Effect of Spironolactone on Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: Post-Hoc Analysis of the Randomized, Placebo-Controlled TOPCAT Trial

Background: Mineralocorticoid receptor antagonists (MRAs) reduce the risk of atrial fibrillation (AF) in patients with heart failure (HF) and a reduced ejection fraction. The efficacy of MRAs for AF prevention in patients with HF and a preserved ejection fraction (HFpEF) is unclear. Objectives: We performed a secondary analysis of a randomized placebo-controlled trial to determine the efficacy of spironolactone in reducing new-onset AF and recurrence of AF in 2733 patients with symptomatic HFpEF. Methods: Patients with and without prevalent AF at baseline were included, and those with permanent AF were excluded. Patients were randomized 1:1 to spironolactone or placebo. The risk of new-onset AF or the recurrence of AF was quantified using hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Results: At baseline, 2228 (64.7%) patients had no history of AF (spironolactone, n = 1111; placebo, n = 1117), whereas 505 (18.4%) patients had prevalent AF (spironolactone, n = 260; placebo, n = 245). During a median follow-up of 3.1 years (interquartile range [IQR] 2.0–4.9), the incidence of new-onset AF was similar in both treatment arms: spironolactone 5.2% (n = 58) versus placebo 4.4% (n = 49); p = 0.41. The risk of new-onset AF was similar in both treatment arms: HR 1.19; 95% CI 0.81–1.74; p = 0.38. AF recurrence was also similar in both treatment arms during a median follow-up of 3.3 years (IQR 1.9–4.7): spironolactone 11.5% (n = 30) versus placebo 11.8% (n = 29); p = 1.00. The risk of recurrence of AF did not differ per treatment arm: HR 0.94; 95% CI 0.57–1.58; p = 0.83. Conclusion: Spironolactone does not reduce the risk of new-onset AF or AF recurrence in patients with HFpEF. This is in contrast to results in cohorts of patients with HF and a reduced ejection fraction. Clinical trial registration: ClinicalTrials.gov identifier no. NCT00094302 (TOPCAT)

MicroRNAs in Atrial Fibrillation: from Expression Signatures to Functional Implications

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with pronounced morbidity and mortality. Its prevalence, expected to further increase for the forthcoming years, and associated frequent hospitalizations turn AF into a major health problem. Structural and electrical atrial remodelling underlie the substrate for AF, but the exact mechanisms driving this remodelling remain incompletely understood. Recent studies have shown that microRNAs (miRNA), short non-coding RNAs that regulate gene expression, may be involved in the pathophysiology of AF. MiRNAs have been implicated in AF-induced ion channel remodelling and fibrosis. MiRNAs could therefore provide insight into AF pathophysiology or become novel targets for therapy with miRNA mimics or anti-miRNAs. Moreover, circulating miRNAs have been suggested as a new class of diagnostic and prognostic biomarkers of AF. However, the origin and function of miRNAs in tissue and plasma frequently remain unknown and studies investigating the role of miRNAs in AF vary in design and focus and even present contradicting results. Here, we provide a systematic review of the available clinical and functional studies investigating the tissue and plasma miRNAs in AF and will thereafter discuss the potential of miRNAs as biomarkers or novel therapeutic targets in A

Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation

Background: Acetylcholine (ACh) shortens action potential duration (APD) in human atria. APD shortening facilitates atrial fibrillation (AF) by reducing the wavelength for reentry. However, the influence of ACh on electrical conduction in human atria and its contribution to AF are unclear, particularly when combined with impaired conduction from interstitial fibrosis. Objective: To investigate the effect of ACh on human atrial conduction and its role in AF with computational, experimental, and clinical approaches. Methods: S1S2 pacing (S1 = 600 ms and S2 = variable cycle lengths) was applied to the following human AF computer models: a left atrial appendage (LAA) myocyte to quantify the effects of ACh on APD, maximum upstroke velocity (Vmax), and resting membrane potential (RMP); a monolayer of LAA myocytes to quantify the effects of ACh on conduction; and 3) an intact left atrium (LA) to determine the effects of ACh on arrhythmogenicity. Heterogeneous ACh and interstitial fibrosis were applied to the monolayer and LA models. To corroborate the simulations, APD and RMP from isolated human atrial myocytes were recorded before and after 0.1 μM ACh. At the tissue level, LAAs from AF patients were optically mapped ex vivo using Di-4-ANEPPS. The difference in total activation time (AT) was determined between AT initially recorded with S1 pacing, and AT recorded during subsequent S1 pacing without (n = 6) or with (n = 7) 100 μM ACh. Results: In LAA myocyte simulations, S1 pacing with 0.1 μM ACh shortened APD by 41 ms, hyperpolarized RMP by 7 mV, and increased Vmax by 27 mV/ms. In human atrial myocytes, 0.1 μM ACh shortened APD by 48 ms, hyperpolarized RMP by 3 mV, and increased Vmax by 6 mV/ms. In LAA monolayer simulations, S1 pacing with ACh hyperpolarized RMP to delay total AT by 32 ms without and 35 ms with fibrosis. This led to unidirectional conduction block and sustained reentry in fibrotic LA with heterogeneous ACh during S2 pacing. In AF patient LAAs, S1 pacing with ACh increased total AT from 39.3 ± 26 ms to 71.4 ± 31.2 ms (p = 0.036) compared to no change without ACh (56.7 ± 29.3 ms to 50.0 ± 21.9 ms, p = 0.140). Conclusion: In fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry

Thoracoscopic surgical atrial fibrillation ablation in patients with an extremely enlarged left atrium

Purpose: Efficacy of pulmonary vein isolation (PVI) for atrial fibrillation (AF) decreases as left atrial (LA) volume increases. However, surgical AF ablation with unknown efficacy is being performed in patients with a giant LA (GLA). We determined efficacy of thoracoscopic AF ablation in patients with compared to without a GLA. Methods: Patients underwent thoracoscopic PVI with additional left atrial ablations lines (in persistent AF) and were prospectively followed up. GLA was defined as LA volume index (LAVI) ≥ 50 ml/m 2. Follow-up was performed with ECGs and 24-h Holters every 3 months. After a 3-month blanking period, all antiarrhythmic drugs were discontinued. The primary outcome was freedom of any atrial tachyarrhythmia ≥ 30 s during 2 years of follow-up. Results: At baseline, 68 (15.4%) patients had a GLA (LAVI: 56.7 [52.4–62.8] ml/m 2), while 374 (84.6%) had a smaller LA (LAVI: 34.8 [29.2–41.3] ml/m 2). GLA patients were older (61.9 ± 6.9 vs 59.4 ± 8.8 years, p = 0.02), more often diagnosed with persistent AF (76.5% vs 58.6%, p = 0.008). Sex was equally distributed (with approximately 25% females). GLA patients had more recurrences compared to non-GLA patients at 2-year follow-up (42.6% vs 57.2%, log rank p = 0.02). Freedom of AF was 69.0% in non-GLA paroxysmal AF patients compared to 43.8–49.3% in a combined group of GLA and/or persistent AF patients(log rank p < 0.001). Furthermore, freedom was 62.4% in non-GLA male patients, compared to 43.8–47.4 in a combined group of GLA and/or female sex(log rank p = 0.02). Conclusion: Thoracoscopic AF ablation is an effective therapy in a substantial part of GLA patients. Thoracoscopic AF ablation may serve as a last resort treatment option in these patients

Quality of life improves after thoracoscopic surgical ablation of advanced atrial fibrillation: Results of the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study

We evaluated health-related quality of life at 12 months after thoracoscopic surgical ablation in patients enrolled in the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery study. The Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery study assessed the efficacy and safety of ganglion plexus ablation in patients with symptomatic advanced atrial fibrillation undergoing thoracoscopic surgical ablation. Patients (n = 240) underwent thoracoscopic pulmonary vein isolation with additional ablation lines in patients with persistent atrial fibrillation. Subjects were randomized to additional ganglion plexus ablation or control. Short Form 36 quality of life questionnaires were collected at baseline and at 6 and 12 months of follow-up. A total of 201 patients were eligible for quality of life analysis (age 59 ± 8 years, 72% were men, 68% had an enlarged left atrium, 57% had persistent atrial fibrillation). Patients improved in physical and mental health at 6 months (both P < .01) and 12 months (both P < .01) relative to baseline, with no difference between the ganglion plexus (n = 101) and control (n = 100) groups. Short Form 36 subscores in patients with 1 or no atrial fibrillation recurrences were similar to those in the general Dutch population after 12 months. Patients with multiple atrial fibrillation recurrences (30%) improved in mental (P < .01), but not physical health, and 6 of 8 Short Form 36 subscales remained below those of the general Dutch population. Patients with irreversible, but not with reversible procedural complications had persistently diminished quality of life scores at 12 months. Thoracoscopic surgery for advanced atrial fibrillation results in improvement in quality of life, regardless of additional ganglion plexus ablation. Quality of life in patients with no or 1 atrial fibrillation recurrence increased to the level of the general Dutch population, whereas in patients with multiple atrial fibrillation recurrences quality of life remained lower. Irreversible but not reversible procedural complications were associated with persistently lower quality of lif

PREventive left atrial appenDage resection for the predICtion of fuTure atrial fibrillation: Design of the PREDICT AF study

Atrial fibrillation is the most common cardiac arrhythmia, posing a heavy burden on patients'wellbeing and healthcare budgets. Patients undergoing cardiac surgery are at risk of developing postoperative atrial fibrillation (POAF), new-onset atrial fibrillation and subsequent atrial fibrillationrelated complications, including stroke. Sufficient clinical identification of patients at risk fails while the pathological substrate changes that precede atrial fibrillation remain unknown. Here, we describe the PREDICT AF study design, which will be the first study to associate tissue pathophysiology and blood biomarkers with clinical profiling and follow-up of cardiothoracic surgery patients for the prediction of future atrial fibrillation. Methods PREDICT AF will include 150 patients without atrial fibrillation and a CHA2DS2-VASc score of at least 2 undergoing cardiac surgery. The left atrial appendage will be excised during surgery and blood samples will be collected before surgery and at 6 and 12 months' follow-up. Tissue and blood analysis will be used for the discovery of biomarkers including microRNAs and protein biomarkers. The primary study endpoint is atrial fibrillation, which will be objectified by 24 h Holters and ECGs after 30 days for POAF and after 6, 12 and 24 months for new-onset atrial fibrillation. Secondary endpoints include the dynamic changes of blood biomarkers over time and other atrial arrhythmias. PREDICT AF participants may benefit from extensive postoperative care with clinical phenotyping, rhythm monitoring and primary prevention of stroke. Conclusion We here describe the PREDICT AF trial design, which will enable the discovery of biomarkers that truly predict POAF and new-onset atrial fibrillation by combining tissue and plasma-derived biomarkers with comprehensive clinical follow-up data

Left atrial strain and recurrence of atrial fibrillation after thoracoscopic surgical ablation: a subanalysis of the AFACT study

To assess transthoracic echocardiographic (TTE) left atrial (LA) strain parameters and their association with atrial fibrillation (AF) recurrence after thoracoscopic surgical ablation (SA) in patients in sinus rhythm (SR) or in AF at baseline. Patients participating in the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery trial were included. All patients underwent thoracoscopic pulmonary vein isolation with LA appendage exclusion and were randomized to ganglion plexus (GP) or no GP ablation. In TTEs performed before surgery, LA strain and mechanical dispersion (MD) of the LA reservoir and conduit phase in all patients, and of the contraction phase in patients in SR were obtained. Recurrence of AF was defined as any documented atrial tachyarrhythmia lasting > 30 s during one year of follow-up. Two hundred and four patients (58.6 ± 7.8 years, 73% male, 57% persistent AF) were included. At baseline TTE 121 (59%) were in SR and 83 (41%) had AF. Patients with AF recurrence had lower LA strain of the reservoir phase (13.0% vs. 16.6%; p = < 0.001) and a less decrease in strain of the conduit phase (−9.0% vs. −11.8%; p = 0.006), regardless of rhythm. MD of the conduit phase was larger in patients with AF recurrence (79.4 vs. 43.5 ms; p = 0.012). Multivariate cox regression analysis demonstrated solely an association between LA strain of the reservoir phase and AF recurrence in patients in SR (HR 0.95, p = 0.046) or with AF (HR 0.90, p = 0.038). A reduction in LA strain of the reservoir phase prior to SA predicts recurrence of AF in both patients with SR or AF. Left atrial strain assessment may therefore add to a better patient selection for SA

Left atrial strain and recurrence of atrial fibrillation after thoracoscopic surgical ablation: a subanalysis of the AFACT study

To assess transthoracic echocardiographic (TTE) left atrial (LA) strain parameters and their association with atrial fibrillation (AF) recurrence after thoracoscopic surgical ablation (SA) in patients in sinus rhythm (SR) or in AF at baseline. Patients participating in the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery trial were included. All patients underwent thoracoscopic pulmonary vein isolation with LA appendage exclusion and were randomized to ganglion plexus (GP) or no GP ablation. In TTEs performed before surgery, LA strain and mechanical dispersion (MD) of the LA reservoir and conduit phase in all patients, and of the contraction phase in patients in SR were obtained. Recurrence of AF was defined as any documented atrial tachyarrhythmia lasting > 30 s during one year of follow-up. Two hundred and four patients (58.6 ± 7.8 years, 73% male, 57% persistent AF) were included. At baseline TTE 121 (59%) were in SR and 83 (41%) had AF. Patients with AF recurrence had lower LA strain of the reservoir phase (13.0% vs. 16.6%; p = < 0.001) and a less decrease in strain of the conduit phase (−9.0% vs. −11.8%; p = 0.006), regardless of rhythm. MD of the conduit phase was larger in patients with AF recurrence (79.4 vs. 43.5 ms; p = 0.012). Multivariate cox regression analysis demonstrated solely an association between LA strain of the reservoir phase and AF recurrence in patients in SR (HR 0.95, p = 0.046) or with AF (HR 0.90, p = 0.038). A reduction in LA strain of the reservoir phase prior to SA predicts recurrence of AF in both patients with SR or AF. Left atrial strain assessment may therefore add to a better patient selection for SA