The normal action of insulin to vasodilate and redistribute blood flow in support of skeletal muscle metabolism is impaired in insulin-resistant states. Increased endogenous endothelin contributes to endothelial dysfunction in obesity and diabetes. Here, we test the hypothesis that increased endogenous endothelin action also contributes to skeletal muscle insulin resistance via impairments in insulin-stimulated vasodilation. We studied nine lean and seven obese humans, measuring the metabolic and hemodynamic effects of insulin (300 mU ⅐ m ؊2 ⅐ min ؊1 ) alone and during femoral artery infusion of BQ123 (an antagonist of type A endothelin receptors, 1 mol/min). Endothelin antagonism augmented skeletal muscle responses to insulin in obese subjects through changes in both leg blood flow (LBF) and glucose extraction. Insulin-stimulated LBF was significantly increased in obese subjects only. These changes, combined with differential effects on glucose extraction, resulted in augmented insulin-stimulated leg glucose uptake in obese subjects (54.7 ؎ 5.7 vs. 107.4 ؎ 18.9 mg/min with BQ123), with no change in lean subjects (103.7 ؎ 11.4 vs. 88.9 ؎ 16.3, P ‫؍‬ 0.04 comparing BQ123 across groups). BQ123 allowed augmented leg glucose extraction in obese subjects even in the face of NOS antagonism. These findings suggest that increased endogenous endothelin action contributes to insulin resistance in skeletal muscle of obese humans, likely through both vascular and tissue effects. Diabetes 56:728 -734, 2007

Diastolic dysfunction refers to abnormal diastolic filling properties of the left ventricle regardless of whether systolic function is normal or the patient has symptoms. Diastolic heart failure (HF), or more accurately, HF with preserved systolic function, is a distinct clinical entity characterized by the presence of the triad of impaired diastolic function, normal systolic function (left ventricular ejection fraction > 50%), and symptoms of HF. Patients with HF with preserved systolic function are frequently symptomatic from both acute and chronic elevations in left ventricular end-diastolic pressure and/or left atrial pressure.

No abstract

Effective anticoagulation is mandatory for pregnant women with mechanical heart valves. Oral anticoagulants offer the best maternal protection against thrombosis, but their use might be associated with an appreciable risk of fetal malformations and pregnancy loss. By contrast, heparin derivatives are associated with a reduced risk of fetal damage, but an increased risk of valve thrombosis in the mother, even with appropriate dose adjustment and monitoring of therapeutic efficacy. Given the varying risks of available anticoagulation strategies, and the paucity of data to inform the optimal approach, no single accepted treatment option exists for pregnant women with mechanical prosthetic valves. Although low-molecular-weight heparin is considered more efficacious than unfractionated heparin, treatment failures, even at therapeutic levels of factor Xa inhibition, have been reported. The risk of warfarin-related embryopathy might be overstated, particularly at doses ≤ 5 mg daily. We advocate an individualized anticoagulation strategy that takes into account the patient's preferences, calls for the use of vitamin K antagonists throughout pregnancy (substituted with a heparin derivative only close to term) for those patients at the greatest risk of thromboembolism, and relies on close multidisciplinary collaboration between the cardiac and obstetric care teams.