José Luis Vukasovic

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.

Relation between oxidative stress, catecholamines, and impaired chronotropic response to exercise in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

O stress has been implicated in the pathogenesis of chronic heart failure (HF). Different studies have shown that reactive oxygen species are produced in the failing myocardium, causing injury in cardiac myocytes.1–3 Different factors classically associated with cardiomyocyte dysfunction and death in chronic HF, such as increased plasma catecholamine levels, are well-known stimuli for the generation of reactive oxygen species.4 In patients with advanced chronic HF at rest, the circulating norepinephrine concentrations are much higher, generally 2 to 3 times the level found in normal subjects.5,6 During comparable levels of exercise, much greater elevations in circulating norepinephrine occur in patients with chronic HF than in normal subjects. However, despite the increase in norepinephrine with exercise, patients with chronic HF had an attenuated heart rate response to exercise; this finding has been attributed to postsynaptic desensitization of the -adrenergic receptor pathway.7 A relation between cardiac exercise capacity and oxidative stress determined by malondialdehyde (MDA) plasma levels, a marker of lipid peroxidation, has been proposed.8 Experimental data also suggest that hydrogen peroxide may attenuate the -adrenoceptor– linked signal transduction in the heart by changing the functions of Gs proteins and the catalytic subunit of the adenylyl cyclase.9 In the present study we investigated the association between MDA plasma levels, catecholamines at peak exercise, and impaired heart rate response to exercise in patients with chronic HF. • • • We enrolled 27 patients with chronic HF secondary to coronary heart disease (n 15) or idiopathic dilated cardiomyopathy (n 12). They fulfilled the following criteria: (1) chronic stable HF in New York Heart Association functional classes II to IV; (2) ability to complete a symptom-limited treadmill exercise test; (3) evidence of left ventricular (LV) dilation and LV ejection fraction 40% as determined by radionuclide-gated pool scan; and (4) treatment with diuretics, digitalis, and vasodilators. We excluded patients with (1) coronary artery bypass surgery, angioplasty, or myocardial infarction in the last 6 months; (2) chronic angina; (3) uncontrolled hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 90 mm Hg); (4) hypertensive myocardiopathy; (5) change in maintenance therapy or use of blockers in the last 2 months; (6) implanted pacemaker; (7) significant valvular disease; and (8) presence of other conditions that affect determination of oxidative stress status, such as renal insufficiency (plasma creatinine 2 mg/dl), autoimmune diseases, neoplasia, advanced liver or pulmonary disease, and acute or chronic inflammation. All patients signed an informed consent approved by our institutional review board and ethics committee. For clinical assessment we used New York Heart Association functional class and the Mahler et al10 clinical score (range 0 to 12 points), which evaluates the severity of dyspnea. The score depends on ratings for 3 different categories: functional impairment, magnitude of task, and magnitude of effort. Dyspnea is rated in 5 degrees from 0 (severe) to 4 (unimpaired) for each category. The ratings for each of the 3 categories are added to form the score. LV end-diastolic and LV end-systolic diameters were determined by Doppler 2-dimensional echocardiography, and LV ejection fraction was determined by radionuclide ventriculography. Each patient performed a 6-minute corridor walk test and a maximal exercise test with gas exchange. Plasma norepinephrine and epinephrine specimens were collected from an indwelling venous line after patients had been in the supine position in a quiet room for 30 minutes. Measurements were repeated at maximal exercise. Determination of catecholamines was performed by high-performance liquid chromatography using a commercial kit (Chromsystems Instruments & Chemicals GmbH, Munchen, Germany). The interand intra-assay coefficients were 6% and 5%, respectively. The ratio of the increment in heart rate divided by the increment in norepinephrine from From the Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile; and the Departments of Biochemistry and Molecular Biology and Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Faculty of Medicine and the FONDAP Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile. Dr. Castro was supported in part by Grant FONDECYT 1010992, Santiago; and Dr. Lavandero was supported in part by Grant FONDAP 15010006, Santiago, Chile. Dr. Castro’s address is: Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile, Marcoleta 367, Santiago, Chile. E-mail: pcastro@med.puc.cl. Manuscript received January 23, 2003; revised manuscript received and accepted April 7, 2003.

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.

Effects of Carvedilol on Functional Capacity, Left Ventricular Function, Catecholamines, and Oxidative Stress in Patients With Chronic Heart Failure

INTRODUCTION AND OBJECTIVE Carvedilol is an antioxidant and adrenergic antagonist with demonstrated benefits in terms of mortality from heart failure (HF). The aim of the present study was to evaluate clinical parameters, left ventricular function, oxidative stress levels and neurohumoral status at baseline and after 6 months of treatment with carvedilol in patients with chronic HF. PATIENTS AND METHOD Thirty patients with chronic HF that was stable without beta blocker treatment were included. Functional class was II or III, and left ventricular ejection fraction (LVEF) was < 40%. Mahler score, distance walked in 6 min, peak oxygen consumption, LVEF, plasma catecholamine (norepinephrine) concentration and oxidative stress parameters were evaluated at baseline and after 6 months of treatment with carvedilol. RESULTS Mean age was 59 (2) years, and 23 patients were men. After 6 months of treatment there were clinical improvements as measured by the Mahler score (from 6.8 to 11.0 points; P=.001) and the 6-min walk distance (from 499 [18] to 534 [17] m; P =.032), but no changes in peak oxygen consumption. The LVEF increased from 24 (1) to 31 (2)% (P=.003). In patients with chronic HF, plasma malondialdehyde concentration was significantly lower after 6 months (decrease from 2.4 [0.2] to 1.1 [0.2] micromol/l; P<.001). No significant changes were observed in plasma catecholamine levels or antioxidant enzyme activities. CONCLUSIONS In patients with chronic HF, carvedilol treatment for 6 months was associated with clinical improvements, increased left ventricular function and decreased plasma concentrations of malondialdehyde, with no changes in plasma catecholamine levels.

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

Influencia de factores socio-culturales en la evolución alejada de pacientes con insuficiencia cardíaca

Objetivo: Evaluar el impacto de los factores socioculturales (SC) en las caracteristicas del cuidado de la insuficiencia cardiaca (IC) y la evolucion post alta en pacientes admitidos con diagnostico de IC descompensada a hospitales del registro ICARO en el periodo 2006-2008. Metodo: Registro prospectivo de 14 hospitales. Se incorporaron en forma consecutiva pacientes admitidos con el diagnostico de IC descompensada entre enero 2006 y mayo 2008. La mortalidad al fin del seguimiento se determino por la base de datos del Servicio Nacional de Registro Civil e Identificacion. Se definio como terapia optima la combinacion de un betabloqueador con cualquiera de los siguientes: inhibidores de la enzima convertidora de angiotensina (IECA), antagonistas del receptor de angiotensina II (ARAII), hidralazina/isosorbide o espironolactona. Las caracteristicas de los pacientes se compararon mediante t de Student o chi cuadrado segun correspondia. La sobrevida se evaluo mediante Kaplan-Meier. Resultados: Los pacientes de bajo nivel SC son de mayor edad (71±11 v/s 66±15 anos respectivamente, p de 70 anos, HR=2,17 (1,55-3,03), un bajo nivel SC, HR=1,57(1,17-2,09), una fraccion de eyeccion < a 50%, HR=1,49 (1,04-2,14) y la ausencia de una terapia optima al alta, HR=0,52 (0,41-0,66). La supervivencia fue marcadamente inferior en el grupo con menor nivel SC (mediana 761±47.9 v/s 975±82.3, log rank test p=0,02). Conclusion: La poblacion con IC y menor nivel SC y edad avanzada constituye un grupo especialmente vulnerable. Los resultados ponen en evidencia la necesidad de intervenciones destinadas a asegurar accesos igualitarios a las prestaciones de salud e implementar estrategias para mejorar la adherencia a las guias de tratamiento de la IC.

Polución por material particulado fino (PM 2,5) incrementa las hospitalizaciones por insuficiencia cardiaca

Resumen: Antecedentes: Estudios recientes han reportado una asociacion entre la contaminacion ambiental por material particulado (PM) y el riesgo de hospitaliza-ciones de pacientes con insuficiencia cardiaca (IC). La region metropolitana de nuestro pais constituye un area geografica en la cual la contaminacion es especialmente relevante, asociandose a incrementos periodicos en la morbimortalidad por causa respiratoria. Sin embargo el efecto de la polucion por PM en la morbilidad de pa-cientes con IC no ha sido evaluado en forma sistematica. Objetivo: Evaluar la asociacion entre el PM fino y las hospitalizaciones por IC descompensada en hospitales pertenecientes al registro ICARO del area metropolita-na. Metodos: Estudio prospectivo. Entre enero 2002 a diciembre de 2008 se recolectaron las fichas medicas de 529 pacientes residentes de Santiago hospitaliza-dos por IC descompensada. Las variables meteorolo-gicas y de contaminacion fueron obtenidas de la red MACAM. Para estudiar la asociacion entre las hospi-talizaciones y los niveles de contaminacion (PM10 y PM2,5), se aplico un diseno de Casos cruzados estra-tificado por tiempo (Time-stratified Case-crossover), controlando por temperatura y punto de rocio. El im-pacto de los niveles de contaminacion en el numero de hospitalizaciones se evaluo asumiendo una latencia en el efecto de la polucion de 0 a 10 dias.

El tratamiento con atorvastatina reduce la actividad de xantina-oxidasa unida al endotelio en pacientes con insuficiencia cardíaca crónica: ¿Un posible nuevo efecto pleiotrópico?

ResumenIntroduccion: El aumento en la actividad de la xantina-oxidasa unida al endotelio (XOec) puedeparticipar como un importante mediador de la disfuncion endotelial en la insuficiencia cardiaca cronica (IC).Las estatinas son capaces de reducir el estres oxidativo y restaurar la disfuncion endotelial a traves demecanismos independientes de la reduccion del colesterol. Sin embargo, el efecto de estos farmacos en laactividad de XOec es completamente desconocido. Nosotros estudiamos la hipotesis que atorvastatinadurante 8 semanas reduce la actividad de XOec de manera independiente de los cambios en elcolesterol. Metodologia: Un total de 25 pacientes con IC (Fraccion de eyeccion < 40 % y Clase funcional NYHA II-III)recibieron placebo por 4 semanas, seguido por 8 semanas de atorvastatina 20 mg por dia. Muestras desangre fueron recolectadas basalmente, 4 semanas y 12 semanas. La actividad de XOec y los niveles deacido urico fueron medidos por espectrofotometria. Resultados: El tratamiento con atorvastatina, pero no el placebo, redujo la actividad de ecXO (p<0.01), losniveles de acido urico (p<0.05), colesterol total (p<0.01), LDL-colesterol (p<0.01) ytrigliceridos (p<0.05) sin cambios en los niveles de HDL-colesterol y creatinina. Ademas, no se encontraroncorrelaciones estadisticas entre la fraccion de cambio de XOec y las fracciones de cambio de parametroslipidicos.

Interacción entre los polimorfismos del receptor ß1 y ß2 adrenérgico como predictor de riesgo de insuficiencia cardiaca crónica

e ha propuesto que los polimorfismos geneti-cos se asocian a la genesis o desarrollo dediversas enfermedades cardiovasculares y a lavariabilidad individual a la respuesta farmacologi-ca. Los receptores s-adrenergicos (s-RA) sonreguladores importantes de la homeostasis cardio-vascular, siendo ademas un atractivo modelo parainvestigar las interacciones entre sus polimorfis-mos con la respuesta a farmacos o su relacion conla susceptibilidad o progresion de las enfermeda-des cardiovasculares