Stress ossidativo ed infiammazione: basi fisiopatologiche per un nuovo approccio terapeutico nello scompenso cardiaco. Risultati di due trials randomizzati, controllati con placebo.

Background: Heart failure (HF) is a complex pathophysiological condition of chronic deterioration of oxidative mechanisms. Hyperuricemia, a common finding in this context, reflects the degree of oxidative stress. It has been previously shown that diastolic dysfunction, which is frequently observed in patients with dilated cardiomyopathy and is associated with poor prognosis, relates to serum uric acid levels. Furthermore, HF represents an inflammatory state characterized by overproduction of pro-inflammatory cytokines involved in the pathogenesis of some typical aspects of HF, such as pulmonary oedema. Previous studies showed positive effects of statin treatment in a stable phase of the disease. Aim of the project: to determine whether inhibition of XO with allopurinol might affect diastolic function and NT-proBNP levels in a group of patients with chronic HF (Chronic HF Study); to evaluate the effects of statin therapy on left ventricular (LV) remodeling and symptoms in a group of subjects in the early stage of acute HF (Acute HF Study). Methods: Chronic HF study: 53 stable chronic HF outpatients with LV systolic dysfunction on optimal background therapy and clinically stable for at least three months, were randomly assigned to receive allopurinol (A), 300 mg/day, or placebo (P) for three months, in a double-blind trial. Every patient underwent a complete clinical and echocardiographic evaluation at baseline and at the end of the study. Acute HF study: 61 patients, admitted to our clinic for acute HF episode, with left ventricular dysfunction, were randomized to receive Atorvastatin (A) 20 mg/day or placebo (P) for three months, in a double-blind trial. A biochemical and clinical examination and a complete echocardiogram was performed for each patient at baseline, at one week and at the end of the study period. Results: Chronic HF study: mean age was 66±10 years and mean NYHA class was 2.2±0.6; mean serum uric acid levels were 400±100 mmol/L. At follow-up, in the allopurinol group there was a significant reduction in NT-proBNP levels compared with baseline (-191±583 mmol/L, p=0.0004), while no significant difference was observed in the placebo group, with a significant treatment effect (p=0.0033). In the allopurinol group there was a significant reduction of mitral E wave velocity (E) (0.6±0.2 vs. 07±0.2 m/s, p=0.01), and of the ratio between E and the velocity of early myocardial lengthening (E’) (10.7±6.7 vs. 15.1±11.8), but no significant changes of these two parameters in the placebo group, with a significant treatment effect for both (p=0.01 and p=0.02, respectively). Acute HF study: the two groups did not differ in clinical and echocardiographic baseline characteristics (mean age 72±7 years group P; 68±12 years group A; Colesterol 3.6±1 mmol/L group P; 3.5±1.3 mmol/L group A; EF 29±7 % group P; 25±6 % group A). At follow up NYHA class and congestion score improved in both groups, however more and without worsening of renal function in group A. There was a reduction in LV volumes, in particular in end-systolic volume ( 3 months 26 ml; p=0.001) and EF improved ( 3 months: -5; p=0.0005) only in the Atovarstatin group. Furthermore, in the same group there was a reduction of left atrium volume ( 3 months: 12.7 ml; p=0.05) and diastolic parameters improved. Conclusions: in CHF patients, the addition of allopurinol on top of optimal medical therapy for three months significantly improves echocardiographic parameters of diastolic function and lowers NT-proBNP levels. Early statin treatment in acute HF patients improves symptoms and affects cardiac remodeling by improving EF and reducing LV volumes.