Hernán Alcaíno

Pleiotropic effects of atorvastatin in heart failure: role in oxidative stress, inflammation, endothelial function, and exercise capacity.

BACKGROUND Increased oxidative stress, a common feature in chronic heart failure, has been associated with inflammation, endothelial dysfunction, and extracellular matrix degradation. Statins have known anti-inflammatory and anti-oxidant effects; however, their role in chronic heart failure is still controversial. METHODS This was a prospective study of 38 patients with stable systolic chronic heart failure. Patients received a 4-week placebo course, followed by atorvastatin 20 mg/day for 8 weeks. Oxidative stress, inflammation and remodeling markers, brachial artery flow-mediated vasodilation, and 6-minute walk test were evaluated at baseline, 4, and 8 weeks. RESULTS Mean age was 58 +/- 12. Mean left ventricular ejection fraction was 27% +/- 12%. No significant differences were observed between measurements at baseline and after placebo. Atorvastatin induced a significant decrease of matrix metalloproteinase-9 activity, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, interleukin-6, and malondialdehyde, and a significant increase of endothelial superoxide dismutase activity when compared with placebo. No differences in tissue inhibitor of matrix metalloproteinase and matrix metalloproteinase-2 activities were observed. Atorvastatin use was associated with an improved flow-dependent brachial vasodilation and exercise capacity in the 6-minute walk test. CONCLUSIONS In chronic heart failure patients, atorvastatin therapy is associated with a decrease of inflammation and extracellular matrix remodeling, improving both endothelial function and exercise capacity.

Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure

Our previous studies suggest that the increase in heart rate from rest to peak exercise is reduced in patients with chronic heart failure (CHF) and this is associated with increased oxidative stress, as determined by malondialdehyde (MDA) plasma levels.

Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure.

Increased serum uric acid has been identified as an independent risk factor for cardiovascular disease. However, because of its antioxidant capacity, uric acid may play a beneficial role in endothelial function. This paradoxical relationship between uric acid and endothelial function in chronic heart failure patients remains poorly understood. Thirty‐eight chronic heart failure patients (New York Heart Association functional class II–III, mean age 58±10 years and mean left ventricular ejection fraction 25±8%) and twelve age‐and‐sex‐matched healthy controls were studied. Chronic heart failure patients showed higher uric acid levels (7.3±2.3 mg/dL vs. 6.1±0.2 mg/dL, p<0.05) and lower extracellular superoxide dismutase activity (136±36 U ml−1 min−1 vs. 203±61 U ml−1 min−1, p<0.01) and endothelium‐dependent vasodilatation (4.0±1.6% v. 9.1±3.0%, p<0.01) when compared with control subjects. In chronic heart failure patients, correlations between both uric acid levels and extracellular superoxide dismutase activity (r=0.45; p<0.01), and uric acid and endothelium‐dependent vasodilatation (r=0.35; p=0.03) were detected. These correlations were not observed in healthy individuals, suggesting a positive effect of uric acid on endothelial function partially mediated by modulation of extracellular superoxide dismutase activity in chronic heart failure.

Xanthine-oxidase inhibitors and statins in chronic heart failure: effects on vascular and functional parameters.

BACKGROUND Increased oxidative stress in heart failure (HF) leads to inflammation and endothelial dysfunction (ED). Both statins and allopurinol have known anti-oxidant properties, but their utility in HF has not been fully assessed. METHODS This investigation was a prospective, double-blind, double-dummy study, performed between March 2007 and June 2009. Seventy-four HF patients, with New York Heart Association (NYHA) Class II or III status and left ventricular ejection fraction (LVEF) <40%, were included. Patients received placebo during 4 weeks and were then randomized to receive 4 weeks of either atorvastatin 20 mg/day plus placebo (ATV+PLA group) or atorvastatin 20 mg/day orally plus allopurinol 300 mg/day orally (ATV+ALLO group). Malondialdehyde (MDA), extracellular superoxide dismutase (ecSOD) activity and uric acid (UA) levels, among others, were determined at baseline and after 4 weeks of treatment. ED was assessed by flow-dependent endothelial-mediated vasodilation (FDD), and functional capacity by 6-minute walk test (6MWT). RESULTS Thirty-two patients were randomized to ATV+PLA and 38 to ATV+ALLO. Mean age was 59 ± 2 years, 82% were male, and 22% had an ischemic etiology. Hypertension was present in 60% and diabetes in 15% of those studied. No significant differences were observed between baseline measurements and after placebo. After 4 weeks of treatment, both groups showed a significant decrease on MDA (0.9 ± 0.1 to 0.8 ± 0.1 and 1.0 ± 0.5 to 0.9 ± 0.1 μmol/liter, p = 0.88), UA (7.4 ± 0.4 to 6.8 ± 0.3 and 7.2 ± 0.4 to 5.0 ± 0.3 mg/dl, p < 0.01) and FDD (3.9 ± 0.2% to 5.6 ± 0.4% and 4.6 ± 0.3% to 7.1 ± 0.5%, p = 0.07) with increased ecSOD activity (109 ± 11 to 173 ± 13 and 98 ± 10 to 202 ± 16, U/ml/min, p = 0.41) and improved 6MWT (447 ± 18 to 487 ± 19 and 438 ± 17 to 481 ± 21 m, p = 0.83), with all values for ATV+PLA and ATV+ALLO, respectively; p-values are for comparison between groups after treatment. CONCLUSION Short-term ATV treatment in heart failure (HF) patients reduces oxidative stress and improves FDD and functional capacity. These beneficial effects are not strengthened by the addition of allopurinol.

Matrix metalloproteinase-9 activity is associated to oxidative stress in patients with acute coronary syndrome

Abstract In the present work we evaluate the relationship between oxidative stress and matrix metalloproteinases-2 and -9 (MMP-2 and -9) activities in 44 patients with non ST-elevation acute coronary syndrome. We found an early increase in malondialdehyde (MDA) levels (oxidative stress marker) and MMP-9, with decrease of both at day five. A positive correlation was found between fractional changes of MDA and MMP-9, suggesting a common role in the pathophysiology of the acute coronary syndrome.

Ácido úrico: una molécula con acciones paradójicas en la insuficiencia cardiaca

Complications and mortality of heart failure are high, despite the availability of several forms of treatment. Uric acid, the end product of purine metabolism would actively participate in the pathophysiology of heart failure. However, there is no consensus about its action in cardiovascular disease. Serum uric acid would have a protective antioxidant activity. This action could help to reduce or counteract the processes that cause or appear as a result of heart failure. However, these protective properties would vanish in the intracellular environment or in highly hydrophobic areas such as atherosclerotic plaques and adipose tissue. This review discusses the paradoxical action of uric acid in the pathophysiology of heart failure.

Inflamación y disfunción endotelial en pacientes con insuficiencia cardiaca crónica

14 years (80% male) with a CHF in functional capacity II-III (New York HeartAssociation) and an ejection fraction (EF) <40% were consecutively studied. Patients wereclassified according to the presence or absence of ED, evaluated by reactive vasodilationmeasured by ultrasound, after brachial artery compression. Circulating levels of highly sensitiveC reactive protein (usCRP), tumor necrosis factor

Ancho de distribución eritrocitaria como potencial biomarcador clínico en enfermedades cardiovasculares

Red cell distribution width (RDW) is a measurement of the variation in size, as well as an index of heterogeneity of erythrocytes, which is used in combination with other hematologic parameters as an aid to the differential diagnosis of hypochromic anemia. RDW could also serve as a biomarker in the diagnosis and prognosis patients with cardiovascular diseases. However, it is unclear whether the increased heterogeneity is the cause or consequence of other pathophysiological conditions such as renal failure, malnutrition, inflammation and oxidative stress, which among other conditions are actively involved in the genesis and progression of cardiovascular diseases. The aim of this review is to show and discuss recent evidence about the role of RDW measurement as an aid in the diagnosis and prognosis of patients with such diseases. Besides being a simple, inexpensive and routinely measured parameter, it could help in the stratification of patients according to their risk in clinical practice.

Uric acid, xanthine oxidase and heart failure: Unresolved issues

As stated in our article [1], the role of uric acid in heart disease remains poorly understood. Although epidemiological studies have shown independent associations between elevated uric acid serum levels and mortality [2], this association may depend largely on other related risk factors [3,4], generating an obvious limitation for the interpretation of a causative role of endogenously-generated uric acid in cardiovascular disease. Animal models have established that xanthine oxidase participates in the development of heart failure [5–7]. However, the relative contribution of xanthine oxidase-derived superoxide (as opposed to other sources of superoxide) is unclear. In a previous work by Landmesser et al. [8], xanthine oxidase activity explained barely 12% of the observed changes in endothelial function (r=0.12). In our heart failure cohort no correlation was observed (Fig. 1, unpublished data); this difference may depend on demographic or aetiologic factors, disease stage [9], etc. A commonly disregarded fact is that, within physiologic levels, uric acid levels and xanthine oxidase activity are tightly regulated. Tan et al. showed that uric acid 150 and 300 mM decreased the oxidation of xanthine to uric acid and formation of superoxide by 23 and 32%, respectively [10]. These results indicate that uric acid is an effective inhibitor of the formation of superoxide and hydrogen peroxide by xanthine oxidase at the levels found in human plasma, reflecting the complex interaction between oxidative and antioxidant systems. In humans, uric acid is maintained at a concentration close to maximum solubility and is the most important aqueous antioxidant, contributing near two thirds of total plasma antioxidant capacity [11]. Besides its ability to directly scavenge oxygen radicals, uric acid stabilizes ascorbate through iron-chelation in a reaction that does not

Marcadores de inflamación endotelial subclínica en una familia con hiperaldosteronismo familiar tipo I por mutación de novo

Type I familial hyperaldosteronism is caused by thepresence of a chimaeric gene CYP11B1/CYP11B2 which encodes an enzyme with aldosteronesynthetase activity regulated by adrenocorticotrophic hormone (ACTH). Therefore, in patients with FH-I is possible to normalize the aldosterone levels with glucocorticoid treatment. Recently it has beenshown that aldosterone plays a role in the production of endothelial oxidative stress and subclinicalinflammation.