Atrial fibrillation (AF), the most common, progressive tachyarrhythmia is associated with serious complications, such as stroke and heart failure. Early recognition of AF, essential to prevent disease progression and therapy failure, is hampered by the lack of accurate diagnostic serum biomarkers to identify the AF stage. As we previously showed mitochondrial dysfunction to drive experimental and human AF, we evaluated whether cell-free circulating mitochondrial DNA (cfc-mtDNA) represents a potential serum marker. Therefore, the levels of two mtDNA genes, COX3 and ND1, were measured in 84 control patients (C), 59 patients undergoing cardiac surgery without a history of AF (SR), 100 paroxysmal (PAF), 116 persistent (PeAF), and 20 longstanding-persistent (LS-PeAF) AF patients undergoing either cardiac surgery or AF treatment (electrical cardioversion or pulmonary vein isolation). Cfc-mtDNA levels were significantly increased in PAF patients undergoing AF treatment, especially in males and patients with AF recurrence after AF treatment. In PeAF and LS-PeAF, cfc-mtDNA levels gradually decreased. Importantly, cfc-mtDNA in serum may originate from cardiomyocytes, as in vitro tachypaced cardiomyocytes release mtDNA in the medium. The findings suggest that cfc-mtDNA is associated with AF stage, especially in males, and with patients at risk for AF recurrence after treatment.

Background: Staging of atrial fibrillation (AF) is essential to understanding disease progression and the accompanied increase in therapy failure. Blood-based heat shock protein (HSP) levels may enable staging of AF and the identification of patients with higher risk for AF recurrence after treatment. Objective: This study evaluates the relationship between serum HSP levels, presence of AF, AF stage and AF recurrence following electrocardioversion (ECV) or pulmonary vein isolation (PVI). Methods: To determine HSP27, HSP70, cardiovascular (cv)HSP and HSP60 levels, serum samples were collected from control patients without AF and patients with paroxysmal atrial fibrillation (PAF), persistent (PeAF) and longstanding persistent (LSPeAF) AF, presenting for ECV or PVI, prior to intervention and at 3-, 6- and 12-months post-PVI. Results: The study population (n = 297) consisted of 98 control and 199 AF patients admitted for ECV (n = 98) or PVI (n = 101). HSP27, HSP70, cvHSP and HSP60 serum levels did not differ between patients without or with PAF, PeAF or LSPeAF. Additionally, baseline HSP levels did not correlate with AF recurrence after ECV or PVI. However, in AF patients with AF recurrence, HSP27 levels were significantly elevated post-PVI relative to baseline, compared to patients without recurrence. Conclusions: No association was observed between baseline HSP levels and the presence of AF, AF stage or AF recurrence. However, HSP27 levels were increased in serum samples of patients with AF recurrence within one year after PVI, suggesting that HSP27 levels may predict recurrence of AF after ablative therapy.

BACKGROUND Recent research findings have revealed a key role of oxidative DNA damage in the pathogenesis of atrial fibrillation (AF). Therefore, the circulating oxidative DNA damage marker 8-hydroxy-2 0 -deoxyguanosine (8-OHdG) may represent a biomarker for staging AF and identifying patients at risk for AF recurrence and postoperative atrial fibrillation (POAF) after treatment.OBJECTIVE The purpose of this study was to investigate whether serum levels of 8-OHdG correlate with the stage of AF, recurrence after AF treatment, and onset of POAF after cardiac surgery.METHODS In this prospective observational study, 8-OHdG levels were detected by enzyme-linked immunosorbent assay in human serum samples. Blood samples were collected from control patients without AF history; patients with paroxysmal AF and persistent AF undergoing electrical cardioversion or pulmonary vein isolation (PVI); and patients with sinus rhythm (SR) undergoing cardiac surgery. AF recurrence was determined during 12-month follow-up. Univariate and multivariate analyses were used to identify changes in 8-OHdG levels between the groups.RESULTS Compared to the control group, 8-OHdG levels in the patient groups gradually and significantly increased during arrhythmia progression. 8-OHdG levels in AF patients showing AF recurrence after PVI treatment were significantly increased compared to patients without AF recurrence. Moreover, in SR patients undergoing cardiac surgery, 8-OHdG levels were significantly elevated in those showing POAF compared to patients without POAF.CONCLUSION 8-OHdG level may represent a potential diagnostic biomarker for AF staging as well as for predicting AF recurrence and POAF after treatment.

Pharmaco-therapeutic strategies of atrial fibrillation (AF) are moderately effective and do not prevent AF onset and progression. Therefore, there is an urgent need to develop novel therapies. Previous studies revealed heat shock protein (HSP)-inducing compounds to mitigate AF onset and progression. Such an HSP inducing compound is L-glutamine. In the current study we investigate the effect of L-glutamine supplementation on serum HSP27 and HSP70 levels and metabolite levels in patients with AF patients (n = 21). Hereto, HSP27 and HSP70 levels were determined by ELISAs and metabolites with LC-mass spectrometry. HSP27 levels significantly decreased after 3-months of L-glutamine supplementation [540.39 (250.97–1315.63) to 380.69 (185.68–915.03), p = 0.004] and normalized to baseline levels after 6-months of L-glutamine supplementation [634.96 (139.57–3103.61), p < 0.001]. For HSP70, levels decreased after 3-months of L-glutamine supplementation [548.86 (31.50–1564.51) to 353.65 (110.58–752.50), p = 0.045] and remained low after 6-months of L-glutamine supplementation [309.30 (118.29–1744.19), p = 0.517]. Patients with high HSP27 levels at baseline showed normalization of several metabolites related to the carbohydrates, nucleotides, amino acids, vitamins and cofactors metabolic pathways after 3-months L-glutamine supplementation. In conclusion, L-glutamine supplementation reduces the serum levels of HSP27 and HSP70 within 3-months and normalizes metabolite levels. This knowledge may fuel future clinical studies on L-glutamine to improve cardioprotective effects that may attenuate AF episodes.

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.

Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) to persistent and finally permanent AF. It has been recognized that AF persistence is related to the presence of electropathology. Electropathology is defined as structural damage, including degradation of sarcomere structures, in the atrial tissue which, in turn, impairs electrical conduction and subsequently the contractile function of atrial cardiomyocytes. Recent research findings indicate that derailed proteostasis underlies structural damage and, consequently, electrical conduction impairment. A healthy proteostasis is of vital importance for proper function of cells, including cardiomyocytes. Cells respond to a loss of proteostatic control by inducing a heat shock response (HSR), which results in heat shock protein (HSP) expression. Emerging clinical evidence indicates that AF-induced proteostasis derailment is rooted in exhaustion of HSPs. Cardiomyocytes lose defense against structural damage-inducing pathways, which drives progression of AF and induction of HSP expression. In particular, small HSPB1 conserves sarcomere structures by preventing their degradation by proteases, and overexpression of HSPB1 accelerates recovery from structural damage in experimental AF model systems. In this review, we provide an overview of the mechanisms of action of HSPs in preventing AF and discuss the therapeutic potential of HSP-inducing compounds in clinical AF, as well as the potential of HSPs as biomarkers to discriminate between the various stages of AF and recurrence of AF after treatment.

Atrial Fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF is difficult to treat and therefore there is a great need to dissect root causes of AF with the ultimate goal to develop mechanism-based (drug) therapies. New findings related to mechanisms driving AF progression indicate a prime role for DNA damage-induced metabolic remodeling. A recent study uncovered that AF results in oxidative DNA damage and consequently excessive poly-ADP-ribose polymerase 1 (PARP1) activation and nicotinamide adenine dinucleotide (NAD +) depletion and finally atrial cardiomyocyte electrical and contractile dysfunction. This newly elucidated role of DNA damage in AF opens opportunities for novel therapeutic strategies. Recently developed PARP inhibitors, such as ABT-888 and olaparib, provide beneficial effects in limiting experimental AF, and are also found to limit atherosclerotic coronary artery disease and heart failure. Another therapeutic option to protect against AF is to replenish the NAD + pool by supplementation with NAD + or its precursors, such as nicotinamide and nicotinamide riboside. In this review, we describe the role of DNA damage-mediated metabolic remodeling in AF and other cardiovascular diseases, discuss novel druggable targets for AF and highlight future directions for clinical trials with drugs directed at PARP1-NAD + pathway with the ultimate aim to preserve quality of life and to attenuate severe complications such as heart failure or stroke in patients with AF.

The most common clinical tachyarrhythmia, atrial fibrillation (AF), is present in 1–2% of the population. Although common risk factors, including hypertension, diabetes, and obesity, frequently underlie AF onset, it has been recognized that in 15% of the AF population, AF is familial. In these families, genome and exome sequencing techniques identified variants in the non-coding genome (i.e., variant regulatory elements), genes encoding ion channels, as well as genes encoding cytoskeletal (-associated) proteins. Cytoskeletal protein variants include variants in desmin, lamin A/C, titin, myosin heavy and light chain, junctophilin, nucleoporin, nesprin, and filamin C. These cytoskeletal protein variants have a strong association with the development of cardiomyopathy. Interestingly, AF onset is often represented as the initial manifestation of cardiac disease, sometimes even preceding cardiomyopathy by several years. Although emerging research findings reveal cytoskeletal protein variants to disrupt the cardiomyocyte structure and trigger DNA damage, exploration of the pathophysiological mechanisms of genetic AF is still in its infancy. In this review, we provide an overview of cytoskeletal (-associated) gene variants that relate to genetic AF and highlight potential pathophysiological pathways that drive this arrhythmia.