Mechanical Stretch of Atrial Myocyte Monolayer Decreases Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Expression and Increases Susceptibility to Repolarization Alternans

Tsai, Chia Ti; Chiang, Fu-Tien; Tseng, Chuen Den; Yu, Chih Chieh; Wang, Yi Chih; Lai, Ling‐Ping; Hwang, Juey Jen; Lin, Jiunn Lee

doi:10.1016/j.jacc.2011.07.039

Cited by 49 publications

(65 citation statements)

References 22 publications

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“…In vitro and in vivo studies on myocardial tissue have provided evidence for acute stretch-activated Ca 2+ channels which produce functionally significant repolarisation gradients and promote both early and delayed after-depolarisations, thereby predisposing to ventricular arrhythmias [49,50]. Similar results were found in an animal model, in which negative intrathoracic pressure during obstructive respiratory events induced shortening of the right atrial refractory period and consequently increased the susceptibility to premature beats and atrial fibrillation [51].…”

Section: Increased Negative Intrathoracic Pressurementioning

confidence: 71%

Effects of obstructive sleep apnoea on heart rhythm

2012

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Symptomatic obstructive sleep apnoea (OSA) has been proven to be a risk factor for hypertension and vascular dysfunction, and has been proposed to be causally related with cardiac arrhythmias and sudden cardiac death.Searches of bibliographical databases revealed that several mechanisms seem to underpin the association between OSA and cardiac arrhythmias: intermittent hypoxia associated with autonomic nervous system activation and increased oxidative stress, which may lead to cardiac cellular damage and alteration in myocardial excitability; recurrent arousals, resulting in sympathetic activation and coronary vasoconstriction; and increased negative intrathoracic pressure which may mechanically stretch the myocardial walls and, thus, promote acute changes in myocardial excitability as well as structural remodelling of the myocardium.Findings from cross-sectional studies suggest a high prevalence of cardiac arrhythmias in patients with OSA and a high prevalence of OSA in those with cardiac arrhythmias. Preliminary evidence from uncontrolled interventional studies suggests that treatment of OSA may prevent cardiac arrhythmias.In conclusion, there is preliminary evidence that OSA is associated with the development of cardiac arrhythmias. Data from randomised controlled studies are needed to definitively clarify the role of OSA in arrhythmogenesis.

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Section: Increased Negative Intrathoracic Pressurementioning

confidence: 71%

Effects of obstructive sleep apnoea on heart rhythm

2012

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“…However, the development of effective research models of chronic AF is one of the main barriers to elucidating the underlying mechanisms of this arrhythmia and enabling design of effective therapies. Atrial murine immortalized cells (HL-1) under conditions of fast activation rates display some characteristics consistent with fibrillation-related remodeling as those found in atrial tissue from patients with chronic AF (7,30,31).…”

Section: This Is the First Report To Detect Electrophysiological Remomentioning

confidence: 91%

Role of atrial tissue remodeling on rotor dynamics: an in vitro study

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Guillem

Fuentes

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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The objective of this article is to present an in vitro model of atrial cardiac tissue that could serve to study the mechanisms of remodeling related to atrial fibrillation (AF). We analyze the modification on gene expression and modifications on rotor dynamics following tissue remodeling. Atrial murine cells (HL-1 myocytes) were maintained in culture after the spontaneous initiation of AF and analyzed at two time points: 3.1 ± 1.3 and 9.7 ± 0.5 days after AF initiation. The degree of electrophysiological remodeling (i.e., relative gene expression of key ion channels) and structural inhomogeneity was compared between early and late cell culture times both in nonfibrillating and fibrillating cell cultures. In addition, the electrophysiological characteristics of in vitro fibrillation [e.g., density of phase singularities (PS/cm2), dominant frequency, and rotor meandering] analyzed by means of optical mapping were compared with the degree of electrophysiological remodeling. Fibrillating cell cultures showed a differential ion channel gene expression associated with atrial tissue remodeling (i.e., decreased SCN5A, CACN1C, KCND3, and GJA1 and increased KCNJ2) not present in nonfibrillating cell cultures. Also, fibrillatory complexity was increased in late- vs. early stage cultures (1.12 ± 0.14 vs. 0.43 ± 0.19 PS/cm2, P < 0.01), which was associated with changes in the electrical reentrant patterns (i.e., decrease in rotor tip meandering and increase in wavefront curvature). HL-1 cells can reproduce AF features such as electrophysiological remodeling and an increased complexity of the electrophysiological behavior associated with the fibrillation time that resembles those occurring in patients with chronic AF.

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“…[29][30][31] In the diseased atrium, changes in calcium handling have been shown to cause the APD to alternate as a consequence of calcium instabilities. 32 During calciumdependent APD alternans, APD restitution is not necessarily altered. We show here for the first time that APD alternans underlying reentry can be caused by constitutive activation of I K,ACh , which steepens APD restitution.…”

Section: Apd Alternans and Afmentioning

confidence: 99%

Atrium-Specific Kir3.x Determines Inducibility, Dynamics, and Termination of Fibrillation by Regulating Restitution-Driven Alternans

et al. 2013

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Background— Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current ( I K,ACh-c ) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how I K,ACh-c contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of I K,ACh-c blockade and Kir3.x downregulation on atrial fibrillation. Methods and Results— Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3 - or Kcnj5 -specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0 to 128.8±16.9 milliseconds; P <0.0001) in atrial cultures during reentry, indicating the presence of I K,ACh-c . Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0 Hz; P <0.05) and complexity (6.6±7.7 to 0.6±0.8 phase singularities; P <0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of I K,ACh-c prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (eg, >50% reduction in atrial fibrillation inducibility after I K,ACh-c blockade). Conclusions— Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with I K,ACh-c . This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.

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Mechanical Stretch of Atrial Myocyte Monolayer Decreases Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Expression and Increases Susceptibility to Repolarization Alternans

Abstract: Mechanical stretch increased the susceptibility to alternans in atrial myocytes, which may explain the susceptibility to AF in conditions of atrial stretch, such as mitral valvular heart disease, heart failure, and hypertension.

Cited by 49 publications

References 22 publications

Effects of obstructive sleep apnoea on heart rhythm

Effects of obstructive sleep apnoea on heart rhythm

Role of atrial tissue remodeling on rotor dynamics: an in vitro study

Atrium-Specific Kir3.x Determines Inducibility, Dynamics, and Termination of Fibrillation by Regulating Restitution-Driven Alternans

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