Identification of Subclinical Heart Failure With Preserved Ejection Fraction in Patients With Symptomatic Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. We hypothesize that patients with symptomatic AF but without overt clinical HF commonly exhibit subclinical HFpEF according to established hemodynamic criteria. OBJECTIVES: The authors sought to use invasive hemodynamics to investigate the prevalence and implications of subclinical HFpEF in AF ablation patients. METHODS: Consecutive symptomatic AF ablation patients were prospectively recruited. Diagnosis of subclinical HFpEF was undertaken by invasive assessment of left atrial pressure (LAP). Participants had HFpEF if the baseline mean LAP was >15 mm Hg and early HFpEF if the mean LAP was >15 mm Hg after a 500-mL fluid challenge. LA compliance was assessed invasively by monitoring the LAP and LA diameter during direct LA infusion of 15 mL/kg normal saline. LA compliance was calculated as Δ LA diameter/ΔLAP. LA cardiomyopathy was further studied with exercise echocardiography and electrophysiology study. Functional impact was evaluated using cardiopulmonary exercise testing and the AF Symptom Severity questionnaire. RESULTS: Of 120 participants, 57 (47.5%) had HFpEF, 31 (25.8%) had early HFpEF, and 32 (26.7%) had no HFpEF. Both HFpEF and early HFpEF were associated with lower LA compliance compared with those without HFpEF (P < 0.001). Participants with HFpEF and early HFpEF also displayed decreased LA emptying fraction (P = 0.004), decreased LA voltage (P = 0.001), decreased VO2peak (P < 0.001), and increased AF symptom burden (P = 0.002) compared with those without HFpEF. CONCLUSIONS: Subclinical HFpEF is common in AF ablation patients and is characterized by a LA cardiomyopathy, decreased cardiopulmonary reserve and increased symptom burden. The diagnosis of HFpEF may identify patients with AF with the potential to benefit from novel HFpEF therapies. (Characterising Left Atrial Function and Compliance in Atrial Fibrillation; ACTRN12620000639921).

Impact of Adenosine on Wavefront Propagation in Persistent Atrial Fibrillation: Insights From Global Noncontact Charge Density Mapping of the Left Atrium.

Background Adenosine shortens action potential duration and refractoriness and provokes atrial fibrillation. This study aimed to evaluate the effect of adenosine on mechanisms of wavefront propagation during atrial fibrillation. Methods and Results The study included 22 patients undergoing catheter ablation for persistent atrial fibrillation. Left atrial mapping was performed using the AcQMap charge density system before and after administration of intravenous adenosine at 1 or more of 3 time points during the procedure (before pulmonary vein isolation, after pulmonary vein isolation, and after nonpulmonary vein isolation ablation). Wave-front propagation patterns were evaluated allowing identification and quantification of localized rotational activation (LRA), localized irregular activation, and focal firing. Additional signal processing was performed to identify phase singularities and calculate global atrial fibrillation cycle length and dominant frequency. A total of 35 paired maps were analyzed. Adenosine shortened mean atrial fibrillation cycle length from 181.7±14.3 to 165.1±16.3, (mean difference 16.6 ms; 95% CI, 11.3-21.9, P<0.0005) and increased dominant frequency from 6.0±0.7 Hz to 6.6±0.8 Hz (95% CI, 0.4-0.9, P<0.0005). This was associated with a 50% increase in the number of LRA occurrences (16.1±7.6-24.2±8.1; mean difference 8.1, 95% CI, 4.1-12, P<0.0005) as well as a 20% increase in the number of phase singularities detected (30.1±7.8-36.6±9.3; mean difference 6.5; 95% CI, 2.6-10.0, P=0.002). The percentage of left atrial surface area with LRA increased with adenosine and 42 of 70 zones (60%) with highest density of LRA coincided with high density LRA zones at baseline with only 28% stable across multiple maps. Conclusions Adenosine accelerates atrial fibrillation and promotes rotational activation patterns with no impact on focal activation. There is little evidence that rotational activation seen with adenosine represents promising targets for ablation aimed at sites of stable arrhythmogenic sources in the left atrium.

High-Density Mapping and Ablation of Primary Nonfocal Left Atrial Tachycardia: Characterizing a Distinct Arrhythmogenic Substrate.

OBJECTIVES: This study sought to characterize primary left atrial tachycardia (LAT) mechanisms, electrical properties and substrate using high-density mapping. BACKGROUND: Nonfocal LAT can be found in patients without prior substrate modifying interventions. METHODS: Of 223 catheter ablation procedures for LAT 15 patients (60% male, age 74 ± 6 years) had nonfocal AT and no history of LA ablation or cardiac surgery. RESULTS: AT (mean cycle length 244 ± 32 ms) were identified as macro-re-entry (12 of 15) or localized re-entry (3 of 15). High-density electroanatomical mapping (EAM, performed in 13 patients) revealed a high proportion of low voltage areas (LVA, <0.45 mV, 41 ± 22%). Anterior LVA regions were predominantly related to the macro-re-entry and directly perpetuating the re-entrant circuit in 8 patients by formation of a conductive channel (width: 14 ± 7 mm, length: 11 ± 3 mm) between the inferior pole of the scar and the mitral valve (MV) annulus with electrophysiological features of diseased tissue. A tailored anterior ablation line successfully terminated AT in 9 patients (6 dominant circuit MV dependent, 3 dominant circuit scar dependent AT), while a lateral isthmus line was performed in 2 patients. Localized re-entries were successfully targeted by local ablation. Acute successful ablation could be achieved in 14 of 15 patients leading to a freedom from any arrhythmias in 9 of 15 patients (60%) after follow-up of 343 ± 203 days. CONCLUSIONS: Patients with nonfocal left atrial tachycardia without previous iatrogenic interventions show evidence for advanced atrial myopathy. High-density mapping revealed involvement of the anterior LA and allows for an individualized ablation approach beyond strategies usually applied in consecutive AT.

Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System.

Since its invention in the late 19th century, the Langendorff ex vivo heart perfusion system continues to be a relevant tool for studying a broad spectrum of physiological, biochemical, morphological, and pharmacological parameters in centrally denervated hearts. Here, we describe a setup for the modulation of the intracardiac autonomic nervous system and the assessment of its influence on basic electrophysiology, arrhythmogenesis, and cyclic adenosine monophosphate (cAMP) dynamics. The intracardiac autonomic nervous system is modulated by the mechanical dissection of atrial fat pads-in which murine ganglia are located mainly-or by the usage of global as well as targeted pharmacological interventions. An octapolar electrophysiological catheter is introduced into the right atrium and the right ventricle, and epicardial-placed multi-electrode arrays (MEA) for high-resolution mapping are used to determine cardiac electrophysiology and arrhythmogenesis. Förster resonance energy transfer (FRET) imaging is performed for the real-time monitoring of cAMP levels in different cardiac regions. Neuromorphology is studied by means of antibody-based staining of whole hearts using neuronal markers to guide the identification and modulation of specific targets of the intracardiac autonomic nervous system in the performed studies. The ex vivo Langendorff setup allows for a high number of reproducible experiments in a short time. Nevertheless, the partly open nature of the setup (e.g., during MEA measurements) makes constant temperature control difficult and should be kept to a minimum. This described method makes it possible to analyze and modulate the intracardiac autonomic nervous system in decentralized hearts.

Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias.

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.

Development of Time- and Voltage-Domain Mapping (V-T-Mapping) to Localize Ventricular Tachycardia Channels During Sinus Rhythm.

BACKGROUND: In ventricular scar, impulse spread is slow because it traverses split and zigzag channels of surviving muscle. We aimed to evaluate scar electrograms to determine their local delay (activation time) and inequality in voltage splitting (entropy), and their relationship to channels. We reasoned that unlike innocuous channels, which are often short with multiple side branches, ventricular tachycardia (VT) supporting channels have very slow impulse spread and possess low entropy because of their longer protected length and relative lack of side-branching. METHODS AND RESULTS: Patients with ischemic cardiomyopathy and multiple VT were studied. In initial mapping stage (16 patients and 58 VTs), left ventricular endocardial mapping was performed in sinus rhythm. Detailed pace mapping was used to identify VT channels and confirmed, when feasible, by entrainment. Scar electrograms were analyzed in time and voltage domains to determine mean activation time, dispersion in activation time, and entropy. Predictive performances of these properties to detect VT channels were tested. In the application stage (7 patients and 20 VTs), these properties were prospectively tested to guide catheter ablation. A mean number of 763±203 sampling points were taken. From 1770 pace maps, 47 channels corresponded to VTs. A combination of scar electrograms with the latest mean activation time and minimum entropy, in a high activation dispersion region, accurately recognized regions containing VT channels (κ=0.89, sensitivity=86%, specificity=100%, positive predictive value=93%, and negative predictive value=100%). Finally, focused ablation within 5-mm rim of the prospective channel regions eliminated 18 of 20 inducible VTs. CONCLUSIONS: Activation time and entropy mapping in the scar accurately identify VT channels during sinus rhythm. The method integrates principles of reentry formation to recognize VT channels without pace mapping or mapping during VT.

Atrial Fibrillation Complexity Parameters Derived From Surface ECGs Predict Procedural Outcome and Long-Term Follow-Up of Stepwise Catheter Ablation for Atrial Fibrillation.

BACKGROUND: The success rate of catheter ablation for persistent atrial fibrillation (AF) is still far from satisfactory. Identification of patients who will benefit from ablation is highly desirable. We investigated the predictive value of noninvasive AF complexity parameters derived from standard 12-lead ECGs for AF termination and long-term success of catheter ablation and compared them with clinical predictors. METHODS AND RESULTS: The study included a training (93 patients) and a validation set (81 patients) of patients with persistent AF undergoing stepwise radiofrequency ablation. In the training set AF terminated in 81% during catheter ablation, 77% were in sinus rhythm after 6 years and multiple ablations. ECG-derived complexity parameters were determined from a baseline 10-s 12-lead ECG. Prediction of AF termination was similar using only ECG (cross-validated mean area under the curve [AUC], 0.76±0.15) or only clinical parameters (mean AUC, 0.75±0.16). The combination improved prediction to a mean AUC of 0.79±0.13. Using a combined model of ECG and clinical parameters, sinus rhythm at long-term follow-up could be predicted with a mean AUC of 0.71±0.12. In the validation set AF terminated in 57%, 61% were in sinus rhythm after 4.6 years. The combined models predicted termination with an AUC of 0.70 and sinus rhythm at long-term follow-up with an AUC of 0.61. Overall, fibrillation-wave amplitude provided the best rhythm prediction. CONCLUSIONS: The predictive performance of ECG-derived AF complexity parameters for AF termination and long-term success of catheter ablation in patients with persistent AF is at least as good as known clinical predictive parameters, with fibrillation-wave amplitude as the best predictor.

Loss of Pace Capture on the Ablation Line During Pulmonary Vein Isolation versus "Dormant Conduction": Is Adenosine Expendable?

INTRODUCTION: Permanent pulmonary vein isolation (PVI) remains an essential goal of ablation therapy in patients with atrial fibrillation. Aim of this study was the intraindividual comparison of unexcitability to pacing along the ablation line versus dormant conduction (DC) as additional procedural endpoints. METHODS: A total of 58 patients with paroxysmal atrial fibrillation (PAF) underwent PVI by circumferential ablation of ipsilateral pulmonary veins (PVs), followed by testing for DC by adenosine administration. Irrespective of the presence of DC, pacing along the ablation line for left atrium capture was performed and additional radio frequency energy applied if necessary. PVs with initial DC were retested after achieving unexcitability. RESULTS: PVI was achieved in 224 of 224 PVs. In 33 of 224 PVs (15%) DC was revealed. At 92 of 112 ablation lines (82%) sites of excitability were found. Three (9%) of the initial 33 PVs with DC showed further DC after achieving unexcitability at repeated testing. Thirty-two of 33 assumed areas of unmasked PV-LA reconduction as revealed by DC-testing showed a corresponding site of excitability on the ablation line. After a follow-up of 11.6 ± 3.4 months 79% of patients were free of arrhythmia. CONCLUSIONS: Pacing for unexcitability can safely identify potential sites of DC and even sites that would have not been detected by testing for DC. Unexcitability, therefore, serves as a suitable and safe procedural endpoint not only for patients with contraindications to adenosine administration. Our data suggest that adenosine may be expendable when achieving unexcitability along the ablation line.

Reduction of Radiation Exposure in Atrial Fibrillation Ablation Using a New Image Integration Module: A Prospective Randomized Trial in Patients Undergoing Pulmonary Vein Isolation.

INTRODUCTION: Recently, a new image integration module (IIM, CartoUnivu™ Module) has been introduced to combine and merge fluoroscopy images with 3-dimensional-(3D)-electroanatomical maps (Carto® 3 System) into an accurate 3D view. The aim of the study was to investigate the influence of IIM on the fluoroscopy exposure during pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) in a prospective randomized trial. METHODS AND RESULTS: Between June and November 2014, a total of 60 patients with PAF (73.3% male, 64.0 ± 9.2 years), who underwent PVI with the endpoint of unexcitability of the ablation line, were randomized to either a conventional 3D mapping system (Carto® 3 System) or to an additional IIM on the basis of an assumed reduction of fluoroscopy exposure by the use of IIM. There were no significant differences in baseline characteristics. The median ablation procedure time was identical in both groups (140.7 ± 27.8 minutes vs. 140.8 ± 39.5 minutes; P = 0.851). A significant decrease of mean fluoroscopy time from 11.9 ± 2.1 to 7.4 ± 2.6 minutes (P < 0.0006) and median fluoroscopy dose from 882.9 to 476.5 cGycm(2) (P < 0.001) was achieved. The main reduction of radiation could be realized during creation of the 3D-map. No major complications occurred during the procedures. After a median follow-up of 125.7 ± 45.6 days 80% of the patients were free from any atrial arrhythmias. CONCLUSION: CartoUnivu™ module easily integrates into the workflow of PVI with the endpoint of unexcitability of the ablation line without prolonging the procedure time. It is associated with a marked reduction in fluoroscopic dose when compared to a conventional 3D mapping system.

Indices of bipolar complex fractionated atrial electrograms correlate poorly with each other and atrial fibrillation substrate complexity.

BACKGROUND: The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood. OBJECTIVE: The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF. METHODS: Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined. RESULTS: All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block. CONCLUSION: The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the divergent and limited success rates of catheter ablation strategies targeting CFAE.

Far-field effect in unipolar electrograms revisited: High-density mapping of atrial fibrillation in humans.

Unipolar electrogram can detect local as well as remote electrical activity of the heart. Information on how the amplitude and morphology of the recorded signal changes with the distance from the source tissue undergoing depolarization can help to better understand unipolar electrograms fractionation and provide insights into the passive conduction properties of the atrial tissue. Ten second unipolar atrial fibrillation (AF) electrograms were recorded using high-density electrode array from the posterior left atrium (LA) and right atrium (RA) of 19 (8 persistent - PERS & 11 paroxysmal - PAF) AF patients undergoing cardiac surgery. Conduction along lines of conduction block was detected in the recorded activation patterns by a proposed automated algorithm. Changes of the amplitude of the unipolar electrogram with increasing distance from the conduction blocks were assessed and compared to predictions of a theoretical model. For each recording, the median far-field decay space constant (FF0.5) was calculated. Overall, we found a significant difference between FF0.5 for patients with paroxysmal and persistent AF. Estimation of maximum FF0.5 from both RA and LA resulted in a mean FF0.5 of 1.5±0.2 mm for PERS patients and 2.1±0.6 mm for PAF patients (p=0.03). Moreover, detected conduction blocks demonstrated high spatial organization and appeared in distinctive areas of the mapped area in all patients, regardless of the type of AF, while the total number of detected block lines was higher in PERS patients.

Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation.

BACKGROUND: Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown. OBJECTIVE: To examine the effect of progressive weight gain on the substrate for AF. METHODS: Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor ß1, and connective tissue growth factor. RESULTS: Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor ß1 (P = .02) and platelet-derived growth factor (P = .02) levels. CONCLUSIONS: Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.