Folates dysmetabolism promotes atrial cardiomyopathy/fibrillation through a cardiac-bone marrow networking involving endothelial progenitor cell dysfunction and erythropoiesis diversion
Authors: Sgarra L , Caccavo VP , Katsouras G , Di Monaco A , Quadrini F , Vitulano N , Troisi F , Solimando A , Cicco S , Nacci C , Potenza MA , Desantis V , Vacca A , Montagnani M , Grimaldi M 
Published: May 2022

Funding Acknowledgements

Type of funding sources: Private hospital(s). Main funding source(s): dedicated cardiovascular research foud

Background

Recent advances support the concept that pre-persistent Atrial Fibrillation (AF) does not explain the wholeness of embolic strokes, suggesting the recently postulated hypothesis of a broad Atrial Cardiomyopathy (AC). In contrast to its worldwide distribution and its very inclusive definition, pathogenic mechanisms underlying AC are still largely unknown. Folate cycle disorders (FCD) are a yet underrated dysmetabolism only partly explained by methylene tetrahydrofolate reductase (MTHFR)-inherited defects. On a translational basis, FCD could hinder both endothelial and circulating endothelial progenitor cell (EPCs) functioning, therefore providing one-shot explanation to both atrial stasis (increasing atrial fibrosis and generating atrial hypocontractility) and endothelial dysfunction (ED). If such cardiac-bone marrow networking would be verified, a fundamental pathogenic mechanism of AC and subsequent AF would be unraveled.

Purpose

This study aims to enquire for the hypothesis that: 1) atrial fibrosis (AFib) would relate to FCD (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 by relative % of low-voltage (&lt;0,5 mV) bipolar peak-to-peak points, with respect to the wholeness of the endocavitary mapping. Blood count cell was evaluated. MTHFR C677T genotypes were elucidated by RT-PCR. Folate were measured by a commercial laboratory test. EPCs isolation and characterization were performed by Ficoll-Hypaque gradient and flow cytometry analysis for cell surface antigens: CD45, CD34, CD133, VEGFR2 and KDR. EPCs functional wound healing assay was performed.

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-C677T MTHFR homozygosis patients (n=44) (Fig.1 – Right graph. - p &lt; 0,02). Once univariate analysis was performed, subsequent multivariate analysis highlights highest fit once merged RBC, RDW-SD and folates values were inputed: Goodness of fit was proper, modelling good (Fig.2 – superior graph. - R2=0,39; p=0,0001). Either RBC, RDW-SD and folates coefficient reached significance (p &lt; 0,0001; p &lt; 0,01; p &lt; 0,05 respectively). Number of EPCs significantly differs between AF patients and matched controls (Fig 2 – inferior graph. – p &lt; 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 circulating EPCs and unraveled by erythropoiesis diversions. Such results suggest a pathogenic role of folate cycle disorders in the AC development.