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.

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OBJECTIVE Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps (NETs). This extracellular DNA exerts potent pro-inflammatory, prothrombotic and cytotoxic properties. The goal of this study was to examine the relationships between extracellular DNA formation, coronary atherosclerosis and the presence of a prothrombotic state. APPROACH AND RESULTS In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease (CAD), we examined the severity, extent, and phenotype of coronary atherosclerosis by using coronary computed tomographic angiography (CCTA). Double-stranded DNA, nucleosomes, citrullinated histone H4 and myeloperoxidase (MPO)-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes and MPO-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (OR: 2.14, 95% CI 1.26-3.63; p=0.005). Markers of NETs, such as MPO-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events. CONCLUSIONS Our report provides evidence demonstrating that markers of cell death and NET formation are independently associated with CAD, prothrombotic state and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.

Lee and Chandraratna provide evidence of dry gangrene in the right foot of a 62-year-old man and evidence of a mobile arch atheroma. They suggest that thromboembolism from atheroma is an important cause of stroke and peripheral embolism. We agree. However, we would suggest that this is not a case of "thromboembolism," as it is characterized in the second paragraph. The presence of both the dorsalis pedis and posterior tibial pulses in the affected foot suggests that there has not been a fibroplatelet embolic event. Indeed, this constellation is more suggestive of cholesterol crystal embolization -how else to explain the preserved pulses? Also, single-vessel infrapopliteal occlusion typically does not cause intermittent claudication, much less gangrene. We suggest that the transesophageal echocardiogram reveals a ruptured plaque and substrate for cholesterol emboli, not thromboembolism. Burke AP, FarbA, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276-82. 2. Kolodgie FD, Narula J, Burke AP, et al. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 2000;157:1259-68. 3. Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin-V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134-9. 4. Hofstra L, Liem IH, Dumont EA, et al. Visualisation of cell death in vivo in patients with acute myocardial infarction.