Background It is unknown how atrial fibrillation (AF) is actually initiated by triggers. transitions to AF. Sixty-two AF initiations were recorded (spontaneous n=28; induced n=34). Notably AF did not initiate by disorganized mechanisms but by either a dominant reentrant spiral wave (76%) or a repetitive focal driver. Both mechanisms were located 21±17mm from their triggers. AF-initiating spirals formed at the site showing the greatest rate-dependent slowing in each patient. Arry-520 Accordingly in 10/12 patients with multiple observed AF episodes AF initiated using spatially conserved mechanisms despite diverse triggers. Conclusions Human AF initiates from triggers by organized rather than disorganized mechanisms either via spiral wave reentry at sites of dynamic conduction slowing or via repetitive focal drivers. The finding that diverse triggers initiate AF at predictable spatially conserved functional sites in each individual provides a novel deterministic paradigm for AF with therapeutic implications. to AF in a subset of 22 patients during Arry-520 burst pacing. Conduction slowing was defined by activation time prolongation by ≥ 10ms (absolute) and ≥ 20% (relative)11 between fastest and slowest rates. Statistical analysis Continuous data are represented as mean±standard deviation (SD) or if non-normally distributed as median (interquartile range (IQR)). Comparisons were made with Student’s assessments if normally distributed or with Mann-Whitney test otherwise. Paired continuous variables were compared using Wilcoxon Signed-Ranks Test. Categorical data are summarized with frequency counts and percentages. The Fisher exact test was applied to contingency tables. To account for multiple observations per subject mixed model analysis is employed and continuous variables summarized using estimated means and standard errors. A probability of <0.05 was considered statistically significant. Results Patient Characteristics Table I summarizes our study patients. We mapped 62 AF initiations (median 1 (IQR 1-2) per patient) comprising 28 spontaneous and 34 induced (27 burst pacing 3 single extra-stimulus 4 isoproterenol). Control data consisted of 50 spontaneous PACs in 12 patients which failed to initiate AF (median 5 (IQR 2-6) per patient). Differences Between AF-Initiating and Non-Initiating Ectopy Both AF-initiating ectopy (n=28) and non-AF initiating ectopy (n=50) arose bi-atrially (Table 2) with a nonsignificant pattern towards LA predominance (p=0.07) (Table 2). Ectopic beats that initiated AF were more premature than non-AF-initiating ectopy (coupled 370±25 vs. 502±19ms; p<0.001; Table 2). Table 2 Characteristics of Ectopy and Initiating Mechanisms. Identification and Classification of AF-Initiating Mechanisms We found that AF initiation was not disorganized but exhibited 2 spatially organized mechanisms. The first comprised a (Fig. 4) in 27% (n=16) initiations. In 2 AF initiations both mechanisms were observed. Three AF initiations were excluded due to poor electrogram quality that reduced confidence in Gata2 measurements. Physique 3 Multiple AF initiations via a spiral wave in an 81-year-old man with paroxysmal AF. (a) Spontaneous initiation: Arry-520 ECG and intracardiac recordings. Electrograms 1-12 represent sites 1-12 in panel (b). (b) Spatial activation maps show the … Physique 4 Multiple AF initiations via a repetitive focal driver in a 67-year-old man with persistent AF. (a) ECG and intracardiac recordings and (b) bi-atrial spatial activation map displaying the final sinus defeat (top -panel) accompanied by a LA PAC result in (middle) … AF Initiating System 1: Dominant Reentrant Spiral Influx Numbers 3a-b illustrate isochronal maps of AF initiation with a spontaneous Arry-520 PAC in the lateral RA with conduction slowing in the second-rate RA resulting in a spiral influx and AF. Numbers 3c-d show a definite AF initiation with this patient ten minutes later on and from LA burst pacing. Notably these varied causes initiated two AF shows by engaging an extremely identical spatially-conserved spiral influx. General AF-initiating spiral waves shaped in bi-atrial places (Desk 2) and happened after spontaneous causes that were combined 380±12ms from baseline. Supplemental Shape 1 depicts extra types of spiral influx AF initiations. AF Initiating System 2: Repeated Focal Driver The rest of the 27% of AF shows were initiated with a.