Abstract 18012: Modeling of a Rare SCN10A Variant (A1886V) Linked with Early-Onset Atrial Fibrillation Shortens Atrial Action Potential Duration

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Robert L Abraham ◽  
Eleonora Savio-Galimberti ◽  
Tao Yang ◽  
Dan M Roden ◽  
Dawood Darbar
Keyword(s):  
Atrial Fibrillation ◽  
Action Potential ◽  
Early Onset ◽  
Action Potential Duration ◽  
Markov Models ◽  
Phase 1 ◽  
Electrophysiological Studies ◽  
Synonymous Variant ◽  
Onset Atrial Fibrillation

Introduction: SCN10A encodes the tetrodotoxin-resistant sodium channel isoform Nav1.8, which is variably expressed in neuronal tissue and heart and has been associated with atrial fibrillation (AF). We resequenced the SCN10A gene in 274 early-onset AF probands and identified a rare non-synonymous variant (A1886V) that co-segregated with AF in a kindred. In-vitro electrophysiological studies revealed that this variant displayed a “gain-of-function” phenotype with increased peak (INa-peak) and late (INa-L) sodium currents. Hypothesis: Here, we hypothesized that the increased peak and late INa associated with A1886V variant might modulate atrial action potential duration (APD) and thus increase susceptibility to AF. Methods: We used 2 Clancy-Rudy INa Markov models modified to fit wild-type (WT) and A1886V variant. Modeled currents were incorporated into the Courtemanche-Ramirez-Nattel model of human atrial AP. The overall SCN10A/Nav1.8 contribution to the total INa was simulated in the 5-50% range of WT-SCN5A/Nav1.5 current, and for each overall SCN10A magnitude, the contribution of A1886V compared to WT was simulated in the 0-to-100% range. Cycle-length used was 1000 ms (frequency 1 Hz). Results: While the precise magnitude of SCN10A atrial expression (WT and A1886V) has not yet been determined, simulation of a range of contributions of each component to atrial AP demonstrated incremental morphology changes with removal of the “spike and dome” and triangularization of AP associated with progressive shortening of APD90 (301 ms at 0% SCN10A contribution; 281 ms at 10% SCN10A [100% WT, 0% A1886V]; 261 ms at 10% SCN10A [0% WT, 100% A1886V]) (Table). Conclusion: Computational modeling of A1886V-SCN10A rare variant linked with familial AF surprisingly shortened atrial APD by removal of phase 1 “spike and dome” and augmentation of atrial AP “triangularization”, providing a potential mechanism for increased AF susceptibility.

scholarly journals Atrial fibrillation impairs ventricular function by altering excitation-contraction coupling in the human heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Pabel ◽  
M Knierim ◽  
F Alebrand ◽  
M Paulus ◽  
J Herting ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Patch Clamp ◽  
Action Potential ◽  
Action Potential Duration ◽  
Negative Impact ◽  
Prolonged Action ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Prolonged Action Potential Duration

Abstract   Atrial fibrillation (AF) often co-exists in patients with heart failure (HF). Recent clinical evidence suggests that the arrhythmic component of AF alone may contribute to ventricular dysfunction. However, the pathophysiological effects of a non-tachycardic AF on the human ventricle are unknown. To investigate the effects of normofrequent AF on the human ventricle we investigated ventricular myocardium from patients with preserved ejection fraction with sinus rhythm (SR) or AF in the absence of HF (compensated hypertrophy, EF>50%, matched clinical characteristics). In histological analysis we detected no difference between SR (n=9) vs. AF (n=6) regarding the amount and distribution of fibrosis. For functional investigation, Ca-handling was studied (Fura-2 AM). While systolic Ca-transient amplitude was in trend reduced in isolated human ventricular AF cardiomyocytes, we found a significantly prolonged Ca-elimination time (n=17–22 cells/4 pat.). Using caffeine application, a decreased SR Ca-load in AF was detected, which may be explained by a significant decrease in SERCA2a activity (ksys-kCaff, n=10–12/4 pat.). Patch-clamp experiments revealed a prolonged action potential duration in AF cardiomyocytes (n=5/15 cells). For the standardized evaluation of the mechanisms of persistent normofrequent arrhythmia, we simulated AF in vitro by using arrhythmic (1 Hz, 40% R-R-variability) or rhythmic (1 Hz) field stimulation. We performed contractility experiments using in-toto isolated human ventricular trabeculae from explanted human hearts. After 8h of pacing, arrhythmically stimulated human trabeculae showed a significantly reduced systolic force, an increase in diastolic tension and a prolonged relaxation (n=11–12 trabeculae/11 pat.). For studying the cellular effects of persistent normofrequent arrhythmia in a model suitable for chronic pacing (up to 7 days), we utilized human iPSC cardiomyocytes (iPSC-CM) from healthy donors (n=6). After 7 days, arrhythmic paced iPSC-CM showed a significantly reduced systolic Ca-transient amplitude, a prolonged Ca-elimination time (n=35/45 cells) as well as a reduced SR Ca-load and a trend towards a lower SERCA2a activity compared to control (n=11 cells). Confocal line-scans (Fluo-4 AM) showed an increased diastolic SR Ca-release, which might also explain the reduced SR Ca-content (n=45/35 cells). Moreover, in irregularly paced iPSC-CM we found significant increased levels of cytosolic Na (n=69 cells each) and in patch-clamp experiments a significantly prolonged action potential duration (n=14/11 cells/3 diff.). This study demonstrates that a normofrequent arrhythmic ventricular excitation as it occurs in AF impairs human ventricular myocardial function by altering cardiomyocyte excitation-contraction coupling. Thus, this study provides the first translational mechanistic characterization and the potential negative impact of isolated AF in the absence of tachycardia on the human ventricle. Funding Acknowledgement Type of funding source: None

scholarly journals P496Remodeling of atrial action potential duration and atrial chamber deformation: a potential link in the development of atrial fibrillation?

2018 ◽  
Vol 114 (suppl_1) ◽  
pp. S120-S120
Author(s):  
L Sartiani ◽  
L Sartiani ◽  
M Cameli ◽  
L Dini ◽  
S Modillo ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Action Potential ◽  
Action Potential Duration ◽  
Potential Link

scholarly journals Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

JAMA ◽  
2018 ◽  
Vol 320 (22) ◽  
pp. 2354 ◽  
Author(s):  
Seung Hoan Choi ◽  
Lu-Chen Weng ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
Christopher M. Haggerty ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Loss Of Function ◽  
Onset Atrial Fibrillation

scholarly journals Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation

2017 ◽  
Vol 236 ◽  
pp. 187-193 ◽  
Author(s):  
Krystien V. Lieve ◽  
Arie O. Verkerk ◽  
Svitlana Podliesna ◽  
Christian van der Werf ◽  
Michael W. Tanck ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Ventricular Arrhythmias ◽  
Gain Of Function ◽  
Onset Atrial Fibrillation

scholarly journals Probucol-induced hERG Channel Reduction can be Rescued by Matrine and Oxymatrinein vitro

2020 ◽  
Vol 25 (43) ◽  
pp. 4606-4612 ◽  
Author(s):  
Yuan-Qi Shi ◽  
Pan Fan ◽  
Guo-Cui Zhang ◽  
Yu-Hao Zhang ◽  
Ming-Zhu Li ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Surface Expression ◽  
Herg Channel ◽  
Delayed Rectifier ◽  
Patch Clamp Recording ◽  
Herg Current ◽  
Factor Specificity ◽  
Lowering Drug

Background: The human ether-a-go-go-related gene (hERG) potassium channel is the rapidly activating component of cardiac delayed rectifier potassium current (IKr), which is a crucial determinant of cardiac repolarization. The reduction of hERG current is commonly believed to cause Long QT Syndrome (LQTs). Probucol, a cholesterol-lowering drug, induces LQTs by inhibiting the expression of the hERG channel. Unfortunately, there is currently no effective therapeutic method to rescue probucol-induced LQTs. Methods: Patch-clamp recording techniques were used to detect the action potential duration (APD) and current of hERG. Western blot was performed to measure the expression levels of proteins. Results: In this study, we demonstrated that 1 μM matrine and oxymatrine could rescue the hERG current and hERG surface expression inhibited by probucol. In addition, matrine and oxymatrine significantly shortened the prolonged action potential duration induced by probucol in neonatal cardiac myocytes. We proposed a novel mechanism underlying the probucol induced decrease in the expression of transcription factor Specificity protein 1 (Sp1), which is an established transactivator of the hERG gene. We also demonstrated that matrine and oxymatrine were able to upregulate Sp1 expression which may be one of the possible mechanisms by which matrine and oxymatrine rescued probucol-induced hERG channel deficiency. Conclusion: Our current results demonstrate that matrine and oxymatrine could rescue probucol-induced hERG deficiency in vitro, which may lead to potentially effective therapeutic drugs for treating acquired LQT2 by probucol in the future.

scholarly journals Poor Rhythm Outcome of Catheter Ablation for Early-Onset Atrial Fibrillation in Women　― Mechanistic Insight ―

2018 ◽  
Vol 82 (9) ◽  
pp. 2259-2268 ◽  
Author(s):  
Hee Tae Yu ◽  
Pil-Sung Yang ◽  
Tae-Hoon Kim ◽  
Jae-Sun Uhm ◽  
Jong-Youn Kim ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Catheter Ablation ◽  
Early Onset ◽  
Mechanistic Insight ◽  
Onset Atrial Fibrillation

scholarly journals Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation

2020 ◽  
Vol 13 (8) ◽  
Author(s):  
Mark D. McCauley ◽  
Liang Hong ◽  
Arvind Sridhar ◽  
Ambili Menon ◽  
Srikanth Perike ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Action Potential ◽  
Ion Channel ◽  
Sodium Channel ◽  
Action Potential Duration ◽  
Obese Mice ◽  
Atrial Fibrosis ◽  
Structural Remodeling ◽  
Cardiac Sodium Channel ◽  
Channel Expression

Background: Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing I Na , and enhancing susceptibility to AF. Methods: To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F 2 -isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes. Results: Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls ( P <0.01) with increased AF burden. Cardiac sodium channel expression, I Na and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current ( I Kur ) and F 2 -isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored I Na , I Ca,L , I Kur , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls. Conclusions: Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.

scholarly journals Coding and non-coding variants in the SHOX2 gene in patients with early-onset atrial fibrillation

2016 ◽  
Vol 111 (3) ◽  
Author(s):  
Sandra Hoffmann ◽  
Sebastian Clauss ◽  
Ina M. Berger ◽  
Birgit Weiß ◽  
Antonino Montalbano ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Coding Variants ◽  
Onset Atrial Fibrillation
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