In atrial cardiomyopathy, higher serum folate associates with increased left atrial fibrosis and EPC dysfunction, with fibrosis decreasing 18.5% per unit RBC increase (p<0.0001).
Folate cycle disorders and endothelial progenitor cell dysfunction correlate with left atrial fibrosis in patients with paroxysmal atrial fibrillation, suggesting a bone marrow-derived pathogenic mechanism for atrial cardiomyopathy.
Abstract Background "Any complex of structural, architectural, contractile, or electrophysiological changes affecting the atria with the potential to produce clinically relevant manifestations". This is the first definition of atrial cardiomyopathy (AtCM). This definition is of necessity broad, as AtCM is the basis for clinical manifestations of atrial arrhythmia and atrial thrombogenesis. Atrial Fibrillation (AF) may be an epiphenomenon, with the true causal pathway between AtCM and stroke attributed more directly to pro-thrombotic properties of the atria itself. Left atrial fibrosis (Fib) is the marker of AtCM but its pathogenesis is not focused. Folate cycle disorders (FCD) are a dysmetabolism partly explained by MTHFR-inherited defects, leading to stroke. FCD can hinder both methyl handling, thus causing endothelial dysfunction (ED) via Arg/ADMA decrease, and circulating endothelial progenitor cell (EPCs) functioning. Focusing relationship between Fib and FCD might unravel AC pathogenesis. Purpose We aim to enquire for the hypothesis that: Fib relates to: 1) FCD surrogates, explored through a) Sieric folates, b) MTHFR mutations and c) Arg/ADMA. 2) Dysfunctional EPCs enquired through wound healing assay (WHA). Methods We studied 86 consecutive patients admitted to our Cardiology Unit, subjected to paroxysmal AF ablation. Fib was quantified by relative % of low-voltage (0,5 mV) bipolar peak-to-peak points. Blood count cell was evaluated. MTHFR C677T genotypes elucidated. Folate were measured by a commercial test. EPCs were isolated (CD45-, CD34+, CD133+, VEGFR2+) and cultured to be subjected to WHA. Results Univariate analysis seeked for predictive variables (Fig 1). A stepwise forward analysis was performed. Since aging is a non-modifiable risk factor, a multivariate age-weighted least square regression analysis was performed. The model shows a R-squared of 0.417, indicating a moderately strong correlation between independent variables (RBC, Folates, Arg/ADMA) and dependent variable (Fib)-(Fig.2 - p 0,0001). Every 1-unit increase in RBC, Arg/ADMA and folates, Fib respectively decreases by 18.5% for RBC, 0,1% for Arg/ADMA and increases by 0,9% for folates. WHA showed a significantly reduced reparative potential of high-Fib derived EPCs with respect to low-Fib. MTHFR ANOVA analysis across Fib was statistically significant (p 0.01), nonetheless, MTHFR logistic regression did not pass multivariate analysis. Conclusions Our findings support the hypothesis that, apart from aging, FCD causing folate-resistence, intended as an higher folic sieric status, relies to a greater extent of Fib in the context of AC and such pathogenic mechanism arise from bone-marrow since both red-hypoglobulinemia and EPCs dysfunction are over-expressed in high Fib.Univariate analysis Multivariate analysis
Sgarra et al. (2025) studied this question. In atrial cardiomyopathy, higher serum folate associates with increased left atrial fibrosis and EPC dysfunction, with fibrosis decreasing 18.5% per unit RBC increase (p<0.0001).