Regulatory mechanisms of atrial fibrotic remodeling in atrial fibrillation

Lin, Chih‐Sheng; Pan, Chun Hsu

doi:10.1007/s00018-008-7408-8

Cited by 91 publications

(73 citation statements)

References 225 publications

(232 reference statements)

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“…Furthermore, elevation of the H 2 O 2 concentration for up to 2 mM (N=5) in the young/adult hearts still failed to promote EADs and/or atrial ectopic activity consistent with our previous findings [1,7,22] and by Lin CS et al [24]. The discrepancy between the ease of oxidative EAD formation at the single myocyte level isolated from young/adult atria [18,25] and the resistance to EAD formation at the atrial tissue level in young/adult hearts, suggests that atrial tissue factor(s) must have been responsible in the aged tissue to readily promote EAD and EAD-mediated triggered activity.…”

Section: Resultssupporting

confidence: 92%

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

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Background The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (INa-L) blockade. Method and Results High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting. Aged atria (23–24 months) manifested 10-fold increase in atrial tissue fibrosis compared to young/adult (2–4 months) atria (P<0001. Spontaneous AF arose in 39 out of 41 of the aged atria but in 0 out of 12 young/adult hearts (P<001) during arterial perfusion of with 0.1 mm of hydrogen peroxide (H2O2). Optical Action Potential (AP) activation maps showed that the AF was initiated by a focal mechanism in the LA suggestive of EAD-mediated triggered activity. Cellular AP recordings with glass microelectrodes from the LA epicardial sites showing focal activity confirmed optical AP recordings that the spontaneous AF was initiated by late phase 3 EAD-mediated triggered activity. Inhibition of CaMKII activity with KN-93 (1 μM) (N=6) or its downstream target, the enhanced INa-L with GS-967 (1 μM), a specific blocker of INa-L (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to H2O2 (n=6). Conclusions Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity. Specific block of the INa-L with GS-967 effectively suppresses the AF. Drug therapy of oxidative AF in humans with traditional antiarrhythmic drugs remains suboptimal; suppressing INa-L offers a potential new strategy for effective suppression of oxidative human AF that remains suboptimal.

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Section: Resultssupporting

confidence: 92%

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

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“…3,4 Correlative data in biopsy and autopsy specimens from AF patients have demonstrated the presence of atrial fibrosis. 8 -10 Increased amounts of fibrosis were seen in the atria of patients with AF as opposed to those patients in sinus rhythm.…”

Section: Discussionmentioning

confidence: 99%

TGF‐β1 Expression and Atrial Myocardium Fibrosis Increase in Atrial Fibrillation Secondary to Rheumatic Heart Disease

Xiao

Shu

et al. 2010

Clinical Cardiology

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Background:Atrial fibrosis was considered a structural basis for the development and sustaining of atrial fibrillation (AF). Transforming growth factor‐β1 (TGF‐β1) was one of the main factors for accelerating collagen production. The contribution of TGF‐β1 in the pathogenesis of AF needs further investigation.Hypothesis:The altered expression and distribution of TGF‐β1 will be associated with the changes in atrial fibrosis in different types of AF patients with rheumatic heart disease (RHD).Methods:Right atrial specimens obtained from 38 RHD patients undergoing mitral valve replacement surgery were divided into 3 groups: the sinus rhythm group (n = 8), the paroxysmal AF group (pAF; n = 10), and the chronic AF group (cAF; AF lasting ≥ 6 mo; n = 20). The degree of atrial fibrosis, collagen content, serum levels, messenger RNA (mRNA), and protein expression of TGF‐β1 were detected.Results:The collagen content, serum level, TGF‐β1 mRNA, and protein expression of the atrial tissue increased gradually in sinus rhythm, for both pAF and cAF groups, respectively. A positive correlation between TGF‐β1 and the degree of atrial fibrosis was also demonstrated (P < 0.05).Conclusion:The TGF‐β1 expression in atrial tissue increased gradually in proportion to the degree of atrial fibrosis in AF and was associated with the type of AF, which suggests that TGF‐β1 is possibly involved in the pathogenesis of AF in RHD patients. Copyright © 2010 Wiley Periodicals, Inc.

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“…[184][185][186][187] For a full discussion of the complex signaling mechanisms that lead to atrial fibrosis, please see detailed reviews. 167,185,188 Fibrosis can favor atrial arrhythmogenesis in several ways (Figure 4). First, fibrous tissue can physically separate atrial muscle fibers in the longitudinal direction ( Figure 4A), interrupting muscle continuity and creating a physical barrier to conduction.…”

Section: Nature and Role Of Structural Remodelingmentioning

confidence: 99%

The Clinical Profile and Pathophysiology of Atrial Fibrillation

Andrade

Khairy

Dobrev

et al. 2014

Circulation Research

944

364

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Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%–26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca 2+ -handling abnormalities, (3) structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure, myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca 2+ -handling abnormalities that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease. Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to develop improved methods for AF prevention and management.

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Regulatory mechanisms of atrial fibrotic remodeling in atrial fibrillation

Cited by 91 publications

References 225 publications

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

TGF‐β1 Expression and Atrial Myocardium Fibrosis Increase in Atrial Fibrillation Secondary to Rheumatic Heart Disease

The Clinical Profile and Pathophysiology of Atrial Fibrillation

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