Therapeutic Target For Atrial Fibrillation Research Articles

Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation

Atrial fibrillation (AF) remains one of the leading causes of morbidity and mortality in the world which are related to palpitations, fainting, congestive heart failure or stroke. The mechanism for atrial fibrillation has been identified as electrical remodeling, structure remodeling and intracellular calcium handling remodeling. microRNAs (miRNAs) have recently emerged as one of the important factors in regulating gene expression. So far, thousands of miRNA genes have been found in diverse animals with the function of regulating cell death, cell proliferation, haematopoiesis and even participate in the processing of cardiovascular disease. In this review, we summarize the mechanism of AF and the association of microRNAs network with AF. We provide a potential perspective of miRNAs as the therapeutic target for AF.

Abstract 18255: Atrial Fibrillation in RyR2-R2474S Mice

Background: Atrial fibrillation (AF) is one of the most common arrhythmias. Despite a wealth of information on the electrical abnormalities present in the working atrial muscle, a detailed understanding of the cellular events that underlie AF is lacking. Methods: To explore the role of ryanodine receptor (RyR2) in triggering AF, we executed in vivo intra-esophageal burst pacing induced AF and in vitro atrial myocyte SR Ca2+ leak measurements in WT and RyR2-R2474S+/- mice. Results: With the in vivo stimulation protocol, 70% of RyR2-R2474S+/- mice could be stimulated into AF whereas WT mice showed no AF (WT: n = 33, R2474S: n = 10, P < 0.05). Confocal Ca2+ imaging in isolated atrial myocytes from these mice showed that atrial myocytes from RyR2-R2474S+/- mice exhibited a 152% increase in SR Ca2+ leak compared to WT (WT: n = 25, R2474S: n=20, P < 0.01). Further, pretreatment of RyR2-R2474S+/- atrial myocytes for 2 hours with 10 µM S107, a 1,4-benzothiazepine derivative that stabilizes RyR2 by inhibiting depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the RyR2 channel (thereby reducing SR Ca2+ leak), resulted in a 68% decrease in diastolic SR Ca2+ leak AF (n = 23, P < 0.05). Administration of S107 treatment via drinking water (20mg/kg/day) for two weeks in RyR2-R2474S+/- mice prevented burst pacing induced-AF (from 70% to 0%) (n = 10 in both groups, P < 0.05). Conclusions: Thus, SR Ca2+ leak via RyR2 plays a critical role in the pathogenesis of AF and may be a novel therapeutic target for AF in humans.

Autonomic Remodeling in the Left Atrium and Pulmonary Veins in Heart Failure

Background— Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF. Methods and Results— Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular–paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and β-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in β 1 -adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. β-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration. Conclusions— In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.

IKACh at the whim of a capricious M2R

<i>I</i>_KACh at the whim of a capricious M2R

BAS/BSCR16 Time-dependent changes in atrial nitric oxide-redox balance in atrial fibrillation: translational research (from goats to humans)

RationaleOxidative stress has an important role in atrial fibrillation (AF)-induced myocardial remodelling, suggesting that specific oxidases may represent a novel therapeutic target in AF. Here we evaluated how the duration...

Diacylglycerol kinase ζ inhibits Gαq-induced atrial remodeling in transgenic mice

Our previous study showed that diacylglycerol kinase zeta (DGKzeta), which degenerates diacylglycerol (DAG), inhibits ventricular structural remodeling and rescues activated G protein (alpha)q (G(alpha)q)-induced heart failure. However, whether DGKzeta inhibits atrial remodeling is still unknown. This study aimed to elucidate the effects of DGKzeta on atrial remodeling. A transgenic mouse (G(alpha)q-TG) with cardiac expression of activated G(alpha)q and a double transgenic mouse (G(alpha)q/DGKzeta-TG) with cardiac overexpression of DGKzeta and activated G(alpha)q were created. During electrocardiogram (ECG) recording for 10 min, atrial fibrillation was observed in 5 of 11 anesthetized G(alpha)q-TG mice but not in any wild-type (WT) and G(alpha)q/DGKzeta-TG mice (P <.05). All of the ECG parameters measured were prolonged in the G(alpha)q-TG compared with WT mice. Interestingly, in G(alpha)q/DGKzeta-TG mice, although the PR and RR intervals were still prolonged, the P interval, QRS complex, and QT interval were not different from those in WT mice. In Langendorff-perfused hearts, the incidence of atrial tachyarrhythmia induced by rapid atrial pacing was greater in G(alpha)q-TG hearts than in G(alpha)q/DGKzeta-TG hearts (P <.05). Action potential duration prolongation and impulse conduction slowing were observed in G(alpha)q-TG atria compared with G(alpha)q/DGKzeta-TG atria. Dilatation of the left atrium with thrombus formation was observed in 9 G(alpha)q-TG hearts but not in any G(alpha)q/DGKzeta-TG hearts. Moreover, the degree of extensive interstitial fibrosis in the left atrium was greater in G(alpha)q-TG hearts than that in G(alpha)q/DGKzeta-TG hearts (P <.05). These results show that DGKzeta inhibits G(alpha)q-induced atrial remodeling and suggest that DGKzeta is a novel therapeutic target for atrial fibrillation.

Anti-M2 muscarinic acetylcholine receptor autoantibodies: New therapeutic targets in atrial fibrillation

Atrial fibrillation is a major and growing public health problem in the world. Heart failure is one of the most common clinical settings for chronic AF. The mechanism underlying AF is still not fully understood. Increasing evidence suggests that activation of G-protein-coupled receptors by autoantibodies may contribute to the pathophysiology of cardiac diseases and stimulatory anti-M2 muscarinic acetylcholine receptor autoantibodies (M2-AABs) were detected in several heart diseases such as dilated cardiomyopathy and Chagas's heart disease. Functional studies have demonstrated that these autoantibodies are able not only to bind to target receptors in the myocardium, but also to induce receptor-mediated biological responses, as partial agonists, which triggers neurotransmitter-receptor-mediated biological effects. Clinical investigation shows that AF was more common in M2-AAB-positive than in M2-AAB-negative patients. Thus, it is a reasonable hypothesis that M2-AABs may participate in the induction and perpetuation of AF. Studies to confirm this hypothesis may lead to new directions in the study of the pathogenesis of AF and the development of a new therapeutic option for this disorder.

Vasculoprotective effects of angiotensin receptor blockers: beyond the renin–angiotensin–aldosterone system?

Vasculoprotective effects of angiotensin receptor blockers: beyond the renin–angiotensin–aldosterone system?

The G Protein–Gated Potassium Current I K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation

The molecular mechanism of increased background inward rectifier current (IK1) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated I(K,ACh) contributes to enhanced basal conductance in chronic AF (cAF). Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective I(K,ACh) blocker tertiapin was used for inhibition of I(K,ACh). Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated I(K,ACh) was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced I(K,ACh) in a concentration-dependent manner with greater potency in cAF than in SR (-logIC50: 9.1 versus 8.2; P<0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at -100 mV: cAF, -6.7+/-1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, -1.7+/-0.5 pA/pF, n=24/8), suggesting contribution of constitutively active I(K,ACh) to basal current. In single-channel recordings, constitutively active I(K,ACh) was prominent in cAF but not in SR (channel open probability: cAF, 5.4+/-0.7%, n=19/9 versus SR, 0.1+/-0.05%, n=16/9; P<0.05). Moreover, IK1 channel open probability was higher in cAF than in SR (13.4+/-0.4%, n=19/9 versus 11.4+/-0.7%, n=16/9; P<0.05) without changes in other channel characteristics. Our results demonstrate that larger basal inward rectifier K+ current in cAF consists of increased IK1 activity and constitutively active I(K,ACh). Blockade of I(K,ACh) may represent a new therapeutic target in AF.

Remodelage électrophysiologique et traitement médicamenteux de la fibrillation atriale

Since 1995, a number of studies have established and detailed the mechanisms of electrical and structural atrial remodeling induced by atrial fibrillation. Atrial remodeling involves many cellular components, from ionic channels to connexins. The determination of these mechanisms may help to define a new therapeutic targets of atrial fibrillation, a frequent arrhythmia that remains difficult to treat. Atrial remodeling prevention may lead to limit the evolution of the arrhythmia (early recurrences after reduction, AF secondary to atrial tachycardia, permanent AF, decrease in atrial contractility, sinus dysfunction). Except amiodarone, the usual antiarrhythmic drugs have no effect on atrial remodeling. Calcium channel inhibitors prevent early remodeling but have no effect on prolonged remodeling. Digoxin increases remodeling. Angiotensin II receptor inhibitors have been shown to prevent early AF recurrence after reduction and are very promising in such a direction. Other methods such as the one of antioxidant therapy seem to be promising and could define soon a new antiarrhythmic therapeutic class, the antiremodeling drugs.

Pharmacological prevention of atrial tachycardia induced atrial remodeling as a potential therapeutic strategy.

Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring medical therapy, and present treatment modalities are inadequate. Over the past few years, we have learned a great deal about the phenomenon of electrical remodeling, by which rapid atrial activation leads to changes in atrial electrical properties that promote AF initiation and maintenance. This knowledge opens up the possibility that electrical remodeling may itself be a novel therapeutic target in AF. The present paper reviews what is known about the basic mechanisms of atrial electrical remodeling and then discusses the experimental and clinical evidence that remodeling can be prevented by drug therapy. Despite great potential value, the development of pharmacological interventions to prevent atrial electrical remodeling is still in its infancy.

Altering the topology of gap junctions a major therapeutic target for atrial fibrillation

Altering the topology of gap junctions a major therapeutic target for atrial fibrillation

Altering the topology of gap junctions a major therapeutic target for atrial fibrillation

Altering the topology of gap junctions a major therapeutic target for atrial fibrillation