Diagnosis of subclinical atherosclerosis in HIV-infected patients: higher accuracy of the D:A:D risk equation over Framingham and SCORE algorithms.

AIMS: While the detection of subclinical atherosclerosis may provide an opportunity for the prevention of cardiovascular disease (CVD), which currently is a leading cause of death in HIV-infected subjects, its diagnosis is a clinical challenge. We aimed to compare the agreement and diagnostic performance of Framingham, SCORE and D:A:D equations for the recognition of subclinical atherosclerosis in HIV patients and to adjust the D:A:D equation using HIV and CVD variables. METHODS AND RESULTS: Atherosclerosis was evaluated in 203 HIV-infected individuals by measuring the carotid intima-media thickness (IMT). The CVD risk was calculated using the Framingham, SCORE and D:A:D risk equations. Framingham, SCORE and D:A:D equations showed a low agreement with the IMT (Kappa: 0.219, 0.298, 0.244, respectively; p = 0.743) and a moderate predictive performance, (area under the curve [AUC] = 0.686, 0.665 and 0.716, respectively; p = 0.048), with the D:A:D equation being the most accurate. Atherosclerosis was demonstrated in a significant proportion of subjects with low predicted CVD risk by all three algorithms (16.3%, 17.2%, 17.2%, respectively; p = 0.743). In patients with an estimated low CVD risk atherosclerosis was associated with older age (p = 0.012) and low CD4 counts (p = 0.021). A model was developed to adjust the D:A:D equation; a significant increase in accuracy was obtained when CD4 counts and low-grade albuminuria were included (AUC = 0.772; p < 0.001). CONCLUSION: The D:A:D equation overperforms Framingham and SCORE in HIV patients. However, all three equations underestimate the presence of subclinical atherosclerosis in this population. The accuracy of the D:A:D equation improves when CD4 counts and low-grade albuminuria are incorporated into the equation.

Eplerenone enhances cardioprotective effects of standard heart failure therapy through matricellular proteins in hypertensive heart failure.

AIMS: The addition of an aldosterone receptor antagonist on top of current optimal therapy (based on angiotensin II inhibition) has demonstrated an important clinical benefit in heart failure patients with systolic dysfunction. Whether this finding also applies to heart failure patients with preserved systolic function is unknown. Therefore, we have studied the effect of adding eplerenone to standard pharmacological heart failure therapy (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and diuretic and ß-blocker) in the progression of heart failure in spontaneously hypertensive heart failure (SHHF) rats. METHODS AND RESULTS: Two-month-old SHHF rats were randomized to receive no treatment (SHHF group), a standard heart failure therapy (quinapril-torasemide-carvedilol; ST-SHHF group), or the combination of eplerenone and standard heart failure therapy (Eple+ST-SHHF group) for 20 months. Untreated SHHF was characterized by progressive left ventricular hypertrophy, fibrosis, and myocardial contractile and relaxation abnormalities, leading to pulmonary congestion. Despite similar blood pressure control, the addition of eplerenone to standard heart failure therapy further prevented left ventricular hypertrophy, contractile and relaxation alterations, and pulmonary congestion than standard heart failure therapy alone. ST-SHHF and Eple + ST-SHHF rats showed similar inhibition of structural extracellular matrix proteins collagen I, collagen III and fibronectin and metalloproteinase (MMP)-2, MMP-7, MMP-12, and MMP-13. However, only the coadministration of eplerenone with standard heart failure therapy normalized the expression of matricellular proteins thrombospondin 1, tenascin C, periostin, and secreted protein acidic rich in cysteine/osteonectin to values comparable to normotensive rats. CONCLUSION: In a hypertensive heart failure rat model, the addition of eplerenone to conventional heart failure therapy further improves cardiac structural and functional parameters, delaying the progression of heart failure. These beneficial effects of eplerenone were associated with normalization of matricellular protein expression.

Hipertensión por hiperaldosteronismo: más lesión cardiaca, mayor riesgo cardiovascular / Hypertension caused by primary hyperaldosteronism: increased heart damage and cardiovascular risk

Introducción y objetivos. El hiperaldosteronismo primario es la causa de hipertensión arterial secundaria más frecuente. Las concentraciones de aldosterona elevadas producen daño cardiaco y mayor morbimortalidad cardiovascular, por lo que un diagnóstico precoz modificará su evolución. El objetivo es estudiar las características clínicas, la repercusión cardiaca y el riesgo cardiovascular en el hiperaldosteronismo primario. Métodos. Se estudió a 157 pacientes con este diagnóstico. Se revisó el motivo del estudio y las exploraciones complementarias, ecocardiograma incluido. Como comparador se utilizó una cohorte de 720 pacientes con hipertensión arterial esencial seguida en nuestra unidad. Resultados. Los pacientes con hiperaldosteronismo eran más jóvenes que los hipertensos esenciales (56,9 ± 11,7 frente a 60 ± 14,4 años; p < 0,001) y tenían presiones arteriales previas al diagnóstico etiológico mayores (136 ± 20,6 frente a 156 ± 23,2 mmHg), más antecedentes de enfermedad cardiovascular precoz (el 25,5 frente al 2,2%; p < 0,001), mayor prevalencia de hipertrofia ventricular concéntrica (el 69 frente al 25,7%) y mayor riesgo cardiovascular. El tratamiento específico permitió el óptimo control de las presiones arteriales sistólica y diastólica (de 150,7 ± 23,0 y 86,15 ± 14,07 mmHg a 127,69 ± 15,3 y 76,34 ± 9,7 mmHg). Motivaron el estudio de hiperaldosteronismo: hipertensión resistente (33,1%), hipopotasemia (38,2%) y crisis hipertensivas (12,7%). Sólo el 4,6% de los pacientes llegaron remitidos desde atención primaria con diagnóstico de sospecha de hiperaldosteronismo. Conclusiones. Debe sospecharse hiperaldosteronismo en pacientes con hipertensión resistente, hipopotasemia o crisis hipertensivas. El diagnóstico de hiperaldosteronismo permite un mejor control de la presión arterial. La hipertrofia ventricular izquierda es la lesión de órgano diana más frecuente(AU)

Introduction and objectives. Primary hyperaldosteronism is the most common cause of secondary hypertension. Elevated aldosterone levels cause heart damage and increase cardiovascular morbidity and mortality. Early diagnosis could change the course of this entity. The objective of this report was to study the clinical characteristics, cardiac damage and cardiovascular risk associated with primary hyperaldosteronism. Methods. We studied 157 patients with this diagnosis. We analyzed the reason for etiological investigation, and the routinely performed tests, including echocardiography. We used a cohort of 720 essential hypertensive patients followed in our unit for comparison. Results. Compared with essential hypertensive patients, those with hyperaldosteronism were younger (56.9 [11.7] years vs 60 [14.4] years; P<.001), had higher blood pressure prior to the etiological diagnosis (136 [20.6] mmHg vs 156 [23.2] mmHg), more frequently had a family history of early cardiovascular disease (25.5% vs 2.2%; P<.001), and had a higher prevalence of concentric left ventricular hypertrophy (69% vs 25.7%) and higher cardiovascular risk. Specific treatment resulted in optimal control of systolic and diastolic blood pressures (from 150.7 [23.0] mmHg and 86.15 [14.07] mmHg to 12.69 [15.3] mmHg and 76.34 [9.7] mmHg, respectively). We suspected the presence of hyperaldosteronism because of resistant hypertension (33.1%), hypokalemia (38.2%), and hypertensive crises (12.7%). Only 4.6% of these patients had been referred from primary care with a suspected diagnosis of hyperaldosteronism. Conclusions. Hyperaldosteronism should be suspected in cases of resistant hypertension, hypokalemia and hypertensive crises. The diagnosis of hyperaldosteronism allows better blood pressure control. The most prevalent target organ damage is left ventricular hypertrophy(AU)

Hypertension caused by primary hyperaldosteronism: increased heart damage and cardiovascular risk.

INTRODUCTION AND OBJECTIVES: Primary hyperaldosteronism is the most common cause of secondary hypertension. Elevated aldosterone levels cause heart damage and increase cardiovascular morbidity and mortality. Early diagnosis could change the course of this entity. The objective of this report was to study the clinical characteristics, cardiac damage and cardiovascular risk associated with primary hyperaldosteronism. METHODS: We studied 157 patients with this diagnosis. We analyzed the reason for etiological investigation, and the routinely performed tests, including echocardiography. We used a cohort of 720 essential hypertensive patients followed in our unit for comparison. RESULTS: Compared with essential hypertensive patients, those with hyperaldosteronism were younger (56.9 [11.7] years vs 60 [14.4] years; P<.001), had higher blood pressure prior to the etiological diagnosis (136 [20.6] mmHg vs 156 [23.2] mmHg), more frequently had a family history of early cardiovascular disease (25.5% vs 2.2%; P<.001), and had a higher prevalence of concentric left ventricular hypertrophy (69% vs 25.7%) and higher cardiovascular risk. Specific treatment resulted in optimal control of systolic and diastolic blood pressures (from 150.7 [23.0] mmHg and 86.15 [14.07] mmHg to 12.69 [15.3] mmHg and 76.34 [9.7] mmHg, respectively). We suspected the presence of hyperaldosteronism because of resistant hypertension (33.1%), hypokalemia (38.2%), and hypertensive crises (12.7%). Only 4.6% of these patients had been referred from primary care with a suspected diagnosis of hyperaldosteronism. CONCLUSIONS: Hyperaldosteronism should be suspected in cases of resistant hypertension, hypokalemia and hypertensive crises. The diagnosis of hyperaldosteronism allows better blood pressure control. The most prevalent target organ damage is left ventricular hypertrophy.

Ezetimibe inhibits PMA-induced monocyte/macrophage differentiation by altering microRNA expression: a novel anti-atherosclerotic mechanism.

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol both in monotherapy or combined with a statin. However, its effect on atherosclerosis plaque progression is certainly unknown. MicroRNAs are short non-encoding RNA molecules dynamically implicated in monocytic differentiation which is considered an essential process during atherosclerosis development. The purpose of this study was to investigate the effect of ezetimibe on monocyte/macrophage differentiation as well as the implication of microRNAs (miRNAs) in this process. THP-1 differentiation with PMA became cells adherent to the plastic surface, and induced the expression of macrophage surface markers (CD11a, CD11b and ICAM-1) and miR-155, miR-222, miR-424 and miR-503. In the presence of ezetimibe, the adhesive capacity of THP-1 cells was decreased in a dose-dependent manner (P<0.05) and the expression of CD11a, CD11b and ICAM-1 was almost totally inhibited (P<0.05). The expression of miR-155, miR-222, miR-424 and miR-503 was reduced by 55%, 100%, 75% and 100%, respectively (P<0.05). Further mechanistic studies demonstrated that ezetimibe suppressed the PMA-induced phosphorylation of ERK/MAPK and inhibited the NF-κB activity, which are upstream signalling molecules in the differentiation process. In conclusion, ezetimibe inhibits PMA-induced THP-1 cell differentiation into macrophage-like cells in association with the inhibition of miRNA pathways. Our study suggests that inhibition of miRNAs might form a novel mechanism of anti-atherosclerotic effect of ezetimibe.

Factores clínicos y biomarcadores asociados a lesión vascular subclínica en la infección por el virus de la inmunodeficiencia humana / Clinical factors and biomarkers associated with subclinical atherosclerosis in the human immunodeficiency virus infection

Fundamento y objetivos: Los pacientes con VIH presentan aterosclerosis acelerada y la enfermedad cardiovascular es una de las principales causas de mortalidad de estos pacientes. Nuestro objetivo fue identificar biomarcadores y factores clínicos relacionados con la aterosclerosis carotídea en pacientes con VIH. Pacientes y método: Estudio transversal en pacientes con VIH. Se determinó el grosor íntima-media carotídeo (GIMc) y diferentes biomarcadores séricos en 235 sujetos. Los pacientes con GIMc≥p75 y/o placa fueron diagnosticados de enfermedad vascular subclínica (EVS). Resultados: Edad 46 (11) años. El GIMc medio fue 0,58 (0,13)mm. Sesenta y cinco (27,8%) pacientes presentaron EVS. En comparación con los pacientes sin EVS, estos mostraron mayor frecuencia de lipodistrofia (OR:2,7; IC95%:1,4-4,9) e inmunodepresión (OR:2,5; IC95%:1,1-5,8), mayor tiempo de diagnóstico del VIH (≥p50 [10 años], OR:1,4; IC95%:1,1-2,9), exposición a análogos de nucleósidos (≥p50 [132 meses], OR:3,2; IC95%:1,7-6) e inhibidores de proteasa (≥p50 [24 meses], OR:2,2; IC95%:1,1-3,6). Mostraron mayores niveles de diferentes biomarcadores séricos, destacando el NT-proBNP (≥p75 [72,6pg/ml], OR:2,0; IC95%:1,0-4,1) y el cociente albúmina/creatinina en orina (≥p50 [5mg/g], OR:3,8; IC95%:1,3-11). Tras el análisis multivariado, la EVS se relacionó con la edad (≥p50 [46 años], (OR:6,6; IC95%: 2,2-19,5; p=0,001), el tiempo de diagnóstico del VIH (≥p50 [10 años], OR:3,1; IC95%:1,0-11,0; p=0,044) y la inmunodepresión (OR:2,8, IC95%:1-8,3; p=0,048). Conclusiones: En pacientes con VIH, la edad, el tiempo de evolución de la infección y la inmunodepresión se relacionan independientemente con la EVS. Los pacientes con EVS presentaron niveles aumentados de biomarcadores de daño vascular, destacando el cociente albúmina/creatinina en orina y el NT-proBNP (AU)

Background and objective: HIV-infected patients present accelerated cardiovascular disease (CVD) and CVD is among the most important causes of mortality in this population. We aimed to identify biomarkers and clinical factors associated with subclinical atherosclerosis in HIV-infected patients. Patients and methods: Carotid intima-media thickness (cIMT) and cardiovascular biomarkers were measured in 235 HIV-infected patients. Individuals with a cIMT≥75th percentile or plaque were classified as having subclinical atherosclerosis and compared with patients without subclinical atherosclerosis. Results: Age was 46 (11) years old. Mean cIMT was 0.58 (0.13)mm. Sixty-five (27.8%) patients had subclinical atherosclerosis. These subjects had more frequently lipodystrophy (OR:2.7; CI95%:1.4-4.9), immunosuppression (OR:2.5; CI95%:1.1-5.8), longer time to HIV diagnosis (≥p50 [10 years], OR:1.4; CI95%:1.1-2.9), longer exposure to nucleoside analogues (≥p50 [132 months], OR:3.2; CI95%:1.7-6) and to protease inhibitors (≥p50 [24 months], OR:2.2; CI95%:1.1-3.6). They also showed higher levels of several biomarkers such as NT-proBNP (≥p75 [72.6pg/ml], OR:2.0; CI95%:1-4.1) and albumin/creatinine urine ratio (≥p50 [5mg/g], OR:3.8; CI95%:1.3-11). After the multivariate analysis, subclinical atherosclerosis was associated with age (OR:6.6; CI95%:2.2-19.5; P=.001), a longer time to HIV diagnosis (OR:3.1; CI95%:1.0-11.0; P=.044) and immunosuppression (OR:2.8; CI95%:1-8.3; P=.048).Conclusions: Among HIV-infected patients, time to HIV diagnosis and immunosuppression were independently associated with subclinical atherosclerosis. Patients with subclinical atherosclerosis showed increased levels of vascular damage biomarkers, especially albumin/creatinine urine ratio and NT-proBNP (AU)

Circulating endothelial progenitor cells are reduced in rat oxygen-induced retinopathy despite a retinal SDF-1/CXCR4 and VEGF proangiogenic response.

AIMS: The purpose of this study is to investigate circulating endothelial progenitor cells (EPCs) and the signaling pathways involved in their recruitment in the ischemic retina of the 50/10 rat model of oxygen-induced retinopathy (OIR). MAIN METHODS: Within 12h after birth, litters of Sprague-Dawley rats and their mothers were exposed to alternating oxygen concentrations, followed by a room air exposition, to induce OIR. Retinopathy was quantified by ADPase stain in flat-mounted retinas and pre-ILM nuclei count in retinal sections. Semiquantitative real-time PCR and immunofluorescence were assessed in retinas to study stromal cell-derived factor 1 (SDF-1), its receptor CXCR4 and vascular endothelial growth factor (VEGF) expression. Circulating EPCs were evaluated by flow cytometry in peripheral blood. KEY FINDINGS: Our results showed increased immunolabelling of SDF-1 in endothelial cells and strong expression of CXCR4 in Müller cells in OIR retinas as compared to control retinas. We found increased levels of CXCR4 and VEGF mRNA in OIR retinas, especially during the vascular attenuation stage. The number of circulating EPCs was decreased in OIR rats as compared to control rats. SIGNIFICANCE: The decrease in circulating EPCs could be implied in vessel growth arrest during normal retinal development in OIR rats, while pro-angionenic signals released by Müller cells in the hypoxic retina could drive pathological neovascularization in the ischemic retina. These data warrant further studies to investigate new therapeutic approaches for ROP.

Association of HIV-Infection and antiretroviral therapy with levels of endothelial progenitor cells and subclinical atherosclerosis.

BACKGROUND: Although in the general population circulating vascular progenitor cell levels have been implicated in the homeostasis of the vascular wall through differentiation into endothelium and/or smooth muscle cells, it has not yet been assessed in HIV-infected patients. We herein investigated the number of progenitor cell subpopulations in HIV-infected patients and its relationship to carotid intima-media thickness (c-IMT). METHODS: Blood samples were collected from 200 HIV-infected patients and CD34/KDR, CD34/VE-cadherin, and CD14/Endoglin progenitor cells were identified by flow cytometry. c-IMT was determined by ultrasonography. A group of 27 healthy subjects was used as control group. RESULTS: In our population (20 ART-naive patients and 180 treated patients), traditional cardiovascular risk factors were not found predictive of vascular progenitor cell levels. However, antiretroviral therapy (ART)-treatment was identified as the main predictive value for low CD34/KDR cells and high CD14/Endoglin cells after adjustment by cardiovascular risk factors (age, sex, hypertension, diabetes, and hyperlipidaemia) and HIV-related characteristics (HIV duration and ART treatment). Low levels of circulating CD34/KDR or CD34/VE-cadherin endothelial progenitor cells tended to be associated with increased c-IMT. However, a positive association was found between CD14/Endoglin cells and c-IMT. Low number of CD34/KDR cells was also associated with the longest exposure to nucleoside reverse transcriptase inhibitors and/or protease inhibitors. CONCLUSIONS: ART exposure is the main predictor of circulating vascular progenitor cell levels. However, their levels are only partially associated with high c-IMT in HIV-infected patients. ART has already been found to have proatherogenic effect, but our data first describe its relationship with vascular progenitor cells and c-IMT.

[Clinical factors and biomarkers associated with subclinical atherosclerosis in the human immunodeficiency virus infection]. / Factores clínicos y biomarcadores asociados a lesión vascular subclínica en la infección por el virus de la inmunodeficiencia humana.

BACKGROUND AND OBJECTIVE: HIV-infected patients present accelerated cardiovascular disease (CVD) and CVD is among the most important causes of mortality in this population. We aimed to identify biomarkers and clinical factors associated with subclinical atherosclerosis in HIV-infected patients. PATIENTS AND METHODS: Carotid intima-media thickness (cIMT) and cardiovascular biomarkers were measured in 235 HIV-infected patients. Individuals with a cIMT ≥ 75th percentile or plaque were classified as having subclinical atherosclerosis and compared with patients without subclinical atherosclerosis. RESULTS: Age was 46 (11) years old. Mean cIMT was 0.58 (0.13)mm. Sixty-five (27.8%) patients had subclinical atherosclerosis. These subjects had more frequently lipodystrophy (OR:2.7; CI95%:1.4-4.9), immunosuppression (OR:2.5; CI95%:1.1-5.8), longer time to HIV diagnosis (≥ p50 [10 years], OR:1.4; CI95%:1.1-2.9), longer exposure to nucleoside analogues (≥ p50 [132 months], OR:3.2; CI95%:1.7-6) and to protease inhibitors (≥ p50 [24 months], OR:2.2; CI95%:1.1-3.6). They also showed higher levels of several biomarkers such as NT-proBNP (≥ p75 [72.6 pg/ml], OR:2.0; CI95%:1-4.1) and albumin/creatinine urine ratio (≥ p50 [5mg/g], OR:3.8; CI95%:1.3-11). After the multivariate analysis, subclinical atherosclerosis was associated with age (OR:6.6; CI95%:2.2-19.5; P=.001), a longer time to HIV diagnosis (OR:3.1; CI95%:1.0-11.0; P=.044) and immunosuppression (OR:2.8; CI95%:1-8.3; P=.048). CONCLUSIONS: Among HIV-infected patients, time to HIV diagnosis and immunosuppression were independently associated with subclinical atherosclerosis. Patients with subclinical atherosclerosis showed increased levels of vascular damage biomarkers, especially albumin/creatinine urine ratio and NT-proBNP.

Incipient renal impairment as a predictor of subclinical atherosclerosis in HIV-infected patients.

INTRODUCTION: HIV-infected patients present increased incidence of cardiovascular disease (CVD). Although incipient kidney function impairment has been associated with CVD in the general population, this association has not been properly addressed in HIV-infected patients. We assessed the relationship between incipient renal impairment (IRI) and subclinical atherosclerosis in HIV-infected patients. METHODS: Estimated glomerular filtration rate (eGFR), carotid intima-media thickness (cIMT), and cardiovascular biomarkers were measured in 145 HIV-infected patients. IRI was defined as a composite variable: eGFR <90 mL/min, rate of eGFR decrease >3% annually over a period of 3 years, and albumin/creatinine urine ratio above the median (≥5 mg/g). Individuals with a cIMT ≥75th percentile or plaque were classified as having subclinical atherosclerosis. RESULTS: Ninety-five patients (64.1%) met the criteria for IRI. As for HIV-related factors, patients with IRI more frequently had lipodystrophy (41.3% vs. 21.6%; P = 0.017), a lower CD4 lymphocyte nadir [210 (125-343) vs. 302 (178-408) cells/mL; P = 0.046], and longer exposure to nucleoside reverse transcriptase inhibitors [187 (84-259) vs. 104 (34-170) months; P = 0.001], to nonnucleoside reverse transcriptase inhibitors [32 (7-77) vs. 20 0-40) months; P = 0.043], and to protease inhibitors [42 (0-115] vs. 2.5 (0-59) months; P = 0.007]. Patients with IRI more frequently had subclinical atherosclerosis (40.7% vs. 13.7%; odds ratio: 4.3; 95% confidence interval: 1.8 to 10.6; P = 0.001), even after adjustment for cardiovascular and HIV-related parameters (odds ratio: 3.8; 95% confidence interval: 1.3 to 11; P = 0.012). CONCLUSIONS: The presence of IRI is an independent predictor of increased cIMT in HIV-infected patients and may help to identify patients with subclinical atherosclerosis and, therefore, increased risk of CVD.

Ezetimibe inhibe la adhesión y la migración de monocitos a través de la ruta de las proteincinasas activadas extracelularmente (p44/p42 ERK1/2 / Ezetimibe suppresses adhesion and chemotaxis of human monocytes through the p44/p42ERK1/2-dependent pathway

Introducción Recientemente nuestro grupo ha demostrado que ezetimibe, un inhibidor específico de la absorción intestinal, es capaz de inhibir la inflamación vascular en un modelo de arteriosclerosis en conejo. Nuestro objetivo ha sido investigar el efecto de ezetimibe sobre la adhesión y la migración de monocitos humanos THP-1, así como la participación de la vía de señalización de las proteincinasas activadas extracelularmente (p44/p42ERK1/2) sobre el efecto observado. Material y métodos La adhesión se valoró como la capacidad de las células THP-1 para unirse a placas de cultivo, y la migración se determinó con el empleo de cámaras de quimiotaxis. La expresión de moléculas de adhesión se cuantificó mediante citometría de flujo, y la activación de p44/p42ERK1/2 se estudió mediante Western Blot. Resultados La adhesión y la migración de los monocitos THP-1 inducidas con PMA o MCP-1, respectivamente, se inhibió de forma dependiente de la dosis al preincubar las células con ezetimibe. Además, el tratamiento con ezetimibe inhibió la expresión de las integrinas CD11a y CD11b, así como la fosforilación de p44/p42ERK1/2 (la forma activa) inducida por MCP-1. Más del 90% de las células (evaluadas mediante azul tripán) eran viables tras 1 ó 2 días de exposición a ezetimibe. Conclusiones Nuestros resultados indican que ezetimibe, además de su actividad hipolipemiante, puede inhibir el proceso de adhesión y migración de los monocitos. Parece que el bloqueo de la ruta de señalización de las MAPK p44/p42ERK1/2 podría estar implicado en el efecto observado (AU)

Introduction: Recently, our group has demonstrated that ezetimibe, a specific inhibitor of intestinal absorption, is able to inhibit vascular inflammation in a rabbit model of atherosclerosis. In this study, we investigated the effect of ezetimibe on the adhesion and migration of human THP-1 monocytes in vitro. We also studied the involvement of the MAP kinase signaling pathway,p44/p42ERK1/2, as a potential mechanism responsible for the observed effect. Material and methods: Adhesion of THP-1 monocytes was measured as the ability of cells tobind to plates. Migration was studied using two-compartment chambers. The expression of adhesion molecules was assessed by flow cytometry. Activation of p44/p42ERK1/2 was measured by Western Blot. Results: Preincubation of THP-1 monocytes with ezetimibe prevented PMA-induced adhesion and MCP-1-induced migration in a dose-dependent manner. Preincubation of THP-1 monocytes with ezetimibe also inhibited the expression of the integrins CD11a and CD11b, as well asphosphorylation of p-p44/p42ERK1/2 (the active form) induced by MCP-1. More than 90% of cells(evaluated through trypan blue) were viable 1 or 2 days after exposure to ezetimibe. Conclusions: Our results indicate that, in addition to its lipid lowering activity, ezetimibe isable to inhibit the process of adhesion and migration of monocytes in vitro. Blocking of thep44/p42ERK1/2 MAPK signalling pathway seems to play a role in this anti-inflammatory effect (AU)

Management of resistant arterial hypertension: role of spironolactone versus double blockade of the renin-angiotensin-aldosterone system.

BACKGROUND: Currently there is no consensus regarding which add-on therapy to use in resistant hypertension. This study was designed to compare two treatment options, spironolactone (SPR) versus dual blockade of the renin-angiotensin-aldosterone system (RAAS). METHODS: Forty-two patients with true resistant hypertension were included in the study. An open-label prospective crossover design was used to add a second RAAS blocker to previous treatment and then SPR following 1 month of wash-out. BP was measured in the office and by ambulatory blood pressure monitoring (ABPM). Changes in laboratory tests were also studied for both treatments. The predictive values of aldosterone-renin ratio (ARR) and serum potassium of determining the antihypertensive response were analyzed for both arms. RESULTS: Following the first stage of dual blockade, SBP dropped significantly both in office (reduction of 12.9 ± 19.2 mmHg)) and by ABPM (reduction of 7.1 ± 13.4 mmHg). Office DBP was unchanged but was significantly reduced as measured by ABPM (3.4 ± 6.2 mmHg). On SPR treatment, office BP was reduced 32.2 ± 20.6/10.9 ± 11.6 mmHg. By ABPM the reduction was 20.8 ± 14.6/8.8 ± 7.3 mmHg (P < 0.001). The BP control was achieved by 25.6% of patients in dual blockade and 53.8% in SPR with office blood pressure. By ABPM, 20.5% were controlled on dual blockade and up to 56.4% with SPR. Serum potassium was a weak inverse predictor of the blood pressure-lowering effect of SPR. CONCLUSION: SPR has a greater antihypertensive effect than dual blockade of the RAAS in resistant hypertension. SPR at daily doses of 25-50 mg shows a potent antihypertensive effect when added to prior regimes of single RAAS axis blockade in patients with resistant arterial hypertension.

Rosuvastatin added to standard heart failure therapy improves cardiac remodelling in heart failure rats with preserved ejection fraction.

AIMS: Although statins may provide potential therapeutic pathways for patients with heart failure with preserved ejection fraction (HFpEF), no studies have evaluated statins in combination with standard HF therapy, which would reflect clinical practice more closely. To address this question, we evaluated whether rosuvastatin added to a standard HF therapy provides additional improvement in cardiac structure and function in rats with hypertensive heart failure (SHHF). METHODS AND RESULTS: Two-month-old SHHF rats were randomly assigned to four groups: (i) non-treated SHHF rats; (ii) rosuvastatin-treated SHHF rats; (iii) SHHF rats treated with quinapril plus torasemide plus carvedilol (considered as standard HF therapy); and (iv) SHHF rats treated with the combination of standard HF therapy and rosuvastatin. The administration of a standard anti-hypertensive HF therapy to SHHF rats for 17 months attenuated left ventricular (LV) chamber dilatation, cardiac hypertrophy, fibrosis, and inflammation compared with non-treated SHHF rats. Rosuvastatin alone prevented LV dilatation and cardiac inflammation similar to standard HF therapy-treated SHHF, despite being unable to normalize blood pressure (BP) or influence cardiac hypertrophy. However, and importantly, the addition of rosuvastatin to the standard HF therapy further prevented LV dilatation, preserved cardiac function, and normalized inflammation. CONCLUSION: These data show that the use of rosuvastatin plus a standard HF therapy results in a significant additional improvement in HF and cardiac remodelling in a rat model of HFpEF. These beneficial effects were independent of BP and plasma lipid changes, and seem to be due, at least in part, to decreased myocardial inflammation.

Local non-esterified fatty acids correlate with inflammation in atheroma plaques of patients with type 2 diabetes.

OBJECTIVE: Atherosclerosis is prevalent in diabetic patients, but there is little information on the localization of nonesterified fatty acids (NEFAs) within the plaque and their relationship with inflammation. We sought to characterize the NEFA composition and location in human diabetic atheroma plaques by metabolomic analysis and imaging and to address their relationship with inflammation activity. RESEARCH DESIGN AND METHODS: Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used for metabolomic analysis imaging of frozen carotid atheroma plaques. Carotid endarterectomy specimens were used for conventional immunohistochemistry, laser-capture microdissection quantitative PCR, and in situ Southwestern hybridization. Biological actions of linoleic acid were studied in cultured vascular smooth muscle cells (VSMCs). RESULTS: TOF-SIMS imaging evidenced a significant increase in the quantity of several NEFA in diabetic versus nondiabetic atheroma plaques. Higher levels of NEFA were also found in diabetic sera. The presence of LPL mRNA in NEFA-rich areas of the atheroma plaque, as well as the lack of correlation between serum and plaque NEFA, suggests a local origin for plaque NEFA. The pattern of distribution of plaque NEFA is similar to that of MCP-1, LPL, and activated NF-kappaB. Diabetic endarterectomy specimens showed higher numbers of infiltrating macrophages and T-lymphocytes-a finding that associated with higher NEFA levels. Finally, linoleic acid activates NF-kappaB and upregulates NF-kappaB-mediated LPL and MCP-1 expression in cultured VSMC. DISCUSSION: There is an increased presence of NEFA in diabetic plaque neointima. NEFA levels are higher in diabetic atheroma plaques than in nondiabetic subjects. We hypothesize that NEFA may be produced locally and contribute to local inflammation.

Influence of metabolic syndrome on risk stratification in hypertensive patients: differences between 2003 and 2007 ESH-ESC guidelines.

OBJECTIVE: To investigate the influence of metabolic syndrome (MS) on risk stratification and ulterior classification in hypertensive patients at entry into a hypertension unit by comparing the criteria of ESH-ESC 2003 and 2007 guidelines. METHODS: 720 consecutive patients attending a hospital-located hypertension unit were included in the study. They were classified with or without MS according to the ATP-III 2005 report. Patients underwent repeated office BP measurements and routine blood/urine examinations. In addition ultrasensitive CRP (uCRP), echocardiogram, fasting insulin, urinary albumin excretion were determined and HOMA index was calculated. RESULTS: The prevalence of MS was 58.8 %. Abdominal obesity and fasting glucose were the most prevalent components of MS, and HDL-cholesterol the least prevalent. MS group had higher levels of LDL-cholesterol and higher prevalence of left ventricular hypertrophy and microalbuminuria. Patients with MS also presented a significant elevation in uCRP, fasting insulin and HOMA. BP was controlled in 55.6%. When we applied the 2003 guideline, 48.9% patients showed a high or very high added cardiovascular risk. With the applications of the 2007 guide the prevalence of this two categories reach 73.9%. CONCLUSIONS: A significant difference in the risk pattern distribution is found when MS is considered in risk stratification in our hypertensive population. The accompanying increase in the levels of other cardiovascular risk factors and in the prevalence of target organ damage justifies the global intervention on cardiovascular risk recommended by 2007 ESH-ESC guidelines.

A prospective study of the management of non-massive pulmonary embolism in the home.

BACKGROUND: The objective of this study is to compare the characteristics, outcomes, and clinical complications of patients with pulmonary embolism (PE) who were treated at home as outpatients versus traditional hospitalization. METHODS: Prospective study from January 2006 to June 2007. Selected patients diagnosed at the Emergency Department with stable non-massive pulmonary embolism that met standard inclusion criteria of Hospital at Home (HH) were treated at home. Patients that did not meet these criteria were admitted to Conventional Hospitalization (CH). Major and minor bleeding, re-thrombosis, clinical course, unexpected returns to hospital, and need for hospital re-admission in the following 3 months were recorded. RESULTS: 61 patients with PE were included (30 HH and 31 CH). Mean age 66.8 and 66.7 years in HH and CH, respectively. A history of neoplasm was found to be present in 13.3% and 9.7% of HH and CH patients. In the CH group, 19.3% of patients had prior thromboembolic disease. Concomitant DVT was seen in 40% and 29% of HH and CH patient. Pulmonary embolism was bilateral in 30% and 38.7% of HH and CH patients. No major bleeding, re-thrombosis, or death occurred. The home treatment was successfully completed in 100% of the patients. Three patients in the CH group had hospital-acquired infections. CONCLUSIONS: Patients with stable non-massive pulmonary embolism may be safely treated under conditions of home hospitalization.

Prevalencia, distribución y variabilidad geográfica de los principales factores de riesgo cardiovascular en España. Análisis agrupado de datos individuales de estudios epidemiológicos poblacionales: estudio ERICE / Prevalence, geographic distribution and geographic variability of major cardiovascular risk factors in Spain. Pooled analysis of data from population-based epidemiological studies: the ERICE study

Introducción y objetivos. La insuficiencia cardiaca congestiva (ICC) tiene elevadas incidencia, morbilidad y mortalidad y una gran prevalencia. Sin embargo, no hay datos directos sobre este aspecto en nuestro país. El objetivo de nuestro estudio es evaluar la prevalencia de ICC en España. Métodos. Se diseñó un estudio poblacional en el que participaron 15 centros repartidos por toda España. Se seleccionó de forma aleatoria una muestra de la población de 45 o más años de edad atendida en cada área de salud, que fue estudiada por sus médicos de atención primaria. Se utilizaron los criterios de Framingham para el diagnóstico. Las personas con criterios de ICC fueron remitidas a una consulta de cardiología para confirmación diagnóstica y realización de ecocardiograma. Resultados. Se evaluó a 1.776 personas, con una media ± desviación estándar (intervalo) de edad de 64 ± 12 (45-100) años; eran varones el 44%. Se remitió a cardiología a 242 pacientes. La prevalencia ponderada de ICC fue del 6,8% (intervalo de confianza [IC] del 95%, 4%-8,7%). La prevalencia fue similar en varones (6,5%; IC del 95%, 4,7%-8,4%) y en mujeres (7%; IC del 95%, 4,4%-9,6%). Por edades, la prevalencia fue del 1,3% (0,4%-2,1%) entre los 45 y 54 años; el 5,5% (2,4%-8,5%) entre 55 y 64 años; el 8% (4,2%-11,8%) entre 65 y 74 años, y el 16,1% (11%-21,1%) en personas de 75 o más años. Conclusiones. La prevalencia de ICC en España es alta, en torno a un 7-8%. La prevalencia es similar en varones y mujeres, y parece aumentar con la edad (AU)

Introduction and objectives. Congestive heart failure is associated with substantial morbidity and mortality and both its incidence and prevalence are high. Nevertheless, comprehensive data on this condition in Spain are lacking. The aim of this study was to determine the prevalence of congestive heart failure in Spain. Methods. A demographic study which involved the participation of 15 healthcare centers throughout Spain was carried out. In each health area, a random sample was taken of the population aged 45 years or more. These individuals were examined by their primary care physicians, who made their diagnoses using Framingham criteria. Individuals who satisfied criteria for congestive heart failure were referred to a cardiologist for confirmation of the diagnosis and for echocardiography. Results. Overall, 1776 individuals were evaluated. Their mean age was 64±12 years (range, 45-100 years) and 44% were male. Of these, 242 were referred to a cardiologist. The weighted prevalence of congestive heart failure was 6.8% (95% confidence interval [CI] 4-8.7). The prevalence was similar in men (6.5%, 95% CI 4.7-8.4) and women (7%, 95% CI 4.4-9.6). When analyzed by age, the prevalence was 1.3% (0.4%-2.1%) in those aged 45-54 years, 5.5% (2.4%-8.5%) in those aged 55-64 years, 8% (4.2%-11.8%) in those aged 65-74 years, and 16.1% (11%-21.1%) in those aged over 74 years. Conclusions. Prevalence of congestive heart failure in Spain is high, at about 7%-8%. The prevalence was similar in males and females, and appeared to increase with age (AU)

Prevalence, geographic distribution and geographic variability of major cardiovascular risk factors in Spain. Pooled analysis of data from population-based epidemiological studies: the ERICE Study.

INTRODUCTION AND OBJECTIVES: To determine the prevalence and geographic distribution of major cardiovascular risk factors in the Spanish population. To investigate whether geographic variability exists. METHODS: Data were pooled from eight cross-sectional epidemiologic studies carried out in Spain between 1992 and 2001 whose methodological quality satisfied predefined criteria. Individual data were reassessed and analyzed by age group (20-44 years, 45-64 years, and 365 years), sex and geographic area. The study population included 19,729 individuals. Mean values and unadjusted and adjusted prevalence rates were derived for various risk factors. RESULTS: The most common cardiovascular risk factors in the Spanish population were, in descending order: hypercholesterolemia (i.e., total cholesterol >200 mg/dL) in 46.7%, hypertension in 37.6%, smoking in 32.2%, obesity in 22.8%, and diabetes mellitus in 6.2%. The mean values for blood pressure, body mass index, high-density lipoprotein cholesterol and glycemia varied considerably with age, sex and geographic area. The highest levels of cardiovascular risk factors were observed in Mediterranean and south-eastern areas of the country and the lowest, in northern and central areas. CONCLUSIONS: The prevalence of major cardiovascular risk factors in Spain was high. Their distribution varied considerably with geographic area.

Apoptosis in the trabecular meshwork of glaucomatous patients.

We established and validated an in toto method to perform TdT-mediated dUTP nick end labeling to study apoptosis in human trabecular meshwork tissue obtained during trabeculectomy in glaucoma patients. In specimens from patients with primary open-angle glaucoma and primary angle-closure glaucoma, we detected a tendency for more apoptotic cells to accumulate in patients with primary open-angle glaucoma. The utility of this method to study apoptosis in the trabecular meshwork is discussed, as well as its application as a tool in biologic samples.