La combinación de atorvastatina y meloxicam inhibe la neuroinflamación y atenúa el daño celular en la isquemia cerebral experimental por embolia arterial / Atorvastatin-meloxicam association inhibits neuroinflammation and attenuates the cellular damage in cerebral ischemia by arterial embolism.

Introducción. El accidente cerebrovascular es la segunda causa de muerte y la primera de discapacidad en el mundo, y más de 85 % es de origen isquémico. Objetivo. Evaluar en un modelo de infarto cerebral por embolia arterial el efecto de la atorvastatina y el meloxicam, administrados por separado y de forma conjunta, sobre la respuesta neuronal, los astrocitos y la microglia. Materiales y métodos. Se sometieron ratas Wistar a embolia de la arteria carótida y a tratamiento con meloxicam y atorvastatina, administrados por separado y conjuntamente, a las 6, 24, 48 y 72 horas. Se evaluó la reacción de las proteínas COX-2, GFAP y OX-42 en las neuronas, los astrocitos y la microglia mediante inmunohistoquímica y estudios morfológicos y de densitometría. Los datos obtenidos se evaluaron por medio de un análisis de varianza y de pruebas no paramétricas de comparación múltiple. Resultados. La isquemia cerebral por embolia arterial incrementó significativamente (p<0,001) la reacción de los astrocitos y la microglia, en tanto que la atorvastatina y el meloxicam, administrados por separado y de forma conjunta, la redujeron. La isquemia produjo acortamiento de las proyecciones de los astrocitos, engrosamiento celular, ruptura de las expansiones protoplásmicas (clasmatodendrosis) y cambios morfológicos en la microglia propios de diversas etapas de actividad. En las zonas circundantes del foco se incrementó la reacción inmunológica de la COX-2 y se redujo en el foco isquémico, en tanto que el meloxicam y la atorvastatina redujeron significativamente (p<0,001) la reacción inmunológica en la zona circundante del foco, restableciendo la marcación de la ciclooxigenasa en el foco isquémico. Conclusión. La combinación de meloxicam y atorvastatina atenúa la respuesta de los astrocitos y la microglia en el proceso inflamatorio posterior a la isquemia cerebral por embolia arterial, reduciendo la degeneración neuronal y restableciendo el equilibrio morfológico y funcional del tejido nervioso.

Introduction: Stroke is the second leading cause of death and the first cause of disability in the world, with more than 85% of the cases having ischemic origin. Objective: To evaluate in an embolism model of stroke the effect of atorvastatin and meloxicam on neurons, astrocytes and microglia. This evaluation was done administering each medication individually and in association. Materials and methods: Wistar rats were subjected to carotid arterial embolism and treatment with meloxicam and atorvastatin at 6, 24, 48 and 72 hours. Using immunohistochemistry, we evaluated the immunoreactivity of COX-2 protein, GFAP and OX-42 in neurons, astrocytes and microglia by densitometric and morphological studies. Data were evaluated by variance analysis and non-parametric multiple comparison. Results: Cerebral ischemia by arterial embolism increased significantly the reactivity of microglia and astrocytes (p<0.001), whereas it was reduced by atorvastatin, meloxicam and their association. Ischemia produced astrocytic shortening, cellular thickening, protoplasmic rupture expansions (clasmatodendrosis) and microglial morphological changes characteristic of various activity stages. In perifocal areas, immunoreactivity of COX-2 was increased and in the ischemic focus it was reduced, while meloxicam and atorvastatin significantly reduced (p<0.001) perifocal immunoreactivity, restoring the marking of cyclooxygenase in the ischemic focus. Conclusion: These results suggest that the meloxicam-atorvastatin association attenuates astrocytic and microglial response in the inflammatory process after cerebral ischemia by arterial embolism, reducing neurodegeneration and restoring the morphological and functional balance of nervous tissue .

The modified 2VO ischemia protocol causes cognitive impairment similar to that induced by the standard method, but with a better survival rate

Permanent bilateral occlusion of the common carotid arteries (2VO) in the rat has been established as a valid experimental model to investigate the effects of chronic cerebral hypoperfusion on cognitive function and neurodegenerative processes. Our aim was to compare the cognitive and morphological outcomes following the standard 2VO procedure, in which there is concomitant artery ligation, with those of a modified protocol, with a 1-week interval between artery occlusions to avoid an abrupt reduction of cerebral blood flow, as assessed by animal performance in the water maze and damage extension to the hippocampus and striatum. Male Wistar rats (N = 47) aged 3 months were subjected to chronic hypoperfusion by permanent bilateral ligation of the common carotid arteries using either the standard or the modified protocol, with the right carotid being the first to be occluded. Three months after the surgical procedure, rat performance in the water maze was assessed to investigate long-term effects on spatial learning and memory and their brains were processed in order to estimate hippocampal volume and striatal area. Both groups of hypoperfused rats showed deficits in reference (F(8,172) = 7.0951, P < 0.00001) and working spatial memory [2nd (F(2,44) = 7.6884, P < 0.001), 3rd (F(2,44) = 21.481, P < 0.00001) and 4th trials (F(2,44) = 28.620, P < 0.0001)]; however, no evidence of tissue atrophy was found in the brain structures studied. Despite similar behavioral and morphological outcomes, the rats submitted to the modified protocol showed a significant increase in survival rate, during the 3 months of the experiment (P < 0.02).

Estudio con ultrasonido doppler color en la caracterización de la enfermedad aterosclerotica carotidea oclusiva sintomática / Study with color doppler ultrasound in the characterization of symptomatic carotid atherosclerotic occlusive disease

Objective: To determine the association between risk factors and atherosclerosis in the carotid arteries in occlusive cerebrovascular disease. Method: A prospective, descriptive, cross-sectional study in 274 patients with clinical and CT diagnosis ofischemic ictus was conducted. Examination by the means of carotid artery color Doppler ultrasound was performed in the study Group. Results and Conclusions: The mean age of patients was 68.7 years anda male predominance (54.1 percent) was reported. Arterial hypertension, which was present in 214 patients (78.1 percent), constituted the most prevalent atherogenic risk factor, followed by age over 60 years (75.9 percent), and smoking (58 percent). The atherothrombotic and cardioembolic origins were predominant (54 percent and 19.7 percent, respectively), followed by lacunar (13.9 percent), and undetermined origin (11.3 percent). Atherosclerotic involvement occurs bilaterally with a predominance of the right axis, appearing low shear stress areas as the sites of the greatest severity.

Objetivo: Determinar la asociación entre los factores de riesgos y la aterosclerosis de las arterias carótidas, en la enfermedad cerebrovascular oclusiva. Método: Se realizó un estudio prospectivo, descriptivo y transversal en 274 pacientes con diagnóstico clínico y tomográfico de ictus isquémico, realizándoles estudio con ultrasonido Doppler color carotídeo. Resultados y Conclusiones: La edad media de los pacientes fue 68,7años. Se observó predominio de sexo masculino (54,1 por ciento). EI factor de riesgo aterogénico que predominó fue HTA, presente en 214 (78.1 por ciento), seguido por edad mayor de 60 (75.9 por ciento) y tabaquismo (58 por ciento). El origen aterotrombótico y cardioembólico fueron predominantes (54 y 19.7 por ciento respectivamente), seguidos por el lacunar (13.9 por ciento) y el origen indeterminado (11.3 por ciento). La afectación aterosclerótica ocurre bilateralmente, con un predominio del eje derecho, siendo las zonas de bajo shear stress los sectores de mayor severidad.

Association of Blood Pressure Levels with Carotid Intima-Media Thickness and Plaques / 예방의학회지

OBJECTIVES: The aim of this study was to investigate the association of blood pressure levels with the common carotid artery intima-media thickness (CCA-IMT) and carotid plaques. METHODS: Data were obtained from 2,635 subjects, aged 50 years and over, who participated in the Community Health Survey (a population-based, cross-sectional study) in Dong-gu, Gwangju city between 2007 and 2008. Participants were categorized into three groups according to blood pressure levels; normotensives ( or =140/90 mmHg). Prehypertensives were further categorized as low prehypertensives (120-129/80-84 mmHg) and high prehypertensives (130-139/85-89 mmHg). Carotid intima-media thickness and plaques were evaluated with a high-resolution B-mode ultrasound. Statistical analyses were performed using chi-square test, ANOVA, and multiple logistic regression. RESULTS: Prehypertensives had significantly greater maximal CCA-IMT values than normotensives, with a multivariate adjusted odds ratio of 1.78 (95% CI=1.36-2.32) for abnormal CCA-IMT (maximal CCA-IMT > or =1.0 mm), and 1.45 (95% CI=1.19-1.77) for carotid plaques. The multivariate adjusted odds ratio of low prehypertensives was 1.64 (95% CI=1.21-2.21) for abnormal CCA-IMT, and 1.30 (95% CI=1.04-1.63) for carotid plaques compared with normotensives. Subject with hypertension had higher frequency of abnormal CCA-IMT (odds ratio, 2.18; 95% CI=1.49-3.18), and carotid plaques (odds ratio, 1.98; 95% CI=1.46-2.67) compared with normotensives after adjustment for other cardiovascular risk factors. CONCLUSIONS: Our results indicate that there is a significant increase in the prevalence of carotid atherosclerosis in subjects with prehypertension (even in low prehypertensives) compared with normotensive subjects. Further studies are required to confirm the benefits and role of carotid ultrasonography in persons with prehypertension.

Avaliação da doença aterosclerótica da artéria carótida em pacientes submetidos à cirurgia de revascularização miocárdica por lesão do tronco da artéria coronária esquerda / Evaluation of Carotid Artery Atherosclerotic Disease in Patients Submitted to Myocardial Revascularization Surgery with Left Coronary Artery Lesion

Objetivo: Conhecer a prevalência e severidade da doença aterosclerótica da artéria carótida em pacientes com estenose significativa do tronco da artéria coronária esquerda (TCE) submetidos à cirurgia de revascularização do miocárdio.Métodos: A população estudada consistiu em 18 pacientes submetidos à cirurgia de revascularização do miocárdio no Hospital São José de Criciúma (SC) de fevereiro de 2002 a novembro de 2006 devido à estenose no TCE. A ultra-sonografia (US) foi o exame de eleição para detectar estenose de artérias carótidas, e o cateterismo para detectar estenose do TCE. Resultados: O sexo masculino foi o mais prevalente (77,8%) e a idade média foi de 63,1 anos. O grau de estenose do TCE mais prevalente foi o de 90% em 27,8% dos pacientes. O segmento do TCE predominantemente lesado foi o terço distal em 72,2% dos casos. A US mostrou estenose em 33,3% das carótidas, independente de sua gravidade. Destes, 66,6% tinham, concomitantemente, lesão de carótida direita. Dentre os casos com aterosclerose de carótidas, metade possuía lesão bilateral e significativa (grau de estenose ≥70%). Os segmentos carotídeos mais acometidos foram o bulbo e a carótida interna em 66,6% dos casos. Conclusões: A literatura médica realça uma relação importante da doença aterosclerótica de carótidas com a lesão significativa do TCE. O rastreamento de estenose de carótidas é recomendado a todos os pacientes com aterosclerose de artérias coronárias.

Objectives: Know prevalence and severity of atherosclerotic disease of carotid artery in patients with significative stenosis of left coronary artery (LCA) submitted to myocadial revascularization surgery. Methods: The sample was composed by 18 patients submitted to myocadial evascularization surgery in São José Hospital from Criciúma, South Brazil, between February 2002 to November 2006 due to LCA stenosis. Ultrasonography (US) was the exam of choice to detect stenosis of carotid arteries and the Hearth Catheterization to detect stenosis of LCA. Results: Male sex was the most prevalent (77.8%) and the mean age was 63.1 years old. The LCA stenosis degree most prevalent was of 90% in 27.8% of patients. The LCA segment mainly lesioned was the distal third in 72.2% of the cases. US shows stenosis in 33.3% of carotids, independent of its gravity. Among this patients, 66,6% also had right carotid lesion. Between the cases with carotid atherosclerosis, half had bilateral and significative lesion (stenosis degree ≥70%). The carotid segments most affected was the bulb and internal carotid in 66.6% of the cases.Conclusions: The medical literature enhalces an important relation of carotid atherosclerotic disease with significative lesion of LCA. Screening of carotide stenosis is recommended to all patients with atherosclerosis in coronary arteries.

Association of carotid intima-media thickness with left main coronary artery disease.

BACKGROUND: Previous studies have shown that carotid intima-media thickness correlates well with the presence and extent of coronary artery disease. This study was conducted to determine whether it could reliably predict the presence of left main coronary artery disease. METHODS: Common carotid intima-media thickness was measured in 50 patients with angiographically proven significant (> or =50%stenosis) left main coronary artery disease and in another 50 age- and sex-matched patients with coronary artery disease without the involvement of the left main coronary artery. Measurements of the carotid intima-media thickness were made on the far wall 1 cm from the distal end of the common carotid artery bilaterally, and the average and the greater of the two values thus obtained for each patient were used for analysis. Plaques were not included in the measurement of carotid intima-media thickness. RESULTS: The average and greater of the two values were significantly higher in patients with left main coronary artery disease as compared to those without it (average intima-media thickness: 0.926 +/- 0.12 vs. 0.78 9 +/- 0.16 mm; p< 0.001; greater intima-media thickness: 0.994 +/- 0.13 vs. 0.844 +/- 0.20 mm; p< 0.001). The cut-off values of 0.81 mm for the average carotid intima-media thickness and 0.87 mm for the greater carotid intima-media thickness were found to have optimum sensitivity (92% and 90%, respectively) and specificity (60% and 64%, respectively) for the detection of left main coronary artery disease. A higher cut-off value of 1.0 mm increased specificity to 92% and 84%, respectively, for the average and greater thicknesses, but sensitivity decreased markedly. CONCLUSIONS: There is a significant association between increased carotid intima-media thickness and the presence of left main coronary artery disease. The measurement of carotid intima-media thickness can be used with reasonably good sensitivity and specificity for the detection of left main coronary artery disease in patients who are undergoing evaluation for suspectedcoronary artery disease.

Percutaneous carotid intervention in patients combined carotid and coronary artery disease

Cerebrovascular accidents [CVA] are the third leading cause of death world wide. Carotid stenosis accounts for 20% to 30% of all CVAs. Thromboembolization of the atherosclerotic stenotic carotid arteries leads to cerebrovascular strokes and transient ischemic attacks [TIAs]. By far the most common lesion found in patients with intracranial cerebral vascular disease is an atherosclerotic plaque at carotid bifurcation. Recently carotid angioplasty and stent implantation appears to be a feasible method for the treatment of carotid stenosis. To assess safety and feasibility of percutaneous intervention in the treatment of carotid artery stenosis in patients with concomitant coronary artery disease. Forty patients with concomitant coronary and carotid artery disease were enrolled in this study, their carotid lesions were managed by carotid artery stenting [CAS] and distal protection devices [filter type] were used. Twenty seven males [67.5%] and 13 females [32.5%] were enrolled in this study their age ranged from 49-82 with the mean of 64.3 years, all had ischemic heart disease and internal carotid artery [1CA] stenosis that ranged from 60 to 99% with the mean of 82.4% +/- 10.5. Optimal results were obtained in 38 patients [95%] and the procedure was incomplete in 2 patients [5%]. Mean stenosis post stenting was 6% +/- 4. In recent outcome, mortality rate was 0% while 5 patients [12.5%] developed minor strokes, and 5 patients [12.5%] developed TIAs. In 18 months follow up, 31 patients [81%] were free from major cerebro-vascular events. Coronary artery stenting [CAS] resulted in reduction of neurological symptoms and major cerebral insult and found to be feasible and safe especially in high risk patients [those with severe coronary artery disease] for surgical interventions

Spontaneous extracranial carotid atherosclerosis evolution in asymptomatic individuals: a three-year prospective study

OBJETIVO: avaliar a evolução espontânea da aterosclerose carotídea. MÉTODO: estudo prospectivo com pessoas de ambos os sexos, idade de 40 a 70 anos, sem sinais e sintomas de doença cerebrovascular e sem os principais fatores de risco para aterosclerose. Foram excluídos os doentes que estavam em uso ou os que, durante o período de acompanhamento, usaram medicações que potencialmente pudessem influir no curso espontâneo da aterosclerose. As avaliações da placa e do grau de estenose foram obtidas por ultrassonografia com Doppler (USG). Investigou-se separadamente a presença de placa e o grau de estenose. O seguimento foi feito por 36 meses, com exame clínico, neurológico e novo USG repetidos com intervalo de 6 a 8 meses. Completaram o estudo 96 indivíduos (48 mulheres) quanto à presença da placa e 52 (26 mulheres) quanto ao grau de estenose. RESULTADOS: Quanto ao grau de estenose, 25% dos indivíduos pioraram, 69% permaneceram estáveis e 6% melhoraram. Quando se considerou apenas a presença ou ausência da placa, 20% pioraram (desenvolveram placa durante o seguimento), 7% melhoraram (desaparecimento da placa) e 73% permaneceram estáveis. Não houve diferença em relação ao sexo. CONCLUSAO: Estes resultados confirmam as características dinâmicas da placa. Em indivíduos assintomáticos e sem tratamento específico, a melhora espontânea ocorre, porém é pequena. Estes dados podem contribuir para auxiliar na tomada de uma decisão, em doentes de alto risco.

Carotid intima-media thickness and brachial-ankle pulse wave velocity in patients with and without coronary artery disease.

BACKGROUND: Carotid intima-media thickness and pulse wave velocity are non-invasive markers of atherosclerosis and have been shown to reliably predict presence and extent of atherosclerotic vascular disease. However, studies examining their association with each other have shown inconsistent results. Hence it was sought to assess correlation between carotid intima-media thickness and pulse wave velocity in patients with and without coronary artery disease. METHODS AND RESULTS: Sixty-four patients with angiographically proven coronary artery disease and 84 age-matched individuals without coronary artery disease but having one or more conventional cardiovascular risk factors were included in the study. Individuals with established cerebrovascular disease and peripheral vascular disease were excluded from the study. Carotid intima-media thickness of far wall was measured at three predefined sites (distal common carotid, carotid bifurcation and proximal internal carotid artery) on each side. Brachial-ankle pulse wave velocity was measured non-invasively using VP 1000 (Colin Corporation) automated ABI/ PWV analyzer. There was no significant difference in gender and presence of cardiovascular risk factors in the two groups. Mean and maximum carotid intima-media thickness and brachial-ankle pulse wave velocity were all significantly higher in coronary artery disease patients as compared to patients without coronary artery disease (0.842 v. ( 0.657 mm, p <0.0001; 1.076 v. 0.795 mm, p <0.0001; 1708.63 v. 1547.26 cm/s, p <0.0004 respectively). There was a significant correlation between brachial-ankle pulse wave velocity and both mean and maximum carotid intima-media thickness in patients with coronary artery disease (r = 0.47, p <0.0001 and r=0.41, p < 0.0008 respectively) but not in individuals without coronary artery disease (r=0.01 and -0.1 respectively). CONCLUSIONS: Presence of significant correlation between carotid intima-media thickness and brachial-ankle pulse wave velocity in patients with coronary artery disease but absence of the same in individuals without major atherosclerotic vascular disease suggests that the correlation between carotid intima-media thickness and brachial-ankle pulse wave velocity becomes stronger with increasing extent of atherosclerosis.

Prevalencia de aterosclerosis carotídea en una población de la ciudad de México / Prevalance of carotid atherosclerosis in a cohort of Mexico City

Para conocer la prevalencia de aterosclerosis en personas mayores de 60 años, se realizó ultrasonografía de alta resolución y Doppler con imagen de flujo codificada a color, de las arterias carótidas a participantes del proyecto CUPA (estudio de vigilancia epidemiológica iniciado en 1989 en el Distrito Federal). En cada participante se evaluó la presencia de las siguientes lesiones ateroscleróticas: 1) engrosamiento de la última y la media; 2) acodamientos y tortuosidades; 3) placas de ateroma no estenosantes y 4) estenosis carotídea significativa (50 por ciento). El análisis de 198 estudios llevados a cabo en 56 hombres y 142 mujeres mostró que 130 personas presentaron alguna de las lesiones investigadas (65.6 por ciento) y que su frecuencia aumenta con la edad, de tal forma que en menores de 65 años fue de 38 por ciento, en los sujetos de 65 a 74 años de 71 por ciento y en mayores de 75 años de 88 por ciento. La frecuencias de lesiones estenóticas avanzadas fue más bien baja (6 por ciento), mientras que la frecuencia global de las placas de ateroma no estenosante y el engrosamiento de la íntima y la media fue mayor del 60 por ciento. Este último fue mas usual en hombres, mientras que las placas no estenosantes y la estenosis de mayor grado, se observaron con más frecuencia en las mujeres. Sin embargo, no hubo diferencias significativas entre hombres y mujeres al analizarse las lesiones por grupos de edad. Es el primer estudio sobre la prevalencia de aterosclerosis carotídea en México basado en evaluación ultrasonográfica. Los hallazgos de la investigación documentan una elevada frecuencia de ateroclerosis entre residentes de 60 años de la ciudad de México

Metaloproteinasas en placas de endarterectomía carotídea: actividad aumentada en áreas de estenosis crítica / Metalloproteinase in carotid endarterectomy plaques: increased activity in critical stenosis zones

The presence of metalloproteinases in etherosclerotic plaques has been described but their role is not well understood. An increased secretion of these proteolytic enzymes could explain plaque instability and distal embolization. Plaque were divided in 1 segment with and 1 segement without stenosis, the latter being used as control. Both segments were incubated in culture media for 48 h or were fixed for histology. The conditioned medium was studied using gelatin zimography and digital densitometry. Melloproteinases were identified by their molecular weight, inhibition with EDTA or Western blot. Standard histologic study and immunohistochemistry were done. In stenotic areas, metalloproteinase 9 (92kD) secretion was 269 percent higher than in regular plaques (191 and 73 kilopixels/ug protein respectively p<0.02). The histological study of stenotic areas showed macrophage infiltration and neoformation of blood vessels. The increased secretion of cellular matrix degrading enzyme metalloproteinase 9 in stenotic areas of atherosclerotic plaques could axplain plaque instability and subsequent embolization

Endarterectomía carotídea / Carotid endarterectomy

Objetivo: La endarterectomía carotídea fue introducida en los años 50 como procedimiento necesario para la prevención de la enfermedad carotídea. Material y métodos: En el Instituto Cardiovascular de Buenos Aires entre octubre de 1993 y mayo de 1995 fueron operados a 130 endarterectomías carotídeas. Ochenta y ocho eran hombres, con una edad promedio de 65 años. Como factores de riesgo el 77,6 por ciento era hipertenso, el 16,8 por ciento era diabético, el 63 por ciento dislipémico y el 61 por ciento tabaquista. El 18,4 por ciento había tenido un IAM previamente, el 23,6 por ciento angina crónica estable y el 24 por ciento presentaba claudicación en miembros inferiores. Del total de pacientes operados el 38 por ciento había presentado síntomas neurológicos hemisféricos: AIT 25 por ciento, amaurosis fugax 8,8 por ciento o stroke 3,2 por ciento. La operación realizada fue la endarterectomía carotídea común e interna luego de realizar arteriotomía longitudinal amplia y endarterectomía carotídea externa por eversión. Si la endarterectomía de la externa no era considerada satisfactoria también se realizaba arteriotomía de la misma. En todos los casos se utilizó shunt de Javid. Se fijó la placa distal y se realizó angioplastía con parche en la mayoría de los casos. Se realizó estudio anatomopatológico de 88 de dichas piezas de endarterectomía. Resultados: De las 130 endarterectomías realizadas la incidencia de déficit neurológico central (transitorio o definitivo) homolateral fue de 2,3 por ciento y contralateral 0,7 por ciento. La mortalidad perioperatoria fue 1,5 por ciento y la morbimortalidad global fue del 4,5 por ciento. Conclusiones: La endarterectomía carotídea para estenosis carotídeas mayores al 60 por ciento es el tratamiento de elección para prevenir eventos neurológicos mayores