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      Routine versus aggressive upstream rhythm control for prevention of early atrial fibrillation in heart failure: background, aims and design of the RACE 3 study

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          Abstract

          Background

          Rhythm control for atrial fibrillation (AF) is cumbersome because of its progressive nature caused by structural remodelling. Upstream therapy refers to therapeutic interventions aiming to modify the atrial substrate, leading to prevention of AF.

          Objective

          The Routine versus Aggressive upstream rhythm Control for prevention of Early AF in heart failure (RACE 3) study hypothesises that aggressive upstream rhythm control increases persistence of sinus rhythm compared with conventional rhythm control in patients with early AF and mild-to-moderate early systolic or diastolic heart failure undergoing electrical cardioversion.

          Design

          RACE 3 is a prospective, randomised, open, multinational, multicenter trial. Upstream rhythm control consists of angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers, mineralocorticoid receptor antagonists, statins, cardiac rehabilitation therapy, and intensive counselling on dietary restrictions, exercise maintenance, and drug adherence. Conventional rhythm control consists of routine rhythm control therapy without cardiac rehabilitation therapy and intensive counselling. In both arms, every effort is made to keep patients in the rhythm control strategy, and ion channel antiarrhythmic drugs or pulmonary vein ablation may be instituted if AF relapses. Total inclusion will be 250 patients. If upstream therapy proves to be effective in improving maintenance of sinus rhythm, it could become a new approach to rhythm control supporting conventional pharmacological and non-pharmacological rhythm control.

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          Most cited references26

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          Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats.

          In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6 +/- 3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (> 24 hours) after 7.1 +/- 4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146 +/- 19 to 95 +/- 20 ms (-35%) (S1S1, 400 ms). At high pacing rates the shortening was less (-12%), pointing to a reversion of the normal adaptation of the AERP to heart rate. In 5 goats, after 2 to 4 weeks of AF, sinus rhythm was restored and all electrophysiological changes were found to be reversible within 1 week. Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF. All these changes were completely reversible within 1 week of sinus rhythm.
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            Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study.

            We sought to determine whether structured exercise training (ET) improves maximal exercise capacity, left ventricular diastolic function, and quality of life (QoL) in patients with heart failure with preserved ejection fraction (HFpEF). Nearly one-half of patients with heart failure experience HFpEF, but effective therapeutic strategies are sparse. A total of 64 patients (age 65 ± 7 years, 56% female) with HFpEF were prospectively randomized (2:1) to supervised endurance/resistance training in addition to usual care (ET, n = 44) or to usual care alone (UC) (n = 20). The primary endpoint was the change in peak Vo(2) after 3 months. Secondary endpoints included effects on cardiac structure, diastolic function, and QoL. Peak Vo(2) increased (16.1 ± 4.9 ml/min/kg to 18.7 ± 5.4 ml/min/kg; p < 0.001) with ET and remained unchanged (16.7 ± 4.7 ml/min/kg to 16.0 ± 6.0 ml/min/kg; p = NS) with UC. The mean benefit of ET was 3.3 ml/min/kg (95% confidence interval [CI]: 1.8 to 4.8, p < 0.001). E/e' (mean difference of changes: -3.2, 95% CI: -4.3 to -2.1, p < 0.001) and left atrial volume index (milliliters per square meter) decreased with ET and remained unchanged with UC (-4.0, 95% CI: -5.9 to -2.2, p < 0.001). The physical functioning score (36-Item Short-Form Health Survey) improved with ET and remained unchanged with UC (15, 95% CI: 7 to 24, p < 0.001). The ET-induced decrease of E/e' was associated with 38% gain in peak Vo(2) and 50% of the improvement in physical functioning score. Exercise training improves exercise capacity and physical dimensions of QoL in HFpEF. This benefit is associated with atrial reverse remodeling and improved left ventricular diastolic function. (Exercise Training in Diastolic Heart Failure-Pilot Study: A Prospective, Randomised, Controlled Study to Determine the Effects of Physical Training on Exercise Capacity and Quality of Life [Ex-DHF-P]; ISRCTN42524037). Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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              Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation.

              Structural remodelling occurring before, due to the underlying heart disease, and during atrial fibrillation (AF) sets the stage for permanent AF. Current therapy in AF aims to maintain sinus rhythm in symptomatic patients, but outcome is unfortunately poor. Stretch of the atria is a main contributor to atrial remodelling. In this review, we describe different aspects of structural remodelling as seen in animal models and in patients with AF, including atrial enlargement, cellular hypertrophy, dedifferentiation, fibrosis, apoptosis, and loss of contractile elements. In the second part, we describe downstream signals of mechanical stretch and their contribution to AF and structural remodelling. Ultimately, knowledge of mechanisms underlying structural remodelling may help to identify new pharmacological targets for AF prevention.
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                Author and article information

                Contributors
                +31-50-3611327 , +31-50-3614391 , i.c.van.gelder@umcg.nl
                Journal
                Neth Heart J
                Neth Heart J
                Netherlands Heart Journal
                Bohn Stafleu van Loghum (Houten )
                1568-5888
                1876-6250
                23 May 2013
                23 May 2013
                July 2013
                : 21
                : 7-8
                : 354-363
                Affiliations
                [ ]Department of Cardiology, Amphia Hospital, Breda, the Netherlands
                [ ]Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands
                [ ]Department of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands
                [ ]Department of Cardiology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands
                [ ]Cardiac Rehabilitation Center, University Medical Center Groningen, Groningen, the Netherlands
                [ ]Trial Coordination Center, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
                [ ]University of Birmingham Center for Cardiovascular Sciences, City Hospital, Birmingham, UK
                [ ]Department of Cardiology, University Medical Center Nijmegen, Nijmegen, the Netherlands
                [ ]Department of Cardiology, Martini Hospital Groningen, Groningen, the Netherlands
                [ ]Department of Cardiology, Kennemer Gasthuis, Haarlem, the Netherlands
                [ ]Department of Cardiology, Rijnstate Hospital, Arnhem/Velp, the Netherlands
                Article
                428
                10.1007/s12471-013-0428-5
                3722377
                23700039
                bf740aeb-1428-4acb-b4ed-72b99abc9f96
                © The Author(s) 2013

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Categories
                Design Study Article
                Custom metadata
                © The Author(s) 2013

                Cardiovascular Medicine
                atrial fibrillation,secondary prevention,upstream therapy,heart failure

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