Atrial fibrillation (AF) is a multifactorial disease with a strong genetic background. It is assumed that common and rare genetic variants contribute to the progression and recurrence of AF. The pathophysiological impact of those variants, especially when they are synonymous or non-coding, is often elusive and translation into functional experiments is difficult. In this study, we propose a method to go straight from genetic variants to defined gene targets. We focused on 55 genes from calcium signaling and 26 genes from extra cellular matrix ECM–receptor interaction that we found to be associated with the progression and recurrence of AF. These genes were mapped on protein–protein interaction data from three different databases. Based on the concept that central regulators are highly connected with their neighbors, we identified central hub proteins according to random walk analysis derived scores representing interaction grade. Our approach resulted in the identification of EGFR, RYR2, and PRKCA (calcium signaling) and FN1 and LAMA1 (ECM–receptor interaction) which represent promising targets for further functional characterization or pharmaceutical intervention.

Previous studies have suggested PITX2, KCNN3 and ZFHX3 as atrial fibrillation (AF) susceptibility genes. Single common genetic polymorphisms of those genes have been linked with AF phenotypes and rhythm outcome of AF catheter ablation although their mechanisms remain elusive. New gene-based association tests may help clarifying genotype–phenotype correlations. Therefore, we hypothesized that PITX2, KCNN3 and ZFHX3 associate with left atrial enlargement and persistent AF and subsequently with ablation outcome. Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing AF catheter ablation were genotyped for ~1,000,000 SNPs. Gene-based association was investigated using two different gene-based association tests (VEGAS, minSNP). Among the three candidate genes, only ZFHX3 associated with left atrial dilatation and AF recurrence after catheter ablation. This study suggests a contribution of ZFHX3 to AF remodeling and response to therapy. Future and larger studies are necessary to replicate and apply these findings with an emphasis on designing AF pathophysiology-based multi-locus risk scores.

Aims Establishing a diagnosis of inflammatory cardiomyopathy (iCMP) by non‐invasive means remains challenging despite advances in cardiac magnetic resonance imaging. Previous studies suggested the involvement of microRNAs in the pathogenesis of iCMP. We examined the association of a predefined set of circulatory microRNAs with clinical characteristics of iCMP and evaluated their diagnostic performance in suspected iCMP. Methods and results Eighty‐nine patients with clinical suspicion of iCMP were included in the analysis. All patients underwent cardiac catheterization with left ventricular endomyocardial biopsy, echocardiography, and cardiac magnetic resonance imaging applying the Lake Louise criteria (LLC). Plasma levels of miR‐21, miR‐126, miR‐133a, miR‐146b, miR‐155, and miR‐206 were determined using real‐time polymerase chain reaction. Based on immunohistological findings on endomyocardial biopsy, iCMP was diagnosed in 67% of study participants (n = 60). Plasma levels of miR‐155 and miR‐206 were significantly increased in patients with iCMP as compared with patients with dilated cardiomyopathy (P = 0.008 and P = 0.009, respectively). In receiver operating characteristic curve analysis, miR‐155 and miR‐206 demonstrated superior diagnostic performance for iCMP (0.68 and 0.67, respectively) compared with LLC [area under the curve (AUC) 0.60], Troponin T (AUC 0.51), and N‐terminal pro‐brain natriuretic peptide (AUC 0.51). While baseline miR‐155 and miR‐206 plasma levels were predictive for biopsy‐proven iCMP (odds ratio = 2.61, 95% confidence interval = 1.28–5.31, P = 0.008 and odds ratio = 2.65, 95% confidence interval = 1.27–5.52, P = 0.009) on univariate logistic regression analysis, the presence of positive LLC, high baseline C‐reactive protein, or presence of clinical symptoms and signs of viral infection failed to predict iCMP (P > 0.05, respectively). Conclusions The present data suggest that plasma levels of miR‐206 and miR‐155 are potential novel biomarkers for confirming the diagnosis of iCMP.

The human gut microbiome and its metabolite Trimethylamine N-oxide (TMAO) are sensitive to the human diet and are involved in the complex pathomechanisms that underpin diabetes, obesity, and cardiovascular diseases. A potential involvement of increased TMAO in atrial fibrillation (AF) manifestation and progression is not clear. We measured TMAO in peripheral blood of 45 AF patients and 20 non-AF individuals (matched for age, sex, BMI, prevalence of hypertension and diabetes). TMAO levels in AF (median [IQR] 3.5 µM [2.51–4.53]) were comparable with those in non-AF individuals (3.62 µM [2.49–5.46]) (p = 0.629). There was no association between TMAO and AF progression phenotypes (p = 0.588). In 35 AF patients, TMAO was additionally measured 12–18 months after AF catheter ablation. TMAO levels at baseline and follow-up were correlated (r = 0.481, p = 0.003), and TMAO was increased independent from the success (restoration of sinus rhythm) of the ablation procedure.