Atrial fibrillation (AF) affects over 33 million individuals worldwide1 and has a complex heritability.2 We conducted the largest meta-analysis of genome-wide association studies for AF to date, consisting of over half a million individuals including 65,446 with AF. In total, we identified 97 loci significantly associated with AF including 67 of which were novel in a combined-ancestry analysis, and 3 in a European specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait loci (eQTL) analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Background Little is known about the relationship between intrinsic cardiac nerve activity (ICNA) and spontaneous arrhythmias in ambulatory animals. Methods and Results We implanted radiotransmitters to record extrinsic cardiac nerve activity (ECNA, including stellate ganglion nerve activity, SGNA; vagal nerve activity, VNA) and ICNA (including superior left ganglionated plexi nerve activity, SLGPNA; ligament of Marshall nerve activity, LOMNA) in 6 ambulatory dogs. Intermittent rapid left atrial pacing was performed to induce paroxysmal atrial fibrillation (PAF) or atrial tachycardia (PAT). The vast majority (94%) of LOMNA were preceded or co-activated with ECNA (SGNA or VNA), whereas 6% of episodes were activated alone without concomitant SGNA or VNA. PAF and PAT were invariably (100%) preceded (<5 s) by ICNA. Most of PAT events (89%) were preceded by ICNA and sympathovagal co-activation, whereas 11% were preceded by ICNA and SGNA-only activation. Most of PAF events were preceded only by ICNA (72%); the remaining 28% by ECNA and ICNA together. Complex fractionated atrial electrograms (CFAEs) were observed during ICNA discharges that preceded the onset of PAT and PAF. Immunostaining confirmed the presence of both adrenergic and cholinergic nerve at ICNA sites. Conclusions There is a significant temporal relationship between ECNA and ICNA. However, ICNA can also activate alone. All PAT and PAF episodes were invariably preceded by ICNA. These findings suggest that ICNA (either alone or in collaboration with ECNA) is an invariable trigger of paroxysmal atrial tachyarrhythmias. ICNA might contaminate local atrial electrograms, resulting in CFAE-like activity.

The prevalence of occult CAD in apparently healthy individuals was not negligible, although their midterm prognosis was good. CTA has a potential to provide a better insight about the occult CAD in this population. However, on the basis of our results and considering present radiation exposure data, we cannot recommend that CTA be used as a screening tool for this population at this point.

Objectives This study sought to find out more about the relationship between sympathetic and vagal nerve activity and the cardiac repolarization in a canine model of pacing-induced tachycardia congestive heart failure (CHF). Background The QT variability index (QTVI), a noninvasive marker of temporal cardiac repolarization dispersion, is among the risk factors for sudden death during CHF. Among factors influencing this variable are the myocardial damage and the autonomic nervous system activity typical of dilated cardiomyopathy. Methods We assessed autonomic nervous system activity recorded from an implanted data transmitter that monitored integrated left stellate-ganglion nervous activity, integrated vagus nerve activity, and electrocardiogram. We collected 36 segments recorded at baseline and 36 after induced CHF. We then arbitrarily identified recording segments as containing low or high sympathetic activity values, and we compared corrected QT intervals and the QTVI under a given sympathetic activity condition at baseline and after inducing CHF. Results In the high sympathetic activity subgroup, both QT variables increased from baseline to CHF (corrected QT intervals, p < 0.01; QTVI, p < 0.05) whereas in the low sympathetic activity subgroup they remained unchanged. The baseline QTVI correlated inversely with integrated vagus nerve activity (r2 = 0.16; β = −0.47; p < 0.05) whereas, during CHF, the QTVI correlated directly with integrated left stellate-ganglion nervous activity (r2 = 0.32; β = 0.27, p < 0.01). Conclusions During CHF, sympathetic activation is associated with an increase in the QT interval and QTVI. Because these changes vary over time, they could result from myocardial structural damage and sympathetic activation combined. Conversely, under normal conditions, no relationship exists between sympathetic activation and the QT variables.

Key Words: intracellular Ca Ⅲ delayed afterdepolarization Ⅲ Purkinje fiber Ⅲ inward rectifying K current Ⅲ electric defibrillation P ostshock arrhythmias, including ventricular tachycardia (VT) and ventricular fibrillation (VF), can occur after initial successful defibrillation shocks. During cardiopulmonary resuscitation, recurrent spontaneous VF occurred in more than half of the patients after initial successful defibrillation, and was associated with poor outcomes. 1 Electrical storm, a condition in which multiple temporally related episodes of spontaneous VT/VF occur, is known to be associated with high morbidity and mortality. 2,3 The mechanisms of postshock arrhythmias are unclear, although some reports implicate Purkinje fibers as sources of spontaneous VT/VF. 2,4 It is well established that delayed afterdepolarizations (DADs) result from Ca-activated transient inward currents (I ti ), which are induced by spontaneous sarcoplasmic reticulum (SR) Ca release. 5 DADs can be induced in Purkinje fibers and atrial/ventricular myocytes. 6 However, the vulnerability to DADs is higher in Purkinje fibers than other types of cardiac myocytes. 7 Possible explanations for the greater vulnerability in Purkinje fibers to DADs include a higher propensity for SR Ca release than working myocardium, or a larger membrane potential (V m ) response to elevated intracellular calcium (Ca i ) during diastole (diastolic Ca i -voltage coupling gain). The differential coupling gain may produce differential vulnerability to DADs. The purpose of this study was to test the hypotheses that: (1) DAD-mediated triggered activities (TAs) secondary to spontaneous SR Ca release underlie the mechanism of postshock arrhythmias; and (2) MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Hearts of New Zealand White rabbits (nϭ45) were perfused with 37°C oxygenated normal Tyrode's solution. We simultaneously mapped Ca i and V m using Rhod-2 AM and RH237 on epicardial (nϭ14) or endocardial (nϭ14) surface of ventricles. In additional hearts, we mapped epicardial surfaces to explore the effect of I K1 suppression (nϭ8), and endocardial surfaces to study the effect of ryanodine (nϭ3) and I Kr blocker, E-4031 (nϭ2). Transmembrane potential (TMP) was recorded in an additional 4 rabbits. Cytochalasin D (10 mol/L, nϭ7) or blebbistatin (10 to 20 mol/L, nϭ15) or both (nϭ23) was used to inhibit contraction during optical and TMP recordings (Online Figure I). Atrioventricular block was created in all hearts with cryoablation. VF was induced with burst ventricular pacing, and defibrillated with transvenous electrodes. To characterize spontaneous Ca i elevation (SCaE), we performed ventricular pacing for 100 beats at a pacing cycle length (PCL) of 600, 500, 400, 300, and 200 ms and the minimum cycle length with 1:1 pacing capture. When substantial SCaEs emerged, pacing at the same PCL with different numbers of paced beats (50, 200, 300, and 400) were performed (nϭ6) to study a dependence of SCaE o...

Background-Whether autonomic nerve activity is important in the development of pacinginduced sustained atrial fibrillation (AF) is unclear.

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