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Balance shift of activin/inhibin cytokines as part of the atrial structural remodelling of patients with aortic stenosis in atrial fibrillation


 
 
 Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto Salud Carlos III
 Fondos Feder
 INNVAL 18/20
 Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, particularly in aortic stenosis (AS) patients. AF increases the risk of embolic stroke, heart failure, and mortality. The pathophysiological substrate for persistent AF is atrial fibrosis. Key players of fibrosis homeostasis are cytokines of the transforming growth factor-β (TFG-β) superfamily. In particular, dysregulation towards upregulating profibrotic TGF-β signalling versus antifibrotic bone morphogenetic protein 7 (BMP7) may result in pathological atrial remodelling and AF development in AS patients. However, the role of activins/inhibins in the clinical pathogenesis and vulnerability to AF remains unknown. In contrast to activins, inhibins do not signal directly but function by antagonizing activin signalling.
 
 
 
 To assess the contribution of activin A [homodimer of inhibin βA (INHβA)] and inhibin A [heterodimer of INHβA and inhibin α (INHα)] to the arrhythmogenic atrial remodelling and AF in AS patients.
 
 
 
 The study was performed with intraoperative biopsies of the right atrium (RA) obtained from AS patients with AF (n=23) or sinus rhythm (SR) (n=23), matched for sex, age and systolic function. The specificity of the findings was validated in AF patients (n=10) without AS. mRNA (qPCR) and protein (co-immunoprecipitation and western blot) were quantified in  RA. Stepwise multiple logistic regression analysis was used to identify predictors of AF, including as independent variables the transcript levels of TGF-β family members and remodelling-related elements.
 
 
 
 INHβA and INHα transcripts were downregulated in the RA of AF compared to SR patients (INHβA: 0.52±0.1 vs 0.99±0.1**; INHα: 0.16±0.03 vs 0.59±0.1***). The fraction of INHβA protein co-immunoprecipitated with an antibody to INHα showed lower levels in AF than in SR patients (0.83±0.03 vs 1.21±0.09*). On the other hand, in the fraction of unbound proteins, INHβA did not differ between SR and AF patients. These results suggest that the INHβA subunits coupled into the antagonistic dimer inhibin A were downregulated in the RA from AS patients with AF.
 Logistic regression analysis shows that RA transcript levels of TGF-ß1 (B=1.34) and COL1A1 (B=0.39) constituted significant positive predictors of AF, whereas INHβA (B=-6.8) and BMP-7 (B=-0.92) were significant negative predictors. A ROC analysis confirmed the accuracy of the model and yielded an area under the curve of 0.93 (CI 95% 0.86 to 1, ***). In addition, the variables determined as significant to predict presence of AF in patients with AS, did not constitute significant predictors of AF in patients with no LV pressure overload.
 
 
 
 Our results provide new insights into a change in the balance between activin and inhibin cytokines in the atrial tissue that may have a pathogenetic role in the appearance of atrial fibrillation in valvular AS patients.
