Safety and Effectiveness of Pulsed Field Ablation to Treat Atrial Fibrillation: One-Year Outcomes From the MANIFEST-PF Registry.

BACKGROUND: Pulsed field ablation is a novel nonthermal cardiac ablation modality using ultra-rapid electrical pulses to cause cell death by a mechanism of irreversible electroporation. Unlike the traditional ablation energy sources, pulsed field ablation has demonstrated significant preferentiality to myocardial tissue ablation, and thus avoids certain thermally mediated complications. However, its safety and effectiveness remain unknown in usual clinical care. METHODS: MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-Approval Clinical Use of Pulsed Field Ablation) is a retrospective, multinational, patient-level registry wherein patients at each center were prospectively included in their respective center registries. The registry included all patients undergoing postapproval treatment with a multielectrode 5-spline pulsed field ablation catheter to treat atrial fibrillation (AF) between March 1, 2021, and May 30, 2022. The primary effectiveness outcome was freedom from clinical documented atrial arrhythmia (AF/atrial flutter/atrial tachycardia) of ≥30 seconds on the basis of electrocardiographic data after a 3-month blanking period (on or off antiarrhythmic drugs). Safety outcomes included the composite of acute (<7 days postprocedure) and latent (>7 days) major adverse events. RESULTS: At 24 European centers (77 operators) pulsed field ablation was performed in 1568 patients with AF: age 64.5±11.5 years, female 35%, paroxysmal/persistent AF 65%/32%, CHA2DS2-VASc 2.2±1.6, median left ventricular ejection fraction 60%, and left atrial diameter 42 mm. Pulmonary vein isolation was achieved in 99.2% of patients. After a median (interquartile range) follow-up of 367 (289-421) days, the 1-year Kaplan-Meier estimate for freedom from atrial arrhythmia was 78.1% (95% CI, 76.0%-80.0%); clinical effectiveness was more common in patients with paroxysmal AF versus persistent AF (81.6% versus 71.5%; P=0.001). Acute major adverse events occurred in 1.9% of patients. CONCLUSIONS: In this large observational registry of the postapproval clinical use of pulsed field technology to treat AF, catheter ablation using pulsed field energy was clinically effective in 78% of patients with AF.

Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial.

AIMS: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. METHODS AND RESULTS: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]. CONCLUSION: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

Acute lesion extension following pulmonary vein isolation with two novel single shot devices: Pulsed field ablation versus multielectrode radiofrequency balloon.

INTRODUCTION: Pulsed-field ablation (PFA) and the multielectrode radiofrequency balloon (RFB) are two novel ablation technologies to perform pulmonary vein isolation (PVI). It is currently unknown whether these technologies differ in lesion formation and lesion extent. We compared the acute lesion extent after PVI induced by PFA and RFB by measuring low-voltage area in high-density maps and the release of biomolecules reflecting cardiac injury. METHODS: PVI was performed with a pentaspline catheter (FARAPULSE) applying PFA or with the compliant multielectrode RFB (HELIOSTAR). Before and after PVI high-density mapping with CARTO 3 was performed. In addition, blood samples were taken before transseptal puncture and after post-PVI remapping and serum concentrations of high-sensitive Troponin I were quantified by immunoassay. RESULTS: Sixty patients undergoing PVI by PFA (n = 28, age 69 ± 12 year, 60% males, 39.3% persistent atrial fibrillation [AF]) or RFB (n = 32, age 65 ± 13 year, 53% males, 21.9% persistent AF) were evaluated. Acute PVI was achieved in all patients in both groups. Mean number of PFA pulses was 34.2 ± 4.5 and mean number RFB applications was 8.5 ± 3 per patient. Total posterior ablation area was significantly larger in PFA (20.7 ± 7.7 cm²) than in RFB (7.1 ± 2.09 cm²; p < .001). Accordingly, posterior ablation area for each PV resulted in larger lesions after PFA versus RFB (LSPV 5.2 ± 2.7 vs. 1.9 ± 0.8 cm², LIPV 5.5 ± 2.3 vs. 1.9 ± 0.8 cm², RSPV 4.7 ± 1.9 vs. 1.6 ± 0.5 cm², RIPV 5.3 ± 2.1 vs. 1.6 ± 0.7 cm,² respectively; p < .001). In a subset of 38 patients, increase of hsTropI was higher after PFA (625 ± 138 pg/mL, n = 28) versus RFB (148 ± 36 pg/mL, n = 10; p = .049) supporting the evidence of larger lesion extent by PFA. CONCLUSION: PFA delivers larger acute lesion areas and higher troponin release upon successful PVI than multielectrode RFB-based PVI in this single-center series.

Repolarization indicates electrical instability in ventricular arrhythmia originating from papillary muscle.

AIMS: Cardiac arrhythmia originating from the papillary muscle (PM) can trigger ventricular fibrillation (VF) and cause sudden cardiac death even in the absence of structural heart disease. Most premature ventricular contractions, however, are benign and hitherto difficult to distinguish from a potentially fatal arrhythmia. Altered repolarization characteristics are associated with electrical instability, but electrophysiological changes which precede degeneration into VF are still not fully understood. METHODS AND RESULTS: Ventricular arrhythmia (VA) was induced by aconitine injection into PMs of healthy sheep. To investigate mechanisms of degeneration of stable VA into VF in structurally healthy hearts, endocardial high-density and epicardial mapping was performed during sinus rhythm (SR) and VA. The electrical restitution curve, modelling the relation of diastolic interval and activation recovery interval (a surrogate parameter for action potential duration), is steeper in VA than in non-arrhythmia (ventricular pacing and SR). Steeper restitution curves reflect electrical instability and propensity to degenerate into VF. Importantly, we find the parameter repolarization time in relation to cycle length (RT/CL) to differentiate self-limiting from degenerating arrhythmia with high specificity and sensitivity. CONCLUSION: RT/CL may serve as a simple index to aid differentiation between self-limiting and electrically instable arrhythmia with the propensity to degenerate to VF. RT/CL is independent of cycle length and could easily be measured to identify electrical instability in patients.

Recapitulation of dyssynchrony-associated contractile impairment in asymmetrically paced engineered heart tissue.

BACKGROUND: One third of heart failure patients exhibit dyssynchronized electromechanical activity of the heart (evidenced by a broad QRS-complex). Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. Technically demanding and laborious large animal models have been developed to better predict responders of CRT and to investigate molecular mechanisms of dyssynchrony and CRT. The aim of this study was to establish a first humanized in vitro model of dyssynchrony and CRT. METHODS: Cardiomyocytes were differentiated from human induced pluripotent stem cells and cast into a fibrin matrix to produce engineered heart tissue (EHT). EHTs were either field stimulated in their entirety (symmetrically) or excited locally from one end (asymmetrically) or they were allowed to beat spontaneously. RESULTS: Asymmetrical pacing led to a depolarization wave from one end to the other end, which was visualized in human EHT transduced with a fast genetic Ca2+-sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca2+-signal throughout the EHT. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5-0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Contractile dysfunction that can be evoked by an increased afterload was aggravated in the asymmetrically paced group. Consistent with reports from paced dogs, p38MAPK and CaMKII-abundance was higher under asymmetrical than under symmetrical pacing while pAKT was considerably lower. CONCLUSIONS: This model allows for long-term pacing experiments mimicking electrical dyssynchrony vs. synchrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT.

Human Engineered Heart Tissue Patches Remuscularize the Injured Heart in a Dose-Dependent Manner.

BACKGROUND: Human engineered heart tissue (EHT) transplantation represents a potential regenerative strategy for patients with heart failure and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices, and determination of the effective dose. METHODS: Cardiomyocytes were differentiated from 3 different human induced pluripotent stem cell lines including one reprogrammed under good manufacturing practice conditions. Protocols for human induced pluripotent stem cell expansion, cardiomyocyte differentiation, and EHT generation were adapted to substances available in good manufacturing practice quality. EHT geometry was modified to generate patches suitable for transplantation in a small-animal model and perspectively humans. Repair efficacy was evaluated at 3 doses in a cryo-injury guinea pig model. Human-scale patches were epicardially transplanted onto healthy hearts in pigs to assess technical feasibility. RESULTS: We created mesh-structured tissue patches for transplantation in guinea pigs (1.5×2.5 cm, 9-15×106 cardiomyocytes) and pigs (5×7 cm, 450×106 cardiomyocytes). EHT patches coherently beat in culture and developed high force (mean 4.6 mN). Cardiomyocytes matured, aligned along the force lines, and demonstrated advanced sarcomeric structure and action potential characteristics closely resembling human ventricular tissue. EHT patches containing ≈4.5, 8.5, 12×106, or no cells were transplanted 7 days after cryo-injury (n=18-19 per group). EHT transplantation resulted in a dose-dependent remuscularization (graft size: 0%-12% of the scar). Only high-dose patches improved left ventricular function (+8% absolute, +24% relative increase). The grafts showed time-dependent cardiomyocyte proliferation. Although standard EHT patches did not withstand transplantation in pigs, the human-scale patch enabled successful patch transplantation. CONCLUSIONS: EHT patch transplantation resulted in a partial remuscularization of the injured heart and improved left ventricular function in a dose-dependent manner in a guinea pig injury model. Human-scale patches were successfully transplanted in pigs in a proof-of-principle study.

The established and the challenger: A direct comparison of current cryoballoon technologies for pulmonary vein isolation.

INTRODUCTION: Cryoballoon (CB) ablation for pulmonary vein isolation (PVI) is an effective treatment of atrial fibrillation (AF). Recently, a novel cryoablation system was introduced. The aim of the study was to compare the safety, efficacy and biophysical characteristics of a novel cryoablation system (POLARx™; Boston Scientific) to a commonly used and clinically well characterized system (Arctic Front Advance Pro™, AFA; Medtronic). METHODS AND RESULTS: Fifty consecutive patients with symptomatic AF, who underwent CB-based ablation with the POLARx were compared to 50 consecutive patients treated with the AFA. Acute PVI was achieved in 99.8% (POLARx 99.5%, AFA 100%, p = 1.00). Time to isolation (TTI) was comparable in both groups (POLARx 35 [27, 48] s, AFA 30 [21, 43] s, p = 0.165). The POLARx showed a lower balloon temperature at TTI (POLARx -44 [-50, -36] °C, AFA -31 [-38, -21] °C, p < 0.001) and lower nadir temperature (POLARx -60 [-65, -55] °C, AFA -48 [-54, -45] °C, p < 0.001). Procedure time (POLARx 80 [60, 105] min, AFA 62 [42, 80] min, p < 0.001), fluoroscopy time (POLARx 17 [13, 22] min, AFA 11 [7, 16] min, p < 0.001) and freeze cycles per patient (POLARx 5 [4, 6], AFA 4.5 [4, 5], p = 0.002) were higher in the POLARx group. Two cerebral ischemic events occurred in the POLARx group, two patients in each group had phrenic nerve injury. CONCLUSION: Both systems enable effective isolation of pulmonary veins. The POLARx required longer procedure and fluoroscopy times. Larger, prospective and randomized studies are needed to assess long-term efficacy and safety of this technology.

Revival of the Forgotten.

Pulmonary vein (PV) isolation (PVI) by continuous, transmural and durable lesions is decisive for ensuring long-term freedom from atrial fibrillation (AF). AF ablation requires irrigated tip catheters to reduce thromboembolic complications. This precluded temperature-controlled delivery of radiofrequency (RF) energy.The aim of this study was to evaluate feasibility, acute efficacy, and safety of an irrigated, temperature-controlled ablation catheter [DiamondTemp™ (DT) Medtronic®] for PVI.Consecutive patients with AF underwent PVI using the DT catheter combined with high-power short-duration RF applications. Ablation settings were (1) a catheter tip temperature limit of 60°C, (2) a temperature-controlled power of 50 W, and (3) application duration of 10 seconds. The primary endpoint was acute isolation of PVs, reassessed after a 30-minute waiting period. Secondary endpoints included procedural parameters (defined as a catheter tip temperature of 50°C > 3 seconds, an impedance drop of 5-10 Ω) and the occurrence of serious adverse events.Fifty consecutive patients [mean age 66 ± 12 years, 38 (76%) women, 24 patients with paroxysmal AF (48%)] were included. Median procedure and left atrial dwell time was 89 [68; 107] and 63 [52; 79] minutes, respectively. Mean number of RF applications was 59 ± 20, and mean total RF duration was 14 ± 6 minutes. Acute PVI was achieved in all patients solely using DT ablation. Acute PV reconnection within the waiting period occurred in five patients; all reconnected PVs were successfully reisolated. One major complication occurred.In this study, the DT ablation system demonstrated high acute efficacy for PVI. Temperature-controlled ablation in conjunction with high-power short-duration applications might be effectively supported.

Translational investigation of electrophysiology in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) patients are at increased risk of ventricular arrhythmias and sudden cardiac death, which can occur even in the absence of structural changes of the heart. HCM mouse models suggest mutations in myofilament components to affect Ca2+ homeostasis and thereby favor arrhythmia development. Additionally, some of them show indications of pro-arrhythmic changes in cardiac electrophysiology. In this study, we explored arrhythmia mechanisms in mice carrying a HCM mutation in Mybpc3 (Mybpc3-KI) and tested the translatability of our findings in human engineered heart tissues (EHTs) derived from CRISPR/Cas9-generated homozygous MYBPC3 mutant (MYBPC3hom) in induced pluripotent stem cells (iPSC) and to left ventricular septum samples obtained from HCM patients. We observed higher arrhythmia susceptibility in contractility measurements of field-stimulated intact cardiomyocytes and ventricular muscle strips as well as in electromyogram recordings of Langendorff-perfused hearts from adult Mybpc3-KI mice than in wild-type (WT) controls. The latter only occurred in homozygous (Hom-KI) but not in heterozygous (Het-KI) mouse hearts. Both Het- and Hom-KI are known to display pro-arrhythmic increased Ca2+ myofilament sensitivity as a direct consequence of the mutation. In the electrophysiological characterization of the model, we observed smaller repolarizing K+ currents in single cell patch clamp, longer ventricular action potentials in sharp microelectrode recordings and longer ventricular refractory periods in Langendorff-perfused hearts in Hom-KI, but not Het-KI. Interestingly, reduced K+ channel subunit transcript levels and prolonged action potentials were already detectable in newborn, pre-hypertrophic Hom-KI mice. Human iPSC-derived MYBPC3hom EHTs, which genetically mimicked the Hom-KI mice, did exhibit lower mutant mRNA and protein levels, lower force, beating frequency and relaxation time, but no significant alteration of the force-Ca2+ relation in skinned EHTs. Furthermore, MYBPC3hom EHTs did show higher spontaneous arrhythmic behavior, whereas action potentials measured by sharp microelectrode did not differ to isogenic controls. Action potentials measured in septal myectomy samples did not differ between patients with HCM and patients with aortic stenosis, except for the only sample with a MYBPC3 mutation. The data demonstrate that increased myofilament Ca2+ sensitivity is not sufficient to induce arrhythmias in the Mybpc3-KI mouse model and suggest that reduced K+ currents can be a pro-arrhythmic trigger in Hom-KI mice, probably already in early disease stages. However, neither data from EHTs nor from left ventricular samples indicate relevant reduction of K+ currents in human HCM. Therefore, our study highlights the species difference between mouse and human and emphasizes the importance of research in human samples and human-like models.

High anatomical accuracy of a novel high-resolution wide-band dielectric imaging system in cryoballoon-based ablation.

PURPOSE: Recently, a novel cardiac imaging system based on a wide-band dielectric technology (KODEX-EPD) was introduced to guide catheter ablation. The aim of the study was to evaluate this 3D wide-band dielectric imaging system (WDIS) during cryoballoon (CB)-based atrial fibrillation (AF) ablation focusing on accuracy of pulmonary vein (PV)-anatomy. METHODS: In consecutive patients with symptomatic AF, CB-based ablation was performed in conjunction with the 3D WDIS. Selective PV-angiographies were performed, and 3D anatomy of the left atrium (LA) and PVs using the 3D WDIS was created. The ostial diameters of the ipsilateral right-sided and left-sided PVs and ostial diameters of the right-/left-sided upper/lower PVs demonstrated by selective angiographies were analyzed and compared to 3D WDIS-based PV visualization. RESULTS: In 65 patients (42/65 (65%) male, age 65 ± 9 years, 29/65 (45%) paroxysmal AF) a total of 260 PVs were identified. Median ostial PV-diameters for the ipsilateral left- and right-sided PVs were 38 [34; 43] and 37 [34; 40.3] mm when assessed fluoroscopically and 40 [35.7; 43] and 39 [35.0; 43] mm as demonstrated by 3D WDIS. There was no statistically significant difference between both methods regarding PV-diameter measurements. KODEX-EPD overestimated fluoroscopy measurements by 1.08 mm (95% limits of agreement of -1.93 mm and 4.1 mm). CONCLUSION: The novel wide-band dielectric 3D-imaging system is feasible to create high-resolution images of cardiac structures during CB ablation procedures and accurately visualizes PV-anatomy.

Intermittent Optogenetic Tachypacing of Atrial Engineered Heart Tissue Induces Only Limited Electrical Remodelling.

ABSTRACT: Atrial tachypacing is an accepted model for atrial fibrillation (AF) in large animals and in cellular models. Human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CM) provide a novel human source to model cardiovascular diseases. Here, we investigated whether optogenetic tachypacing of atrial-like hiPSC-CMs grown into engineered heart tissue (aEHT) can induce AF-remodeling. After differentiation of atrial-like cardiomyocytes from hiPSCs using retinoic acid, aEHTs were generated from ∼1 million atrial-like hiPSC-CMs per aEHT. AEHTs were transduced with lentivirus expressing channelrhodopsin-2 to enable optogenetic stimulation by blue light pulses. AEHTs underwent optical tachypacing at 5 Hz for 15 seconds twice a minute over 3 weeks and compared with transduced spontaneously beating isogenic aEHTs (1.95 ± 0.07 Hz). Force and action potential duration did not differ between spontaneously beating and tachypaced aEHTs. Action potentials in tachypaced aEHTs showed higher upstroke velocity (138 ± 15 vs. 87 ± 11 V/s, n = 15-13/3; P = 0.018), possibly corresponding to a tendency for more negative diastolic potentials (73.0 ± 1.8 vs. 68.0 ± 1.9 mV; P = 0.07). Tachypaced aEHTs exhibited a more irregular spontaneous beating pattern (beat-to-beat scatter: 0.07 ± 0.01 vs. 0.03 ± 0.004 seconds, n = 15-13/3; P = 0.008). Targeted expression analysis showed higher RNA levels of KCNJ12 [Kir2.2, inward rectifier (IK1); 69 ± 7 vs. 44 ± 4, P = 0.014] and NPPB (NT-proBNP; 39,690 ± 4834 vs. 23,671 ± 3691; P = 0.024). Intermittent tachypacing in aEHTs induces some electrical alterations found in AF and induces an arrhythmic spontaneous beating pattern, but does not affect resting force. Further studies using longer, continuous, or more aggressive stimulation may clarify the contribution of different rate patterns on the changes in aEHT mimicking the remodeling process from paroxysmal to persistent atrial fibrillation.

Rat atrial engineered heart tissue: a new in vitro model to study atrial biology.

Engineered heart tissue (EHT) from rat cells is a useful tool to study ventricular biology and cardiac drug safety. Since atrial and ventricular cells differ significantly, EHT and other 3D cell culture formats generated from ventricular cells have been of limited value to study atrial biology. To date, reliable in vitro models that reflect atrial physiology are lacking. Therefore, we established a novel EHT model using rat atrial cells (atrial EHT, aEHT) to assess atrial physiology, contractility and drug response. The tissue constructs were characterized with regard to gene expression, histology, electrophysiology, and the response to atrial-specific drugs. We observed typical functional properties of atrial tissue in our model such as more regular spontaneous beating with lower force, shorter action potential duration, and faster contraction and relaxation compared to ventricular EHT (vEHT). The expression of atrial-specific genes and proteins was high, whereas ventricle-specific transcripts were virtually absent. The atrial-selective drug carbachol had a strong negative inotropic and chronotropic effect on aEHT only. Taken together, the results demonstrate the feasibility of aEHT as a novel atrial 3D model and as a benchmark for tissue engineering with human induced pluripotent stem cell-derived atrial-like cardiomyocytes. Atrial EHT faithfully recapitulates atrial physiology and shall be useful to study atrial molecular physiology in health and disease as well as drug response.

Risk stratification of patients with left atrial appendage thrombus prior to catheter ablation of atrial fibrillation: An approach towards an individualized use of transesophageal echocardiography.

INTRODUCTION: The need for transesophageal echocardiography (TEE) before catheter ablation of atrial fibrillation (CA-AF) is still being questioned. The aim of this study is to analyze patients' (patients) risk factors of left atrial appendage thrombus (LAAT) prior to CA-AF in daily clinical practice, according to oral anticoagulation (OAC) strategies recommended by current guidelines. METHODS AND RESULTS: All patients scheduled for CA-AF from 01/2015 to 12/2016 in our center were included and either treated with NOACs (novel-OAC; paused 24-hours preablation) or continuous vitamin K antagonists (INR 2.0-3.0). All patients received a preprocedural TEE at the day of ablation. Two groups were defined: (1) patients without LAAT, (2) patients with LAAT. The incidence of LAAT was 0.78% (13 of 1,658 patients). No LAAT was detected in patients with a CHA2 DS2 -VASc score of ≤1 (n = 640 patients) irrespective of the underlying AF type. Independent predictors for LAAT are: higher CHA2 DS2 -VASc scores (odds ratio [OR] 1.54, 95%-confidence interval [CI]: 1.07-2.23, P = 0.0019), a history of nonparoxysmal AF (OR 7.96, 95%-CI: 1.52-146.64, P = 0.049), hypertrophic cardiomyopathy (HCM; OR 9.63, 95% CI: 1.36-43.05, P = 0.007), and a left ventricular ejection fraction (LVEF) < 30% (OR 8.32, 95% CI: 1.18-36.29, P = 0.011). The type of OAC was not predictive (P = 0.70). CONCLUSIONS: The incidence of LAAT in patients scheduled for CA-AF is low. Therefore, periprocedural OAC strategies recommended by current guidelines seem feasible. Preprocedural TEE may be dispensed in patients with a CHA2 DS2 -VASc score ≤1. However, a CHA2 DS2 -VASc score ≥2, reduced LVEF, HCM, or history of nonparoxysmal AF are independently associated with an increased risk for LAAT.

Repeat pulmonary vein isolation and anterior line ablation using a novel point-by-point pulsed-field ablation system.

BACKGROUND: Pulsed-field ablation (PFA) is a nonthermal energy source for ablation of cardiac arrhythmias. This study investigated the prospective outcomes of a novel PFA generator in conjunction with a commercially available, contact force-sensing, focal ablation catheter. OBJECTIVE: The purpose of this study was to assess the feasibility, safety, and lesion characteristics of point-by-point PFA in consecutive patients undergoing repeat ablation of atrial fibrillation (AF). METHODS: The study involved reisolation of pulmonary veins (PVs) with electrical reconnection and the creation of an anterior line (AL) in patients with anterior substrate or durable pulmonary vein isolation (PVI). RESULTS: In 24 patients (46% female; mean age 67 ± 10 years; 67% persistent AF), successful reisolation of 27 of 27 reconnected PVs (100%) was performed. In 19 patients, AL ablation was performed, with bidirectional block in 16 (84%), median ablation time 26 [21, 33] minutes, and first-pass bidirectional block in 13 patients (68%). Acute AL reconduction occurred in 8 of 19 patients (42%). Among these 8 patients, a subsequent sustained block of the AL was achieved in 5 (63%). Ultra-high-density electroanatomic mapping revealed homogeneous but relatively large low-voltage areas in the ablated regions. Median procedural, left atrial dwell, and fluoroscopy times were 100 [90, 109] minutes, 83 [75, 98] minutes, and 10 [8, 13] minutes, respectively. No major or minor complications occurred. CONCLUSION: This study demonstrated feasibility, acute efficacy, and safety of point-by-point PFA for repeat PVI and AL ablation. Further studies are warranted to assess the long-term durability and comparison with established ablation methods.

Safety and Effectiveness of Pulsed Field Ablation for Atrial Fibrillation in Patients With Heart Failure.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) coexist, increasing morbidity and mortality. Studies have demonstrated improved outcomes following AF ablation in HF patients with reduced ejection fraction (EF). OBJECTIVE: This study sought to assess the outcomes of pulsed field ablation (PFA) in HF. METHODS: MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-Approval Clinical Use of Pulsed Field Ablation) is a multicenter, patient-level registry of consecutive patients undergoing PFA for paroxysmal AF or persistent AF (PerAF). In this substudy, patients were stratified as no history of HF (no-HF), HF with preserved EF (HFpEF) (left ventricular EF of ≥50%) or HF with reduced/mildly reduced EF (HFmr/rEF) (left ventricular EF of <50%). The primary effectiveness and safety endpoints were freedom from documented atrial arrhythmias lasting ≥30 seconds and major adverse events, respectively. RESULTS: Of the 1,381 patients, 85% (n = 1,174) were no-HF, 6.2% (n = 87) were HFpEF, and 8.6% (n = 120) were HFmr/rEF. No-HF patients had less PerAF than patients with HF (P < 0.001), with no difference between HF subtypes (P = >0.99). The 1-year freedom from atrial arrhythmia was significantly higher in no-HF patients than in those with HFpEF or HFmr/rEF (79.9%, 71.3%, and 67.5%, respectively; P < 0.001) but similar between patients with HFmr/rEF and HFpEF (P = 0.26). However, there was no significant difference in freedom from atrial arrhythmia among patients with no-HF vs HFpEF vs HFmr/rEF for those with paroxysmal AF (82.8%, 82.4%, and 71.7%, respectively; P = 0.09) and PerAF (73.3%, 64.2%, and 64.9%, respectively; P = 0.14). Major adverse event rates were similar between the no-HF, HFpEF, and HFmr/rEF groups (1.9%, 0%, and 2.5%, respectively). CONCLUSIONS: PFA appears to be potentially safe and effective in AF patients with HF. Freedom from atrial arrhythmia post-PFA was higher in patients without a history of HF, with no significant difference between HF subtypes.

Safety and Effectiveness of Pulsed Field Ablation for Atrial Fibrillation in Patients with Heart Failure: A MANIFEST-PF Sub-analysis.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) coexist, increasing morbidity and mortality. Studies have demonstrated improved outcomes following AF ablation in HF patients with reduced ejection fraction (EF). OBJECTIVE: To assess the outcomes of pulsed-field ablation (PFA) in HF. METHODS: MANIFEST-PF is a multicenter patient-level registry of consecutive patients undergoing PFA for paroxysmal (PAF) or persistent AF (PerAF). In this sub-study, patients were stratified as: no history of HF (no-HF), HF with preserved EF (HFPEF; LVEF≥50%) or HF with reduced/mildly-reduced EF (HFMR/REF; LVEF<50%). The primary effectiveness and safety endpoints were freedom from documented atrial arrhythmias lasting ≥30s and major adverse events (MAEs), respectively. RESULTS: Of the 1,381 patients, 85% (n=1,174) were no-HF, 6.2% (n=87) were HFPEF, and 8.6% (n=120) were HFMR/REF. No-HF patients had less PerAF than patients with HF (p<0.001), with no difference between HF subtypes (p=1.00). The 1-year freedom from atrial arrhythmia was significantly higher in no-HF than with HFPEF or HFMR/REF (79.9%, 71.3%, 67.5%, p<0.001), but similar between HFMR/REF and HFPEF (p=0.26). However, there was no significant difference in freedom from atrial arrhythmia among patients with no-HF vs HFPEF vs HFMR/REF for those with PAF (82.8%/82.4%/71.7%, p=0.09) and PerAF (73.3%, 64.2%, and 64.9%, p=0.14.MAE rates were similar between the no-HF, HFPEF and HFMR/REF groups (1.9%, 0%, and 2.5%, respectively). CONCLUSION: PFA appears to be potentially safe and effective in AF patients with HF. Freedom from atrial arrhythmia post-PFA was higher in patients without a history of HF, with no significant difference between HF subtypes.

Impact of Left Atrial Posterior Wall Ablation During Pulsed-Field Ablation for Persistent Atrial Fibrillation.

BACKGROUND: Pulmonary vein isolation (PVI) alone is insufficient to treat many patients with persistent atrial fibrillation (PersAF). Adjunctive left atrial posterior wall (LAPW) ablation with thermal technologies has revealed lack of efficacy, perhaps limited by the difficulty in achieving lesion durability amid concerns of esophageal injury. OBJECTIVES: This study aims to compare the safety and effectiveness of PVI + LAPW ablation vs PVI in patients with PersAF using pulsed-field ablation (PFA). METHODS: In a retrospective analysis of the MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-approval Clinical Use of Pulsed Field Ablation) registry, we studied consecutive PersAF patients undergoing post-approval treatment with a pentaspline PFA catheter. The primary effectiveness outcome was freedom from any atrial arrhythmia of ≥30 seconds. Safety outcomes included the composite of acute and chronic major adverse events. RESULTS: Of the 547 patients with PersAF who underwent PFA, 131 (24%) received adjunctive LAPW ablation. Compared to PVI-alone, patients receiving adjunctive LAPW ablation were younger (65 vs 67 years of age, P = 0.08), had a lower CHA2DS2-VASc score (2.3 ± 1.6 vs 2.6 ± 1.6, P = 0.08), and were more likely to receive electroanatomical mapping (48.1% vs 39.0%, P = 0.07) and intracardiac echocardiography imaging (46.1% vs 17.1%, P < 0.001). The 1-year Kaplan-Meier estimate for freedom from atrial arrhythmias was not statistically different between groups in the full (PVI + LAPW: 66.4%; 95% CI: 57.6%-74.4% vs PVI: 73.1%; 95% CI: 68.5%-77.2%; P = 0.68) and propensity-matched cohorts (PVI + LAPW: 71.7% vs PVI: 68.5%; P = 0.34). There was also no significant difference in major adverse events between the groups (2.2% vs 1.4%, respectively, P = 0.51). CONCLUSIONS: In patients with PersAF undergoing PFA, as compared to PVI-alone, adjunctive LAPW ablation did not improve freedom from atrial arrhythmia at 12 months.

Management of pericardial tamponade in the electrophysiology laboratory: results from a national survey.

BACKGROUND: Despite continued efforts to improve the safety of catheter ablation, pericardial tamponade remains one of its more frequent, potentially life-threatening complications. Management of cardiac tamponade is not standardized and uncertainties regarding acute treatment remain. METHODS: This survey sought to evaluate the management of cardiac tamponade in German EP centers via a standardized postal questionnaire. All 341 identified German EP centers were invited to return a questionnaire on their standards for the management of cardiac tamponade. RESULTS: A total of 189 German EP centers completed the questionnaire. Several precautions are followed to avoid pericardial tamponade: A minority of centers preclude very old patients (19%) or those with a high body mass index (30%) from ablation. Non-vitamin K antagonist oral anticoagulants are briefly paused in most centers (88%) before procedures, while vitamin K antagonists are continued. Pericardial tamponade is usually treated using reversal of heparin by applying protamine (86%) and pericardiocentesis under both, fluoroscopic and echocardiographic guidance (62%). A pigtail catheter is mostly inserted (97%) and autotransfusion of aspirated blood is performed in 47% of centers. The decision for surgical repair depends on different clinical and infrastructural aspects. The timing of reinitiation of anticoagulation widely differs between the centers. Approximately 1/3 of centers prescribe nonsteroidal anti-inflammatory agents, colchicine or steroids after pericardiocentesis. CONCLUSION: The present survey shows that the management of cardiac tamponade is still inhomogeneous in German ablation centers. However, multiple findings of this survey can be generalized and might guide especially less experienced operators and centers in their treatment and decision strategies.

PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation.

BACKGROUND: Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to PITX2 (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2-/-) in human induced pluripotent stem cell-derived atrial cardiomyocytes. METHODS: CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete PITX2 in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements. RESULTS: PITX2-/- atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2-/- than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2-/- versus isogenic control; P<0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca2+ current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P<0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P=0.001), despite normal inward rectifier currents (both IK1 and IK,ACh) and carbachol-induced shortening of action potential duration. CONCLUSIONS: Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.