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Catheter ablation has brought major advances in the management of patients with atrial fibrillation (AF). As evidenced by multiple randomized trials, AF catheter ablation can reduce the risk of recurrent AF and improve quality of life. In some studies, AF ablation significantly reduced cardiovascular hospitalizations. Despite the existing data on AF catheter ablation, numerous knowledge gaps remain concerning this intervention. This report is based on a recent virtual workshop convened by the National Heart, Lung, and Blood Institute to identify key research opportunities in AF ablation. We outline knowledge gaps related to emerging technologies, the relationship between cardiac structure and function and the success of AF ablation in patient subgroups in whom clinical benefit from ablation varies, and potential platforms to advance clinical research in this area. This report also considers the potential value and challenges of a sham ablation randomized trial. Prioritized research opportunities are identified and highlighted to empower relevant stakeholders to collaborate in designing and conducting effective, cost-efficient, and transformative research to optimize the use and outcomes of AF ablation.

Introduction: Atrial fibrillation (AF) is the most common arrhythmia and is associated with deleterious remodelling processes. In AF patients, the plasmatic succinate content increases, indicating a potential role for metabolic remodelling in AF progression. Objective: To assess the impact of succinate on the electrophysiological properties of right atria (RA) in a persistent AF sheep model. Methods: Optical mapping experiments were performed in ex vivo RA from a burst pacing AF sheep model (SHAM=5; AF=5). The right coronary artery was perfused with Tyrode solution initially containing glucose (5.6mM), subsequently replaced by succinate (5mM). Action potential durations at 80% of repolarization (APD80) and mean conduction velocities (CV) were assessed from 2 to 5Hz pacing frequency and during sinus rhythm (SR). An S1S2 protocol was used to determine effective refractory period (ERP) and a burst pacing procotol (20Hz) to assess ex vivo AF vulnerability. Finally, an organ donation program allowed us to investigate these properties in a human RA from an AF patient. Results: SR frequency was higher in AF than SHAM sheep (2.0 vs. 1.6 Hz; p=0.19). Succinate perfusion decreased SR frequency by 18% in SHAM sheep (1.7 vs. 1.4 Hz; p=0.12) and by 43% in AF sheep (2.0 vs. 1.2 Hz; p=0.009). The ERP was lower in AF than SHAM sheep (184 vs. 210 ms; p=0.5) and succinate induced a significant increase of 136% in SHAM sheep (210 vs. 286 ms; p=0.06) and of 188% in AF sheep (184 vs. 346 ms; p=0.0008). Epicardial APD80 was lower when pacing at 2.5Hz in AF than SHAM sheep (165 vs. 197 ms ; p=0.3). Succinate increased APD80 in both SHAM and AF RA (191 to 224 ms; 165 to 231 ms) but its effect was more important in AF than SHAM sheep (148 vs. 117 %; p=0.1). Mean CV was slower in AF sheep than SHAM sheep (110 vs. 130 cm/s; p=0.47). Succinate slowed mean CV on AF sheep (110 vs. 76; p=0.4) but did not affect SHAM RA. In the human RA, APD80 (257 vs; 309 ms) and total activation time were increased by succinate. Conclusions: Our results indicate that succinate alters atrial electrophysiological properties, most likely through the associated ROS overproduction. Importantly, AF sheep showed an increased sensitivity to succinate perfusion. Preliminary data in a human RA are in line with these observations.

Introduction: The best treatment option for the management of patients (pts) with heart failure (HF) and persistent AF is unknown. The AATAC trial showed that catheter ablation (CA) is superior to Amiodarone in achieving freedom from AF at follow up. In this analysis we present the outcome sorted by type of AF procedure. Methods: AATAC was a randomized multicenter study. Pts with persistent AF, dual chamber ICD or CRTD, NYHA II-III and LV EF Results: PVI was performed in 22 patients undergoing ablation, while PVI+PW+NPV ablation was performed in 80 patients. Baseline characteristics were not different between the groups. At 26±8 months follow-up, the success rates in PVI, PVI+PW+NPV, and AMIO groups were 8 [36.4%] and 63 [78.8%] and 34 (34.0%) respectively, p Conclusion: This randomized study shows that PVI alone has a low success rate similar to Amiodarone when compared to PVI plus posterior wall plus non pv trigger in patients with heart failure and persistent AF.

Hypoxic states of the cardiovascular system are often associated with severe cardiac diseases. In spite of impairments in contractile activity, mitochondrial content, cell energy status and calcium transients, we recently demonstrated an improved energy homeostasis in chronic hypoxic hearts explained by a higher mitochondrial sensitivity to ATP/PCr changes, based on combined 31P-NMR spectroscopy and the analytical framework of metabolic control analysis. In the present study, we describe the role of calcium in co-variations in cellular energy status (PCr, ATP) and cardiac work (RPP), in perfused hearts from mice adapted for three weeks to a simulated altitude of 5500 m in a barochamber. Under basal conditions, lower cardiac work and PCr concentration confirmed energetic impairments in chronic hypoxic hearts. At high calcium concentration, cardiac work increased by 40% both in control and hypoxic hearts while a smaller PCr drop in hypoxic hearts, indicating an improved energy homeostasis and higher mitochondrial sensitivity to PCr changes. Stimulating calcium transients by adrenaline and thereby parallel activation of supply and demand components increased cardiac work twice as much only in control hearts (RPP +100%) without any significant PCr variation. The blunted effect of adrenaline in hypoxic hearts is likely the consequence of attenuated ß1-adrenergic receptors stimulation. Inhibition of mitochondrial calcium uniporter by ruthenium red which abolished the mitochondrial-mediated adrenergic regulation was not effective in chronic hearts in contrast of control. We conclude that although chronic hypoxic hearts failed to use calcium transients to optimize their inotropic response to a specific adrenergic stimulation, they present specific adaptation of the energetic homeostasis based on improved energy supply sensitivity. Interestingly this better regulation of the energetic system is not explained by a direct effect of calcium on mitochondria but rather by an optimized metabolic feedback.

Our aim is to propose an inovative non-invasive analysis of heart contraction energetics, to be used for diagnosis and therapeutics follow-up in human heart pathologies. The analysis is based on the combination of non-invasive 31P-NMR and IRM techniques and the analytical background of metabolic modular control analysis (MoCA). Metabolic control analysis’ based approaches have been used by us and others to overcome the complexity of intra-cellular regulations and to describe and quantify controls and regulations in complex systems. We previously demonstrated that MoCA does bring new informations on the interplay between ATP demand and supply in heart contraction energetics. In the present study, MoCA was applied to beating Langendorff perfused guinea pig heart to describe qualitatively and quantitatively the global action of various inotropic effectors effector modifying (Adrenaline) or not (Levosimendan, a calcium-sensitizer; Frank-Starling effect) cytosolic calcium transients. MoCA allows to describe the relative importance of the different routes within the heart by which the inotropic effects are transmitted. The results show that in the absence of calcium transient changes, an energetic feed-back control occurs at the expense of total energy, like in skeletal muscle, while parallel activation of both supply and demand occurs after adrenaline addition, maintaining energy homeostasis (heart energetic paradigm). In conclusion, clinical application of System’s biology to the study of contraction energetics in patients may help to the understanding of the links between molecular events in pathologies and whole organ function / dysfunction.

Background: Persistent/Permanent atrial fibrillation (Per AF) and electromechanical left ventricular (LV) dyssynchrony are frequently associated in patients with systolic heart failure. Their relationships have not been investigated yet. Objective: We hypothesized that Per AF could induce or worsen ventricular dyssynchrony. The aim of this prospective study was to evaluate the degree of LV dyssynchrony in patients with Per AF and depressed LV function; to describe the evolution of dyssynchrony after AF catheter ablation. Methods: 28 patients with isolated Per AF and depressed LV function were investigated with a VIVID7 (General Electric) before ablation (D-1), at 1 month (M+1) and at 6 month (M+6) after the procedure and compared to 28 controls. LV ejection fraction was evaluated by biplane Simpson rule. LV dyssynchrony was quantified by tissue Doppler imaging in apical views using a triplane 3D/4D acquisition. Maximal difference between times to peak (mdTP) was determined. TP was measured as the delays between the onset of the QRS and the peak velocity of systolic wave on the 6 basal LV segments. Values were averaged on 3 consecutive cardiac cycles. LV dyssynchrony was defined for a mdTP value >65ms. Parameters of dyssynchrony were normalized to RR interval. Results: Before ablation, mdTP was >65ms for 10 (36%) of the patients (group1) and >65ms for 18 patients (group 2). Ejection fraction was significantly lower in group 1 than in group 2. During the follow-up, the LV ejection fraction increase was similar in the 2 groups (+42%; +41%)(Table ). In the whole population, mdTP decreased from 57.5±35ms to 44.1±35ms (P Conclusions: In this study, LV dyssynchrony was present in 36% of the patients with permanent AF and impaired LV ejection fraction. Catheter ablation significantly improved both LV ejection fraction and LV dyssynchrony in this population. Table