FOLATES–RELATED AND BONE MARROW DISORDERS PROMOTE ATRIAL CARDIOMYOPATHY INPATIENTS AFFECTED BY PAROXYSMAL ATRIAL FIBRILLATION VIA BOTH EPCS AND ENDOTHELIAL DYSFUNCTION

Abstract

Abstract Background Atrial Cardiomyopathy (AC) has been recently postulated to explain those embolic strokes not due to atrial fibrillation (AF) and paradoxical embolism. Pathogenic mechanisms underlying AC are still largely unknown. Folate cycle disorders (FD) are a yet underrated pro–thrombotic dysmetabolism. FD could hinder both endothelial and circulating endothelial progenitor cell (EPCs) functioning, therefore providing one–shot explanation to both atrial fibrosis and endothelial dysfunction (ED). Purpose This study aims to enquire for the hypothesis that: 1) atrial fibrosis (AFib) would relate to FD (intended as both: a)MTHFR C677T inherited mutations and b)bone–marrow function disorders, here referring to erythropoiesis diversions) and 2) AF patients would show dysfunctional EPCs. Methods We studied 59 consecutive patients admitted to the cardiology Unit of the General Hospital“F.Miulli”, with preserved EF, subjected to AF ablation. AFib was quantified in term of percentage of bipolar peak–to–peak voltage points below 0,5mV with respect to the wholeness of picked points. Blood count cell was evaluated at the admission. MTHFR C677T genotypes and serum folate were assessed. EPCs isolation and characterization were performed by cytometry analysis (CD45, CD34, CD133, VEGFR2 and KDR). EPCs functional wound healing assay was performed to determine the percentage of EPCs able to "fix the wound” and compared with matched–controls. Results Baseline characteristics did not differ between Sample and Control groups (Fig. 1 – Left Table). % of Afib significantly differs between C677T MTHFR homozigosis patients (n=15) with respect to non–C677TMTHFR homozygosis patients (n=44) (Fig.1 – Right graph. – p < 0,02). Once univariate analysis was performed, subsequent multivariate analysis highlight highest fit, once merged RBC, RDW–SD and folates values were inputed (Fig.2 – superior graph. – R2=0,39;p=0,0001). Either RBC, RDW–SD and folates coefficient reached significance (p < 0,0001; p < 0,01; p < 0,05 respectively). Number of EPCs signifi cantly differs between AF patients and matched controls (Fig 2 – inferior graph. –p < 0,001). Conclusions Our findings support the hypothesis that genetically determined folates dysmetabolism (MTHFR dysfunction) promotes AFib via a complex cardiac–bone marrow networking involving circulatingEPCs and unraveled by erythropoiesis diversions. Such results suggest a pathogenic role of folate cycle disorders in the AC development.