Quantifying DNA Lesions and Circulating Free DNA: Diagnostic Marker for Electropathology and Clinical Stage of AF

Abstract

Background: Atrial fibrillation (AF) persistence is associated with molecular remodeling that fuels electrical conduction abnormalities in atrial tissue. Previous research revealed DNA damage as a molecular driver of AF.

Objectives: This study sought to explore the diagnostic value of DNA damage in atrial tissue and blood samples as an indicator of the prevalence of electrical conduction abnormalities and stage of AF.

Methods: High-sensitivity long-run real-time PCR was performed on mitochondrial (ND1) and nuclear (P53) DNA from atrial tissue samples from paroxysmal (PAF), persistent (PeAF), and longstanding persistent (LS-PeAF) AF, and sinus rhythm (SR) patients (n = 83). PicoGreen assay and quantitative polymerase chain reaction were used on circulating free DNA (cfDNA) markers (total cfDNA, β-globin, ND1, and P53) in blood samples of 70 patients with AF or SR. High-resolution epicardial mapping of the atria (n = 48) was conducted to quantify electrical conduction abnormalities.

Results: The number of DNA lesions gradually and significantly increased in PAF and PeAF and in patients with <3 years of AF compared with SR. In SR, the quantity of nuclear DNA damage significantly correlated with the proportion of fractionated potentials. Mitochondrial DNA lesions correlated with slower conduction velocity and lower potential amplitudes in AF samples. Also, mitochondrial cfDNA levels decreased in patients with >3 years of AF compared with <3 years of AF (P = 0.004).

Conclusions: The quantity of DNA lesions in atrial tissue samples is associated with atrial conduction abnormalities and stage of AF. Serum DNA damage markers discriminate short- from long-term AF. Therefore, the quantity of DNA damage may have diagnostic value in clinical AF management.

Keywords: DNA damage; atrial fibrillation; circulating free DNA; diagnostics; electrical conduction abnormalities; serum.