The new antiarrhythmic drug vernakalant: ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation

Wettwer, Erich; Christ, Torsten; Endig, S.; Rozmaritsa, Nadiia; Matschke, Klaus; Lynch, Joseph J.; Pourrier, Marc; Gibson, John K.; Fedida, David; Knaut, Michael; Ravens, Ursula

doi:10.1093/cvr/cvt006

Cited by 98 publications

(101 citation statements)

References 38 publications

(50 reference statements)

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“…10 Accordingly, the data from the present study indicate that both drugs slow conduction in all layers in the LV wall to a similar extent. This implicates that Vernakalant also has a potent effect on sodium currents, which is in line with a recent study by Wettwer et al 17 that strongly suggests that the main mode of action of Vernakalant is through the blockage of sodium channels instead of the assumed more potent and atrial selective blockage of I Kur .…”

Section: Electrophysiological Effectssupporting

confidence: 89%

Electrophysiological and Hemodynamic Effects of Vernakalant and Flecainide During Cardiac Resynchronization in Dyssynchronous Canine Hearts

Middendorp

Strik

Houthuizen

et al. 2014

Journal of Cardiovascular Pharmacology

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INTRODUCTION: Patients with heart failure and left bundle branch block (LBBB) are frequently treated with biventricular pacing (BiVP). Approximately one-third of them suffer from atrial fibrillation. Pharmacological conversion of atrial fibrillation is performed with drugs that slow ventricular conduction, but the effects of these drugs on the benefit of BiVP are poorly understood. METHODS: Experiments were performed in dogs with chronic LBBB, investigating the effects of Vernakalant and Flecainide (n = 6 each) on hemodynamics and electrophysiology during epicardial (EPI) and endocardial BiVP. The degree of dyssynchrony and conduction slowing was quantified using QRS width and EPI electrical mapping. RESULTS: Compared with LBBB, EPI and endocardial BiVP reduced QRS duration by 7% ± 9% (P < 0.05 compared with LBBB) and 20% ± 13% (P < 0.05 compared with LBBB, P < 0.05 between modes), respectively. During BiVP, the administration of Vernakalant and Flecainide increased QRS duration by 20% ± 14% (P < 0.05 compared with predrug BiVP) and 34% ± 10% (P < 0.05 compared with predrug BiVP, P < 0.05 between drugs). left ventricular (LV) dP/dtmax decreased by 16% ± 8% (P < 0.05 compared with predrug BiVP) during Vernakalant and by 14% ± 15% (P < 0.05 compared with predrug BiVP) during Flecainide. The drugs did not affect the relative changes in QRS width and LV dP/dtmax induced by BiVP. CONCLUSIONS: Vernakalant and Flecainide decrease contractility, slow myocardial conduction velocity, and increase activation time. The electrical and hemodynamic benefits of BiVP are not altered by the drugs.

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Section: Electrophysiological Effectssupporting

confidence: 89%

Electrophysiological and Hemodynamic Effects of Vernakalant and Flecainide During Cardiac Resynchronization in Dyssynchronous Canine Hearts

Middendorp

Strik

Houthuizen

et al. 2014

Journal of Cardiovascular Pharmacology

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“…158,159 However, recent studies reported reduced peak I Na in patients with AF that could contribute to re-entry-promoting conduction slowing. 160,161 In addition, persistent/late I Na is increased in some studies. 160 Although the exact functional consequences are presently unknown, patients with early-onset lone AF also exhibit a high prevalence of Na + channel mutations that increase persistent/late I Na .…”

Section: Conduction Abnormalities and Structural Remodelingmentioning

confidence: 98%

Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

Heijman

Voigt

Nattel

et al. 2014

Circulation Research

556

603

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Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca 2+ -handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management.

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“…Only small, about 10 to 20% changes in I Na density in atrial myocytes of patients with chronic AF have been detected [151][152]. In atrial tachycardia induced AF animal models, however, a marked decrease in I Na was observed [153].…”

Section: +mentioning

confidence: 99%

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

Baczkó

Leprán

Kiss

et al. 2014

CPD

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Heart failure (HF) is a clinical syndrome characterized by significant impairment of cardiac ventricular function. Atrial fibrillation (AF) is the most commonly observed sustained arrhythmia in clinical practice. Both HF and AF are associated with increased morbidity and mortality and their prevalence increases with age. Approximately 50% of patients with moderate HF die due to ventricular fibrillation that leads to sudden cardiac death. Patients with AF exhibit increased mortality due to HF and stroke. HF and AF often co-exist, and the development of the other condition further deteriorates prognosis. Both chronic HF and AF lead to structural and electrophysiological changes in the heart called remodeling, modifying therapeutic targets including those for antiarrhythmic intervention. Current pharmacological treatment of arrhythmias has major limitations due to low efficacy and serious adverse effects. In this review, the main aspects of electrical remodeling in HF and AF are discussed along with possible novel targets identified for future pharmacological antiarrhythmic therapy.Keywords: Heart failure, atrial fibrillation, cardiac arrhythmias, electrical remodeling, potassium channel expression, multi-channel blocking drugs. I. OVERVIEW AND CURRENT STATUS Epidemiology of Heart Failure, Atrial Fibrillation and their CombinationHeart failure (HF) is a clinical syndrome resulting from a wide range of cardiovascular disorders, featuring significant impairment of cardiac function that leads to reduced ventricular filling or ejection of blood. HF markedly reduces health-related quality of life [1], causes significant morbidity and high mortality and represents an enormous economic burden for the health care system [2]. The incidence of HF is increasing with age, with 20 per 1000 persons 65-69 years old and more than 80 per 1000 persons older than 85 [3] and its prevalence is increasing in a continuously aging population [2]. In spite of the significant advances in the treatment of HF, mortality rates remain poor at approximately 50% of patients dying within 5 years of diagnosis [4]. Serious ventricular arrhythmias are common in HF [5] and approximately 50% of HF patients die due to ventricular fibrillation leading to sudden cardiac death (SCD), the rate of which is several times higher in HF patients compared to the general population [6]. In addition to severe ventricular arrhythmias, atrial arrhythmias often develop in heart failure. Bradycardia can develop due to sinoatrial function impairment [7] that can exacerbate cardiac dysfunction [8], can lead to syncope and haemodynamic collapse and can be resolved by application of implantable devices [9].Atrial fibrillation (AF) is the most common sustained arrhythmia and it is associated with significant morbidity and mortality, especially due to the increased risk of heart failure and stroke [10][11][12]. The prevalence of AF increases with age, with 0.5% of patients affected in the 50 year old range, ~10% over the age of 80 [13] and the prediction is that it...

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The new antiarrhythmic drug vernakalant: ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation

Abstract: Rate-dependent block of Na(+) channels represents the main antiarrhythmic mechanism of vernakalant in the fibrillating atrium. Open channel block of early transient outward currents and IK,ACh could also contribute.

Cited by 98 publications

References 38 publications

Electrophysiological and Hemodynamic Effects of Vernakalant and Flecainide During Cardiac Resynchronization in Dyssynchronous Canine Hearts

Electrophysiological and Hemodynamic Effects of Vernakalant and Flecainide During Cardiac Resynchronization in Dyssynchronous Canine Hearts

Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

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