[Red cell distribution width as a risk marker in patients with cardiovascular diseases]. / 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.

Ancho de distribución eritrocitaria como potencial biomarcador clínico en enfermedades cardiovasculares / Red cell distribution width as a risk marker in patients with cardiovascular diseases

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.

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.

Niveles aumentados de estrés oxidativo se asocian a disfunción endotelial periférica y respuesta vascular pulmonar disminuida frente a vasodilatadores en pacientes con hipertensión pulmonar / Increased oxidative stress are associated with peripheral endothelial dysfunction and diminished vascular response to vasodilators in pulmonary hypertensive patients

Introducción: La Hipertensión arterial pulmonar (HP) se caracteriza por remodelado vascular y disfunción endotelial. Evidencia experimental muestra que el estrés oxidativo juega un rol importante en la patogénesis de la HP. El rol del estrés oxidativo, su relación con la función endotelial periférica y con la respuesta vascular pulmonar a vasodilatadores en pacientes con HP no está aclarada. Objetivo: evaluar parámetros de estrés oxidativo y función endotelial periférica en pacientes con HP y estudiar su relación con la respuesta vascular pulmonar frente a vasodilatadores. Métodos: estudio transversal. Se incluyeron 14 pacientes con HP y 14 controles pareados por edad y sexo. En todos los sujetos se midieron: niveles plasmáticos de malondialdehido (MDA), superóxido dismutasa ligada a endotelio (eSOD) y xantino oxidasa (eXO). Vasodilatación dependiente de endotelio mediada por flujo en arteria braquial fue usada como marcador de función endotelial (FDD). Función ventricular derecha y reactividad del lecho vascular pulmonar frente a iloprost inhalado fueron evaluadas ecocardiográficamente en los pacientes con HP Resultados: Los pacientes con HP presentaron FDD disminuida versus los controles (2,8 +/- 0,6 vs 10,7 por ciento +/- 0,6, p< 0,01). Niveles de MDA y eXO aumentados (0,61 +/- 0,17 vs 0,34 +/- 0,15uM, p<0,01 y 0,039 +/- 0,005 vs 0,034 +/- 0,004 U/mL1, p=0,02 respectivamente) y actividad de eSOD disminuida (235,55 +/- 23 vs 461,41 +/- 33 ABC, p<0,01). Iloprost mejora significativamente el gasto cardíaco derecho y disminuye la resistencia vascular pulmonar en los pacientes con HP y este cambio se correlaciona con la actividad de eSOD (Rho: 0,61, p<0,01) y FDD (Rho: 0,63, p=0,01). Conclusiones: Pacientes con HP presentan parámetros de estrés oxidativo elevados y disfunción endotelial periférica La respuesta hemodinámica frente al uso de Iloprost se correlaciona con estos parámetros sugiriendo un rol en la HP cuyo valor clínico deberá ser evaluado.

Background: Pulmonary Arterial Hypertension (PAH) is characterized by endothelial dysfunction and vascular remodeling. Several lines of experimental evidence indicate that oxidative stress plays an important role in the pathogenesis of PAH. The role of oxidative stress and its relation with peripheral endothelial function and pulmonary vascular response to vasodilators remains unknown. Aim: To evaluate whether systemic oxidative stress and endothelial dysfunction markers are associated with the response of the pulmonary vascular bed to inhaled vasodilators in PAH patients. Methods: Cross-sectional study Fourteen patients with PAH and 14 age and gender-matched controls were included. Systemic oxidative stress was assessed through plasma malondialdehyde (MDA), xanthine oxidase (eXO) levels and endothelial-bound superoxide dismutase (eSOD) activity Brachial artery endothelial-de-pendent flow-mediated vasodilation (FDD) was used to evaluate endothelial function. Right ventricular function and pulmonary vascular bed reactivity to inhaled vasodilators was determined with echocardiography in PAH patients. Results: Compared to controls, PAH patients showed impaired FDD (2.8 +/- 0.6 vs 10.7 percent +/- 0.6, p< 0.01), increased MDA and eXO levels (0.61 +/- 0.17 vs 0.34 +/- 0.15uM, p<0.01 and 0.039 +/- 0.005 vs 0.034 +/- 0.004 U/ mL1, p=0.02 , respectively) and decreased eSOD activity 235.55 +/- 23 vs 461.41 +/- 33 AUC, p<0.01). Iloprost significantly improved right cardiac output (RCO) and decreased pulmonary vascular resistance. The amount of change in RCO after iloprost inhalation correlated significantly with baseline eSOD activity and FDD (Rho: 0.61, p<0.01 and Rho: 0.63, p=0.01 respectively). Conclusions: PAH patients show increased oxidative stress and endothelial dysfunction markers. Response to inhaled iloprost is closely related with baseline endothelial function and oxidative stress parameters, suggesting an important role of these elements that re...

El tratamiento con atorvastatina reduce la actividad de xantina-oxidasa unida al endotelio en pacientes con insuficiencia cardíaca crónica: ¿un posible nuevo efecto pleiotrópico? / Treatment with atorvastatin reduces the activity of xanthine oxydase bound to endothelium in patients with chronic heart failure

El aumento en la actividad de la xantina-oxidasa unida al endotelio (XOec) puedeparticipar como un importante mediador de la disfunción endotelial en la insuficiencia cardíaca crónica (IC). Las estatinas son capaces de reducir el estrés oxidativo y restaurar la disfunción endotelial a través de mecanismos independientes de la reducción del colesterol. Sin embargo, el efecto de estos fármacos en la actividad de XOec es completamente desconocido. Nosotros estudiamos la hipótesis que atorvastatina durante 8 semanas reduce la actividad de XOec de manera independiente de los cambios en el colesterol. Metodología: Un total de 25 pacientes con IC (Fracción de eyección < 40 por ciento y Clase funcional NYHA II-III) recibieron placebo por 4 semanas, seguido por 8 semanas de atorvastatina 20 mg por día. Muestras desangre fueron recolectadas basalmente, 4 semanas y 12 semanas. La actividad de XOec y los niveles de ácido úrico fueron medidos por espectrofotometría.Resultados: El tratamiento con atorvastatina, pero no el placebo, redujo la actividad de ecXO (p<0.01), los niveles de ácido úrico (p<0.05), colesterol total (p<0.01), LDL-colesterol (p<0.01) y triglicéridos (p<0.05) sin cambios en los niveles de HDL-colesterol y creatinina. Además, no se encontraron correlaciones estadísticas entre la fracción de cambio de XOec y las fracciones de cambio de parámetros lipídicos. Conclusión: El efecto beneficioso a corto plazo de la atorvastatina en relación a la mejoría de la función endotelial demostrado en estudios previos, estaría asociado a una disminución en la actividad de XOec de una manera independiente a los cambios en el colesterol, lo que sugiere la presencia de un nuevo efecto pleiotrópico de las estatinas.

An increased activity of endothelium bound xanthine oxydase (XOeb) may play an important role as a mediator of endothelial dysfunction in chronic heart failure (CHF). Statins reduce oxydative stress and improve endothelial dysfunction through mechanisms unrelated to cholesterol lowering. However, the effect of statins on XOeb activity is unknown. We hypothesized that atorvastatin administered for 6 weeks would reduce XOeb independently of changes in serum cholesterol levels. Methods: 25 patients with CHF (NYHA class II or III with ejection fraction <40 percent received placebo for 4 weeks followed by atorvastatin, 20mg per day, for 8 weeks. Blood samples were obtained before statin administration and 4 and 12 weeks later. Spectrophotometry was used to determine XOeb and uric aced levels. Results: Atorvastatin, but not placebo, reduced XOeb activity (p<0.01), and uric acid (p<0.05), total cholesterol (p<0.01), LDL-cholesterol (p<0.01) and triglyceride levels (p<0.05). No changes were observed inHDL and creatinine levels. There was no correlation between XOeb changes and changes in the other lipid parameters. Conclusion: The known improvement in endothelial dysfuncion related to statin use previously reported is associated to a decrease in XOec activity independently of changes in cholesterol levels, suggesting a new pleiotropic effect of statins.

[Subclinical endothelial inflammation markers in a family with type I familial hyperaldosteronism caused by a de novo mutation]. / Marcadores de inflamación endotelial subclínica en una familia con hiperaldosteronismo familiar tipo I por mutación de novo.

BACKGROUND: Type I familial hyperaldosteronism is caused by the presence of a chimaeric gene CYPl 1B1/CYP11BZ which encodes an enzyme with aldosterone synthetase 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 been shown that aldosterone plays a role in the production of endothelial oxidative stress and subclinical inflammation. AIM: To evaluate subclinical endothelial inflammation markers, like Metalloproteinase 9 (MMP-9) and ultrasensitive C reactive protein (usPCR), before and after glucocorticoid treatment in family members with FH-I caused by a de novo mutation. PATIENTS AND METHODS: We report three subjects with FH-I in a single family (proband, father and sister). We confirmed the presence of a chimaeric CYPl 1B1/CYP11B2 gene by long-PCR in all of them. Paternal grandparents were unaffected by the mutation. The proband was a 13-year-old boy with hypertension stage 2 (in agree to The Joint National Committee VII, JNC-VII), with an aldosterone/plasma rennin activity ratio equal to 161. A DNA paternity test confirmed the parental relationship between the grandparents and father with the index case. MMP-9 and usPCR levels were determined by gelatin zymography and nephelometry, respectively. RESULTS: All affected subjects had approximately a 50% increase in MMP-9 levels. Only the father had an elevated usPCR. The endothelial inflammation markers returned to normal range after glucocorticoid treatment. CONCLUSIONS: We report a family carrying a FH-I caused by a de novo mutation. The elevation of endothelial inflammation markers in these patients and its normalization after glucocorticoid treatment provides new insight about the possible deleterious effect of aldosterone on the endothelium.

[Inflammation and endothelial dysfunction in patients with chronic heart failure]. / Inflamación y disfunción endotelial en pacientes con insuficiencia cardiaca crónica.

BACKGROUND: In chronic heart failure (CHF), endothelial dysfunction (ED) is a consequence of an imbalance of vascular tone regulating substances. The relationship between ED and inflammation has not been fully investigated. AIM: To assess the association between inflammation and ED in CHF. MATERIAL AND METHODS: Forty two patients aged 56+/-14 years (80% male) with a CHF in functional capacity II-III (New York Heart Association) and an ejection fraction (FE) <40% were consecutively studied. Patients were classified according to the presence or absence of ED, evaluated by reactive vasodilation measured by ultrasound, after brachial artery compression. Circulating levels of highly sensitive C reactive protein (usCRP), tumor necrosis factor a (TNFá) and interleukin-6 (IL-6) were determined by ELISA. A group of 15 healthy subjects of similar age, were studied as controls. RESULTS: Sixty seven percent of patients had ED. Compared to controls, patients with CHF had higher usCRP (0.58+/-0.4 and 4.9+/-7.1 mg/dl respectively, p <0.01) and IL-6 (1.38+/-0.06 and 3.1+/-1.7 mg/dl respectively, p <0.01). Compared to patients without ED, patients with CHF and ED had higher levels of usCRP (3.0+/-0.4 and 6.0+/-5.7 mg/dl respectively, p <0.01) and TNFá (0.31+/-0.26 and 1.0+/-1.1 pg/ml, p =0.02). No differences in IL-6 were found between CHF groups. CONCLUSIONS: In CHF patients, the presence of ED was associated with increased levels of inflammatory markers.

Marcadores de inflamación endotelial subclínica en una familia con hiperaldosteronismo familiar tipo I por mutación de novo / Subclinical endothelial inflammation markers in a family with type I familial hyperaldosteronism caused by a de novo mutation

Background: Type I familial hyperaldosteronism is caused by the presence of a chimaetic gene CYPl 1B1/CYP11BZ which encodes an enzyme with aldosterone synthetase activityregulated by adrenocorticotrophic hormone (ACTH). Therefore, in patients with FH I is possible to normalize the aldosterone levels with glucocorticoid treatment. Recently it has been shown that aldosterone plays a role in the production of endothelial oxidative stress and subclinical inflammation. Aim: To evaluate subclinical endothelial inflammation markers, Me Metalloproteinase 9 (MMP-9) and ultrasensitive C reactive protein (usPCR), before and after glucocorticoid treatment in family members with FH-I caused by a de novo mutation. Patients and methods: We report three subjects with FH-I in a single family (proband, father and sister). We confirmed the presence of a chimaeric CYPl 1B1/CYP11B2 gene by ¡ong-PCR in all of them. Paternal grandparents were unaffected by the mutation. The proband was a 13year-old boy with hypertension stage 2 (in agree to The JointNational Committee VII, JNC-vIl), with an aldosterone/plasma rennin activity ratio equal to 161. A DNA paternity test confirmed the parental relationship between the grandparents and father with the index case. MMP-9 and usPCR levels were determined by gelatin zymography and nephelometry, respectively. Results: All affected subjects had approximately a 50 percent increase in MMP-9 levels. Only the father had an elevated usPCR. The endothelial inflammation markers returned to normal range after glucocorticoid treatment. Conclusions: We report a family canying a FH-I caused by a de novo mutation. The elevation of endothelial inflammation markers in these patients and its normalization after glucocorticoid treatment provides new insight about the possible deleterious effect of aldosterone on the endothelium.

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.

Inflamación y disfunción endotelial en pacientes con insuficiencia cardiaca crónica / Inflammation and endothelial dysfunction in patients with chronic heart failure

Background: In chronic heart failure (CHF), endothelial dysfunction (ED) is a consequence of an imbalance of vascular tone regulating substances. The relationship between ED and inflammation has not been fully investigated. Aim: To assess the association between inflammation and ED in CHF. Material and methods: Forty two patients aged 56±14 years (80 percent male) with a CHF in functional capacity II-III (New York Heart Association) and an ejection fraction (FE) <40 percent were consecutively studied. Patients were classified according to the presence or absence of ED, evaluated by reactive vasodilation measured by ultrasound, after brachial artery compression. Circulating levels of highly sensitive C reactive protein (usCRP), tumor necrosis factor a (TNFá) and interleukin-6 (IL-6) were determined by ELISA. A group of 15 healthy subjects of similar age, were studied as controls. Results: Sixty seven percent of patients had ED. Compared to controls, patients with CHF had higher usCRP (0.58±0.4 and 4.9±7.1 mg/dl respectively, p <0.01) and IL-6 (1.38±0.06 and 3.1±1.7 mg/dl respectively, p <0.01). Compared to patients without ED, patients with CHF and ED had higher levéis of usCRP (3.0±0.4 and 6.0±5.7 mg/dl respectively, p <0.01) and TNFá (0.31±0.26 and 1.0±1.1 pg/ml, p =0.02). No differences in IL-6 were found between CHF groups. Conclusions: In CHF patients, the presence of ED was associated with increased levéis of inflammatory markers.

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.

Variabilidad fenotípica y estrés oxidativo endotelial en una familia con hiperaldosteronismo familiar tipo I / Phenotypical variability and endothelial oxidative stress in a family with type I familial hyperaldosteronism

Type I familial hyperaldosteronism (HAF-I) is caused by the presence of a chimeric gene CYP11B1/CYP11B2 which encodes an enzyme with aldosterone synthetase activity regulated by ACTH. HAF-I patients present with severe hypertension at young ages and a greater risk of stroke. AIM: To characterize clinical and biochemical presentation of family members with HAF-I. To evaluate endothelial oxidative stress markers before and after glucocorticoid treatment. PATIENTS AND METHODS: We evaluated three family members with HAF-I confirmed with a genetic test (XL-PCR) for chimeric gene CYP11B1/CYP11B2. The index case was a 13 years old boy with stage 2 hypertension (Joint National Committee VIIth report), plasma aldosterone/ plasma renin activity (AP/ARP) ratio of161 and normal plasma potassium. His father had primary hyperaldosteronism diagnosed at 25 years of age with hypertension and hypokalemia. His sister was 15 years old, with a normal blood pressure and an AP/ARP ratio of 37.6. RESULTS: All subjects had plasma xanthine-oxidase levels in the upperlimit of normal. Malondialdehyde was above normal in the index case and his father. These markers returned to normal with glucocorticoid treatment. CONCLUSIONS: We report a HAF-I carrying family with a wide phenotypical variability between affected members. Elevation of endothelial oxidativestress markers and its normalization after glucocorticoid treatment, may indicate that aldosterone produces endothelial damage and increases cardiovascular risk.

Superóxido dismutasa ligada al endotelio es un sensible marcador de estrés oxidativo y disfunción endotelial en la insuficiencia cardíaca / Endothelial linked superoxide dismutase is a sensitive marker of oxidative stress and endothelial dysfunction in patients with congestive heart failure

Introducción: En pacientes con insuficiencia cardíaca (IC) existe activación neurohumoral que contribuye a la progresión clínica de la enfermedad y se ha asociado a aumento del estrés oxidativo (EO) y deterioro de la capacidad funcional. Pacientes con IC avanzada tienen niveles aumentados de malodihaldehido, un marcador de EO, pero niveles normales de enzimas antioxidantes. En la pared vascular, la enzima superóxido dismutasa ligada a endotelio (SODec) representa un importante sistema enzimático antioxidante que contribuye a la inactivación de especies reactivas del oxígeno (ROS) y a la modulación del tono vascular. Objetivo: Estudiar el rol de SODec como marcador de EO en IC y su correlación con la función endotelial. Métodos: Estudiamos 20 pacientes con IC moderada (Clase II-III) con fracción de eyección de ventrículo izquierdo (FEVI) < 40 por ciento. Se determinaron los niveles plasmáticos de MDA por sustancias reactivas del ácido tiobarbitúrico y los sistemas de defensa antioxidantes eritrocitarios SOD y catalasa (CAT) por espectofotometría. La enzima ecSOD se liberó de la superficie endotelial mediante la administración de heparina en bolo (5000 U) en la arteria braquial determinando su actividad en sangre venosa. La función endotelial se determinó mediante ecografía de arteria braquial para determinar la vasodilatación dependiente de endotelio. Se utilizó un grupo control de personas sanas pareadas por edad y sexo. Los resultados se expresan como promedio ± DES y en el análisis estadístico se utilizó t-Student y correlación lineal de Pearson. Resultados: Edad promedio de 59 ± 16 años, 17 hombres (85 por ciento). Nueve con etiología isquémica (45 por ciento). La FEVI fue de 33 ± 5 por ciento, el test de caminata de 6 minutos de 412 ± 90 m. Los niveles plasmáticos de MDA y de SOD y CAT eritrocitarios fueronsimilares en pacientes con IC y en grupo control. En los pacientes con IC encontramos una disminución significativa de la actividad de SODec (p< 0.001)...

La actividad de metaloproteinasa-9 se asocia a estrés oxidativo en el síndrome coronario agudo / Metalloproteinase-9 activity is associated with oxidative stress in acute coronary syndrome

Antecedentes: La metaloproteinasas (MMPs) son enzimas proteolíticas que participan en la inestabilidad de la placa aterosclerótica. En cultivos celulares, la actividad de metaloproteinasas-2 y 9 (MMP-2 y MMP-9) aumenta en presencia de radicales libres del oxígeno. En una experiencia preliminar en pacientes con síndrome coronario agudo (SCA) hemos encontrado una posible asociación entre ambos fenómenos. Objetivo: Evaluar la relación entre actividad de enzimas de degradación de la matriz extracelular y estrés oxidativo (EO) en el SCA. Métodos: Estudiamos en forma prospectiva a 40 pacientes con SCA sin supradesnivel del segmento ST, puntaje TIMI ≥ 3 y alteraciones al electrocardiograma o elevación de Troponina I, que no presentaran un proceso inflamatorio. Se midió actividad de MMP-2 y MMP-9 (por zimografía en geles), malondialdehido (MDA) (mediante sustancias reactivas al ácido tiobarbitúrico) y PCR ultrasensible (PCRus) (ELISA), al ingreso y al quinto día. Se utilizó test t de Student para muestras pareadas y correlación lineal de Pearson. Resultados: De los 40 pacientes, 31 fueron hombres, la edad promedio fue 61+/-12 (38-85) años, todos con elevación de Troponina I. El puntaje TIMI fue de 4 (3-7). El 85 por ciento de los pacientes presentaron elevación de PCRus al ingreso (15,0+/-28,7 mg/L) y ésta aumentó al día 5 (35,3+/-38 mg/L, p=0,01); los niveles plasmáticos de MDA se encontraron elevados al ingreso (1,54+/-0,75 µM/L) y descendieron al quinto día (1,04+/-0,32 µM/L, p<0,0001). Al quinto día, la actividad de MMP-9 cayó a un 74+/-27 por ciento del valor basal (p<0,0001). No se observó cambio en la actividad de MMP-2. Se demostró una correlación positiva entre las fracciones de cambio de MDA y MMP-9 (r=0,43, p<0,0001). Conclusiones: En pacientes con SCA se observa un aumento precoz en el grado de inflamación, actividad de MMP-9 y de EO...

Background: Metalloproteinases are proteolytic enzymes that participate in atherosclerotic plaque instability. In cellular cultures there is increased activity of metalloproteinases-2 and 9 (MMP-2 and MMP-9) in the presence of free oxygen radicals. In a preliminary experience in patients with acute coronary syndrome (ACS) we have found a possible association between both phenomena. Objective: To evaluate the relation between activity of matrix degradation proteins and oxidative stress (OS) in acute coronary syndrome. Methods: Fourty patients with non-ST segment elevation acute coronary syndrome were prospectively studied. All had a TIMI risk score ≥ 3, ischemic changes on electrocardiogram or Troponin I elevation, without a concomitant inflammatory condition. We determined MMP-2 and MMP-9 activities (gel zymography), malondialdehyde (MDA) (thiobarbituric acid reactive species) and high sensitive C reactive protein (hsCRP) plasma levels at admission and 5 days later. Paired samples Student’ t test and Pearson’s lineal correlation were used for statistical analysis. Results: Of the 40 patients, 31 were male, mean age 61+/-12 years old (range 38-85), all of them with Troponin I elevation. The TIMI risk score was 4 (3-7). 85 percent presented hsCRP elevation (15.0+/-28,7 mg/L at admission and 35.3+/-38 mg/L at day 5). MDA plasma levels were increased at admission (1,54+/-0,75 µM/L) and diminished at day 5 (1,04+/-0,32 µM/L, p<0,0001). Compared to basal values, MMP-9 activity decreased to 74+/- 27 percent at day 5, (p<0,001). No significant change was observed in MMP-2 activity between both measurements. A significant positive correlation was found between change fractions of MDA levels and MMP-9 activity (r=0,43, p<0,0001). Conclusions: In patients with ACS we observed an early increase in inflammation markers, MMP-9 activity and OS. The correlation demonstrated between MMP-9 activity and OS suggests a common role of both phenomena in the pathophysiology...

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

BACKGROUND: 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. AIM: To investigate the effects of carvedilol on the heart rate response to exercise and oxidative stress in patients with CHF. METHODS AND RESULTS: Thirty stable NYHA classes II-III CHF patients received carvedilol therapy for 6 months, at a mean maintenance dose of 25 mg (range 6.25-50 mg/day). After treatment, the patients showed a significant improvement in their functional NYHA class (p=0.013), increased left ventricular ejection fraction (LVEF) (24+/-1.4% to 31+/-2.3%, p=0.003) and 6-min walk distance (499+/-18 to 534+/-18 m, p=0.03), without changes in the peak VO2. At baseline, norepinephrine (NE) plasma levels increased with exercise (510+/-51 to 2513+/-230 pg/mL, p<0.001), and these levels were not affected by carvedilol. Chronotropic responsiveness index (increase in heart rate divided by the increase in NE from rest to peak exercise) was not changed by carvedilol (0.049+/-0.001 to 0.042+/-0.001, p=0.6). MDA levels of CHF patients decreased after treatment with carvedilol (2.4+/-0.2 to 1.1+/-0.2 microM, p<0.001), without changes in antioxidant enzyme activities. CONCLUSIONS: Carvedilol treatment in patients with CHF results in reduced oxidative stress without restoration of the chronotropic responsiveness index.