Effect of IKr Blocker Nifekalant on Atrial Action Potential Duration After Successful Internal Cardioversion of Chronic Atrial Fibrillation

Action potential duration (APD) alternans (APD-ALT), defined as beat-to-beat oscillations in APD, has been proposed as an important clinical marker for chronic atrial fibrillation (cAF) risk when it occurs at pacing rates of 120–200 beats/min. Although the ionic mechanisms for occurrence of APD-ALT in human cAF at these clinically relevant rates have been investigated, little is known about the effects of myofilament protein kinetics on APD-ALT. Therefore, we used computer simulations of single cell function to explore whether remodeling in myofilament protein kinetics in human cAF alters the occurrence of APD-ALT and to uncover how these mechanisms are affected by sarcomere length and the degree of cAF-induced myofilament remodeling. Mechanistically based, bidirectionally coupled electromechanical models of human right and left atrial myocytes were constructed, incorporating both ionic and myofilament remodeling associated with cAF. By comparing results from our electromechanical model with those from the uncoupled ionic model, we found that intracellular Ca2+ concentration buffering of troponin C has a dampening effect on the magnitude of APD-ALT (APD-ANM) at slower rates (150 beats/min) due to the cooperativity between strongly bound cross-bridges and Ca2+-troponin C binding affinity. We also discovered that cAF-induced enhanced thin filament activation enhanced APD-ANM at these clinically relevant heart rates (150 beats/min). In addition, longer sarcomere lengths increased APD-ANM, suggesting that atrial stretch is an important modulator of APD-ALT. Together, these findings demonstrate that myofilament kinetics mechanisms play an important role in altering APD-ALT in human cAF. NEW & NOTEWORTHY Using a single cell simulation approach, we explored how myofilament protein kinetics alter the formation of alternans in action potential duration (APD) in human myocytes with chronic atrial fibrillation remodeling. We discovered that enhanced thin filament activation and longer sarcomere lengths increased the magnitude of APD alternans at clinically important pacing rates of 120–200 beats/min. Furthermore, we found that altered intracellular Ca2+ concentration buffering of troponin C has a dampening effect on the magnitude of APD alternans.

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

Cardiovascular Research ◽

10.1093/cvr/cvy060.353 ◽

2018 ◽

Vol 114 (suppl_1) ◽

pp. S120-S120

Author(s):

L Sartiani ◽

M Cameli ◽

L Dini ◽

S Modillo ◽

...

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Action Potential Duration ◽

Potential Link

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Impaired Na+-dependent regulation of acetylcholine-activated inward-rectifier K+ current modulates action potential rate dependence in patients with chronic atrial fibrillation

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2013.03.011 ◽

2013 ◽

Vol 61 ◽

pp. 142-152 ◽

Cited By ~ 26

Author(s):

Niels Voigt ◽

Jordi Heijman ◽

Anne Trausch ◽

Elisa Mintert-Jancke ◽

Lutz Pott ◽

...

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Chronic Atrial Fibrillation ◽

Inward Rectifier ◽

Rate Dependence ◽

K Current ◽

Potential Rate

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Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.120.008296 ◽

2020 ◽

Vol 13 (8) ◽

Cited By ~ 1

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.

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