Genetics and Pharmacogenetics of Atrial Fibrillation: A Mechanistic Perspective.

The heritability of atrial fibrillation (AF) is well established. Over the last decade genetic architecture of AF has been unraveled by genome-wide association studies and family-based studies. However, the translation of these genetic discoveries has lagged owing to an incomplete understanding of the pathogenic mechanisms underlying the genetic variants, challenges in classifying variants of uncertain significance (VUS), and limitations of existing disease models. We review the mechanistic insight provided by basic science studies regarding AF mechanisms, recent developments in high-throughput classification of VUS, and advances in bioengineered cardiac models for developing personalized therapy for AF.

Modulation of NOX2 causes obesity-mediated atrial fibrillation.

Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase II (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knock-out (KO) mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility.

Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin's A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that ttna Δ9/Δ9 zebrafish embryos' cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttna Δ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTN Δ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current (I Ks) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of I Ks in both models prevents AF and improves atrial contractility. Thus, a small internal deletion in titin causes developmental abnormalities that increase the risk of AF via ion channel remodeling, with implications for patients who harbor disease-causing variants in sarcomeric proteins.

Ethnic and Gender Variations in Ischemic Stroke Patterns among Arab Populations in Northern Israel: A Preliminary Exploration towards Culturally Aware Personalized Stroke Care.

The Galilee region of Israel boasts a rich ethnic diversity within its Arab population, encompassing distinct Muslim, Christian, Druze, and Bedouin communities. This preliminary exploratory study uniquely examined potential ethnic and gender differences in ischemic stroke characteristics across these Arab subgroups, which are seldom investigated separately in Israel and are typically studied as a homogeneous "Arab" sector, despite significant variations in their ethnicity, culture, customs, and genetics. The current study aimed to comparatively evaluate stroke characteristics, including recurrence rates, severity, and subtypes, within and across these distinct ethnic groups and between genders. When examining the differences in stroke characteristics between ethnic groups, notable findings emerged. The Bedouin population exhibited significantly higher rates of recurrent strokes than Muslims (M = 0.55, SD = 0.85 vs. M = 0.25, SD = 0.56; p < 0.05). Large vessel strokes were significantly more prevalent among Christians (30%) than Druze (9.9%; p < 0.05). Regarding gender differences within each ethnic group, several disparities were observed. Druze women were six times more likely to experience moderate to severe strokes than their male counterparts (p < 0.05). Interestingly, Druze women also exhibited a higher representation of cardio-embolic stroke (19.8%) compared with Druze men (4.6%; p < 0.001). These findings on the heterogeneity in stroke characteristics across Arab ethnic subgroups and by gender underscore the need to reconsider the approach that views all ethnic groups comprising the Arab sector in Israel as a homogeneous population; instead, they should be investigated as distinct communities with unique stroke profiles, requiring tailored culturally aware community-based prevention programs and personalized therapeutic models. The identified patterns may guide future research to develop refined, individualized, and preventive treatment approaches targeting the distinct risk factors, healthcare contexts, and prevention needs of these diverse Arab populations.

Indirect Exposure to Atrocities and Post-Traumatic Stress Disorder Symptoms among Aid Workers: Hemispheric Lateralization Matters.

Background: Humanitarian aid workers (HAWs) are indirectly exposed to atrocities relating to people of concern (POC). This may result in a risk of secondary traumatization demonstrated by post-traumatic stress symptoms (PTSSs). Previous studies have demonstrated that hemispheric lateralization (HL) moderates the relationship between threat exposure and post-traumatic stress symptoms (PTSSs). Aims: We hypothesized that indirect exposure to atrocities (IETA) would be positively correlated with PTSSs among HAWs with right and not left HL. Method: Fifty-four HAWs from several countries that provided humanitarian support in Greece and Colombia participated in this correlational and cross-sectional observation study. They completed scales relating to IETA, PTSSs were assessed using a brief, valid scale, and HL was measured. Results: IETA was positively and significantly related to PTSSs (r = 0.39, p < 0.005). Considering HL, IETA was unrelated to PTSSs among people with right HL (r = 0.29, p = 0.14), while IETA was related to PTSSs among people with left HL (r = 0.52, p = 0.008). Right HL emerged as a protective factor in the relationship between IETA and PTSS. Conclusions: An assessment of dominant HL can serve as one consideration among others when deploying HAWs in specific locations and roles, vis à vis IETA. Moreover, those found to have a higher risk for PTSSs based on their HL could be monitored more closely to prevent adverse reactions to IETA.