 2017Article
- Heart failure modulates electropharmacological characteristics of sinoatrial nodes.Experimental and therapeutic medicine · 2017Article
- Murine Electrophysiological Models of Cardiac Arrhythmogenesis.Physiological reviews · 2017Review
- High-resolution Optical Mapping of the Mouse Sino-atrial Node.Journal of visualized experiments : JoVE · 2016Article
- Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice.American journal of physiology. Heart and circulatory physiology · 2014Article
- Measurement and interpretation of electrocardiographic QT intervals in murine hearts.American journal of physiology. Heart and circulatory physiology · 2014Article
- C/EBP homologous protein deficiency aggravates acute pancreatitis and associated lung injury.World journal of gastroenterology · 2013Article
- Pathophysiological Mechanisms of Sino-Atrial Dysfunction and Ventricular Conduction Disease Associated with SCN5A Deficiency: Insights from Mouse Models.Frontiers in physiology · 2012Article
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Authors and funding
10 authors at 6 institutions in 3 countries.
Funding
Abstract
Mutations in SCN5A, the gene encoding the pore-forming subunit of cardiac Na(+) channels, cause a spectrum of arrhythmic syndromes. Of these, sinoatrial node (SAN) dysfunction occurs in patients with both loss- and gain-of-function SCN5A mutations. We explored for corresponding alterations in SAN function and intracardiac conduction and clarified possible mechanisms underlying these in an established mouse long QT syndrome type 3 model carrying a mutation equivalent to human SCN5A-ΔKPQ. Electrophysiological characterizations of SAN function in living animals and in vitro sinoatrial preparations were compared with cellular SAN and two-dimensional tissue models exploring the consequences of Scn5a+/ΔKPQ mutations. Scn5a+/ΔKPQ mice showed prolonged electrocardiographic QT and corrected QT intervals confirming long QT phenotypes. They showed frequent episodes of sinus bradycardia, sinus pause/arrest, and significantly longer sinus node recovery times, suggesting compromised pacemaker activity compared with wild-type mice. Electrocardiographic waveforms suggested depressed intra-atrial, atrioventricular node, and intraventricular conduction in Scn5a+/ΔKPQ mice. Isolated Scn5a+/ΔKPQ sinoatrial preparations similarly showed lower mean intrinsic heart rates and overall slower conduction through the SAN to the surrounding atrium than did wild-type preparations. Computer simulations of both single SAN cells as well as two-dimensional SAN-atrial models could reproduce the experimental observations of impaired pacemaker and sinoatrial conduction in terms of changes produced by both augmented tail and reduced total Na(+) currents, respectively. In conclusion, the gain-of-function long QT syndrome type 3 murine Scn5a+/ΔKPQ cardiac system, in overlap with corresponding features reported in loss-of-function Na(+) channel mutations, shows compromised SAN pacemaker and conduction function explicable in modeling studies through a combination of augmented tail and reduced peak Na(+) currents.
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