Complications after Heller myotomy in children: a national multicenter study on the impact of prior endoscopic dilatation and identification of risk factors.

BACKGROUND: Although esophageal achalasia has been historically treated by Heller myotomy, endoscopic esophageal dilatations are nowadays often the first-line treatment in children. The aim was to assess whether performing an endoscopic dilatation before a Heller myotomy is associated with higher risks of esophageal perforation in children. METHODS: A retrospective multicentric study was performed, including children that underwent a Heller myotomy (2000-2022, 10 centers). Two groups were compared based on the history of previous dilatation before myotomy. Outcomes esophageal perforation (intra-operative or secondary) and post-operative complications requiring surgery (Clavien-Dindo III). Statistics Comparisons using contingency tables or Kruskal-Wallis when appropriate. Statistical significance: p-value < 0.05. RESULTS: A Heller myotomy was performed in 77 children (median age: 11.8 years), with prior endoscopic dilatation in 53% (n = 41). A laparoscopic approach was used in 90%, with associated fundoplication in 95%. Esophageal perforation occurred in 19% of children (n = 15), including 12 patients with intra-operative mucosal tear and 3 with post-operative complications related to an unnoticed esophageal perforation. Previous endoscopic dilatation did not increase the risk of esophageal perforation (22% vs 17%, OR: 1.4, 95%CI: 0.43-4.69). Post-operative complications occurred in 8% (n = 6), with similar rates regardless of prior endoscopic dilatation. Intra-operative mucosal tear was the only risk factor for post-operative complications, increasing the risk of complications from 5 to 25% (OR: 6.89, 95%CI: 1.38-31.87). CONCLUSIONS: Prior endoscopic dilatations did not increase the risk of esophageal perforation or postoperative complications of Heller myotomy in this cohort of children with achalasia. Mucosal tear was identified as a risk factor for post-operative complications.

Isolated Fallopian Tube Torsion in Children With Hydrosalpinx: Is Conservative Management an Option?

BACKGROUND: Isolated fallopian tube torsion (IFTT) is very rare gynecological emergency in pediatric population. Our objective is to assess treatment options and discuss outcome of a cohort of IFTT with a focus on the association between IFTT and hydrosalpinx (HSX). METHODS: A retrospective review was conducted. Pediatric patients with IFTT operated in the same center were included. RESULTS: Seventeen girls (aged: 11-16 years) were managed for acute abdominal pain between 2008 and 2018, with intraoperative diagnosis of IFTT. All patients underwent laparoscopic exploration, with laparoscopically fallopian tube detorsion in all patients. Based on the association of IFTT with HSX after fallopian tube detorsion, patients were divided into 2 groups: group 1 (IFTT without HSX; 12 girls) and group 2 (IFTT with HSX; 5 girls). During the same surgery, complementary surgical procedures were done. In group 1: salpingectomies (4), partial salpingectomies (2) and cystectomies (6) were done. In group 2: salpingectomy (1), salpingotomy (1), and cyst ablation (1). The treatment was called conservative when the tube was preserved.Follow-up was uneventful in group 1. In group 2, for all patients with initial fallopian tube preservation, further surgical procedures were necessary (1-4 surgeries/patient), and, finally, another 3 patients required salpingectomy. CONCLUSIONS: Conservative treatment with tube preservation of IFTT without HSX appeared to be beneficial compared to those with HSX, with no recurrence of torsion or symptoms during the follow-up. However, the same conservative treatment was not sufficiently effective for IFTT with HSX and required further procedures due to recurrence of torsion. LEVEL OF EVIDENCE: IV.

Basis and applicability of noninvasive inverse electrocardiography: a comparison between cardiac source models.

The body surface electrocardiogram (ECG) is a direct result of electrical activity generated by the myocardium. Using the body surface ECGs to reconstruct cardiac electrical activity is called the inverse problem of electrocardiography. The method to solve the inverse problem depends on the chosen cardiac source model to describe cardiac electrical activity. In this paper, we describe the theoretical basis of two inverse methods based on the most commonly used cardiac source models: the epicardial potential model and the equivalent dipole layer model. We discuss similarities and differences in applicability, strengths and weaknesses and sketch a road towards improved inverse solutions by targeted use, sequential application or a combination of the two methods.

Left Ventricular Abnormal Substrate in Brugada Syndrome.

BACKGROUND: Slow-conductive structural abnormalities located in the epicardium of the right ventricle (RV) underlie Brugada syndrome (BrS). The extent of such substrate in the left ventricle (LV) has not been investigated. OBJECTIVES: This study sought to characterize the extent of epicardial substrate abnormalities in BrS. METHODS: We evaluated 22 consecutive patients (mean age 46 ± 11 years, 21 male) referred for recurrent ventricular arrhythmias (mean 10 ± 13 episodes) in the setting of BrS. The patients underwent clinical investigations and wide genetic screening to identify SCN5A mutations and common risk variants. High-density biventricular epicardial mapping was performed to detect prolonged (>70 ms) fragmented electrograms, indicating abnormal substrate area. RESULTS: All patients presented with abnormal substrate in the epicardial anterior RV (27 ± 11 cm2). Abnormal substrate was also identified on the LV epicardium in 10 patients (45%), 9 at baseline and 1 after ajmaline infusion, covering 15 ± 11 cm2. Of these, 4 had severe LV fascicular blocks. Patients with LV substrate had a longer history of arrhythmia (11.4 ± 6.7 years vs 4.3 ± 4.3 years; P = 0.003), longer PR (217 ± 24 ms vs 171 ± 14 ms; P < 0.001) and HV (60 ± 12 ms vs 46 ± 5 ms; P = 0.005) intervals, and abnormal substrate also extending into the inferior RV (100% vs 33%; P = 0.001). SCN5A mutation was present in 70% of patients with LV substrate (vs 25%; P = 0.035). SCN5A BrS patients with recurrent ventricular arrhythmias present a higher polygenic risk score compared with a nonselected BrS population (median of differences: -0.86; 95% CI: -1.48 to -0.27; P = 0.02). CONCLUSIONS: A subset of patients with BrS present an abnormal substrate extending onto the LV epicardium and inferior RV that is associated with SCN5A mutations and multigenic variants.

Artificial intelligence for detection of ventricular oversensing: Machine learning approaches for noise detection within nonsustained ventricular tachycardia episodes remotely transmitted by pacemakers and implantable cardioverter-defibrillators.

BACKGROUND: Pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs) increasingly automatically record and remotely transmit nonsustained ventricular tachycardia (NSVT) episodes, which may reveal ventricular oversensing. OBJECTIVES: We aimed to develop and validate a machine learning algorithm that accurately classifies NSVT episodes transmitted by PMs and ICDs in order to lighten health care workload burden and improve patient safety. METHODS: PMs or ICDs (Boston Scientific, St Paul, MN) from 4 French hospitals with ≥1 transmitted NSVT episode were split into 3 subgroups: training set, validation set, and test set. Each NSVT episode was labeled as either physiological or nonphysiological. Four machine learning algorithms-2DTF-CNN, 2D-DenseNet, 2DTF-VGG, and 1D-AgResNet-were developed using training and validation data sets. Accuracies of the classifiers were compared with an analysis of the remote monitoring team of the Bordeaux University Hospital using F2 scores (favoring sensitivity over predictive positive value) using an independent test set. RESULTS: A total of 807 devices transmitted 10,471 NSVT recordings (82% ICD; 18% PM), of which 87 devices (10.8%) transmitted 544 NSVT recordings with nonphysiological signals. The classification by the remote monitoring team resulted in an F2 score of 0.932 (sensitivity 95%; specificity 99%) The 4 machine learning algorithms showed high and comparable F2 scores (2DTF-CNN: 0.914; 2D-DenseNet: 0.906; 2DTF-VGG: 0.863; 1D-AgResNet: 0.791), and only 1D-AgResNet had significantly different labeling from that of the remote monitoring team. CONCLUSION: Machine learning algorithms were accurate in detecting nonphysiological signals within electrograms transmitted by PMs and ICDs. An artificial intelligence approach may render remote monitoring less resourceful and improve patient safety.

Investigation into the importance of using natural PVCs and pathological models for potential-based ECGI validation.

Introduction: Premature ventricular contractions (PVCs) are one of the most commonly targeted pathologies for ECGI validation, often through ventricular stimulation to mimic the ectopic beat. However, it remains unclear if such stimulated beats faithfully reproduce spontaneously occurring PVCs, particularly in the case of the R-on-T phenomenon. The objective of this study was to determine the differences in ECGI accuracy when reconstructing spontaneous PVCs as compared to ventricular-stimulated beats and to explore the impact of pathophysiological perturbation on this reconstruction accuracy. Methods: Langendorff-perfused pig hearts (n = 3) were suspended in a human torso-shaped tank, and local hyperkalemia was induced through perfusion of a high-K+ solution (8 mM) into the LAD. Recordings were taken simultaneously from the heart and tank surfaces during ventricular pacing and during spontaneous PVCs (including R-on-T), both at baseline and high K+. Epicardial potentials were reconstructed from torso potentials using ECGI. Results: Spontaneously occurring PVCs were better reconstructed than stimulated beats at baseline in terms of electrogram morphology [correlation coefficient (CC) = 0.74 ± 0.05 vs. CC = 0.60 ± 0.10], potential maps (CC = 0.61 ± 0.06 vs. CC = 0.51 ± 0.12), and activation time maps (CC = 0.86 ± 0.07 vs. 0.76 ± 0.10), though there was no difference in the localization error (LE) of epicardial origin (LE = 14 ± 6 vs. 15 ± 11 mm). High K+ perfusion reduced the accuracy of ECGI reconstructions in terms of electrogram morphology (CC = 0.68 ± 0.10) and AT maps (CC = 0.70 ± 0.12 and 0.59 ± 0.23) for isolated PVCs and paced beats, respectively. LE trended worse, but the change was not significant (LE = 17 ± 9 and 20 ± 12 mm). Spontaneous PVCs were less well when the R-on-T phenomenon occurred and the activation wavefronts encountered a line of block. Conclusion: This study demonstrates the differences in ECGI accuracy between spontaneous PVCs and ventricular-paced beats. We also observed a reduction in this accuracy near regions of electrically inactive tissue. These results highlight the need for more physiologically realistic experimental models when evaluating the accuracy of ECGI methods. In particular, reconstruction accuracy needs to be further evaluated in the presence of R-on-T or isolated PVCs, particularly when encountering obstacles (functional or anatomical) which cause line of block and re-entry.

Iterative antibody-induced bile salt export pump deficiency after successive liver transplantations successfully treated with plasmapheresis and rituximab.

Post-transplantation evolution of progressive familial intrahepatic cholestasis type 2 patients can be complicated by antibody-induced bile salt export pump deficiency (AIBD). There is no consensus on its management. We describe a patient who presented two episodes, 9 years apart. The first episode was refractory to plasmapheresis and intravenous immunoglobulin (IVIG) started 2 months after AIBD onset, leading to graft loss. The second episode responded to plasmapheresis, IVIG and rituximab initiated less than 2 weeks after the beginning of symptoms, allowing for long-term recovery. This case suggests that intensive treatment with minimum delay after symptoms onset could sponsor a better evolution.

Atrial Periodic Source Spectrum From Preoperative Body Surface Potentials Predicts Long-Term Recurrence of Atrial Fibrillation.

OBJECTIVE: About half of patients experience recurrence of atrial fibrillation (AF) within three to five years after a single catheter ablation procedure. The suboptimality of the long-term outcomes likely results from the inter-patient variability of AF mechanisms, which can be remedied by improved patient screening. We aim to improve the interpretation of body surface potentials (BSPs), such as 12-lead electrocardiograms and 252-lead BSP maps, to aid preoperative patient screening. METHODS: We developed the Atrial Periodic Source Spectrum (APSS), a novel patient-specific representation based on atrial periodic content, computed on the f-wave segments of patient BSPs, using a second-order blind source separation and a Gaussian Process for regression. With follow-up data, Cox's proportional hazard model was used to select the most relevant feature from preoperative APSSs responsible for AF recurrence. RESULTS: Over 138 persistent AF patients, the presence of highly periodic content with cycle lengths between 220-230 ms or 350-400 ms indicates higher risks of 4-year post-ablation AF recurrence (log-rank test, p-value ). CONCLUSION AND SIGNIFICANCE: Preoperative BSPs demonstrate effective prediction in the long-term outcomes, highlighting their potential for patient screening in AF ablation therapy.

24-Hour Monitoring of Intraocular Pressure Fluctuations Using a Contact Lens Sensor: Diagnostic Performance for Glaucoma Progression.

Purpose: The purpose of this study was to compare 24-hour intraocular pressure (IOP) related fluctuations monitoring between 2 groups of visual field progression rates in patients with open angle glaucoma (OAG). Methods: Cross-sectional study performed at Bordeaux University Hospital. Twenty-four-hour monitoring was performed using a contact lens sensor (CLS; Triggerfish; SENSIMED, Etagnières, Switzerland). Progression rate was calculated using a linear regression of the mean deviation (MD) parameter of the visual field test (Octopus; HAAG-STREIT, Switzerland). Patients were allocated into two groups: group 1 with an MD progression rate <-0.5 dB/year and group 2 with an MD progression rate ≥-0.5 dB/year. An automatic signal-processing program was developed and a frequency filtering of the monitoring by wavelet transform analysis was used to compare the output signal between the two groups. A multivariate classifier was performed for prediction of the faster progression group. Results: Fifty-four eyes of 54 patients were included. The mean progression rate was -1.09 ± 0.60 dB/year in group 1 (n = 22) and -0.12 ± 0.13 dB/year in group 2 (n = 32). Twenty-four-hour magnitude and absolute area under the monitoring curve were significantly higher in group 1 than in group 2 (group 1: 343.1 ± 62.3 millivolts [mVs] and 8.28 ± 2.10 mVs, respectively, group 2: 274.0 ± 75.0 mV and 6.82 ± 2.70 mVs respectively, P < 0.05). Magnitude and area under the wavelet curve for short frequency periods ranging from 60 to 220 minutes were also significantly higher in group 1 (P < 0.05). Conclusions: The 24-hour IOP related fluctuations characteristics, as assessed by a CLS, may act as a risk factor for progression in OAG. In association with other predictive factors of glaucoma progression, the CLS may help adjust treatment strategy earlier.

Using a Smartwatch to Record Precordial Electrocardiograms: A Validation Study.

Smartwatches that support the recording of a single-lead electrocardiogram (ECG) are increasingly being used beyond the wrist, by placement on the ankle and on the chest. However, the reliability of frontal and precordial ECGs other than lead I is unknown. This clinical validation study assessed the reliability of an Apple Watch (AW) to obtain conventional frontal and precordial leads as compared to standard 12-lead ECGs in both subjects without known cardiac anomalies and patients with underlying heart disease. In 200 subjects (67% with ECG anomalies), a standard 12-lead ECG was performed, followed by AW recordings of the standard Einthoven leads (leads I, II, and III) and precordial leads V1, V3, and V6. Seven parameters (P, QRS, ST, and T-wave amplitudes, PR, QRS, and QT intervals) were compared through a Bland-Altman analysis, including the bias, absolute offset, and 95% limits of agreement. AW-ECGs recorded on the wrist but also beyond the wrist had similar durations and amplitudes compared to standard 12-lead ECGs. Significantly greater amplitudes were measured by the AW for R-waves in precordial leads V1, V3, and V6 (+0.094 mV, +0.149 mV, +0.129 mV, respectively, all p < 0.001), indicating a positive bias for the AW. AW can be used to record frontal, and precordial ECG leads, paving the way for broader clinical applications.

Optimizing graft-recipient size matching in adolescent liver transplantation: Don't forget ex situ right posterior sectionectomy.

BACKGROUND: Graft-recipient size matching is a major challenge in pediatric liver transplantation, especially for adolescent recipients. Indeed, adolescents have the lowest transplantation rate among pediatric recipients, despite prioritization policies and the use of split grafts. In case of an important graft-recipient size mismatch, ex situ graft reduction with right posterior sectionectomy (RPS) may optimize the available donor pool to benefit adolescent recipients. METHODS: We present three cases of liver graft reduction with ex situ RPS for adolescent recipients. The surgical strategy was guided by GRWR (graft/recipient weight ratio), GW/RAP (right anteroposterior distance ratio), and CT-scan volumetric and anthropometric evaluation. RESULTS: Recipients were 12, 13, and 14-year-old and weighed 32, 47, and 35 kg, respectively. All liver grafts were procured from brain-dead donors with a donor/recipient weight ratio >1.5. RPS was performed ex situ, removing 20% of the total liver volume leading to a decrease of the GRWR <4% and the GW/RAP <100 g/cm in each case. All three reduced grafts were successfully transplanted with a static cold storage time ranging from 390 to 510 min without the need for delayed abdominal closure. We did not observe any primary non-function, vascular complication, or delayed graft function with a median follow-up of 6 months. One biliary anastomotic stenosis occurred which required surgical treatment. CONCLUSION: Ex situ liver graft reduction with RPS allowed for successful transplantation in case of anthropometric graft-recipient size mismatch in adolescent liver transplant candidates. Although the use of split grafts remains the gold standard, RPS should be acknowledged as a way to optimize the donor pool, especially for adolescent recipients.

High-resolution mapping of reentrant atrial tachycardias: Relevance of low bipolar voltage.

BACKGROUND: Bipolar voltage is widely used to characterize the atrial substrate but has been poorly validated, particularly during clinical tachycardias. OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of voltage thresholds for identifying regions of slow conduction during reentrant atrial tachycardias (ATs). METHODS: Thirty bipolar voltage and activation maps created during reentrant ATs were analyzed to (1) examine the relationship between voltage amplitude and conduction velocity (CV), (2) measure the diagnostic ability of voltage thresholds to predict CV, and (3) identify determinants of AT circuit dimensions. Voltage amplitude was categorized as "normal" (>0.50 mV), "abnormal" (0.05-0.50 mV), or "scar" (<0.05 mV); slow conduction was defined as <30 cm/s. RESULTS: A total of 266,457 corresponding voltage and CV data points were included for analysis. Voltage and CV were moderately correlated (r = 0.407; P < .001). Bipolar voltage predicted regions of slow conduction with an area under the receiver operating characteristic curve of 0.733 (95% confidence interval 0.731-0.735). A threshold of 0.50 mV had 91% sensitivity and 35% specificity for identifying slow conduction, whereas 0.05 mV had 36% sensitivity and 87% specificity, with an optimal voltage threshold of 0.15 mV. Analyses restricted to the AT circuits identified weaker associations between voltage and CV and an optimal voltage threshold of 0.25 mV. CONCLUSION: Widely used bipolar voltage amplitude thresholds to define "abnormal" and "scar" tissue in the atria are, respectively, sensitive and specific for identifying regions of slow conduction during reentrant ATs. However, overall, the association of voltage with CV is modest. No clinical predictors of AT circuit dimensions were identified.

Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T-wave parameters.

BACKGROUND: The T wave of the electrocardiogram (ECG) reflects ventricular repolarization. Repolarization heterogeneity is associated with reentrant arrhythmias. Several T-wave markers (including QT interval) have been associated with ventricular arrhythmias, but studies linking such markers to underlying local repolarization time (RT) inhomogeneities are lacking. We aimed to investigate the relation of several T-wave markers to controlled drug-induced regional RT gradients in intact pig hearts. METHODS: Repolarization time gradients were created by regional infusion of dofetilide and pinacidil in four atrially paced porcine Langendorff-perfused hearts placed inside a torso tank. From the 12-lead ECG on the torso tank, the mean, maximum, and dispersion (max-min) of QTtime , JTtime , Tpeak-end , Twidth , TQratio , dV/dtmax , Tarea , Tamp , and T-upslope duration were determined, as well as upslope end difference between leads V1 and V6 . RESULTS: Temporal T-wave parameters Tpeak-end , Twidth, and TQratio show a significant and high correlation with RT gradient, best reflected by mean value. Tarea (mean, max and dispersion) and dV/dtmax dispersion show only a moderate significant correlation. T-upslope duration shows a significant correlation in particular for mean values. Mean, maximum, or dispersion of QTtime and V1 -V6 upslope end difference were not significantly correlated with RT gradient. CONCLUSION: Composite 12-lead ECG T-wave parameters Tpeak-end , Twidth , TQratio , upslope duration, and Tarea show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QTtime do not reflect local RT heterogeneity. The composite T-wave metrics may thus provide better insights in arrhythmia susceptibility than traditional QTtime metrics.

Liver transplantation of partial grafts after ex situ splitting during hypothermic oxygenated perfusion-The HOPE-Split pilot study.

Partial liver grafts from ex situ splitting are considered marginal due to prolonged static cold storage. The use of ex situ hypothermic oxygenated perfusion (HOPE) may offer a strategy to improve preservation of ex situ split grafts. In this single-center pilot study, we prospectively performed ex situ liver splitting during HOPE (HOPE-Split) for adult and pediatric partial grafts over a 1-year period (November 1, 2020 to December 1, 2021). The primary safety endpoint was based on the number of liver graft-related adverse events (LGRAEs) per recipient, including primary nonfunction, biliary complications, hepatic vascular complications, and early relaparotomies and was compared with consecutive single-center standard ex situ split transplantations (Static-Split) performed from 2018 to 2020. Secondary endpoints included preservation characteristics and early outcomes. Sixteen consecutive HOPE-Split liver transplantations (8 HOPE-Split procedures) were included and compared with 24 Static-Splits. All HOPE-Split grafts were successfully transplanted, and no graft loss nor recipient death was encountered during the median follow-up of 7.5 months (interquartile range, 5.5-12.5). Mean LGRAE per recipient was similar in both groups (0.31 ± 0.60 vs. 0.46 ± 0.83; p = 0.78) and split duration was not significantly increased for HOPE-Split (216 vs. 180 min; p = 0.45). HOPE-Split grafts underwent perfusion for a median of 125 min, which significantly shortened static cold storage (472 vs. 544 min; p = 0.001), whereas it prolonged total ex vivo preservation (595 vs. 544 min; p = 0.007) and reduced neutrophil infiltration on reperfusion biopsies (p = 0.04) compared with Static-Split. This clinical pilot study presents first feasibility and safety data for transplantation of partial liver grafts undergoing ex situ split during HOPE and suggests improved preservation compared with static ex situ splitting. These preliminary results will allow to set up large-scale trials on the use of machine perfusion in pediatric and split-liver transplantation.

Full left/full right liver graft ex situ split during hypothermic oxygenated perfusion.

BACKGROUND: Ex vivo split liver transplantation in pediatric recipients has shown inferior results compared with whole grafts. One factor among others contributing to split grafts being considered as marginal is the prolonged static cold storage time related to ex vivo liver splitting. End ischemic hypothermic oxygenated perfusion is a validated strategy to improve outcomes of marginal whole grafts and may thus also benefit split liver grafts. METHOD: We present the first case of full left/full right split procedure performed during hypothermic oxygenated perfusion. RESULTS: We present a standardized surgical two-step approach where parenchymal transection was performed during end ischemic hypothermic oxygenated perfusion via the portal vein to shorten static cold storage duration. Both split grafts were successfully transplanted in a 4-year-old pediatric and a 38-year-old adult recipient. Despite high-risk procedure (retransplantation), extended donor criteria including a prolonged cardiac arrest and high donor risk index (2,25), both grafts showed early recovery of hepatic function and low serum transaminase release. At 6 months, both recipients were alive with a normal liver biology and a functioning graft. CONCLUSION: Although challenging, full left/full right liver split procedure during end ischemic hypothermic oxygenated perfusion can be successfully performed and is a promising strategy to improve post-transplant outcomes.

Purkinje network and myocardial substrate at the onset of human ventricular fibrillation: implications for catheter ablation.

AIMS: Mapping data of human ventricular fibrillation (VF) are limited. We performed detailed mapping of the activities underlying the onset of VF and targeted ablation in patients with structural cardiac abnormalities. METHODS AND RESULTS: We evaluated 54 patients (50 ± 16 years) with VF in the setting of ischaemic (n = 15), hypertrophic (n = 8) or dilated cardiomyopathy (n = 12), or Brugada syndrome (n = 19). Ventricular fibrillation was mapped using body-surface mapping to identify driver (reentrant and focal) areas and invasive Purkinje mapping. Purkinje drivers were defined as Purkinje activities faster than the local ventricular rate. Structural substrate was delineated by electrogram criteria and by imaging. Catheter ablation was performed in 41 patients with recurrent VF. Sixty-one episodes of spontaneous (n = 10) or induced (n = 51) VF were mapped. Ventricular fibrillation was organized for the initial 5.0 ± 3.4 s, exhibiting large wavefronts with similar cycle lengths (CLs) across both ventricles (197 ± 23 vs. 196 ± 22 ms, P = 0.9). Most drivers (81%) originated from areas associated with the structural substrate. The Purkinje system was implicated as a trigger or driver in 43% of patients with cardiomyopathy. The transition to disorganized VF was associated with the acceleration of initial reentrant activities (CL shortening from 187 ± 17 to 175 ± 20 ms, P < 0.001), then spatial dissemination of drivers. Purkinje and substrate ablation resulted in the reduction of VF recurrences from a pre-procedural median of seven episodes [interquartile range (IQR) 4-16] to 0 episode (IQR 0-2) (P < 0.001) at 56 ± 30 months. CONCLUSIONS: The onset of human VF is sustained by activities originating from Purkinje and structural substrate, before spreading throughout the ventricles to establish disorganized VF. Targeted ablation results in effective reduction of VF burden. KEY QUESTION: The initial phase of human ventricular fibrillation (VF) is critical as it involves the primary activities leading to sustained VF and arrhythmic sudden death. The origin of such activities is unknown. KEY FINDING: Body-surface mapping shows that most drivers (≈80%) during the initial VF phase originate from electrophysiologically defined structural substrates. Repetitive Purkinje activities can be elicited by programmed stimulation and are implicated as drivers in 37% of cardiomyopathy patients. TAKE-HOME MESSAGE: The onset of human VF is mostly associated with activities from the Purkinje network and structural substrate, before spreading throughout the ventricles to establish sustained VF. Targeted ablation reduces or eliminates VF recurrence.