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João Tomé-Carneiro,
Mar Larrosa,
María J Yáñez-Gascón,
Alberto Dávalos,
Judit Gil-Zamorano,
Manuel Gonzálvez,
Francisco J García-Almagro, José A Ruiz Ros,
Francisco A Tomás-Barberán,
Juan Carlos Espín,
María-Teresa García-Conesa
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ABSTRACT: Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited. Furthermore, the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood. Therefore, the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells (PBMCs) associated to the one-year daily intake of a RES enriched (8mg) grape extract (GE-RES) in hypertensive male patients with type 2 diabetes mellitus (T2DM). We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs (miRs) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES. We also examined the changes in several serobiochemical variables, inflammatory and fibrinolytic markers. Our results showed that supplementation with GE or GE-RES did not affect body weight, blood pressure, glucose, HbAlc or lipids, beyond the values regulated by gold standard medication in these patients. We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels. The expression of the pro-inflammatory cytokines CCL3, IL-1β and TNF-α was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in PBMCs from patients taking the GE-RES extract. Also, a group of miRs involved in the regulation of the inflammatory response: miR-21, miR-181b, miR-663, miR-30c2, miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months. Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect that may contribute to treatment.
Pharmacological Research 04/2013; · 4.44 Impact Factor
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ABSTRACT: PURPOSE: The grape and wine polyphenol resveratrol exerts cardiovascular benefits but evidence from randomized human clinical trials is very limited. We investigated dose-depending effects of a resveratrol-containing grape supplement on stable patients with coronary artery disease (CAD) treated according to currently accepted guidelines for secondary prevention of cardiovascular disease. METHODS: In a triple-blind, randomized, placebo-controlled, one-year follow-up, 3-arm pilot clinical trial, 75 stable-CAD patients received 350 mg/day of placebo, resveratrol-containing grape extract (grape phenolics plus 8 mg resveratrol) or conventional grape extract lacking resveratrol during 6 months, and a double dose for the following 6 months. Changes in circulating inflammatory and fibrinolytic biomarkers were analyzed. Moreover, the transcriptional profiling of inflammatory genes in peripheral blood mononuclear cells (PBMCs) was explored using microarrays and functional gene expression analysis. RESULTS: After 1 year, in contrast to the placebo and conventional grape extract groups, the resveratrol-containing grape extract group showed an increase of the anti-inflammatory serum adiponectin (9.6 %, p = 0.01) and a decrease of the thrombogenic plasminogen activator inhibitor type 1 (PAI-1) (-18.6 %, p = 0.05). In addition, 6 key inflammation-related transcription factors were predicted to be significantly activated or inhibited, with 27 extracellular-space acting genes involved in inflammation, cell migration and T-cell interaction signals presenting downregulation (p < 0.05) in PBMCs. No adverse effects were detected in relation to the study products. CONCLUSIONS: Chronic daily consumption of a resveratrol-containing grape nutraceutical could exert cardiovascular benefits in stable-CAD patients treated according to current evidence-based standards, by increasing serum adiponectin, preventing PAI-1 increase and inhibiting atherothrombotic signals in PBMCs.
Cardiovascular Drugs and Therapy 12/2012; · 3.13 Impact Factor
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Joao Tomé-Carneiro,
Manuel Gonzálvez,
Mar Larrosa,
Francisco J García-Almagro,
Francisco Avilés-Plaza,
Soledad Parra,
María J Yáñez-Gascón, José A Ruiz-Ros,
María T García-Conesa,
Francisco A Tomás-Barberán,
Juan Carlos Espín
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ABSTRACT: The cardioprotective role of resveratrol as part of the human diet is not yet clear. Our aim was to investigate the effect of a grape supplement containing 8 mg resveratrol in oxidized LDL (LDLox), apolipoprotein-B (ApoB), and serum lipids on statin-treated patients in primary cardiovascular disease prevention (PCP).
A triple-blind, randomized, placebo-controlled trial was conducted. Seventy-five patients (three parallel arms) consumed one capsule (350 mg) daily for 6 months containing resveratrol-enriched grape extract (GE-RES, Stilvid®), grape extract (GE, similar polyphenolic content but no resveratrol), or placebo (maltodextrin). After 6 months, no changes were observed in the placebo group and only LDL cholesterol (LDLc) decreased by 2.9% (p = 0.013) in the GE group. In contrast, LDLc (-4.5%, p = 0.04), ApoB (-9.8%, p = 0.014), LDLox (-20%, p = 0.001), and LDLox/ApoB (-12.5%, p = 0.000) decreased in the Stilvid® group, whereas the ratio non-HDLc (total atherogenic cholesterol load)/ApoB increased (8.5%, p = 0.046). No changes were observed in hepatic, thyroid, and renal function. No adverse effects were observed in any of the patients.
This GE-RES reduced atherogenic markers and might exert additional cardioprotection beyond the gold-standard medication in patients from PCP. The presence of resveratrol in the GE was necessary to achieve these effects.
Molecular Nutrition & Food Research 05/2012; 56(5):810-21. · 4.30 Impact Factor
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ABSTRACT: The search for complementary treatments in primary prevention of cardiovascular disease (CVD) is a high-priority challenge. Grape and wine polyphenol resveratrol confers CV benefits, in part by exerting anti-inflammatory effects. However, the evidence in human long-term clinical trials has yet to be established. We aimed to investigate the effects of a dietary resveratrol-rich grape supplement on the inflammatory and fibrinolytic status of subjects at high risk of CVD and treated according to current guidelines for primary prevention of CVD. Seventy-five patients undergoing primary prevention of CVD participated in this triple-blinded, randomized, parallel, dose-response, placebo-controlled, 1-year follow-up trial. Patients, allocated in 3 groups, consumed placebo (maltodextrin), a resveratrol-rich grape supplement (resveratrol 8 mg), or a conventional grape supplement lacking resveratrol, for the first 6 months and a double dose for the next 6 months. In contrast to placebo and conventional grape supplement, the resveratrol-rich grape supplement significantly decreased high-sensitivity C-reactive protein (-26%, p = 0.03), tumor necrosis factor-α (-19.8%, p = 0.01), plasminogen activator inhibitor type 1 (-16.8%, p = 0.03), and interleukin-6/interleukin-10 ratio (-24%, p = 0.04) and increased anti-inflammatory interleukin-10 (19.8%, p = 0.00). Adiponectin (6.5%, p = 0.07) and soluble intercellular adhesion molecule-1 (-5.7%, p = 0.06) tended to increase and decrease, respectively. No adverse effects were observed in any patient. In conclusion, 1-year consumption of a resveratrol-rich grape supplement improved the inflammatory and fibrinolytic status in patients who were on statins for primary prevention of CVD and at high CVD risk (i.e., with diabetes or hypercholesterolemia plus ≥1 other CV risk factor). Our results show for the first time that a dietary intervention with grape resveratrol could complement the gold standard therapy in the primary prevention of CVD.
The American journal of cardiology 04/2012; 110(3):356-63. · 3.58 Impact Factor
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Manuel Gonzálvez, José A Ruiz-Ros,
Matías Pérez-Paredes,
María L Lozano,
Francisco J García-Almagro,
Francisco Martínez-Corbalán,
Diego M Giménez,
Andrés Carrillo,
Andrés Carnero,
Tomás Cubero,
Juan J Gonzálvez,
Isabel Ureña,
Vicente Vicente
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ABSTRACT: Tumor necrosis factor-alpha (TNFalpha in patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to determine the prognostic value of TNFalpha in this clinical setting at six-month follow-up.
The levels of TNFalpha, C-reactive protein (CRP), interleukin 6 and type 1 soluble intercellular adhesion molecules measured within the first 10 h of symptom onset and at 48 h in 74 consecutive patients admitted with STEMI. The relationships between these levels and the incidence of ischemic events (i.e., angina, reinfarction, and death), heart failure (HF), or both (i.e., all cardiovascular events) were studied.
Overall, TNFalpha levels were significantly higher in patients who had an ischemic event or HF than in those who did not (P<.02 for both). At 48 h, the adjusted odds ratios of those in the highest TNFalpha quartile (2.92 pg/mL) for the development of ischemic events, HF, and all cardiovascular events combined were 13.1, 9.59 and 9.75, respectively. A TNFalpha level of 2.04 pg/mL at 48 h had a sensitivity of 78% and a specificity of 72.5% in predicting a cardiovascular event of any form. The CRP level, but not the TNFalpha level, at admission was found to be an independent predictor of the development of a cardiovascular events.
In patients with STEMI, the plasma TNFalpha level 48 h after symptom onset and the CRP level at admission were independent predictors of cardiovascular events.
Revista Espa de Cardiologia 12/2007; 60(12):1233-41. · 2.53 Impact Factor
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ABSTRACT: To analyze the profile of left atrial wall velocities by pulsed wave tissue Doppler imaging, and to compare the relationship between these observations and the transmitral and pulmonary vein flow velocities obtained by conventional pulsed Doppler echocardiography.
We studied 90 patients (50 women and 40 men, mean age 48 [22] years). Pulsed tissue Doppler images of the left atrial wall were obtained and analyzed in all subjects. The study population was then divided in two groups: group I (age < 45 years) and group II (age > 45 years). Transmitral and pulmonary vein flow velocity tracings were obtained simultaneously by pulsed Doppler echocardiography.
With pulsed tissue Doppler interrogation of the left atrial wall, a triphasic signal was recorded in all patients, consisting of a positive wave (A1) followed by two negative waves (A2 and A3). Younger subjects (group I) showed a pattern with a prominent A2 wave and an A2/A3 ratio > 1. In older patients (group II) peak velocity of the A2 wave diminished and peak velocity of the A3 wave increased, so that the A2/A3 ratio was < 1. We found no differences in peak velocity of the A1 wave between the two age groups (13.5 (3.9) cm/s in group I vs 13.1 (5.4) cm/s in group II; P = .59). Significant concordance was observed between the transmitral flow pattern and the left atrial pulsed tissue Doppler tracing (kappa = 0.584; P < .0001).
Evaluation of the left atrial wall using pulsed tissue Doppler imaging is feasible and reproducible. Tissue Doppler imaging provides new quantitative insights of potential use in the assessment of left atrial function.
Revista Espa de Cardiologia 11/2004; 57(11):1059-65. · 2.53 Impact Factor
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ABSTRACT: C-reactive protein (CRP), whose synthesis in the liver is regulated by interleukin 6 (IL-6), is related with the prognosis for ischemic heart disease. The aim of this study was to evaluate the effect of early administration of pravastatin on plasma levels of CRP and IL-6 in patients with acute myocardial infarction and ST segment elevation.
71 patients were randomized during the first 10 hours from the onset of symptoms to receive 40 mg of pravastatin once a day or not. CRP and IL-6 were measured on admission, 48 hours and 7 days later. CRP was also measured 2 months later.
On admission, levels of CRP and IL-6 were similar in both groups. After 7 days of treatment the administration of pravastatin was associated with a lower level of CRP (P=.002). Mean and median CRP levels decreased from 48 hours to day 7 by 48.4% and 51.9% respectively in the pravastatin group, and by 32.5% and 15.9% respectively in the control group. In contrast, no significant differences in IL-6 levels were observed between the two groups. After 2 months of follow-up, 50% of the treated patients and 25% of the control patients had CRP levels lower than 6.6 mg/L (P=.039).
Early administration of pravastatin in the acute phase of myocardial infarction with ST segment elevation was associated with a lower level of CRP after 7 days of treatment, with no concomitant changes in IL-6 levels.
Revista Espa de Cardiologia 11/2004; 57(10):916-23. · 2.53 Impact Factor
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ABSTRACT: Myocardial contractile reserve studies with low-dose dobutamine echocardiography have been shown to be useful to assess functional myocardial status. However, the variables associated with contractile reserve after inotropic stimulation are not well known.
We studied 50 patients (35 men, mean age 56.4 +/- 9.5 years) with nonischemic dilated cardiomyopathy (NIDC), LVEF 28.7% +/- 8.5% and wall motion score index (WMSI) 2.42 +/- 0.34 with low-dose dobutamine echocardiography. Left ventricular contractile reserve was assessed by a differential parameter defined as the difference between rest and stress WMSI (DeltaWMSI).
After dobutamine infusion the WMSI was 1.95 +/- 0.58; from this value we calculated a DeltaWMSI of 0.45 +/- 0.39. None of the clinical variables showed a relationship with the presence of contractile reserve. In contrast, the following echocardiographic parameters correlated with DeltaWMSI: end-diastolic (p=0.05) and end-systolic (p=0.02) diameters, end-systolic volume index (p=0.01) and LVEF (p=0.002). In the multivariate analysis, only end-diastolic diameter was an independent predictor of contractile reserve (hazard ratio=0.852; 95% CI, 0.735-0.987; p=0.03).
Ventricular diameters, end-systolic volume index and LVEF are related with improvements in myocardial contractility after dobutamine infusion, although only end-diastolic diameter was an independent predictor of contractile reserve. Thus, this parameter should receive particular attention in evaluations of the functional status of the myocardium in patients with NIDC.
Revista Espa de Cardiologia 11/2003; 56(10):995-1000. · 2.53 Impact Factor
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ABSTRACT: The benefits of beta blockers in heart failure are highly dependent on dosage. This study aimed to analyze the degree of concordance between targeted (CIBIS II) and achieved doses of bisoprolol in a group of patients with stable heart failure on conventional treatment. We also evaluated functional parameters, adverse effects and the reasons for withdrawal or drop-out.
The study group consisted of 334 patients with stable systolic heart failure who were receiving conventional treatment. Treatment with bisoprolol was initiated according to current guidelines (starting dose 1.25 mg/day, with weekly increments to 5 mg/day, and then increments every four weeks to a targeted dosis of 10 mg/day). The main endpoint was the comparison between targeted dose and dose reached at each follow-up. Secondary endpoints were quality of life assessment (Minnesota Living with Heart Failure Questionnaire), functional status (New York Heart Association), ejection fraction change, and side effects during the 9-month follow-up period.
Thirty-four (10%) patients did not finish the study: 1 because of sudden death, 2 because of surgery, and 31 because of side effects. 63% of the patients attained the maximum targeted dose; the mean dose at the end of follow-up was 8.5 mg. Functional status, quality of life and ejection fraction improved significantly between the beginning and the end of the study. Only 4 patients had severe adverse effects.
This is the first study in Spain to show that bisoprolol can be used effectively at the maximum recommended doses, for the outpatient treatment of heart failure.
Revista Espa de Cardiologia 10/2003; 56(9):873-9. · 2.53 Impact Factor
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ABSTRACT: Introducción y objetivos. La proteína C reactiva (PCR), sintetizada en el hígado bajo el estímulo de la interleucina 6 (IL-6), está relacionada con el pronóstico de la cardiopatía isquémica. El objetivo del estudio fue evaluar el efecto de la administración precoz de pravastatina en los valores sanguíneos de PCR e IL-6 en el infarto agudo de miocardio (IAM) con ST elevado. Pacientes y método. Se estudió a 71 pacientes que fueron aleatorizados dentro de las 10 h siguientes al inicio del dolor a recibir 40 mg/día de pravastatina o no. Se midieron la PCR y la IL-6 al ingreso, a las 48 h y al séptimo día. La PCR se midió también a los 2 meses. Resultados. Al ingreso, los valores de PCR e IL-6 fueron similares en los 2 grupos. Tras 7 días de tratamiento, la administración de pravastatina se asoció con una concentración más baja de PCR (p = 0,002). Esto supuso un descenso de sus valores desde las 48 h hasta el séptimo día, en términos de media y mediana, del 48,4 y el 51,9%, respectivamente, en el grupo tratado, y del 32,5 y el 15,9% en el grupo control. No se observaron diferencias en los valores de IL-6 entre ambos grupos. Tras 2 meses, el 50% del grupo tratado y el 25% del grupo control presentaban una PCR inferior a 6,6 mg/l (p = 0,039). Conclusiones. La administración precoz de pravastatina en la fase aguda del infarto de miocardio con ST elevado se asoció a una menor concentración plasmática de PCR tras 7 días de tratamiento, sin cambios concomitantes en los valores de IL-6.
Revista española de cardiología, ISSN 0300-8932, Vol. 57, Nº. 10, 2004, pags. 916-923.
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ABSTRACT: Introducción y objetivos. Analizar el perfil de velocidades de la pared auricular izquierda mediante Doppler pulsado tisular y su relación con los registros de Doppler convencional obtenidos a partir del flujo transmitral y de las venas pulmonares. Pacientes y método. Estudiamos a 90 sujetos, 50 mujeres y 40 varones, con una edad de 48 ± 22 años. Se obtuvieron los patrones de Doppler pulsado tisular de la pared auricular izquierda. La población fue dividida en 2 grupos: grupo I (< 45 años) y grupo II (> 45 años). Se obtuvieron simultáneamente los registros de Doppler pulsado transmitral y de las venas pulmonares. Resultados. El análisis con Doppler pulsado tisular de la pared auricular izquierda muestra una señal espectral trifásica, con una onda positiva A1, seguida de 2 ondas negativas (A2 y A3). En el grupo más joven (grupo I) se observa un patrón con una onda A2 prominente y una relación A2/A3 > 1. Con la edad (grupo II), el pico de velocidad de A2 disminuye y el de A3 aumenta, por lo que la relación A2/A3 se hace < 1. No se observaron diferencias en las velocidades máximas de A1 entre ambos grupos (13,5 ± 3,9 cm/s en el grupo I frente a 13,1 ± 5,4 cm/s en el grupo II; p = 0,59). Los patrones de Doppler transmitral y de pared auricular mostraron una concordancia significativa (kappa = 0,584; p < 0,0001). Conclusiones. Es posible estudiar de forma reproducible las velocidades de pared de la aurícula izquierda mediante Doppler pulsado tisular. Este análisis nos permite disponer de nuevos datos cuantitativos que quizá puedan ser de utilidad para el estudio de la función auricular.
Revista española de cardiología, ISSN 0300-8932, Vol. 57, Nº. 11, 2004, pags. 1059-1065.
