Circulating Cell-Free Nuclear DNA Predicted an Improvement of Systolic Left Ventricular Function in Individuals with Chronic Heart Failure with Reduced Ejection Fraction

Background: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) demonstrate better clinical outcomes when compared with individuals without restoration of cardiac function. The identification of predictors for HFimpEF may play a crucial role in the individual management of HF with reduced ejection fraction (HFrEF). Cell-free nuclear (cf-nDNA) DNA is released from damaged cells and contributes to impaired cardiac structure and function and inflammation. The purpose of the study was to elucidate whether cf-nDNA is associated with HFimpEF. Methods: The study prescreened 1416 patients with HF using a local database. Between October 2021 and August 2022, we included 452 patients with chronic HFrEF after prescription of optimal guideline-based therapy and identified 177 HFimpEF individuals. Circulating biomarkers were measured at baseline and after 6 months. Detection of cf-nDNA was executed with real-time quantitative PCR (qPCR) using NADH dehydrogenase, ND2, and beta-2-microglobulin. Results: We found that HFimpEF was associated with a significant decrease in the levels of cf-nDNA when compared with the patients from persistent HFrEF cohort. The presence of ischemia-induced cardiomyopathy (odds ration [OR] = 0.75; p = 0.044), type 2 diabetes mellitus (OR = 0.77; p = 0.042), and digoxin administration (OR = 0.85; p = 0.042) were negative factors for HFimpEF, whereas NT-proBNP ≤ 1940 pmol/mL (OR = 1.42, p = 0.001), relative decrease in NT-proBNP levels (>35% vs. ≤35%) from baseline (OR = 1.52; p = 0.001), and cf-nDNA ≤ 7.5 μmol/L (OR = 1.56; p = 0.001) were positive predictors for HFimpEF. Conclusions: We established that the levels of cf-nDNA ≤ 7.5 μmol/L independently predicted HFimpEF and improved the discriminative ability of ischemia-induced cardiomyopathy, IV NYHA class, and single-measured NT-proBNP and led to a relative decrease in NT-proBNP levels ≤35% from baseline in individuals with HFrEF.