Antimicrobial Consumption in Latin American Countries: First Steps of a Long Road Ahead.

BACKGROUND: Irrational antimicrobial consumption (AMC) became one of the main global health problems in recent decades. OBJECTIVE: In order to understand AMC in Latin-American Region, we performed the present research in 6 countries. METHODS: Antimicrobial consumption (J01, A07A, P01AB groups) was registered in Argentina, Chile, Colombia, Costa Rica, Paraguay, and Peru. Source of information, AMC type, DDD (Defined Daily Doses), DID (DDD/1000 inhabitants/day), population were variables explored. Data was analyzed using the Global Antimicrobial Resistance and Use Surveillance System (GLASS) tool. RESULTS: Source of information included data from global, public, and private sectors. Total AMC was highly variable (range 1.91-36.26 DID). Penicillin was the most consumed group in all countries except in Paraguay, while macrolides and lincosamides were ranked second. In terms of type of AMC according to the WHO-AWaRe classification, it was found that for certain groups like "Reserve," there are similarities among all countries. CONCLUSION AND RELEVANCE: This paper shows the progress that 6 Latin-American countries made toward AMC surveillance. The study provides a standardized approach for building a national surveillance system for AMC data analysis. These steps will contribute to the inclusion of Latin-America among the regions of the world that have periodic, regular, and quality data of AMC.

Determinación de factores de riesgo a reacciones adversas a medicamentos mediante farmacovigilancia intensiva en UCI / Risk factors for adverse drug reactions in patients admitted to intensive care units

Background: Patients hospitalized in intensive care units (ICU) are at higher risk of having adverse drug reactions (ADR). Aim: To determine risk factors for ADR, through intensive pharmacological surveillance at the ICU. Patients and Methods: An observational, descriptive and prospective study was made, determining risk parameters in patients who experienced ADR. Results: Eighty-five patients were surveilled and 24 (28%) had an ADR. A total of 48 drugs responsible for at least one ADR were identified. Seventy-three percent ADR were moderate and 27% were severe. The clinical variables significantly associated with ADR were a history of allergies, a high body mass index, the reason for admission, an APACHE II score ≥ 14 points, the use of invasive mechanical ventilation and more than seven days of hospitalization. The pharmacological variables associated with ADR were polypharmacy and medication associations and combinations. Conclusions: The identified risk factors have a great impact on pharmacokinetic and pharmacodynamic parameters, and should be considered to avoid the appearance of ADR.

[Risk factors for adverse drug reactions in patients admitted to intensive care units]. / Determinación de factores de riesgo a reacciones adversas a medicamentos mediante farmacovigilancia intensiva en UCI.

BACKGROUND: Patients hospitalized in intensive care units (ICU) are at higher risk of having adverse drug reactions (ADR). AIM: To determine risk factors for ADR, through intensive pharmacological surveillance at the ICU. PATIENTS AND METHODS: An observational, descriptive and prospective study was made, determining risk parameters in patients who experienced ADR. RESULTS: Eighty-five patients were surveilled and 24 (28%) had an ADR. A total of 48 drugs responsible for at least one ADR were identified. Seventy-three percent ADR were moderate and 27% were severe. The clinical variables significantly associated with ADR were a history of allergies, a high body mass index, the reason for admission, an APACHE II score ≥ 14 points, the use of invasive mechanical ventilation and more than seven days of hospitalization. The pharmacological variables associated with ADR were polypharmacy and medication associations and combinations. CONCLUSIONS: The identified risk factors have a great impact on pharmacokinetic and pharmacodynamic parameters, and should be considered to avoid the appearance of ADR.

Preoperative soluble VCAM-1 contributes to predict late mortality after coronary artery surgery.

BACKGROUND: Soluble vascular cell adhesion molecule-1 has been associated with long-term cardiovascular mortality in patients with stable coronary artery disease and to the development of new atrial fibrillation in subjects with cardiovascular risk factors but no evidence of cardiac disease. HYPOTHESIS: Preoperative soluble vascular cell adhesion molecule-1 predicts the risk of future all-cause death and cardiovascular death among patients submitted to elective coronary artery bypass surgery. METHODS: From a cohort of 312 patients who underwent elective coronary artery bypass surgery prospectively followed for a median of 6.7 years, we evaluated the prognostic role of preoperative soluble vascular cell adhesion molecule-1, inflammatory markers, CHA2DS2-VASc score and development of postoperative atrial fibrillation (POAF). Univariable and multivariable Cox regression analyses were performed to establish an association of these parameters with long term all-cause death and cardiovascular death. RESULTS: During 2112 person-years of follow-up, we observed 41 deaths, 10 were cardiovascular deaths. Independently increased levels of preoperative soluble vascular cell adhesion molecule-1, POAF, and CHA2DS2-VASc score were associated with all-cause mortality. After multivariate adjustment, elevated preoperative soluble vascular cell adhesion molecule-1 and POAF were the only independent predictors of all-cause death. Also, preoperative soluble vascular cell adhesion molecule-1, POAF, and CHA2DS2-VASc score resulted in being independent predictors of cardiovascular mortality. CONCLUSIONS: Increased circulating levels of preoperative soluble vascular cell adhesion molecule-1, together with POAF and CHA2DS2-VASc score, were significantly associated with future all-cause death and cardiovascular death among patients submitted to coronary artery bypass surgery.

Inhibition of mitochondrial fission prevents hypoxia-induced metabolic shift and cellular proliferation of pulmonary arterial smooth muscle cells.

Chronic hypoxia exacerbates proliferation of pulmonary arterial smooth muscle cells (PASMC), thereby reducing the lumen of pulmonary arteries. This leads to poor blood oxygenation and cardiac work overload, which are the basis of diseases such as pulmonary artery hypertension (PAH). Recent studies revealed an emerging role of mitochondria in PAH pathogenesis, as key regulators of cell survival and metabolism. In this work, we assessed whether hypoxia-induced mitochondrial fragmentation contributes to the alterations of both PASMC death and proliferation. In previous work in cardiac myocytes, we showed that trimetazidine (TMZ), a partial inhibitor of lipid oxidation, stimulates mitochondrial fusion and preserves mitochondrial function. Thus, here we evaluated whether TMZ-induced mitochondrial fusion can prevent human PASMC proliferation in an in vitro hypoxic model. Using confocal fluorescence microscopy, we showed that prolonged hypoxia (48h) induces mitochondrial fragmentation along with higher levels of the mitochondrial fission protein DRP1. Concomitantly, both mitochondrial potential and respiratory rates decreased, indicative of mitochondrial dysfunction. In accordance with a metabolic shift towards non-mitochondrial ATP generation, mRNA levels of glycolytic markers HK2, PFKFB2 and GLUT1 increased during hypoxia. Incubation of PASMC with TMZ, prior to hypoxia, prevented all these changes and precluded the increase in PASMC proliferation. These findings were also observed using Mdivi-1 (a pharmacological DRP1 inhibitor) or a dominant negative DRP1 K38A as pre-treatments. Altogether, our data indicate that TMZ exerts a protective role against hypoxia-induced PASMC proliferation, by preserving mitochondrial function, thus highlighting DRP1-dependent morphology as a novel therapeutic approach for diseases such as PAH.

Increased C-reactive protein plasma levels are not involved in the onset of post-operative atrial fibrillation.

BACKGROUND: Increased inflammation biomarkers plasma levels, including C-reactive protein (CRP), have been associated with the initiation and perpetuation of atrial fibrillation (AF). However, it is not known whether an increased CRP plasma level, without concomitant inflammation, is sufficient to induce AF. We investigated whether higher CRP plasma levels, determined by the presence of +219G>A CRP gene polymorphism, is associated with an increased risk of post-operative AF. METHODS: One hundred and fifteen adult patients submitted to elective coronary surgery were genotyped for the CRP +219G>A polymorphism. CRP plasma levels were determined by enzyme-linked immunosorbent assay. RESULTS: CRP plasma levels before surgery were higher in GG than in GA+AA patients (3.4±3.1 vs. 1.7±1.8, p<0.015). Thirteen percent of the patients presented post-operative AF. Despite the positive correlation between the polymorphism and CRP levels, there was no significant difference in the occurrence of post-operative AF between the different genotypes. CONCLUSIONS: These results suggest that increased CRP plasma levels that are not associated with an inflammatory process are not sufficient to trigger AF after cardiac surgery.

Transforming growth factor-beta and Forkhead box O transcription factors as cardiac fibroblast regulators.

Fibroblasts play several homeostatic roles, including electrical coupling, paracrine signaling and tissue repair after injury. Fibroblasts have low secretory activity. However, in response to injury, they differentiate to myofibroblasts. These cells have an increased extracellular matrix synthesis and secretion, including collagen fibers, providing stiffness to the tissue. In pathological conditions myofibroblasts became resistant to apoptosis, remaining in the tissue, causing excessive extracellular matrix secretion and deposition, which contributes to the progressive tissue remodeling. Therefore, increased myofibroblast content within damaged tissue is a characteristic hallmark of heart, lung, kidney and liver fibrosis. Recently, it was described that cardiac fibroblast to myofibroblast differentiation is triggered by the transforming growth factor ß1 (TGF-ß1) through a Smad-independent activation of Forkhead box O (FoxO). FoxO proteins are a transcription factor family that includes FoxO1, FoxO3, FoxO4 and FoxO6. In several cells types, they play an important role in cell cycle arrest, oxidative stress resistance, cell survival, energy metabolism, and cell death. Here, we review the role of FoxO family members on the regulation of cardiac fibroblast proliferation and differentiation.

Novel Therapies Targeting Cardioprotection and Regeneration.

Cardiovascular disease is the leading cause of death worldwide. The heart is susceptible to pathologies that impact the myocardium directly, such as myocardial infarction and consequent heart failure, as well as conditions with indirect cardiac effects, such as cancer treatment-related cardiotoxicity. As the contractile cells of the heart, cardiomyocytes are essential for normal cardiac function. Various stress stimuli may result in transient damage or cell death in cardiomyocytes through apoptosis, necrosis or maladaptive autophagy. Moreover, cardiomyocytes are unable to regenerate; thus, lost cells are replaced with fibrotic tissue, with a potentially severe impact on myocardial function. Several therapeutic agents and strategies to reduce cardiomyocyte damage are currently available. This manuscript reviews the state of the art regarding novel cardioprotective endogenous peptides, such as neuregulin-1, angiotensin-(1-9), growth/differentiation factor-11, growth/differentiation factor- 15 and insulin-like growth factor-1. We discuss their protective effects and therapeutic potential in cardiovascular diseases and the current challenges to harnessing their full cardioprotective power. We also explore targeting of exosomes as a cardioprotective approach along with the therapeutic potential of cardiac regeneration strategies. Further advances associated with these molecules and cardioprotective approaches may provide more effective therapies to attenuate or prevent cardiomyocyte death, thereby preserving the myocardium.

Effects of trimetazidine in nonischemic heart failure: a randomized study.

OBJECTIVES: Heart failure (HF) is associated with changes in myocardial metabolism that lead to impairment of contractile function. Trimetazidine (TMZ) modulates cardiac energetic efficiency and improves outcomes in ischemic heart disease. We evaluated the effects of TMZ on left ventricular ejection fraction (LVEF), cardiac metabolism, exercise capacity, O2 uptake, and quality of life in patients with nonischemic HF. METHODS AND RESULTS: Sixty patients with stable nonischemic HF under optimal medical therapy were included in this randomized double-blind study. Patients were randomized to TMZ (35 mg orally twice a day) or placebo for 6 months. LVEF, 6-minute walk test (6MWT), maximum O2 uptake in cardiopulmonary exercise test, different markers of metabolism, oxidative stress, and endothelial function, and quality of life were assessed at baseline and after TMZ treatment. Left ventricular peak glucose uptake was evaluated with the use of the maximum standardized uptake value (SUV) by 18-fluorodeoxyglucose positron emission tomography ((18)FDG-PET). Etiology was idiopathic in 85% and hypertensive in 15%. Both groups were similar in age, functional class, LVEF, and levels of N-terminal pro-B-type natriuretic peptide at baseline. After 6 months of TMZ treatment, no changes were observed in LVEF (31 ± 10% vs 34 ± 8%; P = .8), 6MWT (443 ± 25 m vs 506 ± 79 m; P = .03), maximum O2 uptake (19.1 ± 5.0 mL kg(-1) min(-1) vs 23.0 ± 7.2 mL kg(-1) min(-1); P = .11), functional class (percentages of patients in functional classes I/II/III/IV 10/3753/0 vs 7/40/50/3; P = .14), or quality of life (32 ± 26 points vs 24 ± 18 points; P = .25) in TMZ versus placebo, respectively. In the subgroup of patients evaluated with (18)FDG-PET, no significant differences were observed in SUV between both groups (7.0 ± 3.6 vs 8.2 ± 3.4 respectively; P = .47). CONCLUSIONS: In patients with nonischemic HF, the addition of TMZ to optimal medical treatment does not result in significant changes of LVEF, exercise capacity, O2 uptake, or quality of life.

Mitochondrial metabolism and the control of vascular smooth muscle cell proliferation.

Differentiation and dedifferentiation of vascular smooth muscle cells (VSMCs) are essential processes of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. Alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of a variety of cardiovascular diseases, including atherosclerosis, hypertension, and vascular stenosis. This review provides an overview of the current state of knowledge of molecular mechanisms involved in the control of VSMC proliferation, with particular focus on mitochondrial metabolism. Mitochondrial activity can be controlled by regulating mitochondrial dynamics, i.e., mitochondrial fusion and fission, and by regulating mitochondrial calcium handling through the interaction with the endoplasmic reticulum (ER). Alterations in both VSMC proliferation and mitochondrial function can be triggered by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion and mitochondrial-ER interaction. Several lines of evidence highlight the relevance of mitochondrial metabolism in the control of VSMC proliferation, indicating a new area to be explored in the treatment of vascular diseases.

Systemic oxidative stress and endothelial dysfunction is associated with an attenuated acute vascular response to inhaled prostanoid in pulmonary artery hypertension patients.

BACKGROUND: Systemic endothelial dysfunction and increased oxidative stress have been observed in pulmonary arterial hypertension (PAH). We evaluate whether oxidative stress and endothelial dysfunction are associated with acute pulmonary vascular bed response to an inhaled prostanoid in PAH patients. METHODS: Fourteen idiopathic PAH patients and 14 controls were included. Oxidative stress was assessed through plasma malondialdehyde (MDA) levels and xanthine oxidase (XO) and endothelial-bound superoxide dismutase (eSOD) activity. Brachial artery endothelial-dependent flow-mediated vasodilation (FMD) was used to evaluate endothelial function. Hemodynamic response to inhaled iloprost was assessed with transthoracic echocardiography. RESULTS: PAH patients showed impaired FMD (2.8 ± 0.6 vs. 10.7 ± 0.6%, P < .01), increased MDA levels and XO activity (0.6 ± 0.2 vs. 0.3 ± 0.2 µM, P < .01 and 0.04 ± 0.01 vs. 0.03 ± 0.01 U/mL, P = .02, respectively) and decreased eSOD activity (235 ± 23 vs. 461 ± 33 AUC, P < .01). Iloprost improved right cardiac output (3.7 ± 0.6 to 4.1 ± 1.2 L/min, P = .02) and decreased pulmonary vascular resistance (4.1 ± 1.1 to 2.9 ± 0.9 Wood U, P = .01). Changes in right cardiac output after prostanoid inhalation correlated significantly with baseline eSOD activity and FMD (Rho: 0.61, P < .01 and Rho: 0.63, P = .01, respectively). CONCLUSION: PAH patients show increased systemic oxidative stress and endothelial dysfunction markers. Response to inhaled prostanoid is inversely related to both parameters.

[The role of uric acid in heart failure]. / 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.

Ácido úrico: una molécula con acciones paradójicas en la insuficiencia cardiaca / The role of uric acid in heart failure

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.

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.

Systemic vascular cell adhesion molecule-1 predicts the occurrence of post-operative atrial fibrillation.

BACKGROUND: Post-operative atrial fibrillation occurs in 30% of patients after on-pump heart surgery and is associated to elevated inflammatory markers. We have evaluated if the systemic biomarkers of inflammation and endothelial damage, vascular cell adhesion molecule-1 (VCAM-1) and soluble thrombomodulin may help in identifying patients prone to development of post-operative atrial fibrillation. METHODS: One hundred and forty-four patients in sinus rhythm submitted to elective coronary artery bypass surgery. Systemic inflammatory, oxidative stress and endothelial damage markers were measured at baseline and 72 h after surgery. During the procedure, a sample of the right atrial appendage was obtained for histochemistry. Electrocardiogram was monitored for 72 h after surgery for event adjudication. RESULTS: 22% of the patients developed post-operative atrial fibrillation. Baseline systemic inflammatory markers did not differ between patients with or without post-operative atrial fibrillation. However, baseline plasma VCAM-1 and thrombomodulin levels were significantly higher in patients who developed post-operative atrial fibrillation. After adjustment for age, gender, comorbidities and concurrent medication, circulating VCAM-1 remained as an independent predictor for post-operative atrial fibrillation development. No association was observed between systemic plasma VCAM-1 and VCAM-1 tissue expression in the right atrial appendage. CONCLUSIONS: In patients undergoing coronary artery bypass surgery, elevated VCAM-1 levels predict a higher risk for post-operative atrial fibrillation. Plasma VCAM-1 elevation is not related to its expression in the right atria, suggesting that systemic endothelial damage rather than local changes pre-exist in patients who develop the arrhythmia.

[Heart energy metabolism and its role in the treatment of heart failure]. / Metabolismo energético del corazón y sus proyecciones en el tratamiento de la insuficiencia cardíaca.

It is unknown why heart failure progresses even when patients are treated with the best therapy available. Evidences suggest that heart failure progression is due to loss of neurohumoral blockade in advanced stages of the disease and to alterations in myocardial metabolism induced, in part, by this neurohumoral activation. Alterations in cardiac energy metabolism, especially those related to substrate utilization and insulin resistance, reduce the efficiency of energy production, causing a heart energy reserve deficit. These events play a basic role in heart failure progression. Therefore, modulation of cardiac metabolism has arisen as a promissory therapy in the treatment of heart failure. This review describes myocardial energy metabolism, evaluates the role of impaired energy metabolism in heart failure progression and describes new therapies for heart failure involving metabolic intervention.

Increased levels of oxidative stress, subclinical inflammation, and myocardial fibrosis markers in primary aldosteronism patients.

BACKGROUND: Patients with primary aldosteronism experience greater left ventricular hypertrophy and a higher frequency of cardiovascular events than do essential hypertensive patients with comparable blood pressure levels. Aldosterone has been correlated with increased oxidative stress, endothelial inflammation, and fibrosis, particularly in patients with heart disease. AIM: To evaluate oxidative stress, subclinical endothelial inflammation, and myocardial fibrosis markers in patients with primary aldosteronism and essential hypertension. DESIGN AND INDIVIDUALS: We studied 30 primary aldosteronism patients and 70 control essential hypertensive patients, matched by age, sex and median blood pressure. For all patients, we measured the serum levels of aldosterone, plasma renin activity, malondialdehyde (MDA), xanthine oxidase, metalloproteinase-9, ultrasensitive C-reactive protein and amino terminal propeptides of type I (PINP), and type III procollagen. We also evaluated the effect of PA treatment in 19 PA individuals. RESULTS: PA patients showed elevated levels of MDA (1.70 ± 0.53 versus 0.94 ± 0.65 µmol/l, P <0.001) and PINP (81.7 ± 50.6 versus 49.7 ± 27 mg/l, P = 0.002) compared with essential hypertensive controls. We found a positive correlation between MDA, PINP, and the serum aldosterone/plasma renin activity ratio in primary aldosteronism patients. Clinically, treating primary aldosteronism patients decreased MDA and PINP levels. CONCLUSION: We detected higher levels of MDA and PINP in primary aldosteronism patients, suggesting increased oxidative stress and myocardial fibrosis in these individuals. Treating primary aldosteronism patients reduced MDA and PINP levels, which may reflect the direct effect of aldosterone greater than endothelial oxidative stress and myocardial fibrosis, possibly mediated by a mineralocorticoid receptor.

Metabolismo energético del corazón y sus proyecciones en el tratamiento de la insuficiencia cardíaca / Heart energy metabolism and its role in the treatment of heart failure

It is unknown why heart failure progresses even when patients are treated with the best therapy available. Evidences suggest that heart failure progression is due to loss of neurohumoral blockade in advanced stages of the disease and to alterations in myocardial metabolism induced, in part, by this neurohumoral activation. Alterations in cardiac energy metabolism, especially those related to substrate utilization and insulin resistance, reduce the efficiency of energy production, causing a heart energy reserve deficit. These events play a basic role in heart failure progression. Therefore, modulation of cardiac metabolism has arisen as a promissory therapy in the treatment of heart failure. This review describes myocardial energy metabolism, evaluates the role of impaired energy metabolism in heart failure progression and describes new therapies for heart failure involving metabolic intervention.

Gln(27)-->Glubeta(2)-adrenergic receptor polymorphism in heart failure patients: differential clinical and oxidative response to carvedilol.

We investigated the clinical response of chronic heart failure patients with beta(2)-adrenergic receptor Gln(27)-->Glu polymorphism treated for 6 months with carvedilol, a alpha/beta-antagonist with antioxidant properties. The 6-min. walk test, the left ventricular ejection fraction, heart rate, plasma norepinephrine and malondialdehyde, a stress oxidative marker, concentrations were evaluated at baseline and after treatment for 6 months with carvedilol in 33 stable chronic heart failure patients with the Gln(27)-->Glubeta(2)-adrenergic receptor polymorphism. Carvedilol significantly increased the left ventricular ejection fraction, while decreasing the heart rate and malondialdehyde plasma concentrations in chronic heart failure patients with the Glu(27)beta(2)-adrenergic receptor allele. There were however, no significant changes in patients with the Gln(27)beta(2)-adrenergic receptor variant.