Background-Restoring sinus rhythm in patients with heart failure (HF) and atrial fibrillation (AF) may improve left ventricular (LV) function and HF symptoms. We sought to compare the effect of a catheter ablation strategy with that of a medical rate control strategy in patients with persistent AF and HF. Methods and Results-Patients with persistent AF, symptomatic HF, and LV ejection fraction <50% were randomized to catheter ablation or medical rate control. The primary end-point was the difference between groups in LV ejection fraction at 6 months. Baseline LV ejection fraction was 32±8% in the ablation group and 34±12% in the medical group. Twentysix patients underwent catheter ablation, and 24 patients were rate controlled. Freedom from AF was achieved in 21/26 (81%) at 6 months off antiarrhythmic drugs. LV ejection fraction at 6 months in the ablation group was 40±12% compared with 31±13% in the rate control group (P=0.015

OBJECTIVE-Insulin resistance is an independent risk factor for the development of cardiovascular atherosclerosis. A key step in the development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioactivity of nitric oxide (NO). Insulin resistance is associated with endothelial dysfunction; however, the mechanistic relationship between these abnormalities and the role of impaired endothelial insulin signaling versus global insulin resistance remains unclear.RESEARCH DESIGN AND METHODS-To examine the effects of insulin resistance specific to the endothelium, we generated a transgenic mouse with endothelium-targeted overexpression of a dominant-negative mutant human insulin receptor (ESMIRO). This receptor has a mutation (Ala-Thr 1134 ) in its tyrosine kinase domain that disrupts insulin signaling. Humans with the Thr 1134 mutation are insulin resistant. We performed metabolic and vascular characterization of this model. RESULTS-ESMIRO mice had preserved glucose homeostasis and were normotensive. They had significant endothelial dysfunction as evidenced by blunted aortic vasorelaxant responses to acetylcholine (ACh) and calcium ionophore. Furthermore, the vascular action of insulin was lost in ESMIRO mice, and insulininduced endothelial NO synthase (eNOS) phosphorylation was blunted. Despite this phenotype, ESMIRO mice demonstrate similar levels of eNOS mRNA and protein expression to wild type. ACh-induced relaxation was normalized by the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride. Endothelial cells of ESMIRO mice showed increased superoxide generation and increased mRNA expression of the NADPH oxidase isoforms Nox2 and Nox4.CONCLUSIONS-Selective endothelial insulin resistance is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction that is secondary to increased generation of reactive oxygen species. This arises independent of a significant metabolic phenotype.

Background— Catheter ablation of atrial fibrillation (AFCA) is an established therapeutic option for rhythm control in symptomatic patients. Its efficacy and safety among patients with left ventricular systolic dysfunction is based on small populations, and data concerning long-term outcome are limited. We performed this meta-analysis to assess safety and long-term outcome of AFCA in patients with left ventricular systolic dysfunction, to evaluate predictors of recurrence and impact on left ventricular function. Methods and Results— A systematic review was conducted in MEDLINE/PubMed and Cochrane Library. Randomized controlled trials, clinical trials, and observational studies including patients with left ventricular systolic dysfunction undergoing AFCA were included. Twenty-six studies were selected, including 1838 patients. Mean follow-up was 23 (95% confidence interval, 18–40) months. Overall complication rate was 4.2% (3.6%–4.8%). Efficacy in maintaining sinus rhythm at follow-up end was 60% (54%–67%). Meta-regression analysis revealed that time since first atrial fibrillation ( P =0.030) and heart failure ( P =0.045) diagnosis related to higher, whereas absence of known structural heart disease ( P =0.003) to lower incidence of atrial fibrillation recurrences. Left ventricular ejection fraction improved significantly during follow-up by 13% ( P <0.001), with a significant reduction of patients presenting an ejection fraction <35% ( P <0.001). N-terminal pro-brain natriuretic peptide blood levels decreased by 620 pg/mL ( P <0.001). Conclusions— AFCA efficacy in patients with impaired left ventricular systolic function improves when performed early in the natural history of atrial fibrillation and heart failure. AFCA provides long-term benefits on left ventricular function, significantly reducing the number of patients with severely impaired systolic function.