Background: Ventricular fibrillation (VF) progresses rapidly from an initial organized stage to chaotic fibrillation. The characteristics of initial drivers, that may be critical for therapeutic interventions, have not been investigated.Objective: To characterize the initial drivers of Human VFMethods: We evaluated 51 patients (44±10 years) who survived VF associated with ischemic heart disease in 15, cardiomyopathy in 14 and Brugada syndrome in 22. VF was mapped by intracardiac and body-surface recordings to analyze spatial organization, cycle lengths (CL), and drivers at the origin of wavefronts. We performed endocardial and epicardial mapping during sinus rhythm. The abnormal substrate was identified as areas of low voltage (≤1mV) and fragmented signals (≥70ms).Results: We mapped 69 episodes of spontaneous (n=12) or induced (n=57) VF for 17±10 s. The VF CL decreased from 208±28 to 172±25 ms (p<0.001) with the fastest acceleration consistently occurring in the initial 5 s. Initial organized VF, lasting 4.3 ± 1s, showed recurring wavefront sequences arising from distinct driver areas of focal or reentrant activity. These drivers were specifically associated with the abnormal ventricular substrate: in Brugada syndrome, they originated from individual locations in the right ventricle whereas in ischemic heart disease or cardiomyopathy, they originated dominantly from scar borderline in the left ventricle. In contrast, during the disorganized VF phase, the drivers were disseminated in both ventricles producing widespread unstable reentries without specific link with underlying ventricular substrate. In 32 patients, the driver areas were ablated using radiofrequency energy resulting in arrhythmia-free outcome in 27 patients at 20±19 months follow- up.Conclusion: The early phase in which human VF appears electrocardiographically well-organized, is unique as it is associated with a limited number of drivers distinctly related to underlying abnormal substrate. These primary drivers will then rapidly accelerate and disseminate to establish disorganized fibrillation.Read less <