• 2018-07
  • 2019-04
  • 2019-05
  • br Conclusion Accumulating clinical data suggest the presenc


    Conclusion Accumulating clinical data suggest the presence of a genetic component in the pathogenesis of AF. In addition to the gene mutations identified in familial AF, the candidate gene approach and GWAS identified genetic risks in the non-familial form of AF. In multiple Western populations, GWASs identified 3 loci associated with AF; 4q25 with Pix2 as the closest gene, 1q21 in KCNN3, and 16q22 in ZFHX3. SNPs in 4q25 may be useful in risk stratification of AF recurrence after PVI, and inhibitors of SK nampt inhibitor encoded by KCNN3 are considered to be novel pharmacological therapeutics for AF. However, the functional relevance of these genetic risks, their clinical implications, and their status in the Japanese population are yet to be fully clarified, and require further study.
    Conflict of interest
    Note added in proof After submission of this manuscript, international meta-analysis of AF GWAS including Japanese one has been published [44].
    Introduction Atrial fibrillation (AF) is the most common type of arrhythmia observed in a clinical setting, and is associated with significant morbidity and mortality [1,2]. The “downstream” approach that targets ion channels using antiarrhythmic drugs, has shown to be limited because antiarrhythmic drugs are ineffective in about half of the patients and often induce adverse effects, including proarrhythmia [3]. However, the “upstream” approach that targets processes involved in the development of the substrates that promote AF, has recently attracted much attention [4]. An atrial tachypacing-induced AF model has been established to represent clinical AF,[5] which is characterized by shortening of the atrial effective refractory period (ERP). Interestingly, Kumagai et al. [6] reported that in a canine AF model with rapid atrial pacing at 400beats/min for 5 weeks, rather than shortening the atrial ERP, extensive interstitial fibrosis was found in the atrial free wall in association with gradual conduction prolongation in the atria. This might be the first report to show “structural remodeling” by atrial tachypacing [6]. However, in patients without structural heart disease, the atrial tachypacing procedure that is followed in “normal” animals may be applicable only by perpetuation of paroxysmal AF into permanent AF. Therefore, we attempted to induce atrial fibrosis with enhanced AF vulnerability using continuous angiotensin II (AII) infusion [7] or pressure overload by abdominal aortic constriction (AAC) [8]. These procedures are more likely to correlate with the mechanisms underlying newly developed AF in patients with lifestyle diseases, such as hypertension. Many review articles in terms of upstream therapies for AF have been published elsewhere [9–11]. Therefore, in this special review article, we introduce our experimental approaches for the prevention of atrial fibrosis.
    AF model by continuous infusion of angiotensin II
    AF model by pressure overload (abdominal aortic constriction)
    Conclusions In a clinical setting, the results observed with upstream therapies appear to be less encouraging. For instance, in GISSI-AF trial, [53] treatment with valsartan was not associated with a reduction in the incidence of recurrent AF. This is in contrast to the results obtained in animal experiments, including our study, which compellingly shows the protective effect of angiotensin-converting enzyme inhibitors, ARBs, statins, and n-3 polyunsaturated fatty acids against electrical and structural atrial remodeling in association with AF [7,8]. One possible explanation is that most of the clinical studies investigated the recurrence of AF, the secondary prevention. In patients who have previously developed AF, atrial structural remodeling may be unexpectedly progressed, and many mechanisms may be involved. In such conditions, the above agents will be less likely to prevent the recurrence of AF as other pathways will still be at play. However, it could be possible that upstream therapies can reduce new-onset AF. In addition, upstream therapies may nampt inhibitor impact mortality and cardiovascular events in this population. Therefore, sophisticated experimental studies, possessing significant clinical relevance, should be challengingly continued.