Abstract-Therapeutic strategies against free radicals have mostly focused on the augmentation of antioxidant defenses (eg, vitamins C and E). A novel approach is to prevent free radical generation by the enzyme system xanthine oxidase. We examined whether the inhibition of xanthine oxidase with allopurinol can improve endothelial function in subjects with type 2 diabetes and coexisting mild hypertension compared with control subjects of a similar age. We examined 23 subjects (11 patients with type 2 diabetes and 12 healthy age-matched control subjects) in 2 parallel groups. The subjects were administered 300 mg allopurinol in a randomized, placebo-controlled study in which both therapies were administered for 1 month. Endothelial function was assessed with bilateral venous occlusion plethysmography, in which the forearm blood flow responses to intra-arterial infusions of endothelium-dependent and -independent vasodilators were measured. Allopurinol significantly increased the mean forearm blood flow response to acetylcholine by 30% (3.16Ϯ1.21 versus 2.54Ϯ0.76 mL ⅐ 100 mL Ϫ1 ⅐ min Ϫ1 allopurinol versus placebo; Pϭ0.012, 95% CI 0.14, 1.30) but did not affect the nitroprusside response in patients with type 2 diabetes. There was no significant impact on either endothelium-dependent or -independent vascular responses in age-matched control subjects. Allopurinol improved endothelial function to near-normal levels. Regarding markers of free radical activity, the level of malondialdehyde was significantly reduced (0.30Ϯ0.04 versus 0.34Ϯ0.05 mol/L for allopurinol versus placebo, Pϭ0.03) in patients with type 2 diabetes but not in control subjects. The xanthine oxidase inhibitor allopurinol improves endothelial dysfunction in patients with type 2 diabetes with mild hypertension but not in matched control subjects. In the former group, allopurinol restored endothelial function to near-normal levels.

Background-The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis. Methods and Results-We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo. Forearm vasculature endothelial function was assessed by bilateral forearm venous occlusion plethysmography using acetylcholine and

Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

Experimental studies have suggested a role for aldosterone and glucocorticoids in the pathogenesis of endothelial dysfunction. We therefore set out to characterize the acute effects of these hormones on vascular function in vivo in normal humans. A randomized, placebo-controlled, double-blind crossover study was performed on 16 healthy male volunteers (aged 19-29 years), examining the vascular effects of acute intravenous aldosterone infusion (12 pmol.min(-1).kg(-1) for 4 h) and of oral prednisolone (single 50 mg dose). Peripheral arterial vascular function was assessed by bilateral forearm venous occlusion plethysmography using two parallel study protocols. In the first protocol, eight subjects received, successively, acetylcholine, sodium nitroprusside, noradrenaline, angiotensin I and angiotensin II. The remaining eight subjects received, successively, acetylcholine, sodium nitroprusside, verapamil and noradrenaline. Aldosterone attenuated endothelium-dependent vasodilatation to acetylcholine as compared with either prednisolone or placebo (maximum vasodilatation: placebo, 357+/-38%; aldosterone, 257+/-21%; P <0.05). However, background endothelium-independent vasodilatation was not affected by either aldosterone or prednisolone. There were also no significant changes in vasoconstriction induced by angiotensin or noradrenaline following aldosterone or prednisolone treatment compared with placebo. Blood pressure and baseline blood flow did not differ between any of the study phases. Thus acute short-term systemic administration of aldosterone results in endothelial vasodilator dysfunction in normal men, providing evidence for an aldosterone-induced vasculopathy, which may be particularly relevant not only in heart failure but also in hypertensive patients with high aldosterone/renin ratios.

Aim We tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with type 2 diabetes (T2D). Methods and results We randomly assigned 66 people (mean age 67 ± 7 years, 38 males) with T2D, LVH, and controlled blood pressure (BP) to receive dapagliflozin 10 mg once daily or placebo for 12 months. Primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging. In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo with an absolute mean change of −2.82g [95% confidence interval (CI): −5.13 to −0.51, P = 0.018]. Additional sensitivity analysis adjusting for baseline LVM, baseline BP, weight, and systolic BP change showed the LVM change to remain statistically significant (mean change −2.92g; 95% CI: −5.45 to −0.38, P = 0.025). Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h systolic BP (P = 0.012), nocturnal systolic BP (P = 0.017), body weight (P &lt; 0.001), visceral adipose tissue (VAT) (P &lt; 0.001), subcutaneous adipose tissue (SCAT) (P = 0.001), insulin resistance, Homeostatic Model Assessment of Insulin Resistance (P = 0.017), and high-sensitivity C-reactive protein (hsCRP) (P = 0.049). Conclusion Dapagliflozin treatment significantly reduced LVM in people with T2D and LVH. This reduction in LVM was accompanied by reductions in systolic BP, body weight, visceral and SCAT, insulin resistance, and hsCRP. The regression of LVM suggests dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to the cardio-protective effects of dapagliflozin. ClinicalTrials.gov Identifier NCT02956811