Block of Na + /Ca 2+ exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation

Because of suboptimal therapeutic strategies, restoration of sinus rhythm in symptomatic atrial fibrillation (AF) often requires in-hospital delivery of high-voltage shocks, thereby precluding ambulatory AF termination. Continuous, rapid restoration of sinus rhythm is desired given the recurring and progressive nature of AF. Here, we present an automated hybrid bioelectronic system for shock-free termination of AF that enables the heart to act as an electric current generator for autogenous restoration of sinus rhythm. We show that local, right atrial delivery of adenoassociated virus vectors encoding a light-gated depolarizing ion channel results in efficient and spatially confined transgene expression. Activation of an implanted intrathoracic light-emitting diode device allows for termination of AF by illuminating part of the atria. Combining this newly obtained antiarrhythmic effector function of the heart with the arrhythmia detector function of a machine-based cardiac rhythm monitor in the closed chest of adult rats allowed automated and rapid arrhythmia detection and termination in a safe, effective, repetitive, yet shock-free manner. These findings hold translational potential for the development of shock-free antiarrhythmic device therapy for ambulatory treatment of AF.

Download Full-text

Abstract 17106: Transition From Adipose to Fibrotic Tissue in the Atrial Subepicardium in Humans and in a Sheep Model of Atrial Fibrillation

Circulation ◽

10.1161/circ.130.suppl_2.17106 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Peter Haemers ◽

Hadhami Hamdi ◽

Piet Claus ◽

Patrick Farahmand ◽

Patrick Bruneval ◽

...

Keyword(s):

Atrial Fibrillation ◽

Adipose Tissue ◽

Histological Study ◽

Artery Bypass ◽

Fatty Infiltration ◽

Inflammatory Cells ◽

Multiple Regression Model ◽

Right Atrial ◽

Human Right ◽

Sheep Model

Epicardial adipose tissue (EAT) is recognized as potentially involved in the pathophysiology of atrial fibrillation (AF). In addition to EAT fatty infiltration commonly observed in myocardium might be also associated with the substrate for AF. We conducted a histological study in 93 human right atrial samples obtained during cardiac surgery and in a sheep model of long-term persistent AF (PAF) induced by atrial tachypacing (24±8 weeks) (15 PAF, 11 SR). Upon Sirius Red and Harris Haematoxylin staining, human atria showed various degree of fatty infiltration starting from the epicardium (rarely from vessels), which could be associated with various degree of subepicardial fibrosis realizing in some cases a true fibro-fatty infiltration. The extent of remodeled epicardium was assessed as % of infiltrating and fibrotic epicardium±adipose tissue to total epicardial length; 44±26 % of the epicardium was remodeled. A multiple regression model (including history of AF, % adipose tissue, age, BodyMassIndex, coronary artery bypass, ejection fraction) significantly predicted the percentage of epicardial remodeling (R=0.501, p=0.003). Only AF and the % adipose tissue were significant predictors (respectively β=0.27;p=0.016 and β=-0.267;p=0.016). To further analyze the relationship between fibro-fatty infiltration and AF, a histological study was performed in LA specimen of a sheep PAF model which revealed 4 grades of subepicardial infiltrates from pure fatty to dense fibro-fatty infiltration (fig A). EAT infiltrates (316) were graded, demonstrating a shift towards more severe grades in the AF group p<0.0001) (fig B). Inflammatory cells were detected in 14 fatty infiltrations (grade 2 and 3) of 6 AF sheep (and only in 1 fatty infiltration of SR sheep). Conclusion: , AF is associated with the transformation of fat into fibro-fatty infiltrations suggesting that the subepicardial adipose tissue plays a role in the atrial fibrotic remodeling.

Download Full-text

Comparison of left versus right atrial myocardium in patients with sinus rhythm or atrial fibrillation - an assessment of mitochondrial function and microRNA expression

Physiological Reports ◽

10.14814/phy2.12124 ◽

2014 ◽

Vol 2 (8) ◽

pp. e12124 ◽

Cited By ~ 12

Author(s):

Katrine Hordnes Slagsvold ◽

Anne Berit Johnsen ◽

Øivind Rognmo ◽

Morten Høydal ◽

Ulrik Wisløff ◽

...

Keyword(s):

Atrial Fibrillation ◽

Sinus Rhythm ◽

Mitochondrial Function ◽

Microrna Expression ◽

Right Atrial ◽

Atrial Myocardium

Download Full-text

Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation

Circulation Research ◽

10.1161/circresaha.121.319425 ◽

2021 ◽

Vol 129 (8) ◽

pp. 804-820

Author(s):

Stephan R. Künzel ◽

Maximilian Hoffmann ◽

Silvio Weber ◽

Karolina Künzel ◽

Susanne Kämmerer ◽

...

Keyword(s):

Atrial Fibrillation ◽

Sinus Rhythm ◽

Knockout Mice ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

De Novo ◽

Low Voltage ◽

Human Fibroblasts ◽

Right Atrial ◽

Atrial Fibrosis

Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways toward effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between PLK2 (polo-like kinase 2) and the profibrotic cytokine OPN (osteopontin) in the pathogenesis of atrial fibrosis and AF. Methods and Results: Atrial PLK2 mRNA expression was 10-fold higher in human fibroblasts than in cardiomyocytes. Compared with sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from patients with AF showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation. Genetic deletion as well as pharmacological inhibition of PLK2 induced profibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN. Accordingly, PLK2-deficient (PLK2 knockout) mice showed cardiac fibrosis and were prone to experimentally induced AF. In line with these findings, OPN plasma levels were significantly higher only in patients with AF with atrial low-voltage zones (surrogates of fibrosis) compared with sinus rhythm controls. Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. Finally, oral treatment with the clinically available drug mesalazine, known to inhibit ERK1/2, prevented cardiac OPN overexpression and reversed the pathological PLK2 knockout phenotype in PLK2 knockout mice. Conclusions: Abnormal PLK2/ERK1/2/OPN axis function critically contributes to AF-related atrial fibrosis, suggesting reinforcing PLK2 activity and/or OPN inhibition as innovative targets to prevent fibrosis progression in AF. Mesalazine derivatives may be used as lead compounds for the development of novel anti-AF agents targeting fibrosis.

Download Full-text

Heterogeneity and Remodeling of Ion Currents in Cultured Right Atrial Fibroblasts From Patients With Sinus Rhythm or Atrial Fibrillation

Frontiers in Physiology ◽

10.3389/fphys.2021.673891 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dorothee Jakob ◽

Alexander Klesen ◽

Elisa Darkow ◽

Fabian A. Kari ◽

Friedhelm Beyersdorf ◽

...

Keyword(s):

Atrial Fibrillation ◽

Patch Clamp ◽

Sinus Rhythm ◽

Cardiac Electrophysiology ◽

Single Channel ◽

Right Atrial ◽

Patch Clamp Technique ◽

Open Probability ◽

Cultured Fibroblasts ◽

Outward Currents

Cardiac fibroblasts express multiple voltage-dependent ion channels. Even though fibroblasts do not generate action potentials, they may influence cardiac electrophysiology by electrical coupling via gap junctions with cardiomyocytes, and through fibrosis. Here, we investigate the electrophysiological phenotype of cultured fibroblasts from right atrial appendage tissue of patients with sinus rhythm (SR) or atrial fibrillation (AF). Using the patch-clamp technique in whole-cell mode, we observed steady-state outward currents exhibiting either no rectification or inward and/or outward rectification. The distributions of current patterns between fibroblasts from SR and AF patients were not significantly different. In response to depolarizing voltage pulses, we measured transient outward currents with fast and slow activation kinetics, an outward background current, and an inward current with a potential-dependence resembling that of L-type Ca2+ channels. In cell-attached patch-clamp mode, large amplitude, paxilline-sensitive single channel openings were found in ≈65% of SR and ∼38% of AF fibroblasts, suggesting the presence of “big conductance Ca2+-activated K+ (BKCa)” channels. The open probability of BKCa was significantly lower in AF than in SR fibroblasts. When cultured in the presence of paxilline, the shape of fibroblasts became wider and less spindle-like. Our data confirm previous findings on cardiac fibroblast electrophysiology and extend them by illustrating differential channel expression in human atrial fibroblasts from SR and AF tissue.

Download Full-text