Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF.

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.

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.

BACKGROUND: Clinical factors discriminate incident atrial fibrillation (AF) risk with moderate accuracy, with only modest improvement after incorporation of polygenic risk scores. Whether emerging large-scale proteomic profiling can augment AF risk estimation is unknown. METHODS: In the UK Biobank cohort, we derived and validated a machine learning model to predict incident AF risk using serum proteins (Pro-AF). We compared Pro-AF to a validated clinical risk score (Cohorts for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation, CHARGE-AF) and an AF polygenic risk score. Models were evaluated in a multiply resampled test set from nested cross-validation (internal test set), and a sample of UK Biobank participants separate from model development (hold-out test set). Metrics included discrimination of 5-year incident AF using time-dependent area under the receiver operating characteristic curve and net reclassification. RESULTS: Trained in 32 631 UK Biobank participants, Pro-AF predicts incident AF using 121 protein levels (out of 2911 protein analytes). When assessed in the internal test set comprising 30 632 individuals (mean age 57±8 years, 54% women, 2045 AF events) and hold-out test set comprising 13 998 individuals (mean age 57±8 years, 54% women, 870 AF events), discrimination of 5-year incident AF was highest using Pro-AF (area under the receiver operating characteristic curve internal: 0.761 [95% CI, 0.745–0.780], hold-out: 0.763 [0.734–0.784]), followed by CHARGE-AF (0.719 [0.700–0.737]; 0.702 [0.668–0.730]) and the polygenic risk score (0.686 [0.668–0.702]; 0.682 [0.660–0.710]). AF risk estimates were well-calibrated, and the addition of Pro-AF led to substantial continuous net reclassification improvement over CHARGE-AF (eg, internal test set 0.410 [0.330–0.492]). A simplified Pro-AF including only the 5 most influential proteins (NT-proBNP [N-terminal pro-brain natriuretic peptide], EDA2R [ectodysplasin A2 receptor], NPPB [B-type natriuretic peptide], BCAN [brevican core protein], and GDF15 [growth/differentiation factor 15]), retained favorable discriminative value (area under the receiver operating characteristic curve internal: 0.750 [0.733–0.768]; hold-out: 0.759 [0.732–0.790]). CONCLUSIONS: A machine learning-based protein score discriminates 5-year incident AF risk favorably compared with clinical and genetic risk factors. Large-scale proteomic analysis may assist in the prioritization of individuals at risk for AF for screening and related preventive interventions.

Purpose: Interestingly, 30–50% of patients undergoing elective cardiothoracic surgery develop postoperative AF (PoAF). Unfortunately, preventive PoAF therapy is still suboptimal. In our previous studies, we showed that oral Geranylgeranylacetone (GGA) administration increased cardioprotective heat shock protein (HSP) protecting against AF onset and progression in clinically relevant animal model studies. Methods: The GENIALITY study is a phase II single-center, double-blind, placebo-controlled randomized trial comparing the efficacy of GGA in preventing PoAF. Participants ( N = 146) are adult patients, without any registered history of AF, undergoing elective open-heart surgery for valvular disease, coronary artery bypass grafting, or concomitant, and are allocated with ratio 1:1 in treatment or placebo groups. Daily administration of 300 mg of GGA or placebo starts 5 days before until 3 days after surgery. Cardiac rhythm will be monitored using a Holter monitoring post-surgery until hospital discharge. Additionally, blood samples, right atrial appendage tissue, and epicardial adipose tissue will be collected to assess proteostasis levels. Results: The primary endpoint is the assessment of PoAF incidence in the GGA group compared to the placebo group. Secondary endpoints include the evaluation of HSP levels through biochemical analysis in both blood and atrial tissue. Conclusion: The GENIALITY study aims to reduce PoAF incidence in the GGA group compared to the placebo group. Herewith, we expect to obtain proof of concept for a beneficial effect of GGA in preventing PoAF in patients undergoing cardiothoracic surgery. Trial Registration: Clinical Trial Information System (CTIS) registry: 2024–514743-28–00. Authorized on September 30th 2024.