Pulsed Field Ablation For Treatment Of Atrial Fibrillation: Preclinical Experiment And Clinical Trial

Objective:Pulsed field ablation（PFA）is a novel energy modality for treatment of atrial fibrillation（AF）.More studies was still be needed for further evaluate the fesibility of PFA on myocardial ablation.The objective of this study was to evaluate the effects of core PFA parameters（voltage,V;pulse width,PW;pulse numbers per application,P;application numbers,N）on lesion formation in a potato model.Secondly,Ablation for of diverse atrial myocardium myocardia were was performed by biphasic and higher frequency PFA system and circular multielectrode catheter using different PFA doses based on the results from ex-vivo study,and the safety and lesion characteristics at 48h and 4w safety and lesion characterization were evaluated.Lastly,Clinical outcomes of pulmonary vein isolation（PVI）were evaluated using Cardio Pulse^TMPFA system and a novel hex spline PFA catheter in treatment of patients with paroxysmal AF.Methods:1.A potato PFA lesion model was established to examine the effect of different ablation parameters on the depth of irreversible lesion using PFA.Step 1:keep total PFA dose（V²×PW×P×N）unchanged and compare the influence degree of different PFA parameters on lesion formation.The following 4 groups depending on parameter setting were designed:1)Comparison between voltage and pulse width;2)Comparison between voltage and pulse numbers per application;3)Comparison between pulse width and pulse numbers per application;4)Comparison between pulse numbers per application and application numbers.Step 2:1)Access the effect of different applied voltage on the depth of PFA lesions（200V,400V,600V,800V,1000V,1200V,1400V,1600V）;2)Evaluate the effect of different pulse numbers on the depth of PFA lesion（2400,4800,7200,9600,12000）.2.Eight dogs were divided into 48h group（n=4）and 4w group（n=4）.PFA was performed on PV antrum（PV,1200V×36 applications）,superior vena cava（SVC,1000V×16 applications）,right/left atrial appendage（RAA/LAA,1000V×24 applications）by using different PFA doses.Ablation efficacy were assessed by observing acute PV electrical isolation（PVI）,areas with low voltage,and lesion feature via necropsy and histopathology after 48-hours and 4-weeks survival.Safety data were also recorded during and post procedures.3.Symptomatic patients with paroxysmal AF were enrolled from October,2021 to January,2022.The PFA catheter had six splines,each containing 3-4electrodes,which could simultaneously deliver biphasic and bipolar pulses and record local electrical signals.The configuration of the catheter tip could be adjusted from basket to flower to fit different anatomies of PVs.PVI was achieved by delivering different pulse intensities at the PV ostium.PV potentials（PVPs）were carefully recorded and verified by PFA catheter before and after ablation.Acute success was defined as PVI at each PV after20 min waiting period.The follow-up was scheduled before discharge and at 3,6,and 12months after the procedure with standard ECG,24h Holter monitoring,and TTE examination.The primary endpoint was the success rate of 12-month freedom from≥30s of AF,AFL or AT.Results:1.Influence degree of PFA parameters on lesion formation:1)voltage and pulse width:lesion depth were 4.43±0.16mm in 900v×5μs group and 4.11±0.09mm in1420v×2us group,the influence degree on PFA lesion:pulse width>voltage;2)voltage and pulse numbers per application:lesion depth were 4.47±0.27mm in 1000V×100（pulse number）group and 4.88±0.32mm in 1300v×60 group,the influence degree on PFA lesion:voltage>pulse number per application;3)pulse width and pluse numbers per application:lesion depth were 4.02±0.18mm in 2μs×500 group and 4.28±0.11mm in 5μs×200 group,the influence degree on PFA lesion:pulse width>pluse number per application;4)pluse number per application and application numbers:lesion depth were 4.25±0.19mm in 300（pulse number）×12（application）group and 5.06±0.30mm in 60×60 group,the influence degree on PFA lesion:pulse numbers per application>application numbers.Step 2:1)the depth of lesion is voltage-dependent,lesion depths on the average were 0mm,1.04±0.17mm,2.06±0.18mm,3.44±0.19mm,4.14±0.16mm,4.60±0.22mm,5.12±0.27mm,5.61±0.23 mm under the voltages of 200V,400V,600V,800V,1000V,1200V,1400V,1600V,respectively.2)PFA lesion depth increased along with rise of total pulses,but there is a saturation when a threshold of total pulse times was 9600.With the rise of total pulse numbers（2400,4800,7200,9600,12000）,lesion depths on the average were 4.28±0.18mm、4.54±0.19mm、4.77±0.19mm、5.25±0.30mm、5.11±0.21 mm,respectively when the PFA application numbers increased;and 4.23±0.16mm、4.49±0.18mm、4.73±0.20mm、4.98±0.19mm、5.03±0.16 mm respectively when the PFA pluses per application increased.2.PFA procedures were successfully performed in all anatomies（PV antrum,SVC,LAA/RAA）,and 100%acute PVI was achieved with different PFA doses.Lesions in necropsy were circumferential,contiguous,and transmural at both 48hour and 4week observation points,and there was no significant difference in lesion dimension between the two groups.Histology demonstrated that degenerating cardiomyocytes being replaced by fibroblasts and mixed inflammatory cells at 48 hours and being completely fibrosis replacement at 4 weeks.No animals experienced phrenic nerve palsy,pericardial effusion,ventricular arrhythmia or thrombus formation,and no temperature rise was detected in esophagus during PFA delivery.In addition,surrounding organs,such as lung,liver,spleen,kidney were normal at 4week.3.51patients were enrolled into this study,the mean age was 60.43±10.68 years,15（29.4%）patients were female,and the mean left atrial diameter was 36.73±4.81 mm.A history of hypertension and diabetes was present in 52.94%and15.69%of patients,respectively.All PVs were mapped,and acute PVI achieved by Cardio Pulse PFA catheter in all the PVs.All patients achieved acute success.Total procedure time,catheter dwelling time,the total X-ray exposure time were 129.0±46.7minutes,65.4±27.0 minutes,31.2±10.8 minutes,respectively.No major adverse events such as death,myocardial infarction,tamponade,or pericardial effusion,esophagus injury,phrenic nerve palsy occurred.All patients completed 12-month follow-up.45 of 51（88.2%）patients were free from AF,AFL or AT.Conclusion:1.The influence strengths of PFA parameters on lesion formation are as followed:if the total PFA doses are equal,pulse width>voltage>pulse numbers per application;pulse numbers per application>application numbers.The depth of lesion created by PFA is dose-dependent,and there is a positive correlation between applied PFA voltages and lesion depth;similarly,lesion depth increased along with the rise of total number of pulses,but there is a saturation when a threshold of pulse numbers was achieved.2.PFA deliveries to the PV antrum,SVC,RAA/LAA resulted in complete circumferential,contiguous,and transmural lesions at both 48hour and 4week post ablation with collateral tissue safety profile.Histology demonstrated that degenerating cardiomyocytes being completely fibrosis replacement at 4 weeks.3.Cardio Pulse^TM PFA system with the novel hex-spline catheter was feasible and safe to achieve PVI,and the results of both acute success and 12-month clinical success were promising.