Background-Coronary artery disease predisposes to atrial fibrillation (AF), but the effects of chronic atrial ischemia/ infarction on AF-related substrates are unknown. Methods and Results-Regional right atrial myocardial infarction (MI) was created in 40 dogs by ligating an artery that supplies the right atrial free wall and not the ventricles; 35 sham dogs with the same artery isolated but not ligated were controls. Dogs were observed 8 days after MI and subjected to open-chest study, in vitro optical mapping, and/or cell isolation for patch-clamp and Ca 2ϩ imaging on day 8. Holter ECGs showed more spontaneous atrial ectopy in MI dogs (eg, 662Ϯ281 on day 7 versus 34Ϯ25 ectopic complexes per day at baseline; 52Ϯ21 versus 1Ϯ1 atrial tachycardia episodes per day). Triggered activity was increased in MI border zone cells, which had faster decay of caffeine-evoked Ca 2ϩ transients and enhanced (by Ϸ73%) Na ϩ -Ca 2ϩ exchange current. Spontaneous Ca 2ϩ sparks (confocal microscopy) occurred under ␤-adrenergic stimulation in more MI dog cells (66Ϯ9%) than in control cells (29Ϯ4%; PϽ0.01). Burst pacing induced long-lasting AF in MI dogs (1146Ϯ259 versus 30Ϯ14 seconds in shams). Increased border zone conduction heterogeneity was confirmed by both bipolar electrode mapping in vivo and optical mapping. Optical mapping demonstrated stable border zone reentry in all 9 MI preparations but in none of 6 shams. Border zone tissue showed increased fibrous tissue content. Conclusions-Chronic atrial ischemia/infarction creates substrates for both spontaneous ectopy (Ca 2ϩ -release events, increased Na ϩ -Ca 2ϩ exchange current) and sustained reentry (conduction abnormalities that anchor reentry). Thus, chronic atrial infarction in dogs promotes both AF triggers and the substrate for AF maintenance. These results provide novel insights into potential AF mechanisms in patients with coronary artery disease. (Circulation. 2011;123:137-146.) Key Words: atrial fibrillation Ⅲ calcium Ⅲ electrophysiology Ⅲ ischemic heart disease Ⅲ myocardial infarction A trial fibrillation (AF) is an extremely common cardiac arrhythmia associated with increased cardiovascular morbidity and mortality. 1,2 However, our understanding of AF pathophysiology remains incomplete. An improved comprehension of mechanisms underlying AF may lead to the development of novel therapeutic options. 3 Coronary artery disease is a significant risk factor for AF. 4,5 Shortterm (several hours) acute atrial ischemia creates a substrate for AF maintenance. 6,7 However, no data are available on the atrial electrophysiological and arrhythmic changes caused by longer-term atrial ischemia/infarction, as might occur in patients with chronic coronary artery disease. Clinical Perspective on p 146Atrial myocardial infarction (MI) is considered unusual because it is rarely diagnosed; however, it is often undetected. The incidence of atrial MI in autopsy series varies from 0.7% to 42%, depending largely on whether or not the atria were specifically examined. 8 The largest series of aut...

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Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, causes retention of CFTR in the endoplasmic reticulum (ER). Some CF abnormalities can be explained by altered Ca(2+) homeostasis, although it remains unknown how CFTR influences calcium signaling. This study examined the novel hypothesis that store-operated calcium entry (SOCE) through Orai1 is abnormal in CF. The significance of Orai1-mediated SOCE for increased interleukin-8 (IL-8) expression in CF was also investigated. CF and non-CF human airway epithelial cell line and primary cells (obtained at lung transplantation) were used in Ca(2+) imaging, electrophysiology, and fluorescence imaging experiments to explore differences in Orai1 function in CF vs. non-CF cells. Protein expression and localization was assessed by Western blots, cell surface biotinylation, ELISA, and image correlation spectroscopy (ICS). We show here that store-operated Ca(2+) entry (SOCE) is elevated in CF human airway epithelial cells (hAECs; ≈ 1.8- and ≈ 2.5-fold for total Ca(2+)(i) increase and Ca(2+) influx rate, respectively, and ≈ 2-fold increase in the I(CRAC) current) and is caused by increased exocytotic insertion (≈ 2-fold) of Orai1 channels into the plasma membrane, which is normalized by rescue of ΔF508-CFTR trafficking to the cell surface. Augmented SOCE in CF cells is a major factor leading to increased IL-8 secretion (≈ 2-fold). CFTR normally down-regulates the Orai1/stromal interaction molecule 1 (STIM1) complex, and loss of this inhibition due to the absence of CFTR at the plasma membrane helps to explain the potentiated inflammatory response in CF cells.