br Conclusions The experimental results
Conclusions The experimental results in isolated sheep hearts presented herein clearly demonstrate that self-sustained rotors exist in the atria. Such rotors are the high frequency sources that give rise to the complex patterns of activation that characterize AF. More specifically, our results suggest that the 3-D dynamics of the high-frequency rotors that generate scroll waves in the atrium determine the organization of AF. It follows that understanding the dynamics of 3-D scroll waves is a crucial step that is needed for the development of novel anti-arrhythmic drugs and more effective ablative therapies. Importantly, recent work in patients gives credence to the idea that mother rotors are capable of maintaining AF in the human heart . However, at this point it is too early to tell whether our observations of 3-D scroll waves in sheep hearts relate to the mechanisms of long-term persistent AF (12 months or longer) in humans. Nevertheless, we propose that the use of persistent AF models in animals together with the use of high-resolution mapping for the localization of rotors in the human heart will certainly help elucidate the mechanisms of AF and hopefully advance its treatment.
Funding sources This work was supported by NHLBI grants (Grant numbers PO1 HL039707, PO1 HL087226, and RO1 HL070074 to J.J.) and Heart Rhythm Society Fellowship Award provided by The Fellowship of Japan Heart Foundation/The Japanese Society of Electrocardiology to M.Y.
Conflict of interest
Introduction Atrial fibrillation (AF) is the most common arrhythmia. Previously, AF was believed to develop during the course of various cardiac pathological conditions, including valvular heart diseases, congestive heart failure, and hypertension. Recent clinical data, however, implicate the involvement of genetic factors in pathogenesis of AF. A familial form of AF has been noted, and several responsible order KN-93 have been identified. A recent study found a positive family history in 5% of AF patients referred to an arrhythmia clinic, including 15% of patients with lone AF, suggesting that familial AF may be more common than previously thought. Furthermore, in the Framingham Heart Study, individuals with a parental history of AF had an increased risk of developing AF themselves (multivariable-adjusted odds ratio, 1.85; 95% confidence interval [CI], 1.12–3.06) . Thus, the genetic background may underlie the pathogenesis of AF in both familial and non-familial AF.
Familial AF Although familial AF, a monogenetic heterogenous disorder with a Mendelian inheritance pattern, is uncommon, it has been noted since its first report in 1943 . However, attention to the genetic background of familial AF was stimulated by a report by Brugada et al. in 1997 . This report described 3 families with apparent autosomal dominant transmission of AF, and demonstrated linkage to a locus on chromosome 10q22–24 in all 3 families. Since then, linkage to 8loci has been described, and 6 responsible genes have been identified within these loci (Table 1). The identified genes include those encoding potassium and sodium channels that are also known to cause other allelic diseases such as long QT syndrome and short QT syndrome, and NPPA encoding atrial natriuretic peptide (ANP). Experimentally, an increase in ANP levels is known to result in electrophysiological derangements in atrial myocytes .
Candidate gene approach in non-familial AF The fact that parental AF is a risk factor for the development of AF in offspring in non-familial AF  suggests the presence of a genetic component for non-familial AF as well. To identify genetic risk factors in non-familial AF, candidate gene approaches were originally undertaken, and at least 13 nuclear genes and 1 mitochondrial gene were found to be associated with AF, including those encoding renin-angiotensin factors, connexin (Cx), and inflammatory proteins (Table 2).