Abstract Background Obesity and atrial fibrillation (AF) are public health issues with significant consequences. Objectives This study sought to delineate the development of global ...electrophysiological and structural substrate for AF in sustained obesity. Methods Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping; hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry); and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-β1 expression. Results Compared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p < 0.001); LA volume (p < 0.001); LA pressure (p < 0.001), and PA pressures (p < 0.001); reduced atrial CV (LA p < 0.001) with increased conduction heterogeneity (p < 0.001); increased fractionated electrograms (p < 0.001); decreased posterior LA voltage (p < 0.001) and increased voltage heterogeneity (p < 0.001); no change in the effective refractory period (ERP) (p > 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p < 0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-β1 protein (p = 0.002) were increased in the obese group. Conclusions Sustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-β1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.
Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown.
To examine the effect of progressive weight gain on the substrate for AF.
Thirty sheep ...were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor.
Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels.
Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.
Airway remodeling in asthma is characterized by structural changes to the airways including extracellular matrix (ECM) deposition and epithelial metaplasia. Extracellular matrix deposition in the ...subepithelial region may play an important role in modulation of epithelial cell and fibroblast structure and function because it lies in immediate contact with these cell types and exists within the functional epithelial mesenchymal trophic unit.
To investigate the effect of aberrant ECM components on airway epithelial cells and fibroblasts and the relationship among subepithelial ECM deposition, other remodeling changes, and airway hyperresponsiveness.
BEAS-2B human airway epithelial cells and WI-38 human airway fibroblast cells were cultured on various ECM protein substrates (Matrigel, representing normal basement membrane matrix, or aberrant matrix proteins collagen I, collagen III, and fibronectin). Airway remodeling changes were determined using morphometry in sections from a murine model of chronic allergic airway disease. Airway reactivity to methacholine was determined, and these parameters correlated.
Abnormal ECM substrates induced epithelial and fibroblast proliferation and altered the cell morphology of both human airway epithelial cells and fibroblasts when compared with normal basement membrane ECM. Subepithelial matrix deposition in the mouse correlated with epithelial thickness, but only weak correlations were noted among the other parameters.
We have demonstrated that ECM may affect the growth of airway epithelial cells and fibroblasts in vitro and may influence epithelial thickness in the mouse. These findings may have implications for understanding the pathogenesis of asthma and future therapeutic targeting of airway remodeling.
Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly ...involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS.
Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model.
Despite having power to detect odds ratio of 1.09-1.14 for overall IS and 1.20-1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons.
Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.
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