Development Of Persistent Atrial Fibrillation Research Articles

Abstract 14782: Expression of Ngf Shrna in the Left Atrial Appendage Alone is Sufficient to Attenuate Global Left Atrial Parasympathetic and Sympathetic Nerve Sprouting and Resulting Development of Persistent Atrial Fibrillation in a Canine Model

Introduction: The autonomic nervous system plays a major role in development of atrial fibrillation (AF), with evidence of marked autonomic remodeling in a canine rapid atrial pacing (RAP) model of AF. Nerve growth factor (NGF), a neurotrophin essential for peripheral neuron growth, was upregulated in fibrillating atria, particularly in the left atrial appendage (LAA). Hypothesis: Inhibiting NGF signaling in the entire atria or the LAA alone can prevent the development of AF. Methods: NGF shRNA was injected in both atria or in the LAA of dogs followed by electroporation to facilitate gene delivery. Animals were subjected to RAP for up to 12 weeks. Duration of AF was recorded. At terminal EP study, residual AF electrograms were recorded in the posterior left atrium, left atrial free wall and LAA for analysis of AF characteristics. Tissue of each region was used for IHC with markers for parasympathetic (acetylcholinesterase) or sympathetic nerves (dopamine beta-hydroxylase). Results: Controls (n=10) developed persistent AF (>8 hours) after a median of 14 days. In contrast, pan-atrial NGF shRNA animals (n=4) never developed this burden of AF. Residual AF was less fractionated (longer fractionation interval), more organized (higher organization index and lower Shannon's entropy) and more homogeneous (coefficient of variation of dominant frequency). RAP-induced nerve bundle hypertrophy and atrial myocardium hyperinnervation was significantly attenuated in pan-atrial NGF shRNA dogs. Importantly, these findings were reproduced when NGF shRNA injection was limited to the LAA alone (n=4), with prevention of development of persistent AF, and global attenuation of left atrial hyperinnervation. Conclusion: Targeted inhibition of atrial autonomic remodeling by NGF shRNA prevents development of persistent AF. NGF Inhibition in the LAA alone is sufficient to attenuate global atrial autonomic remodeling. This approach may lead to a novel, mechanism-guided therapy for AF.

Abstract 15072: Targeted Atrial Inhibition of Parasympathetic Signaling With GiGo Inhibitory Peptides Attenuates Electrical Remodeling and Development of Persistent Atrial Fibrillation in a Canine Model

Background: While vagal contribution to paroxysmal atrial fibrillation (AF) is well demonstrated, a role for parasympathetic signaling in persistent AF is less clear. We have shown marked atrial parasympathetic hyperinnervation in a canine rapid atrial pacing (RAP) model of AF. However, the role of these new nerves in AF development is unknown. Hypothesis: RAP-induced parasympathetic hyperinnervation contributes to the onset and maintenance of AF, and a gene therapy approach inhibiting muscarinic M2 signaling (Gα i and Gα o - GiGo) in the atria can prevent persistent AF. Methods: Plasmids expressing GiGo inhibitory peptides (GiGo_ct) were injected in the atria of 7 dogs followed by electroporation to facilitate gene delivery. RAP was performed for up to 12 weeks. At terminal EP study, residual AF was recorded in the posterior left atrium (PLA), left atrial free wall (LAFW) and left atrial appendage (LAA). Regional atrial ERP was measured. Results: Controls developed ≥30 minutes of AF after a median of 4 days, and persistent AF (≥8 hours) after a median of 14 days. GiGo_ct delayed onset of AF of ≥30 minutes, and attenuated development of persistent AF. ERP was markedly shortened in the PLA and LAA of controls, and this was attenuated by GiGo_ct (p<0.001). Residual AF was slower (lower dominant frequency; PLA 9.4±0.6Hz Vs 11.0±0.7Hz; LAFW 7.8±0.3Hz Vs 10.4±0.7Hz; LAA 8.9±0.6Hz Vs 9.9±0.5Hz p<0.01), less fractionated (longer fractionation interval; PLA 70.0.4±5.2ms Vs 68.1±5.2ms; LAFW 98.8±4.1ms Vs 70.9±3.1ms; LAA 88.9±7.8ms Vs 80.3±2.0ms p<0.01) and more organized (lower Shannon's entropy; p<0.05). Conclusion: Newly sprouted atrial parasympathetic nerves play a functional role in development of persistent AF. Gene-based, selective M2 signaling inhibition by GiGo_ct attenuates electrical remodeling and prevents initiation and maintenance AF. Future optimization of gene therapy targeting autonomic remodeling may lead to novel, mechanism-guided treatments for AF.

Prognostic impact of left atrial function in heart failure with preserved ejection fraction in sinus rhythm vs. atrial fibrillation

Abstract Background Left atrial (LA) function is related with outcome in heart failure with preserved ejection fraction (HFpEF). However, how LA function contributes to outcome in the context of atrial fibrillation (AF) versus sinus rhythm (SR) remains unclear. Purpose To determine the prognostic impact of LA size and phasic function in patients with HFpEF in SR vs. AF. Methods We enrolled consecutive HFpEF patients and assessed indexed LA volumes (LAVi) and emptying fractions (LA-EF) on cardiac magnetic resonance (CMR) imaging. We prospectively followed patients and used Cox regression models to determine the association of LA size and function with a composite endpoint of heart failure hospitalization and cardiovascular death. Results A total of 188 patients (71% female, 70±8 y/o) were included of whom 92 (49%) were in persistent AF (Figure 1A). Patients in persistent AF were older (p=0.017) and had a worse NYHA functional class (p=0.003). Compared to SR, peak and minimal LAVi were increased and LA-EF impaired (each p<0.001 respectively) in persistent AF patients (Figure 2A). A total of 65 patients reached the combined endpoint during a follow-up of 31 (9–57) months. Multivariate Cox regression adjusted for established risk factors revealed that LA-EF was significantly associated with outcome in patients in SR (adj.HR 2.14; 95% CI [1.32–3.47] per 1-SD decline, p=0.002). In persistent AF, however, no LA imaging parameter was related to outcome (Figure 1B). By receiver operating characteristic curve and restricted cubic spline- analyses, we identified an LA-EF ≥40% as best indicator for favorable outcomes in patients with HFpEF and SR (Figure 2B). Persistent AF carried a similar risk for adverse outcome compared to impaired LA-EF (<40%) in SR (log-rank, p=0.340) (Figure 1A). Conclusions In HFpEF patients in SR, impaired LA-EF is independently associated with worse cardiovascular outcome, which is similar to persistent AF. With disease progression including development of persistent AF, LA parameters lose their prognostic ability and thus, are not helpful for further risk stratification. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Dynamic comparisons of epicardial electrograms between the left atrium and pulmonary veins in atrial fibrillation in goat model

Objective: To compare epicardial electrograms between the left atrium (LA) and pulmonary veins (PVs) dynamically at development of persistent atrial fibrillation(AF) in goats PVs. Methods: Ten female goats were instrumented with electrodes at the LA and left side PV. Sustained AF (＞24 h) was induced in the goat by rapid intermittent left atrial pacing for(9.5±2.3)days at a pacing interval of 20 ms for 1 s with a maximum output of 6.0 V, followed by a 2-s period without pacing. Characteristics of PVs and LA epicardial electrograms were analyzed in the development of AF. Results: With prolonged stimulation, the duration of AF was prolonged, complex fractionated atrial electrograms(CFAEs) in LA and was increased gradually, PVs had more CFAEs than LA all the time. When induced AF lasted for more than 24 h, CFAEs in PVs became sustained approximately (2.7%±3.6% vs 92.6%±6.4%, at onset of AF vs AF lasted for more than 24 h, P＜0.05), and the ratio of CFAEs in PVs was more than that in LA (92.6%±6.4% vs 72.8%±5.3%, P＜0.05). Conclusion: The epicardial CFAEs are in specific area, which increase along with electrical remodeling. The epicardial CFAEs may play an important role in the maintenance of AF in this model.

Abstract 14839: High-resolution Spatiotemporal Changes in Dominant Frequency and Structural Organization During Persistent Atrial Fibrillation

Introduction: Spatiotemporal differences in atrial activity are thought to contribute to the maintenance of atrial fibrillation (AF). While recent evidence has identified changes in dominant frequency (DF) during the transition from paroxysmal to persistent AF, little is known about the frequency characteristics of the epicardium during this transition. The purpose of this study was to perform high-resolution mapping of the atrial epicardium and to characterize changes in frequency activity and structural organization during the transition from paroxysmal to persistent AF. Hypothesis: In a porcine model of persistent AF, we tested the hypothesis that the epicardium undergoes spatiotemporal changes in atrial activity and structural organization during persistent AF. Methods: Paroxysmal and persistent AF was induced in adult Yorkshire swine by atrial tachypacing. Atrial morphology was segmented from magnetic resonance imaging and high-resolution patient-specific flexible mapping arrays were 3D printed to match the epicardial contours of the atria. Epicardial activation and DF mapping was performed in four paroxysmal and four persistent AF animals using personalized mapping arrays. Histological analysis was performed to determine structural differences between paroxysmal and persistent AF. Results: The left atrial epicardium was associated with a significant increase in DF between paroxysmal and persistent AF (6.5 ± 0.2 vs. 7.4 ± 0.5 Hz, P = 0.03). High-resolution spatiotemporal mapping identified organized clusters of DF during paroxysmal AF which were lost during persistent AF. The development of persistent AF led to structural remodeling with increased atrial epicardial fibrosis. The organization index (OI) significantly decreased during persistent AF in both the left atria (0.3 ± 0.03 vs. 0.2 ± 0.03, P = 0.01) and right atria (0.33 ± 0.04 vs. 0.23 ± 0.02, P = 0.02). Conclusions: In the porcine model of persistent AF, the epicardium undergoes structural remodeling with increased epicardial fibrosis, reflected by changes in atrial organization index and dominant frequency.

P935Can we predict the occurrence of persistent atrial fibrillation in large animal models to improve study efficiency?

Abstract Funding Acknowledgements British Heart Foundation Project Grant FS/17/54/33126 Background A key consideration when using animals in research is maximising experimental efficiency to minimise the number of animals required. Large animal models have proven an invaluable tool for establishing pathophysiological mechanisms underpinning atrial fibrillation (AF) and testing novel therapeutics, however animals may be resistant to developing the arrhythmias required. While the relationships between atrial refractory periods, conduction velocity, surface area, and vulnerability to fibrillation have been established in clinical practice, these parameters are not regularly used to design animal studies of persistent AF (PsAF). Purpose We investigated whether routinely collected baseline parameters could be used to improve experimental efficiency in an ovine model, by predicting the development of PsAF as opposed to arrhythmia resistance. The aims were to: reduce the number of animals used in future studies, and avoid prolonged experiments in animals likely to be resistant to AF. Methods All procedures were conducted with respect to the Animals [Scientific Procedures] Act, UK, 1986; and were approved by the local ethical review board. The ovine model consisted of healthy adult Welsh mountain sheep that underwent implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 30 second bursts of 50Hz and sheep were monitored over an eight week period for PsAF. Eight variables were collected at time of implant including weight (kg), left atrial diameter (LAD; cm), P wave duration (msec), PR interval (msec), atrial effective refractory period (ERP; msec), atrial conduction velocity (CV; m/s), AF inducibility with 50Hz bursts (secs), and rate threshold of atrial action potential alternans (msec). Analysis of the data was performed using multiple logistic regression and receiver-operator characteristic (ROC) curves. Regression coefficients are presented as natural logarithm of odds ratios (OR) with 95% confidence intervals (CI). Results Seventeen sheep were included in this study. Five (29%) developed PsAF whereas twelve (71%) were resistant (non-sustained or no AF). Univariate analysis found none of the parameters alone could predict PsAF, however ERP (OR -0.05, CI -.01 to 0.01, p = 0.089) and LAD (OR 8.1, CI -1.6 to 17.5, p = 0.095) suggested a combination may be predictive. A multivariate analysis using Fibrillation number (calculated as LAD / [ERP X CV]) was predictive (OR 26.9, CI 1.1 to 52.7; p = 0.04], with an area under ROC curve of 0.85 (p = 0.027). Conclusions Fibrillation number can predict the development of PsAF in healthy sheep. Practically speaking, this means animals with: a larger LAD, shorter ERP and slower CV are more likely to develop PsAF. These findings can be used to optimise the design of future studies, particularly by reducing the number of animals required.

Association of Titin-Truncating Genetic Variants With Life-threatening Cardiac Arrhythmias in Patients With Dilated Cardiomyopathy and Implanted Defibrillators

There is a need for better arrhythmic risk stratification in nonischemic dilated cardiomyopathy (DCM). Titin-truncating variants (TTNtvs) in the TTN gene are the most common genetic cause of DCM and may be associated with higher risk of arrhythmias in patients with DCM. To determine if TTNtv status is associated with the development of life-threatening ventricular arrhythmia and new persistent atrial fibrillation in patients with DCM and implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices. This retrospective, multicenter cohort study recruited 148 patients with or without TTNtvs who had nonischemic DCM and ICD or CRT-D devices from secondary and tertiary cardiology clinics in the United Kingdom from February 1, 2011, to June 30, 2016, with a median (interquartile range) follow-up of 4.2 (2.1-6.5) years. Exclusion criteria were ischemic cardiomyopathy, primary valve disease, congenital heart disease, or a known or likely pathogenic variant in the lamin A/C gene. Analyses were performed February 1, 2017, to May 31, 2017. The primary outcome was time to first device-treated ventricular tachycardia of more than 200 beats/min or first device-treated ventricular fibrillation. Secondary outcome measures included time to first development of persistent atrial fibrillation. Of 148 patients recruited, 117 adult patients with nonischemic DCM and an ICD or CRT-D device (mean [SD] age, 56.9 [12.5] years; 76 [65.0%] men; 106 patients [90.6%] with primary prevention indications) were included. Having a TTNtv was associated with a higher risk of receiving appropriate ICD therapy (shock or antitachycardia pacing) for ventricular tachycardia or fibrillation (hazard ratio [HR], 4.9; 95% CI, 2.2-10.7; P < .001). This association was independent of all covariates, including midwall fibrosis measured by late gadolinium enhancement on cardiac magnetic resonance images (adjusted HR, 8.3; 95% CI, 1.8-37.6; P = .006). Having a TTNtv was also associated with the risk of receiving a shock (HR, 3.6; 95% CI, 1.1-11.6; P = .03). Individuals with a TTNtv and fibrosis had a greater rate of receiving appropriate device therapy than those with neither (HR, 16.6; 95% CI, 3.5-79.3; P < .001). Having a TTNtv was also a risk factor for developing new persistent atrial fibrillation (HR, 3.9; 95% CI, 1.3-12.0; P = .01). Having a TTNtv was an important risk factor for clinically significant arrhythmia in patients with DCM and ICD or CRT-D devices. Having a TTNtv, especially in combination with midwall fibrosis confirmed with cardiovascular magnetic resonance imaging, may provide a risk stratification approach for evaluating the need for ICD therapy in patients with DCM. This hypothesis should be tested in larger studies.

Temporal Changes in Right Ventricular Structure and Function in Patients with Heart Failure and Preserved Ejection Fraction

Background Heart failure with preserved ejection fraction (HFpEF) is often conceptualized as a primary disorder of the left ventricle (LV). No study has evaluated long-term changes in right ventricular (RV) structure and function in HFpEF. Methods Patients with HFpEF (n=271) and controls (n=27) underwent two echocardiographic evaluations >6 months apart (exams 1 and 2). RV dysfunction (RVD) was defined by RV fractional area change (FAC) Results After a median of 4.0 years (IQR 2.0 to 5.9), there was a 10% decline in RV FAC and 21% increase in RV diastolic area in HFpEF (both p Figure 1 ). Of 238 HFpEF patients with normal RV function at exam 1, 55 (23%) developed incident RVD by exam 2. The presence of atrial fibrillation (AF), higher body weight, coronary disease, higher pulmonary artery and LV filling pressures, and RV dilation at exam 1, and the development of persistent AF between exams 1 and 2, were independent predictors of incident RVD. Over a median follow-up of 6.0 years, there were 71 deaths. Patients with HFpEF who developed incident RVD had 2-fold increased risk of death ( Figure 2 and adjusted hazard ratio, 2.08; 95% confidential interval, 1.15-3.64; p=0.02). Conclusions While previous attention has centered on the LV in HFpEF, these data show that right ventricular structure and function deteriorate to greater extent over time as compared to changes in the LV, and worsening RV function is associated with increased mortality. Further study is required to evaluate whether interventions targeting modifiable risk factors for incident RVD, including abnormal hemodynamics, AF, coronary disease and obesity, can prevent RVD and improve outcomes.

Abstract 23094: Titin Truncating Variants Predict Life-threatening Arrhythmias in Patients With Dilated Cardiomyopathy

Introduction: There is an urgent need for better arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy (DCM), where the benefit of ICD implantation is unclear. Titin truncating variants (TTNtv) are the commonest genetic cause of DCM and are associated with early onset non-sustained ventricular tachycardia (NSVT) and atrial fibrillation (AF) in these patients. Hypothesis: We hypothesize that TTNtv status can predict potentially life threatening ventricular tachycardia (VT) or fibrillation (VF) and development of new persistent AF in DCM patients with CRT-D or ICD devices. Methods: We studied 117 DCM patients with an ICD or CRT-D and documented device-recorded arrhythmia over a median period of 4.2 years. Patients were stratified by TTN genotype (28 positive for a TTNtv, 89 negative). The primary outcome was time to first device-treated VT &gt;200bpm or VF. Secondary outcome measures included time to first development of persistent AF. Results: TTNtv predicted the risk of receiving an appropriate ICD therapy for VT/VF (hazard ratio [HR] = 4.9, 95% confidence interval [CI]=2.3-10.7, P&lt;0.0001). This association was independent of all covariates, including replacement fibrosis measured by late-gadolinium enhancement (LGE), (adjusted HR = 8.2, 95% CI 1.9-36.5, P=0.005). Individuals with both a TTNtv and fibrosis had a markedly greater risk for appropriate device therapy than those with neither (HR = 16.6, CI 3.5-79.3, P&lt;0.0001). TTNtv were also a risk factor for developing new persistent AF (HR = 4.4, 95% CI = 1.45-13.1, P=0.006). Conclusion: TTNtv status is an important risk factor for clinically significant arrhythmia in patients with DCM and CRT-D or ICD devices. TTNtv status alone, or more powerfully in combination with fibrosis imaging by MRI, may provide an effective approach for risk stratifying the need for ICD therapy in DCM patients.

CRT-600.04 Left Atrial Volume Index Is the Strongest Predictor of Development of Persistent Atrial Fibrillation in Obese Non-hypertensives

Atrial fibrillation (AF) is associated with a 4-5 fold increased risk of ischemic stroke and a doubled mortality risk and so its prevention is thus of great importance. There are conflicting data if obesity is a risk factor for AF. What are the predictors of development of persistent AF in obese

Effects of carvedilol on cardiac autonomic nerve activities during sinus rhythm and atrial fibrillation in ambulatory dogs

We hypothesized that carvedilol can effectively suppress autonomic nerve activity (ANA) in ambulatory dogs during sinus rhythm and atrial fibrillation (AF), and that carvedilol withdrawal can lead to rebound elevation of ANA. Carvedilol is known to block pre-junctional β2-adrenoceptor responsible for norepinephrine release. We implanted radiotransmitters to record stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and superior left ganglionated plexi nerve activity (SLGPNA) in 12 ambulatory dogs. Carvedilol (12.5 mg orally twice a day) was given for 7 days during sinus rhythm (n = 8). Four of the eight dogs and an additional four dogs were paced into persistent AF. Carvedilol reduced heart rate [from 103 b.p.m. (95% confidence interval (CI), 100-105) to 100 b.p.m. (95% CI, 98-102), P = 0.044], suppressed integrated nerve activities (Int-NAs, SGNA by 17%, VNA by 19%, and SLGPNA by 12%; all P < 0.05 vs. the baseline), and significantly reduced the incidence (from 8 ± 6 to 3 ± 3 episodes/day, P < 0.05) and total duration (from 68 ± 64 to 16 ± 21 s/day, P < 0.05) of paroxysmal atrial tachycardia (PAT). Following the development of persistent AF, carvedilol loading was associated with AF termination in three dogs. In the remaining five dogs, Int-NAs were not significantly suppressed by carvedilol, but SGNA significantly increased by 16% after carvedilol withdrawal (P < 0.001). Carvedilol suppresses ANA and PAT in ambulatory dogs during sinus rhythm.

Persistent Atrial Fibrillation is Associated with a Poor Prognosis in Patients with Atrioventricular Block and Dual‐Chamber Pacemaker

The prognostic significance of development of persistent atrial fibrillation (AF) in patients with atrioventricular (AV) block and dual chamber (DDD) pacemakers has not been separately investigated. We sought to determine whether persistent AF influences clinical outcome in these patients. Three hundred-eight consecutive patients with second- or third-degree AV block and implanted a DDD pacemaker were followed for 36 ± 20 months and retrospectively divided into two groups. Thirty-four patients who developed persistent AF formed persistent AF group, and 278 patients who remained free of this arrhythmia control group. Clinical and outcome data of the two groups were compared. The primary outcome was cardiovascular death. The primary outcome occurred more often among the patients in the persistent AF group (6.8% per year) than among those in the control group (2.9% per year; P = 0.028). This difference was primarily because of higher rate of heart failure-related deaths in the persistent AF group (P = 0.009). Secondary outcomes, hospitalization for heart failure and paroxysmal AF episode ≥5 minutes, occurred also more often among the patients in the persistent AF group (P = 0.008 and P < 0.001, respectively), although the risk of nonfatal stroke was similar in both groups (P = 0.628). In patients with second- or third-degree AV block and DDD pacemaker, the development of persistent AF is associated with an increased risk of cardiovascular death and heart failure.

Abstract 8193: Echocardiographic Predictors of Progression from Paroxysmal to Persistent Atrial Fibrillation: Result from the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II) Study

Background: Several clinical factors such as age, hypertension, and heart failure are known to be associated with progression from paroxysmal to persistent atrial fibrillation (AF). On the other hand, which echocardiographic variables are associated with the progression remains unknown. Method: We used 286 patients in the J-RHYTHM II study, a randomized clinical trial examining effect of calcium channel blocker (amlodipine) and angiotensin receptor blocker (candesartan) in Japanese patients with paroxysmal AF and hypertension. Echocardiographic evaluation was performed at baseline. Left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), left ventricular ejection fraction (LVEF), interventricular septum (IVS), left ventricular posterior wall (LVPW), and left atrial dimension (LAD) were measured in a standard manner. The end point was development of persistent AF, defined as incidence of AF lasting for longer than 7 days and/or need of electrical cardioveresion. Cox proportional hazards models were used to examine the associations between echocardiographic variables and development of persistent AF. Results: Among echocardiographic variables, LVDd, LVDs, and LAD were associated with development of persistent AF (Table). Only LAD was significantly associated with progression from paroxysmal into persistent AF after adjustment by after adjustment by age, sex, and other potential confounding factors. One millimeter increase in LAD was associated with 7% increased risk of developing persistent AF (HR 1.07, 95% CI 1.01-1.14). This means that a 10 mm increase in LAD was associated with twice the risk of developing persistent AF (HR 1.97, 95% CI 1.09-3.58). Conclusion: LAD is associated with progression from paroxysmal to persistent AF in patients with paroxysmal AF and hypertension. LAD may be a good echocardiographic predictor of AF progression.

Trigger-Based Mechanism of the Persistence of Atrial Fibrillation and Its Impact on the Efficacy of Catheter Ablation

We investigated the possibility that a frequent trigger action might play a role in the development of persistent atrial fibrillation (PeAF) and the presence of a substrate. In 263 consecutive patients who underwent catheter ablation (CA) for PeAF, electric cardioversion was performed at the beginning of the procedure to determine the presence or absence of an immediate recurrence of AF (IRAF). We defined an IRAF as a reproducible AF recurrence within 90 s after restoration of sinus rhythm by electric cardioversion. We performed a mean±SD of 1.3±0.5 sessions of CA, including pulmonary vein isolation and ablation of the premature atrial contractions that triggered the IRAF (IRAF triggers), and observed the patients for 17 (10-27) months. An IRAF was observed in 70 patients (27%), but we could not ablate the IRAF triggers in 16 (23%) of these IRAF patients. The recurrence rate of PeAF was higher in patients with an unsuccessful IRAF trigger ablation than in those with successful IRAF trigger ablation (63% versus 11%; P<0.001). A multivariable analysis also revealed that an unsuccessful IRAF trigger ablation was 1 of the independent predictors of recurrent PeAF (odds ratio, 10.9; 95% CI, 3.4-36.7). In the PeAF patients with an IRAF, successful elimination of the IRAF triggers, in addition to pulmonary vein isolation, resulted in a successful CA. These results imply that such triggers play a major role in the AF persistence in these PeAF patients.

Neural mechanisms of atrial arrhythmias

The past 5 years have seen great advances in the knowledge of neural mechanisms of atrial arrhythmogenesis. Direct autonomic nerve recordings demonstrate that simultaneous sympathovagal discharges and intrinsic cardiac nerve activities are common triggers of paroxysmal atrial tachycardia and atrial fibrillation. While activity of the autonomous nervous system (ANS) is crucial in triggering paroxysmal atrial fibrillation, a high incidence of sympathovagal co-activation at baseline is associated with a high vulnerability to pacing-induced sustained atrial fibrillation, suggesting that ANS has a role in the development of persistent atrial fibrillation. Modulation of ANS activity may constitute an important therapeutic strategy for the management of atrial tachyarrhythmias. Specifically, continuous, low-level stimulation of the left cervical vagus nerve effectively suppresses atrial tachyarrhythmias by reducing the nerve activity of the stellate ganglion. Clinically, compared with pulmonary vein isolation alone, the addition of ablation of intrinsic cardiac ganglia may confer better outcomes for patients with paroxysmal atrial fibrillation. These findings suggest that further investigation of the neural mechanisms of atrial arrhythmias might lead to better management of patients with atrial arrhythmias. In this article, we review the role of the ANS in the induction and maintenance of atrial arrhythmias and the role of neural modulation as a treatment strategy for atrial arrhythmias.

Echocardiographic predictors of frequency of paroxysmal atrial fibrillation (AF) and its progression to persistent AF in hypertensive patients with paroxysmal AF: Results from the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study)

Little is known about associations among echocardiographic variables, frequency of atrial fibrillation (AF), and progression from paroxysmal to persistent AF. The purpose of this study was to investigate echocardiographic predictors of frequency of paroxysmal AF and its progression to persistent AF in hypertensive patients with paroxysmal AF. We used data from 286 patients with paroxysmal AF and hypertension in the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study). Echocardiographic evaluation was performed at baseline. Endpoints were (1) percent of AF days measured daily by transtelephonic monitoring over 1 year and (2) development of persistent AF, defined as incidence of AF lasting for longer than 7 days and/or need for electrical cardioversion. Univariate and multivariate linear regression analysis was performed to evaluate the association between echocardiographic variables and percent of AF days. Cox proportional hazards analysis was used to examine the association between echocardiographic variables and development of persistent AF. Among echocardiographic variables, increased left atrial dimension (LAD) was associated with more AF days and development of persistent AF: a 10-mm increase in LAD was associated with a 6.5% increase in AF days (95% confidence interval 2.7%-10.3%) and an 84% increased risk of developing persistent AF (hazard ratio 1.84, 95% confidence interval 1.28-2.67). These associations remained significant after adjustment for age, sex, and other potential confounding factors. Increased LAD is associated with more AF days and progression from paroxysmal to persistent AF in patients with paroxysmal AF and hypertension. Increased LAD may be a good echocardiographic predictor of AF frequency and progression.

Prevention of atrial fibrillation by prevention of ventricular pacing?

This editorial refers to ‘The relationship between right ventricular pacing and atrial fibrillation burden and disease progression in patients with paroxysmal atrial fibrillation: the long-MinVPACE study’ by R.A. Veasey et al., on page 815. Atrial fibrillation (AF) is a frequent problem after pacemaker implantation. It is likely that paroxysmal AF had occurred in many patients before pacemaker insertion but was documented for the first time by stored atrial electrograms of dual-chamber devices. On the other hand, pacing from the right atrial appendage may promote the development of AF by mechanisms such as increased dispersion of atrial refractoriness, or scar tissue formation around the implanted atrial lead. The development of permanent AF after pacemaker implantation for sinus node disease even raises the question whether the device is still needed in this situation. 1 Randomized controlled trials have demonstrated that the incidence of AF is higher with asynchronous right ventricular pacing in the VVI(R) mode compared with dual-chamber pacing. 2 A post hoc analysis of the Mode Selection Trial (MOST) suggested that right ventricular pacing may be responsible for the development of AF, at least in patients with sinus node disease and narrow QRS. 3 In this analysis, a linear association between the percentage of right ventricular pacing and the risk of developing AF was observed especially for dual-chamber pacing. Reports on the development of heart failure with right ventricular pacing confirm and extend these concerns on the risks of unnecessary right ventricular pacing. Can this ‘proarrhythmic’ effect of pacing be prevented? It has been suggested that biventricular pacing might reduce the risk of developing AF with pacing. 4 Post hoc analyses 5 and small studies, 6 however, did not find a reduction in the incidence of AF with cardiac resynchronization therapy compared with right ventricular pacing or standard medical care. In contrast, the systematic prevention of unnecessary right ventricular pacing, facilitated by the use of dedicated pacing algorithms, seems to be associated with a reduction in the occurrence of AF. In the randomized Search AV Extension and managed ventricular Pacing for Promoting Atrioventricular Conduction (SAVE-PACe) trial, prevention of unnecessary right ventricular pacing (present during an average of 99% of the time in the conventional pacing group) was associated with a 40% relative risk reduction for the development of persistent AF. 3 Pacing used to prevent AF has been disappointing in most randomized trials. 7 – 9 In retrospect, this may have been caused by right ventricular pacing that may increase the risk of developing AF. Also biventricular pacing does not seem promising in the prevention of AF. 10 It raises the question: can pacing be more effective in the prevention of AFn if right ventricular pacing is prevented? Some analyses suggest that the reduction in right ventricular pacing may enhance the ability of atrial pacing to prevent AF. In the Pacing In Prevention of Atrial Fibrillation (PIPAF) trial, patients paced in the right ventricle for ,42% of the time had a significant reduction of the cumulative time in AF during atrial preventive pacing, while this effect was absent in patients paced in the ventricle for more than this. 11 In a single-centre experience in 153 patients, right ventricular pacing for ,40% of the time after 1 month was associated with a significantly lower mean AF burden during the following 5 years. 12 In fact, in these patients, AF burden was 6–11% compared with 22– 32% in patients who were paced in the right ventricle for .40% of the time. Other studies did not find this association. In a post hoc analysis in 331 patients from the Atrial Fibrillation Therapy (AFT) trial, AF burden was weakly associated with the percentage of right ventricular pacing with a 0.03% increase in AF burden for every 10% of right ventricular pacing. 13 However, the median percentage of right ventricular pacing in this trial was 97%, rendering any extrapolation questionable. In the same report, data from 79 patients of the Pacemaker Atrial Fibrillation Suppression (PAFS) trial showed no association between the percentage of right ventricular pacing and AF burden. However, the PAFS study consisted of four short (4 weeks each) cross-over study periods with different pacing modalities. Likely, these periods were too short, and there might have been significant carry-over effects. An

Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)

Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension. The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group (P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL. In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

Arrhythmogenic Foci and the Mechanisms of Atrial Fibrillation

In this issue of the Circulation: Arrhythmia and Electrophysiology , Kurotobi et al1 determined the number of arrhythmogenic foci in atria provocable with isoproterenol infusion in patients with paroxysmal, persistent, and permanent atrial fibrillation (AF). The results show that persistent AF has more foci than paroxysmal AF. However, when AF persists for >12 months, the number of foci were reduced. The authors suggest that the increased number of foci probably is involved in the development of persistent AF. However, because this association is not observed for AF that persists for >12 months, the importance of these foci in AF maintenance remains unclear. Article see p 39 In ambulatory canine models, simultaneous sympathovagal discharges (rather than isolated sympathetic activation) are typical triggers of paroxysmal atrial tachycardia (AT) and AF.2,3⇓ These observations are explained by the late phase-3 early afterdepolarization (EAD), which depends on the coexistence of increased amplitude and duration of intracellular calcium (Cai) transient and the shortened action potential duration (APD).4,5⇓ Vagal stimulation shortens APD and therefore is needed to promote the late phase-3 EAD. In the Kurotobi study, however, arrhythmogenic foci were induced by isoproterenol alone, without the need of vagal stimulation or the use of parasympathomimetic agents. These results are different from that obtained in canine studies. The first possible explanation is that the pulmonary veins (PVs) naturally have shorter APDs with elevated (less negative) membrane potentials.6,7⇓ Rapid activation may further shorten the APD in the PVs.8 These changes are independent of the vagal tone. Jais et al9 reported the effective refractory periods of the PVs were shorter …

Persistent atrial fibrillation: current approach and controversies

To address the changing definition of atrial fibrillation as it reflects the major paradigm shift in the comprehension of mechanisms underlying atrial fibrillation and the possible treatment options targeting persistent atrial fibrillation. Persistent atrial fibrillation exists in a spectrum that is linked to paroxysmal atrial fibrillation. The mechanism underlying persistent atrial fibrillation has evolved significantly but requires further understanding in order to improve its management. The role of external factors, such as blood pressure, on the development of persistent atrial fibrillation and its underlying substrate require further exploration. Catheter ablation has evolved significantly but controversy remains regarding the optimal approach for persistent atrial fibrillation. The definition of atrial fibrillation has evolved significantly as a result of knowledge gathered from therapy with catheter ablation for atrial fibrillation. Further trials are required to investigate the causes, mechanisms and optimal therapies for persistent atrial fibrillation.