Long term clinical outcomes and cost-effectiveness of catheter vs thoracoscopic surgical ablation in long-standing persistent atrial fibrillation using continuous cardiac monitoring: CASA-AF randomised controlled trial.

BACKGROUND: Long-term clinical outcomes of catheter ablation (CA) compared to thoracoscopic surgical ablation (SA) to treat patients with long-standing persistent atrial fibrillation (LSPAF) are not known. OBJECTIVES: To compare long-term (36-months) clinical efficacy, quality of life and cost-effectiveness of SA and CA in LSPAF. METHODS: Participants were followed up for 3 years using implantable loop recorder (ILR) and questionnaires to assess change in quality of life. Intention-to-treat analyses were used to report the findings. RESULTS: Of 115 LSPAF patients treated, 104 (90.4%) completed 36-months follow-up (CA=57, SA=47). Following a single procedure without anti-arrhythmic drugs (AAD) 7 (12%) patients in the CA arm and 5 (11%) in the SA arm (HR 1.22, 95% CI 0.81 to 1.83, p = 0.41) were free from AF/AT ≥30 sec at 36 months. Thirty-three patients (58%) in the CA arm and 26 (55%) in the SA arm (HR 1.04, 95% CI 0.57 to 1.88, p = 0.91) had their AF/AT burden reduced by ≥75%. The overall impact on health-related quality of life was similar, with mean QALY estimates of 2.45 (95% CI 2.31 to 2.59) for CA and 2.32 (2.13 to 2.52) for SA. Estimated costs were higher for SA (mean £24,682, 95% CI £21,746 to £27,618) than for CA (mean £18,002, 95% CI £15,422 to £20,581). CONCLUSION: In symptomatic LSPAF, CA and SA were equally effective at achieving arrhythmia outcomes (freedom from AF/AT ≥30s and ≥75% burden reduction) following a single-procedure without AADs. However, SA is significantly more costly than catheter ablation.

Variation in optimal hemodynamic atrio-ventricular delay of biventricular pacing with different endocardial left ventricular lead locations using precision hemodynamics.

INTRODUCTION: It is not known whether the optimal atrioventricular (AVopt ) delay varies between left ventricular (LV) pacing site during endocardial biventricular pacing (BiVP) and may therefore needs consideration. METHODS: We assessed the hemodynamic AVopt in patients with chronic heart failure undergoing endocardial LV lead implantation. AVopt was assessed during atrio-BiVP with a "roving LV lead." Up to four locations were studied: mid-lateral wall, mid-septum (or a close alternative), site of greatest hemodynamic improvement, and LV lead implant site. The AVopt was compared to a fixed AV delay of 180 ms. RESULTS: Seventeen patients were included (12 male, aged 66.5 ± 12.8 years, ejection fraction 26 ± 7%, 16 left bundle branch block or high percentage of right ventricular pacing [RVP], QRS duration 167 ± 27 ms). In most locations (62/63), AVopt increased systolic blood pressure during BiVP compared with RVP (relative improvement 6 mmHg, interquartile range [IQR] 4-9 mmHg). Compared to a fixed AV delay, the hemodynamic improvement at AVopt was higher (1 mmHg, IQR 0.2-2.6 mmHg, p < .001). Within most patients (16/17), we observed a difference in AVopt between pacing sites (median paced AVopt 209 ms, IQR 117-250). Within this range, the hemodynamic impact of these differences was small (median loss 0.6 mmHg, IQR 0.1-2.6 mmHg). CONCLUSION: Within a patient, different endocardial LV lead locations have slightly different hemodynamic AVopt which are superior to a fixed AV delay. The hemodynamic consequence of applying an optimum from a different lead location is small.

Novel aggregated multiposition noncontact mapping of atrial tachycardia in humans: From computational modeling to clinical validation.

BACKGROUND: A novel aggregated multiposition noncontact mapping (AMP-NCM) algorithm is proposed to diagnose cardiac arrhythmias. OBJECTIVE: The purpose of this study was to computationally determine an accuracy threshold and to compare the accuracy and clinical utility of AMP-NCM to gold standard contact mapping. METHODS: In a cellular automata model, the number of catheter positions and chamber coverage were varied to establish accuracy requirements for clinically relevant AMP-NCM. This guided the clinical study protocol. In a prospective cohort of patients with atrial tachycardia (AT), noncontact mapping (NCM) recordings from a single position (SP) and multiple positions were compared to contact mapping with a high-density multipolar catheter using morphology and timing differences of reconstructed signals. Identification of AT mechanisms and ablation targets using both AMP-NCM and contact mapping were randomly evaluated by 5 blinded reviewers. RESULTS: AMP-NCM accuracy was asymptotic at 60 catheter positions in computational modeling. Twenty patients (age 65 ± 12 years; 19 male) with 26 ATs (5 focal, 21 reentrant) were studied. Morphologic correlation of signals derived from AMP-NCM was significantly better than those from SP-NCM compared to contact signals (median 0.93 vs 0.76; P <.001). AMP-NCM generated maps more rapidly than contact mapping (3 ± 1 minutes vs 13 ± 6 minutes; P <.001) and correctly diagnosed AT mechanisms in 25 of 26 maps (96%). Overall, 80% of arrhythmia mechanisms were correctly identified using AMP-NCM by blinded reviewers. CONCLUSION: Once 60 catheter positions were achieved, AMP-NCM successfully diagnosed mechanisms of AT and identified treatment sites equal to gold standard contact mapping in 3 minutes of procedural time.

Individualized ablation strategy to treat persistent atrial fibrillation: Core-to-boundary approach guided by charge-density mapping.

BACKGROUND: Noncontact charge-density mapping allows rapid real-time global mapping of atrial fibrillation (AF), offering the opportunity for a personalized ablation strategy. OBJECTIVE: The purpose of this study was to compare the 2-year outcome of an individualized strategy consisting of pulmonary vein isolation (PVI) plus core-to-boundary ablation (targeting the conduction pattern core with an extension to the nearest nonconducting boundary) guided by charge-density mapping, with an empirical PVI plus posterior wall electrical isolation (PWI) strategy. METHODS: Forty patients (age 62 ± 12 years; 29 male) with persistent AF (10 ± 5 months) prospectively underwent charge-density mapping-guided PVI, followed by core-to-boundary stepwise ablation until termination of AF or depletion of identified cores. Freedom from AF/atrial tachycardia (AT) at 24 months was compared with a propensity score-matched control group of 80 patients with empirical PVI + PWI guided by conventional contact mapping. RESULTS: Acute AF termination occurred in 8 of 40 patients after charge-density mapping-guided PVI alone and in 21 of the remaining 32 patients after core-to-boundary ablation in the study cohort, compared with 8 of 80 (10%) in the control cohort (P <.001). On average, 2.2 ± 0.6 cores were ablated post-PVI before acute AF termination. At 24 months, freedom from AF/AT after a single procedure was 68% in the study group vs 46% in the control group (P = .043). CONCLUSION: An individualized ablation strategy consisting of PVI plus core-to-boundary ablation guided by noncontact charge-density mapping is a feasible and effective strategy for treating persistent AF, with a favorable 24-month outcome.

A Primer on Constructing Plasticity Phenotypes to Classify Experience-Dependent Development of the Visual Cortex.

Many neural mechanisms regulate experience-dependent plasticity in the visual cortex (V1), and new techniques for quantifying large numbers of proteins or genes are transforming how plasticity is studied into the era of big data. With those large data sets comes the challenge of extracting biologically meaningful results about visual plasticity from data-driven analytical methods designed for high-dimensional data. In other areas of neuroscience, high-information content methodologies are revealing more subtle aspects of neural development and individual variations that give rise to a richer picture of brain disorders. We have developed an approach for studying V1 plasticity that takes advantage of the known functions of many synaptic proteins for regulating visual plasticity. We use that knowledge to rebrand protein measurements into plasticity features and combine those into a plasticity phenotype. Here, we provide a primer for analyzing experience-dependent plasticity in V1 using example R code to identify high-dimensional changes in a group of proteins. We describe using PCA to classify high-dimensional plasticity features and use them to construct a plasticity phenotype. In the examples, we show how to use this analytical framework to study and compare experience-dependent development and plasticity of V1 and apply the plasticity phenotype to translational research questions. We include an R package "PlasticityPhenotypes" that aggregates the coding packages and custom code written in RStudio to construct and analyze plasticity phenotypes.

Diverse activation patterns during persistent atrial fibrillation by noncontact charge-density mapping of human atrium.

BACKGROUND: Global simultaneous recording of atrial activation during atrial fibrillation (AF) can elucidate underlying mechanisms contributing to AF maintenance. A better understanding of these mechanisms may allow for an individualized ablation strategy to treat persistent AF. The study aims to characterize left atrial endocardial activation patterns during AF using noncontact charge-density mapping. METHODS: Twenty-five patients with persistent AF were studied. Activation patterns were characterized into three subtypes: (i) focal with centrifugal activation (FCA); (ii) localized rotational activation (LRA); and (iii) localized irregular activation (LIA). Continuous activation patterns were analyzed and distributed in 18 defined regions in the left atrium. RESULTS: A total of 144 AF segments with 1068 activation patterns were analyzed. The most common pattern during AF was LIA (63%) which consists of four disparate features of activation: slow conduction (45%), pivoting (30%), collision (16%), and acceleration (7%). LRA was the second-most common pattern (20%). FCA accounted for 17% of all activations, arising frequently from the pulmonary veins (PVs)/ostia. A majority of patients (24/25; 96%) showed continuous and highly dynamic patterns of activation comprising multiple combinations of FCA, LRA, and LIA, transitioning from one to the other without a discernible order. Preferential conduction areas were typically seen in the mid-anterior (48%) and lower-posterior (40%) walls. CONCLUSION: Atrial fibrillation is characterized by heterogeneous activation patterns identified in PV-ostia and non-PV regions throughout the LA at varying locations between individuals. Clinical implications of individualized ablation strategies guided by charge-density mapping need to be determined.

Validation of Dipole Density Mapping During Atrial Fibrillation and Sinus Rhythm in Human Left Atrium.

OBJECTIVES: This study sought to validate the accuracy of noncontact electrograms against contact electrograms in the left atrium during sinus rhythm (SR) and atrial fibrillation (AF). BACKGROUND: Noncontact mapping offers the opportunity to assess global cardiac activation in the chamber of interest. A novel noncontact mapping system, which records intracardiac voltage to derive cellular charge sources (dipole density), allows real-time mapping of AF to guide ablation. METHODS: Noncontact and contact unipolar electrogram pairs were recorded simultaneously from multiple locations. Morphology correlation and timing difference of reconstructed electrograms obtained from a noncontact catheter were compared with those from contact electrograms obtained from a contact catheter at the same endocardial locations. RESULTS: A total of 796 electrogram pairs in SR and 969 electrogram pairs in AF were compared from 20 patients with persistent AF. The median morphology correlation and timing difference (ms) in SR was 0.85 (interquartile range [IQR]: 0.71 to 0.94) and 6.4 ms (IQR: 2.6 to 17.1 ms); in AF was 0.79 (IQR: 0.69 to 0.88) and 14.4 ms (IQR: 6.7 to 26.2 ms), respectively. The correlation was stronger and the timing difference was less when the radial distance (r) from the noncontact catheter center to the endocardium was ≤ 40 versus > 40 mm; 0.87 (IQR: 0.72 to 0.94) versus 0.73 (IQR: 0.56 to 0.88) and 5.7 ms (IQR: 2.6 to 15.4 ms) versus 15.1 ms (IQR: 4.1 to 27.7 ms); p < 0.01 when in SR; 0.81 (IQR: 0.69 to 0.89) versus 0.67 (IQR: 0.45 to 0.82) and 12.3 ms (IQR: 5.9 to 21.8 ms) versus 28.3 ms (IQR: 16.2 to 36.0 ms); p < 0.01 when in AF. CONCLUSIONS: This novel noncontact dipole density mapping system provides comparable reconstructed atrial electrogram measurements in SR or AF in human left atrium when the anatomical site of interest is ≤40 mm from the mapping catheter.

Classification of Visual Cortex Plasticity Phenotypes following Treatment for Amblyopia.

Monocular deprivation (MD) during the critical period (CP) has enduring effects on visual acuity and the functioning of the visual cortex (V1). This experience-dependent plasticity has become a model for studying the mechanisms, especially glutamatergic and GABAergic receptors, that regulate amblyopia. Less is known, however, about treatment-induced changes to those receptors and if those changes differentiate treatments that support the recovery of acuity versus persistent acuity deficits. Here, we use an animal model to explore the effects of 3 visual treatments started during the CP (n = 24, 10 male and 14 female): binocular vision (BV) that promotes good acuity versus reverse occlusion (RO) and binocular deprivation (BD) that causes persistent acuity deficits. We measured the recovery of a collection of glutamatergic and GABAergic receptor subunits in the V1 and modeled recovery of kinetics for NMDAR and GABAAR. There was a complex pattern of protein changes that prompted us to develop an unbiased data-driven approach for these high-dimensional data analyses to identify plasticity features and construct plasticity phenotypes. Cluster analysis of the plasticity phenotypes suggests that BV supports adaptive plasticity while RO and BD promote a maladaptive pattern. The RO plasticity phenotype appeared more similar to adults with a high expression of GluA2, and the BD phenotypes were dominated by GABAA α1, highlighting that multiple plasticity phenotypes can underlie persistent poor acuity. After 2-4 days of BV, the plasticity phenotypes resembled normals, but only one feature, the GluN2A:GluA2 balance, returned to normal levels. Perhaps, balancing Hebbian (GluN2A) and homeostatic (GluA2) mechanisms is necessary for the recovery of vision.

Characterising the difference in electrophysiological substrate and outcomes between heart failure and non-heart failure patients with persistent atrial fibrillation.

Aims: Characterizing the differences in substrate and clinical outcome between heart failure (HF) and non-heart failure (non-HF) patients undergoing persistent atrial fibrillation (AF) ablation. Methods and results: Using complex fractionated electrograms (CFE) as a surrogate marker of substrate complexity, we compared the bi-atrial substrate in patients with persistent AF with and without HF, at baseline and after ablation, to determine its impact on clinical outcome. In this retrospective analysis of two prospective studies, 60 patients underwent de-novo step-wise left atrial (LA) ablation, 30 with normal left ventricular ejection fraction (LVEF) ≥ 50% (non-HF group) and 30 with LVEF ≤ 35% (HF group). Multiple high-density bi-atrial CFE maps were acquired along with AF cycle length (AFCL) at each procedural stage. Change in bi-atrial CFE areas, AFCL and outcome data were then compared. In the non-HF group, higher CFE-areas were found at baseline and at each step of the procedure in the LA. In both LA and the right atrium (RA), baseline and final CFE area were also higher in the non-HF group. Single procedure, arrhythmia-free survival at 1 year was higher in the HF group compared with the non-HF group (72% vs. 43%, log rank P = 0.04). Final total bi-atrial CFE area was an independent predictor of arrhythmia recurrence. Conclusions: CFE represents an important surrogate marker of atrial substrate complexity. The atrial substrate in persistent AF differs between HF and non-HF with the latter representing a more complex 'primary' bi-atrial myopathy. LA focussed ablation results in more extensive substrate modification in HF and better clinical outcomes as compared with non-HF.

Catheter ablation vs electrophysiologically guided thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: The CASA-AF Study.

BACKGROUND: Catheter ablation (CA) outcomes for long-standing persistent atrial fibrillation (LSPAF) remain suboptimal. Thoracoscopic surgical ablation (SA) provides an alternative approach in this difficult to treat cohort. OBJECTIVE: To compare electrophysiological (EP) guided thoracoscopic SA with percutaneous CA as the first-line strategy in the treatment of LSPAF. METHODS: Fifty-one patients with de novo symptomatic LSPAF were recruited. Twenty-six patients underwent electrophysiologically guided thoracoscopic SA. Conduction block was tested for all lesions intraoperatively by an independent electrophysiologist. In the CA group, 25 consecutive patients underwent stepwise left atrial (LA) ablation. The primary end point was single-procedure freedom from atrial fibrillation (AF) and atrial tachycardia (AT) lasting >30 seconds without antiarrhythmic drugs at 12 months. RESULTS: Single- and multiprocedure freedom from AF/AT was higher in the SA group than in the CA group: 19 of 26 patients (73%) vs 8 of 25 patients (32%) (P = .003) and 20 of 26 patients (77%) vs 15 of 25 patients (60%) (P = .19), respectively. Testing of the SA lesion set by an electrophysiologist increased the success rate in achieving acute conduction block by 19%. In the SA group, complications were experienced by 7 of 26 patients (27%) vs 2 of 25 patients (8%) in the CA group (P = .07). CONCLUSION: In LSPAF, meticulous electrophysiologically guided thoracoscopic SA as a first-line strategy may provide excellent single-procedure success rates as compared with those of CA, but there is an increased up-front risk of nonfatal complications.

Development of Glutamatergic Proteins in Human Visual Cortex across the Lifespan.

Traditionally, human primary visual cortex (V1) has been thought to mature within the first few years of life, based on anatomical studies of synapse formation, and establishment of intracortical and intercortical connections. Human vision, however, develops well beyond the first few years. Previously, we found prolonged development of some GABAergic proteins in human V1 (Pinto et al., 2010). Yet as >80% of synapses in V1 are excitatory, it remains unanswered whether the majority of synapses regulating experience-dependent plasticity and receptive field properties develop late, like their inhibitory counterparts. To address this question, we used Western blotting of postmortem tissue from human V1 (12 female, 18 male) covering a range of ages. Then we quantified a set of postsynaptic glutamatergic proteins (PSD-95, GluA2, GluN1, GluN2A, GluN2B), calculated indices for functional pairs that are developmentally regulated (GluA2:GluN1; GluN2A:GluN2B), and determined interindividual variability. We found early loss of GluN1, prolonged development of PSD-95 and GluA2 into late childhood, protracted development of GluN2A until ∼40 years, and dramatic loss of GluN2A in aging. The GluA2:GluN1 index switched at ∼1 year, but the GluN2A:GluN2B index continued to shift until ∼40 year before changing back to GluN2B in aging. We also identified young childhood as a stage of heightened interindividual variability. The changes show that human V1 develops gradually through a series of five orchestrated stages, making it likely that V1 participates in visual development and plasticity across the lifespan.SIGNIFICANCE STATEMENT Anatomical structure of human V1 appears to mature early, but vision changes across the lifespan. This discrepancy has fostered two hypotheses: either other aspects of V1 continue changing, or later changes in visual perception depend on extrastriate areas. Previously, we showed that some GABAergic synaptic proteins change across the lifespan, but most synapses in V1 are excitatory leaving unanswered how they change. So we studied expression of glutamatergic proteins in human V1 to determine their development. Here we report prolonged maturation of glutamatergic proteins, with five stages that map onto life-long changes in human visual perception. Thus, the apparent discrepancy between development of structure and function may be explained by life-long synaptic changes in human V1.

Characterization and consistency of interactions of triggers and substrate at the onset of paroxysmal atrial fibrillation.

AIMS: Initiating mechanisms of atrial fibrillation (AF) remain poorly understood, involving complex interaction between triggers and the atrial substrate. This study sought to classify the transitional phenomena, hypothesizing that there is consistency within and between patients in trigger-substrate interaction during transition to AF. METHODS AND RESULTS: Non-contact left atrial (LA) mapping was performed in 17 patients undergoing ablation for paroxysmal AF. All had spontaneous ectopy. Left atrial activation from the first ectopic to established AF was examined offline to characterize the initiating and transitional sequence of activation. In 57 fully mapped spontaneous AF initiations in 8 patients, all involved interaction of pulmonary venous/LA triggers with a septopulmonary line of block (SP-LOB) also evident in sinus rhythm, by 4 different transitional mechanisms characterized by (i) continuous focal firing: AF resulted from fragmentation of each ectopic wavefront through gaps in the SP-LOB and persisted only while focal firing continued (n = 18/32%) (ii) transient focal firing, wavefront fragmentation at the SP-LOB produced wavelet re-entry that persisted after cessation of an initiating ectopic source (n = 12/21%), (iii) of two separate interacting ectopic foci (n = 15/26%), or from (iv) transiently stable macroreentry (n = 12/21%), around the SP-LOB extending to the LA roof, resulting in progressive wavefront fragmentation. It was found that 79 ± 22% of each of the initiations in individual patients showed the same triggering mechanism. CONCLUSION: Onset of paroxysmal AF can be described by discrete mechanistic categories, all involving interaction of ectopic activity with a common SP-LOB. Within/between-patient consistency of initiations suggests constancy of the interacting triggers and substrate, and supports the concept of mechanistically tailored treatment.

Pacing in congenital heart disease - A four-decade experience in a single tertiary centre.

BACKGROUND: The increased risk of brady- and tachy-arrhythmias in the congenital heart disease (CHD) population means that cardiac rhythm management devices are often required at an early age and expose patients to device-related complications. The present study drew upon four decades of experience at a tertiary adult congenital heart disease ACHD center and aimed to investigate the indication for cardiac implantable electronic devices (CIEDs) and predictors of late device-related complication requiring re-intervention. METHODS: A retrospective review of pacing records of ACHD patients over forty years was carried out. The primary outcome measure was device related complication requiring re-intervention. RESULTS: Between 1970 and 2009, 238 structural CHD patients who received CIEDs with follow-up data were identified (structural group). As a comparator group, 98 patients with congenital conduction disease or long QT syndrome with a structurally normal heart (electrical group) were included in the study. During a mean follow-up of 9.6±8.5years, 72 (21%) patients (44 structural group, 28 electrical group) required ≥1 re-intervention due to device related complications. Multivariate analysis showed that age at the time of device implant was an independent predictor of late device-related complications (HR 0.77, 95% CI 0.60-0.98, p=0.04). Sub-analysis of the structural group showed that ACHD complexity (Bethesda guideline) was the only predictor late device-related complication in the structural group (HR 2.96, 95% CI: 1.67-5.26, p<0.01). CONCLUSION: Increasing age at device implant was inversely associated with late device-related complications. ACHD patients with complex anatomy are at increased risk of device-related complications at mid and long-term follow-up.

Evaluation of a novel high-resolution mapping system for catheter ablation of ventricular arrhythmias.

BACKGROUND: The mapping of ventricular arrhythmias in humans using a minibasket 64-electrode catheter paired with a novel automatic mapping system (Rhythmia) has not been evaluated. OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of mapping ventricular arrhythmias and clinical outcomes after ablation using this system. METHODS: Electroanatomic maps for ventricular arrhythmias were obtained during 20 consecutive procedures in 19 patients (12 with ventricular tachycardia [VT] and 2 with ventricular ectopy [VE]). High-density maps were acquired using automatic beat acceptance and automatic system annotation of electrograms. RESULTS: Forty-seven electroanatomic maps (including 3 right ventricular and 9 epicardial maps) were obtained. Left ventricular endocardial mapping by transseptal (n = 13) and/or transaortic (n = 11) access was safe with no complications related to the minibasket catheter. VT substrate maps (n = 14; median 10,184 points) consistently demonstrated late potentials with high resolution. VT activation maps (n = 25; median 6401 points) obtained by automatic annotation included 7 complete maps (covering ≥90% of the tachycardia cycle length) in 5 patients in whom the entire VT circuit was accurately visualized. VE timing maps (n = 8) successfully localized the origin of VEs in all, with all accepted beats consistent with clinical VEs. Over a median follow-up of 10 months, no arrhythmia recurrence was noted in 75% after VT ablation and 86% after VE ablation. CONCLUSION: In this first human experience for ventricular arrhythmias using this system, ultra-high-density maps were created rapidly and safely, with a reliable automatic annotation of VT and consistent recording of abnormal electrograms. Medium-term outcomes after ablation were encouraging. Further larger studies are needed to validate these findings.

Biomarkers in Persistent AF and Heart Failure: Impact of Catheter Ablation Compared with Rate Control.

BACKGROUND: To investigate the effects of catheter ablation and rate control strategies on cardiac and inflammatory biomarkers in patients with heart failure and persistent atrial fibrillation (AF). METHODS: Patients were recruited from the ARC-HF trial (catheter Ablation vs Rate Control for management of persistent AF in Heart Failure, NCT00878384), which compared ablation with rate control for persistent AF in heart failure. B-type natriuretic peptide (BNP), midregional proatrial natriuretic peptide (MR-proANP), apelin, and interleukin-6 (IL-6) were assayed at baseline, 3 months, 6 months, and 12 months. The primary end point, analyzed per-protocol, was changed from baseline at 12 months. RESULTS: Of 52 recruited patients, 24 ablation and 25 rate control subjects were followed to 12 months. After 1.2 ± 0.5 procedures, sinus rhythm was present in 22 (92%) ablation patients; under rate control, rate criteria were achieved in 23 (96%) of 24 patients remaining in AF. At 12 months, MR-proANP fell significantly in the ablation arm (-106.0 pmol/L, interquartile range [IQR] -228.2 to -60.6) compared with rate control (-28.7 pmol/L, IQR -69 to +9.5, P = 0.028). BNP showed a similar trend toward reduction (P = 0.051), with no significant difference in apelin (P = 0.13) or IL-6 (P = 0.68). Changes in MR-proANP and BNP correlated with peak VO2 and ejection fraction, and MR-proANP additionally with quality-of-life score. CONCLUSIONS: Catheter ablation, compared with rate control, in patients with heart failure and persistent AF was associated with significant reduction in MR-proANP, which correlated with physiological and symptomatic improvement. Ablation-based rhythm control may induce beneficial cardiac remodeling, unrelated to changes in inflammatory state. This may have prognostic implications, which require confirmation by event end point studies.

Outcomes and costs of left atrial appendage closure from randomized controlled trial and real-world experience relative to oral anticoagulation.

AIMS: The aim of this study was to analyse randomized controlled study and real-world outcomes of patients with non-valvular atrial fibrillation (NVAF) undergoing left atrial appendage closure (LAAC) with the Watchman device and to compare costs with available antithrombotic therapies. METHODS AND RESULTS: Registry data of LAAC from two centres were prospectively collected from 110 patients with NVAF at risk of stroke, suitable and unsuitable for long-term anticoagulation (age 71.3 ± 9.2 years, CHADS2 2.8 ± 1.2, CHA2DS2-VASc 4.5 ± 1.6, and HAS-BLED 3.8 ± 1.1). Outcomes from PROTECT AF and registry study LAAC were compared with warfarin, dabigatran, rivaroxaban, apixaban, aspirin, and no treatment using a network meta-analysis. Costs were estimated over a 10-year horizon. Uncertainty was assessed using sensitivity analyses. The procedural success rate was 92% (103/112). Follow-up was 24.1 ± 4.6 months, during which annual rates of stroke, major bleeding, and all-cause mortality were 0.9% (2/223 patient-years), 0.9% (2/223 patient-years), and 1.8% (4/223 patient-years), respectively. Anticoagulant therapy was successfully stopped in 91.2% (93/102) of implanted patients by 12 months. Registry study LAAC stroke and major bleeding rates were significantly lower than PROTECT AF results: mean absolute difference of stroke, 0.89% (P = 0.02) and major bleeding, 5.48% (P < 0.001). Left atrial appendage closure achieved cost parity between 4.9 years vs. dabigatran 110 mg and 8.4 years vs. warfarin. At 10 years, LAAC was cost-saving against all therapies (range £1162-£7194). CONCLUSION: Left atrial appendage closure in NVAF in a real-world setting may result in lower stroke and major bleeding rates than reported in LAAC clinical trials. Left atrial appendage closure in both settings achieves cost parity in a relatively short period of time and may offer substantial savings compared with current therapies. Savings are most pronounced among higher risk patients and those unsuitable for anticoagulation.

Biatrial linear ablation in sustained nonpermanent AF: Results of the substrate modification with ablation and antiarrhythmic drugs in nonpermanent atrial fibrillation (SMAN-PAF) trial.

BACKGROUND: More advanced atrial fibrillation (AF) is associated with lower success rates after pulmonary vein isolation (PVI), and the optimal ablation strategy is uncertain. OBJECTIVES: To assess the impact of additional linear ablation (lines) compared to PVI alone. METHODS: In this multicenter randomized controlled trial, 122 patients (mean age 61.9 ± 10.5 years; left atrial diameter 43 ± 6 mm) with persistent AF (PeAF) or sustained (>12 hours) paroxysmal AF (SusPAF) with risk factors for atrial substrate were included and followed up for 12 months. Patients were randomized to PVI-only or PVI + lines (left atrial roof line, mitral isthmus line, and tricuspid isthmus line) group. Holter monitoring was performed at 3, 6, and 12 months and according to symptoms. The primary outcome was atrial tachyarrhythmia recurrence lasting ≥30 seconds. RESULTS: Baseline characteristics were comparable between groups; 61% had PeAF and 39% SusPAF. Successful PVI was achieved for 98% of pulmonary veins, and bidirectional block was obtained in 90% of lines. The primary end point occurred in 38% of the PVI + lines group and 32% of the PVI-only group (P = .50), which was consistent in both PeAF (36% vs 28%; P = .45) and SusPAF (42% vs 39%; P = .86). Compared with the PVI-only group, the PVI + lines group had higher procedure duration (209 ± 52 minutes vs 172 ± 44 minutes; P < .001), ablation time (4352 ± 1084 seconds vs 2503 ± 1061 seconds; P < .001), and radiation exposure (Dose-area product 3992 ± 6496 Gy·cm(2) vs 2106 ± 1679 Gy·cm(2); P = .03). Quality of life (disease-specific Atrial Fibrillation Effect on Quality of Life questionnaire and mental component scale of the Short Form 36 Health Survey) improved significantly during the study but did not differ between groups. CONCLUSION: Adding lines to wide antral PVI in substrate-based AF requires significantly more ablation, increases procedure duration and radiation dose, but provides no additional clinical benefit.

Catheter Ablation for Atrial Fibrillation in Heart Failure Patients: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Rhythm control with antiarrhythmic drugs (AADs) is not superior to rate control in patients with heart failure (HF) and atrial fibrillation (AF), but AF ablation may be more successful at achieving rhythm control than AADs. However, risks for both ablation and AADs are likely higher and success rates lower in patients with HF. OBJECTIVE: To compare rate control versus AF catheter ablation strategies in patients with AF and HF. METHODS: We conducted a meta-analysis of trials which randomized HF patients (LVEF<50%) with AF to a rate control or AF catheter ablation strategy and reported change in LVEF, quality of life, 6-minute walk test, or peak oxygen consumption. Study quality and heterogenity were assessed using Jadad scores and Cochran's Q statistics, respectively. Mantel Haenszel relative risks and mean differences were calculated using random effect models. RESULTS: Four trials (N=224) met inclusion criteria; 82.5% (n=185) had persistent AF. AF ablation was associated with an increase in LVEF (mean difference 8.5%; 95%CI 6.4,10.7%; P<0.001) compared to rate control. AF ablation was superior in improving quality of life by Minnesota Living with Heart Failure (MLWHF) questionnaire scores (mean difference -11.9; 95%CI -17.1, -6.6; P<0.001). Peak oxygen consumption and 6-minute walk distance increased in AF ablation compared to rate control patients (mean difference 3.2; 95%CI 1.1,5.2; P=0.003; mean difference 34.8; 95%CI 2.9, 66.7; P = 0.03, respectively). In the persistent AF subgroup LVEF and MLWHF were significantly improved with AF ablation. Major adverse event rates (RR 1.3; 95% CI, 0.4, 3.9; p=0.64) were not significantly different. No significant heterogeneity was evident. CONCLUSIONS: In patients with HF and AF, AF catheter ablation is superior to rate control in improving LVEF, quality of life and functional capacity. Prior to accepting a rate control strategy in HF patients with persistent or drug refractory AF, consideration should be given to AF ablation.

Classic and Golli Myelin Basic Protein have distinct developmental trajectories in human visual cortex.

Traditionally, myelin is viewed as insulation around axons, however, more recent studies have shown it also plays an important role in plasticity, axonal metabolism, and neuroimmune signaling. Myelin is a complex multi-protein structure composed of hundreds of proteins, with Myelin Basic Protein (MBP) being the most studied. MBP has two families: Classic-MBP that is necessary for activity driven compaction of myelin around axons, and Golli-MBP that is found in neurons, oligodendrocytes, and T-cells. Furthermore, Golli-MBP has been called a "molecular link" between the nervous and immune systems. In visual cortex specifically, myelin proteins interact with immune processes to affect experience-dependent plasticity. We studied myelin in human visual cortex using Western blotting to quantify Classic- and Golli-MBP expression in post-mortem tissue samples ranging in age from 20 days to 80 years. We found that Classic- and Golli-MBP have different patterns of change across the lifespan. Classic-MBP gradually increases to 42 years and then declines into aging. Golli-MBP has early developmental changes that are coincident with milestones in visual system sensitive period, and gradually increases into aging. There are three stages in the balance between Classic- and Golli-MBP expression, with Golli-MBP dominating early, then shifting to Classic-MBP, and back to Golli-MBP in aging. Also Golli-MBP has a wave of high inter-individual variability during childhood. These results about cortical MBP expression are timely because they compliment recent advances in MRI techniques that produce high resolution maps of cortical myelin in normal and diseased brain. In addition, the unique pattern of Golli-MBP expression across the lifespan suggests that it supports high levels of neuroimmune interaction in cortical development and in aging.