Background: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. Methods: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. Results: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation—absolute nor spatial—was observed between all electrophysiological parameters and histological fibrosis markers. Conclusions: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF.

Background: The presence of atrial fibrillation (AF) in heart failure (HF) patients with reduced ejection fraction is common and associated with an increased risk of stroke, hospitalization and mortality. Recent research findings indicate that a reduction in nicotinamide adenine dinucleotide (NAD⁺) levels results in mitochondrial dysfunction, DNA damage and consequently cardiomyocyte impairment in experimental and clinical HF and AF. The HF-AF ENERGY trial aims to investigate the cardioprotective effects of the NAD⁺ precursor nicotinamide riboside (NR) treatment in ischemic heart disease patients diagnosed with AF. Study design: The HF-AF ENERGY trial is a prospective intervention study. The study consists of a (retrospective) 4 months observation period and a 4 months intervention period. The cardioprotective effect of NR on AF burden is investigated by remote monitoring software of implantable cardiac defibrillators (ICDs), which enables continuous atrial rhythm monitoring detection. Cardiac dimension and function are examined by echocardiography. Laboratory blood analysis is performed to determine mitochondrial function markers and energy metabolism. All the study parameters are assessed at two fixed time points (pre- and post-treatment). Pre- and post-treatment outcomes are compared to determine the effects of NR treatment on AF burden, mitochondrial function markers and energy metabolism. Conclusion: The HF-AF ENERGY trial investigates the cardioprotective effects of NR on AF burden and whether NR normalizes blood-based mitochondrial function markers and energy metabolites of the NAD metabolome in ischemic heart disease patients diagnosed with AF. The study outcomes elucidate whether NAD⁺ metabolism can be used as a future therapy for HF patients with AF.

Areas of conduction inhomogeneity (CI) during sinus rhythm may facilitate the initiation and perpetuation of atrial fibrillation (AF). Currently, no tool is available to quantify the severity of CI. Our aim is to develop and validate a novel tool using unipolar electrograms (EGMs) only to quantify the severity of CI in the atria. Epicardial mapping of the right atrium (RA) and left atrium, including Bachmann’s bundle, was performed in 235 patients undergoing coronary artery bypass grafting surgery. Conduction inhomogeneity was defined as the amount of conduction block. Electrograms were classified as single, short, long double (LDP), and fractionated potentials (FPs), and the fractionation duration of non-single potentials was measured. The proportion of low-voltage areas (LVAs, <1 mV) was calculated. Increased CI was associated with decreased potential voltages and increased LVAs, LDPs, and FPs. The Electrical Fingerprint Score consisting of RA EGM features, including LVAs and LDPs, was most accurate in predicting CI severity. The RA Electrical Fingerprint Score demonstrated the highest correlation with the amount of CI in both atria (r = 0.70, P < 0.001). The Electrical Fingerprint Score is a novel tool to quantify the severity of CI using only unipolar EGM characteristics recorded. This tool can be used to stage the degree of conduction abnormalities without constructing spatial activation patterns, potentially enabling early identification of patients at high risk of post-operative AF or selection of the appropriate ablation approach in addition to pulmonary vein isolation at the electrophysiology laboratory.

Background: Patients with heart failure (HF) most likely have an extensive arrhythmogenic substrate which increases vulnerability to atrial fibrillation (AF). Conduction disorders underlying this increased AF vulnerability -hidden during sinus rhythm- may be unmasked by spontaneous atrial extrasystole (AES). Objective: The aim of this study is to investigate the impact of AES on potential arrhythmogenic electrophysiological properties in patients with HF and AES. Methods: Intraoperative epicardial mapping of the right and left atrium (RA, LA), Bachmann’s bundle (BB) and pulmonary vein area (PVA) was performed in 132 patients (10 with HF and 122 without HF). Differences in unipolar potential morphologies and conduction disorders during SR and spontaneous AES were determined. Results: A median of 1 (1–3) AES per patient were included. In patients with HF, AES were associated with lower median potential voltages (1.94mV versus 4.02mV, P<0.001), more low voltage areas (10.98% versus 4.97%, P=0.004) and a higher number of short double potentials (28.5% versus 13.0% of short double potentials, P<0.001) compared to patients without HF. Comparing differences (AES - SR) in parameters between patients with and without HF, there was a larger increase in long double potentials (+5.32% versus +0.31%, P<0.001), fractionated potential (+4.18% versus +0.49%, P=0.001), conduction block (+3.39% versus +0.63%, P=0.002) and continuous conduction delay and block (+6.72% versus +1.74%, P=0.001) in HF patients. Conclusions: In HF patients, AES cause lower unipolar potentials voltages and more conduction disorders than in patients without HF. Differences in arrhythmogenic properties between sinus rhythm and atrial extrasystoles are more pronounced in HF patients. These results suggest that HF patients have hidden arrhythmogenic substrates that can be uncovered by AES and may explain the increased AF vulnerability.