Resveratrol in primary and secondary prevention of cardiovascular disease: a dietary and clinical perspective.

Primary prevention of cardiovascular disease (CVD) aims to avoid a first event in subjects that are at risk but have not yet been diagnosed with heart disease. Secondary prevention of CVD aims to avoid new events in patients with established heart disease. Both approaches involve clinical intervention and implementation of healthy lifestyles. The grape and wine polyphenol resveratrol (3,5,4'-trihydroxy-trans-stilbene) has shown cardioprotective benefits in humans. Most of these approaches deal with rather high doses and short follow-ups, and do not address the issue of long-term resveratrol consumption safety, especially in medicated individuals. Here, we review the trials conducted with resveratrol in patients at risk for or with established CVD, focusing on the two longest human clinical trials reported so far (1-year follow-up). We also discuss the expectations for resveratrol from a dietary and clinical perspective in relation to CVD. However, statistically significant changes in CVD-risk markers do not necessarily equal clinical significance in the daily care of patients.

One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease.

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 (8 mg) 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, HbA1c 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-1ß 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 in these patients.

Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease.

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.

Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: a triple-blind, 6-month follow-up, placebo-controlled, randomized trial.

SCOPE: 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). METHODS AND RESULTS: 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. CONCLUSION: 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.

One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease.

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.

Prognostic value of the Thrombolysis in Myocardial Infarction risk score in a unselected population with chest pain. Construction of a new predictive model.

INTRODUCTION: The Thrombolysis in Myocardial Infarction (TIMI) risk score (TRS) has proven to be a useful and simple tool for risk stratification of patients with chest pain in intermediate- and high-risk populations. There is little information on its applicability in daily clinical routine with unselected populations. AIMS: The aims of the study were to prospectively analyze the predictive value of the TRS in a heterogeneous population admitted for chest pain and to construct where possible a new modified model with a greater prognostic capacity. POPULATION AND METHODS: Seven hundred eleven consecutive patients were admitted over a 1-year period to the cardiology unit for chest pain without ST-segment elevation. Thrombolysis in Myocardial Infarction risk score variables, relevant medical history variables, in-hospital examination results, and therapy information were collected. Cardiac events at 1 and 6 months were recorded. RESULTS: Seventy-one (9.8%) patients had a compound event (myocardial infarction/revascularization/cardiac death) at 6 months. On multivariate analysis, the variables associated with cardiac events were left ventricular ejection fraction (EF) of <35% (hazard ratio [HR] = 2.9, P = .002), diabetes (HR = 1.8, P = .02), and TRS (HR = 1.3, P = .007). Events at 6 months were 2.3% for a TRS of 0/1, 4.2% for 2, 10.2% for 3, 11.0% for 4, and 18.7% for a score of more than 5. A new modified scale was constructed to include EF and diabetes as independent variables, and this yielded an increase of 44% in the combined event at 6 months per score unit increase (HR = 1.44, P = .001). The modified scale showed a greater predictive capacity than the original model. CONCLUSIONS: The TRS is an important short- and long-term prognostic predictor when applied to an unselected population consulting for chest pain. The inclusion of diabetes and EF as variables in the model increases predictive capacity at no expense to simplicity.

[Prognostic value of tumor necrosis factor-alpha in patients with ST-segment elevation acute myocardial infarction]. / Valor pronóstico del factor de necrosis tumoral alfa en pacientes con infarto agudo de miocardio con elevación del segmento ST.

INTRODUCTION AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Valor pronóstico del factor de necrosis tumoral alfa en pacientes con infarto agudo de miocardio con elevación del segmento ST / Prognostic value of tumor necrosis factor-alpha in patients with ST-segment elevation acute myocardial infarction

Introducción y objetivos. Entre la variedad de procesos inflamatorios que implican al factor de necrosis tumoral alfa (TNFα), se encuentra la enfermedad cardiovascular. Su valor pronóstico en el infarto agudo de miocardio con elevación del segmento ST (IAMEST) es poco conocido. Este estudio trata de determinar el valor pronóstico del TNFα en este marco clínico tras 6 meses de seguimiento. Métodos. Se midieron las concentraciones de TNFα, proteína C-reactiva (PCR), interleucina 6 y moléculas solubles de adhesión celular tipo 1 en las primeras 10 h tras el inicio de los síntomas y tras 48 h en 74 pacientes con IAMEST. Se correlacionaron sus valores con la incidencia de eventos isquémicos (angina, reinfarto y muerte), insuficiencia cardiaca o ambos (eventos cardiovasculares). Resultados. Los valores de TNFα fueron significativamente mayores en pacientes con eventos isquémicos o insuficiencia cardiaca que en aquellos sin eventos (p < 0,02 para todos). A las 48 h, las odds ratio (OR) ajustadas para el último cuartil de TNFα (2,92 pg/ml) eran OR = 13,1; OR = 9,59 y OR = 9,75 para el desarrollo de eventos isquémicos, insuficiencia cardiaca y eventos cardiovasculares combinados, respectivamente. La concentración de TNFα a las 48 h de 2,04 pg/ml tuvo una sensibilidad del 78% y una especificidad del 72,5% en la predicción conjunta de dichos eventos. Al ingreso, la PCR, pero no el TNFα, mostró valor predictivo independiente en el desarrollo de eventos cardiovasculares. Conclusiones. En pacientes con IAMEST, la concentración plasmática de TNFα a las 48 h y la PCR al ingreso son predictores independientes de eventos cardiovasculares (AU)

Introduction and objectives. Tumor necrosis factor-alpha (TNF-alpha) is implicated in a variety of inflammatory processes, including cardiovascular disease. Little is known about the prognostic value of TNF-alpha in patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to determine the prognostic value of TNF-alpha in this clinical setting at six-month follow-up. Methods. The levels of TNF-alpha, 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. Results. Overall, TNF-alpha 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 TNF-alpha 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 TNF-alpha 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 TNF-alpha level, at admission was found to be an independent predictor of the development of a cardiovascular events. Conclusions. In patients with STEMI, the plasma TNF-alpha level 48 h after symptom onset and the CRP level at admission were independent predictors of cardiovascular events (AU)

[Use of a coronary risk score (the TIMI Risk Score) in a non-selected patient population assessed for chest pain at an emergency department]. / Aplicación de una puntuación de riesgo coronario (TIMI Risk Score) en una población no seleccionada de pacientes que consultan por dolor torácico en un servicio de urgencias.

INTRODUCTION AND OBJECTIVES: Stratification algorithms for acute coronary syndrome enable the identification of high-risk patients who will benefit from more aggressive treatment. The TIMI Risk Score (TRS) has been shown to be useful in intermediate- and high-risk patients. However, little is known about its value in non-selected patients. Our aim was to assess the efficacy of the TRS for risk stratification in a non-selected population with chest pain. PATIENTS AND METHOD: We evaluated 1254 consecutive patients (age, 54 [19] years; 57% male) attending an emergency department for chest pain. Overall, 343 (27%) were admitted and 911 (73%) were discharged. All cardiac events during 6-month follow-up were recorded. RESULTS: Of the 911 discharged patients, 45 (5.3%) were admitted during follow-up: 9 (1.1%) underwent revascularization, 5 (0.6%) had a myocardial infarction (MI), and 2 (0.2%) died from cardiovascular disease. Patients with a high TRS had a significantly higher risk of reaching the composite endpoint of death, MI, or revascularization (relative risk per unit of TRS increase, 3.63; 95% CI, 2.20-6.00; P < .001). Of the patients who were initially admitted, 22 (6.4%) underwent revascularization, 4 (1.2%) had an MI, and 14 died (4.1%) from cardiovascular disease during follow-up. The relative risk of the composite endpoint per unit of TRS increase was 1.72 (95% CI, 1.32-2.24; P < .001). CONCLUSIONS: The TIMI risk score is useful for stratifying cardiovascular event risk in non-selected patients with chest pain. The score can identify high-risk patients who will benefit from hospital admission and early aggressive treatment.

Aplicación de una puntuación de riesgo coronario (TIMI Risk Score) en una población no seleccionada de pacientes que consultan por dolor torácico en un servicio de urgencias / Use of a coronary risk score (the TIMI risk score) in a non-selected patient population assessed for chest pain at an emergency department

Introducción y objetivos. Diferentes algoritmos de estratificación del síndrome coronario agudo (SCA) permiten identificar a los individuos con un mayor riesgo que pueden beneficiarse de tratamientos más agresivos. Se ha demostrado que el TIMI Risk Score (TRS) es útil en pacientes con un riesgo intermedio y alto, pero faltan evidencias acerca de su aplicabilidad clínica en pacientes no seleccionados. El objetivo es comprobar la eficacia del TRS en la estratificación del riesgo en una población con dolor torácico no seleccionada. Pacientes y método. Se incluyó a 1.254 pacientes consecutivos que acudieron a urgencias por dolor torácico no traumático sin ascenso del segmento ST (edad 54 ± 19 años, 57% varones). Se ingresó a 343 (27%) y se dio de alta a 911 (73%). Se registró la aparición de eventos cardíacos a los 6 meses. Resultados. En el grupo dado de alta desde urgencias, 45 (5,3%) pacientes fueron ingresados durante el seguimiento, 9 (1,1%) recibieron tratamiento de revascularización, 5 (0,6%) presentaron un infarto agudo miocárdico (IAM) y 2 (0,2%) fallecieron por causa cardiovascular. Los que obtuvieron una mayor puntuación en el TRS presentaron más riesgo de presentar el evento combinado muerte, infarto o revascularización (riesgo relativo por incremento de unidad = 3,63; intervalo de confianza [IC] del 95%, 2,20-6,00; p < 0,001). En el grupo de ingresados hubo 22 revascularizaciones (6,4%), 4 IAM (1,2%) y 14 muertes de causa cardiovascular (4,1%) durante el seguimiento. El riesgo relativo de evento combinado por cada incremento del TRS fue 1,72 (IC del 95%, 1,32-2,24; p < 0,001). Conclusiones. El TRS es una herramienta eficaz para la estratificación pronóstica de pacientes no seleccionados que consultan por dolor torácico. Permite identificar a los individuos de alto riesgo que se beneficiarían de ingreso hospitalario y tratamiento agresivo precoz

Introduction and objectives. Stratification algorithms for acute coronary syndrome enable the identification of high-risk patients who will benefit from more aggressive treatment. The TIMI Risk Score (TRS) has been shown to be useful in intermediate- and high-risk patients. However, little is known about its value in non-selected patients. Our aim was to assess the efficacy of the TRS for risk stratification in a non-selected population with chest pain. Patients and method. We evaluated 1254 consecutive patients (age, 54 [19] years; 57% male) attending an emergency department for chest pain. Overall, 343 (27%) were admitted and 911 (73%) were discharged. All cardiac events during 6-month follow-up were recorded. Results. Of the 911 discharged patients, 45 (5.3%) were admitted during follow-up: 9 (1.1%) underwent revascularization, 5 (0.6%) had a myocardial infarction (MI), and 2 (0.2%) died from cardiovascular disease. Patients with a high TRS had a significantly higher risk of reaching the composite endpoint of death, MI, or revascularization (relative risk per unit of TRS increase, 3.63; 95% CI, 2.20-6.00; P<.001). Of the patients who were initially admitted, 22 (6.4%) underwent revascularization, 4 (1.2%) had an MI, and 14 died (4.1%) from cardiovascular disease during follow-up. The relative risk of the composite endpoint per unit of TRS increase was 1.72 (95% CI, 1.32-2.24; P<.001). Conclusions. The TIMI risk score is useful for stratifying cardiovascular event risk in non-selected patients with chest pain. The score can identify high-risk patients who will benefit from hospital admission and early aggressive treatment

[Functional assessment of patients with hypertrophic cardiomyopathy by maximal oxygen consumption]. / Evaluación funcional de los pacientes con miocardiopatía hipertrófica mediante análisis del consumo de oxígeno máximo.

INTRODUCTION AND OBJECTIVES: Differences between anatomical severity and clinical manifestations are frequent in patients with hypertrophic cardiomyopathy. Our objective was to assess functional capacity in a consecutive group of patients with hypertrophic cardiomyopathy measuring exercise aerobic parameters, as well as clinical and echocardiographic variables. PATIENTS AND METHOD: We studied 98 consecutive patients with hypertrophic cardiomyopathy. All patients underwent both echocardiographic and cardiopulmonary exercise testing. The control group consisted of 22 untrained persons. We studied exercise capacity by analyzing maximal oxygen consumption and aerobic functional capacity, among other variables. RESULTS: Patients with hypertrophic cardiomyopathy attained significantly lower maximal oxygen consumption values than controls (24.1 5.9 vs 36.4 5.9 ml/kg/min; p = 0.0001). Maximal aerobic capacity was significantly different among patients with NYHA functional capacity class I, II or III (78.9 13.5%; 71.9 14.7%; 63.9 15.7%; p = 0.009). However, considerable overlap was found between groups in maximal aerobic capacity. Functional impairment was greater in patients with left ventricular thickness > 20 mm, ejection fraction < 50%, left atrial dimension > 45 mm and pseudonormal or restrictive transmitral flow pattern. CONCLUSIONS: Patients with hypertrophic cardiomyopathy show significant functional impairment, which is difficult to detect from their clinical manifestations. Optimal assessment requires cardiopulmonary exercise testing.

Evaluación funcional de los pacientes con miocardiopatía hipertrófica mediante análisis del consumo de oxígeno máximo / Functional assessment of patients with hypertrophic cardiomyopathy by maximal oxygen consumption

Introducción y objetivos. En pacientes con miocardiopatía hipertrófica, frecuentemente encontramos discrepancias entre la gravedad de la afección anatómica y la expresión clínica. El objetivo de nuestro estudio fue evaluar la repercusión funcional de la enfermedad mediante el análisis de gases respirados, teniendo en cuenta variables clínicas y ecocardiográficas. Pacientes y método. Estudiamos de forma consecutiva a 98 pacientes con miocardiopatía hipertrófica. A todos ellos se les realizó un estudio ecocardiográfico y un estudio ergométrico con análisis de los gases respirados. El grupo control estaba formado por 22 sujetos sanos, no entrenados. Como parámetros ventilatorios se estudiaron, entre otros, el consumo de oxígeno máximo y la capacidad funcional aeróbica. Resultados. El consumo de oxígeno máximo alcanzado por los pacientes fue significativamente menor que el alcanzado por los controles (24,1 ñ 5,9 frente a 36,4 ñ 5,9 ml/kg/min; p = 0,0001). Al analizar los datos de la capacidad funcional aeróbica, encontramos diferencias significativas según el paciente tuviera un grado funcional I, II o III de la New York Heart Association (NYHA) (78,9 ñ 13,5 por ciento; 71,9 ñ 14,7 por ciento; 63,9 ñ 15,7 por ciento; p = 0,009). Sin embargo, fue notable la presencia de una importante superposición entre los grupos. Los subgrupos más afectados fueron los pacientes con hipertrofia superior a 20 mm, fracción de eyección 45 mm y los que presentaban un patrón de flujo mitral seudonormal o restrictivo. Conclusiones. Los pacientes con miocardiopatía hipertrófica presentan una importante limitación al ejercicio que difícilmente es valorable mediante la expresión clínica de la enfermedad. Una correcta valoración individual requiere el análisis del consumo de oxígeno máximo (AU)