👤 Yaacoub Chahine

Cardiomyopathy (CM) is associated with atrial remodeling and atrial fibrillation (AF), often complicating rhythm management. Ventricular dysfunction contributes to AF through pressure and volume overload, while AF worsens ventricular function via tachycardia and irregular activation. Evidence suggests catheter ablation improves outcomes in CM patients, though success is influenced by the extent of atrial and ventricular remodeling. Patients undergoing their first catheter ablation for AF were divided into hypertrophic (HCM), ischemic (ICM), non-ischemic (NICM), and no-CM groups. Pre-ablation late-gadolinium enhancement cardiac magnetic imaging (LGE-MRI) was used to assess left atrial (LA) fibrosis burden and anatomical distribution. Patients were followed prospectively for arrhythmia recurrence. A total of 552 patients, 39 HCM (69% obstructive), 39 ICM, 115 with NICM, and 359 without CM were included between January 2015 and December 2022. LA fibrosis was significantly higher in patients with CM (19.1 ± 7.5% vs. 16.5 ± 6.9%; P = 0.01). HCM and ICM had the greatest LA fibrosis among the different CM subtypes (21.3 ± 8.7% and 21.9 ± 9.1%, respectively). There was no significant difference in the regional distribution of fibrosis among the various groups. AF recurrence was observed in 321 (58.2%) after 456 (175-1204) days. Multivariate analysis revealed that compared to no CM, HCM was associated with a three-fold increase in AF recurrence (HR = 3.07, 95% CI 2.06-4.58, P < 0.001), followed by ICM (HR 1.61, 95%, CI 0.95-2.72; P = 0.07) and NICM (HR of 1.53, 95% CI 1.14-2.06; P = 0.05). LA fibrosis and volume index were independently associated with recurrence (HR = 1.03, 95% CI 1.01-1.06, P = 0.01 and HR = 1.02, 95% CI 1.01-1.03, P = 0.01). Genetic testing revealed key distinctions between HCM and NICM, with MYBPC3 and MYH7 as prominent genes in HCM and a heterogeneous genetic basis in NICM. Hypertrophic cardiomyopathy is associated with the highest risk of AF recurrence followed by ischemic and non-ischemic cardiomyopathy after catheter ablation. LA fibrosis regional patterns did not differ between cardiomyopathy types, while overall fibrosis and volume predicted recurrence. Show less

Diabetic retinopathy has recently become associated with complications similar to chronic inflammatory diseases. Although it is clear that tumor necrosis factor-α is increased in diabetes, the role of innate immunity is only recently being investigated. As such, we hypothesized that diabetes would increase Toll-like receptor 4 (TLR4) signaling, which could be inhibited by a β-adrenergic receptor agonist (Compound 49b) previously shown to have anti-inflammatory actions. In order to investigate β-adrenergic receptor signaling and TLR4 in the diabetic retina, streptozotocin-injected diabetic mice, as well as human primary retinal endothelial cells (RECs) and rat retinal Müller cells (rMC-1) exposed to high glucose (25 mM), were treated with a novel β-adrenergic receptor agonist, Compound 49b (50 nM), or phosphate-buffered saline (control). TLR4 and its downstream signaling partners (MyD88, IL-1 receptor-associated kinase 1, TNF receptor-associated factor 6 and total and phosphorylated nuclear factor-κB) were examined. In addition, we assessed high-mobility group box 1 (HMGB1) protein levels. Our data showed that diabetes or high-glucose culture conditions significantly increased TLR4 and downstream signaling partners. Compound 49b was able to significantly reduce TLR4 and related molecules in the diabetic animal and retinal cells. HMGB1 was significantly increased in RECs and Müller cells grown in high-glucose culture conditions, which was subsequently reduced with Compound 49b treatment. Our findings suggest that high glucose may increase HMGB1 levels that lead to increased TLR4 signaling. Compound 49b significantly inhibited this pathway, providing a potential mechanism for its protective actions. Show less