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...

Early initiation of steroid therapy may be effective for AV block, and steroid therapy before device implantation is a possible therapeutic strategy for some selected patients.

Collagen-derived hydroxyproline (Hyp)-containing oligopeptides, known to have various physiological functions, are detected in blood at markedly higher concentrations after oral ingestion of collagen hydrolysate. Monitoring the absorption and metabolism of the bioactive peptides is essential to investigate the beneficial effects of collagen hydrolysate. We previously developed an internal standard mixture by sequential protease digestion of stable isotope-labeled collagen, which enabled highly accurate quantitation of collagen-derived oligopeptides by liquid chromatography–mass spectrometry (LC–MS). However, the use of proteases caused a profound imbalance in the generated peptides. Here, we employed partial acid hydrolysis to achieve more efficient and balanced peptide generation. Various stable isotope-labeled oligopeptides were detected after 0.5 h acid hydrolysis, and marked enhancement of peptide generation compared with the previous enzymatic method was observed, especially for Hyp-Gly (27.8 ± 0.6 ng/μg vs 0.231 ± 0.02 ng/μg). The acid hydrolysate was then heated to generate labeled cyclic dipeptides. Using the novel internal standard mixture in LC–MS, we were able to simultaneously quantitate 23 collagen-derived oligopeptides in human plasma and urine after oral administration of collagen hydrolysate.

Levels of short linear hydroxyproline (Hyp)-containing peptides, such as prolyl-hydroxyproline (Pro-Hyp), increase in human blood after the ingestion of collagen hydrolysate, which has been associated with beneficial effects for human skin and joints. The present study demonstrates the presence of a novel food-derived collagen peptide, cyclic Pro-Hyp, in human blood after the ingestion of collagen hydrolysate. The cyclic Pro-Hyp levels in plasma samples were estimated by liquid chromatography mass spectrometry (LC-MS). Cyclic Pro-Hyp levels significantly increased in the plasma after ingestion of collagen hydrolysate, reaching a maximum level after 2 h and then decreasing. The maximum level of cyclic Pro-Hyp in plasma ranged from 0.1413 to 0.3443 nmol/mL, representing approximately 5% of linear Pro-Hyp in plasma after ingestion of collagen hydrolysate. Addition of cyclic Pro-Hyp in medium at 7 nmol/mL significantly enhanced the growth rate of mouse skin fibroblasts on collagen gel more extensively compared to linear Pro-Hyp.