RESUMO
OBJECTIVES: Previous studies have demonstrated that high-dose allopurinol is able to regress left ventricular (LV) mass in cohorts with established cardiovascular disease. The aim of this study was to assess whether treatment with high-dose allopurinol would regress LV mass in a cohort with essential hypertension, LV hypertrophy and well-controlled blood pressure but without established cardiovascular disease. METHODS: We conducted a mechanistic proof-of-concept randomized, placebo-controlled, double-blind trial of allopurinol (600âmg/day) versus placebo on LV mass regression. Duration of treatment was 12 months. LV mass regression was assessed by Cardiac Magnetic Resonance. Secondary outcomes were changes in endothelial function (flow-mediated dilatation), arterial stiffness (pulse wave velocity) and biomarkers of oxidative stress. RESULTS: Seventy-two patients were randomized into the trial. Mean baseline urate was 362.2â±â96.7âµmol/l. Despite good blood pressure control, LV mass regression was significantly reduced in the allopurinol cohort compared with placebo (LV mass -0.37â±â6.08 versus -3.75â±â3.89âg; Pâ=â0.012). Oxidative stress markers (thiobarbituric acid reactive substances) were significantly higher in the allopurinol group versus placebo (0.26â±â0.85 versus -0.34â±â0.83âµmol/l; Pâ=â0.007). Other markers of vascular function were not significantly different between the two groups. CONCLUSION: Treatment with high-dose allopurinol in normouricemic controlled hypertensive patients and LV hypertrophy is detrimental. It results in reduced LV mass regression and increased oxidative stress over a 12-month period. This may be because of an adverse impact on redox balance. Cohort selection for future cardiovascular trials with allopurinol is crucial.
Assuntos
Alopurinol/efeitos adversos , Hipertensão Essencial , Ventrículos do Coração , Hipertrofia Ventricular Esquerda , Alopurinol/farmacologia , Alopurinol/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Hipertensão Essencial/complicações , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Análise de Onda de PulsoRESUMO
AIMS: Chronic heart failure (CHF) is an insulin-resistant state. The degree of insulin resistance (IR) correlates with disease severity and is associated with reduced exercise capacity. In this proof of concept study, we have examined the effect of metformin on IR and exercise capacity in non-diabetic CHF patients identified to have IR. METHODS AND RESULTS: In a double-blind, placebo-controlled study, 62 non-diabetic IR CHF patients (mean age, 65.2 ± 8.0 years; male, 90%; left ventricular ejection fraction, 32.6 ± 8.3%; New York Heart Association class I/II/III/IV, 11/45/6/0) were randomized to receive either 4 months of metformin (n = 39, 2 g/day) or matching placebo (n = 23). IR was defined by a fasting insulin resistance index (FIRI) ≥2.7. Cardiopulmonary exercise testing and FIRI were assessed at baseline and after 4 months of intervention. Compared with placebo, metformin decreased FIRI (from 5.8 ± 3.8 to 4.0 ± 2.5, P < 0.001) and resulted in a weight loss of 1.9 kg (P < 0.001). The primary endpoint of the study, peak oxygen uptake (VO(2)), did not differ between treatment groups. However, metformin improved the secondary endpoint of the slope of the ratio of minute ventilation to carbon dioxide production (VE/VCO(2) slope), from 32.9 ± 15.9 to 28.1 ± 8.8 (P = 0.034). In the metformin-treated group, FIRI was significantly related to the reduction of the VE/VCO(2) slope (R = 0.41, P = 0.036). CONCLUSION: Metformin treatment significantly improved IR but had no effect on peak VO(2), the primary endpoint of our study. However, metformin treatment did result in a significant improvement in VE/VCO(2) slope. TRIAL REGISTRATION: NCT00473876.