Patofisiología de la placa coronaria aterosclerótica vulnerable y síndromes coronarios agudos / Pathophysiology Of The Vulnerable Atherosclerotic Coronary Plaque And Acute Coronary Syndromes

La ruptura de la placa aterosclerótica es responsable por dos tercios de los síndromes coronarios agudos (SCA) y por la muerte súbita cardiaca. El fibroateroma de capa fina (TCFA), se caracteriza por la presencia de un grande acumulo de lípidos recubiertos por una capa fibrosa fina que mide <65 µm, y es reconocido como el precursor de la ruptura de la placa. Las enfermedades cardiovasculares son responsables por 38% de todas las muertes en los Estados Unidos y constituyen la principal causa de muerte en hombres menores de 65 años en Europa. La cardiopatía isquémica (EAC) incluye los síndromes coronarios estables y crónicos (AE), los síndromes coronarios agudos (AI/IAM), insuficiencia cardiaca congestiva, muerte súbita de origen cardiovascular e isquemia silenciosa. Las características más obvias, que diferencian los pacientes con síndromes coronarios agudos (SCA) de los pacientes con EAC estable son: 1) estenosis coronarias complejas; 2) fisuras en las placas coronarias; 3) trombos recientes; e 4) inflamación de la placa. La conversión de una lesión estable y asintomática en una placa rota e inestable envuelve muchos procesos. Los autores se proponen revisar de manera crítica la literatura reciente sobre los mecanismos envueltos en la génesis de la placa coronaria aterosclerótica vulnerable, bien como los mecanismos fisiopatológicos de la ruptura; será discutido el concepto de paciente vulnerable, y serán comentados los métodos diagnósticos (consagrados y experimentales) y las perspectivas de tratamiento de esta patología...(AU)

Limitaciones de la creatinina como marcador de filtración en la nefrotoxicidad inducida por contrastes en pacientes sometidos a cateterismo cardíaco / Limitations of creatinine as a filtration marker in contrast-induced neprhotoxicity in patients undergoing cardiac catheterization

Introducción:El objetivo del estudio fue determinar si el cálculo de la tasa de filtración glomerular (TFG) por la fórmula de Cockroft-Gault proporciona una mejor estimación de la función renal (FR) que la creatinina sérica (CrS) para detectar nefrotoxicidad (NTIC) en pacientes (PS) expuestos a medios de contraste (MC). Métodos: 133 PS con CrS basal hasta 1.2 mg/dL sometidos a cateterismo cardíaco (CC) fueron incluidos, y colectadas muestras de sangre antes y 48 h después del procedimiento. Resultados: En condiciones basales los PS fueron divididos en: Grupo I (TFG<60 mL/min, n=15) y Grupo II (TFG≥60 mL/min, n=118); el Grupo I presentaba CrS más alta (1.01 ± 0.14 vs 0.88 ± 0.18 mg/dL; P=0.007), TFG baja (49.1 ± 6.7 vs 101.1 ± 29.9 mL/min; P<0.0001) y se caracterizaban por ser: personas mayores de edad (P=0.006), predominio en mujeres, menor peso (P<0.0001) y menor estatura. Después del cateterismo la incidencia de nefrotoxicidad fue 20.3%. Los PS fueron divididos en 2 nuevos grupos: con nefrotoxicidad (CPFR, n=27) y sin nefrotoxicidad (SPFR, n=106); en el grupo CPFR la CrS aumentó de 0.80 ± 0.20 para 1.10 ± 0.23 mg/dL (P=0.0001) y la TFG disminuyó de 98.1 ± 46.0 para 69.8 ± 31.0 mL/min (P=0.0001). Conclusiones: La TFG calculada con la fórmula de Cockcroft-Gault fue más eficaz y rápida que la CrS para evaluar la función renal antes y después de la exposición a MC, y permitió identificar pacientes que aun con niveles normales de CrS ya presentan algún grado de disfunción renal (prevalencia de 11.3%

Associação entre remodelamento vascular e núcleo necrótico em artérias coronárias: análise por ultrassom intracoronário com Histologia Virtual® / Association between vascular remodeling and necrotic core in coronary arteries: Virtual Histology intravascular ultrasound analysis

INTRODUÇÃO: Estudos anatomopatológicos sugerem a associação de remodelamento vascular positivo e placas coronárias vulneráveis. O objetivo deste estudo foi avaliar se existe correlação entre o grau de remodelamento vascular positivo e o porcentual de núcleo necrótico em lesões ateroscleróticas coronárias. MÉTODOS: Foram estudados 270 cortes transversais obtidos pela Histologia Virtual® de 30 pacientes, os quais apresentavam remodelamento positivo em segmento de artéria coronária com lesão > 50%, identificada pela angiografia coronária. Foram avaliados 7 cortes transversais por segmento de artéria coronária, incluindo o corte transversal com o maior índice de remodelamento arterial, denominado corte transversal de interesse (corte transversal 4). RESULTADOS: A média de idade foi de 60,8 ± 8,8 anos, 80% eram do sexo masculino e 30% diabéticos. Angina instável foi a apresentação clínica mais frequente (56,6%) e a artéria descendente anterior foi o vaso mais analisado (43%). A área de referência do vaso foi de 15,5 ± 4,9 mm² e o índice de remodelamento no corte transversal 4 foi de 1,2 ± 0,1. Análise de variância de medidas repetidas mostrou maior porcentual de núcleo necrótico no corte transversal de interesse (P < 0,001). Observamos correlação positiva do remodelamento arterial coronário com o núcleo necrótico (r = 0,79; P < 0,001). CONCLUSÕES: O remodelamento positivo da artéria coronária está associado à presença de núcleo necrótico, o qual caracteriza placas ateromatosas vulneráveis. A pesquisa de remodelamento arterial positivo pode ser estratégia útil para a detecção de placas vulneráveis antes de sua ruptura.

BACKGROUND: Anatomopathological studies suggest an association of positive vascular remodeling and vulnerable coronary plaques. The objective of this study was to verify whether there is a correlation between positive vascular remodeling and necrotic core in atherosclerotic coronary lesions. METHODS: We studied 270 cross sections obtained by Virtual Histology® in 30 patients who had positive remodeling in coronary artery segments with lesions > 50%, identified by coronary angiography. Seven cross sections were assessed per segment of coronary artery, including the cross section with the highest remodeling index, denominated cross section of interest (cross section 4). RESULTS: Mean age was 60.8 ± 8.8 years, 80% were male and 30% were diabetic. Unstable angina was the most frequent clinical presentation (56.6%) and the left anterior descending artery was the most analyzed vessel (43%). The vessel reference area was 15.5 ± 4.9 mm² and the remodeling index in cross section 4 was 1.2 ± 0.1. Repeated measures analysis of variance showed a higher percentage of necrotic core in the cross section of interest (P < 0.001). We observed a positive correlation of coronary artery remodeling and necrotic core (r = 0.79; P < 0.001). CONCLUSIONS: Positive coronary artery remodeling is associated to the presence of necrotic core, which characterizes vulnerable atherosclerotic plaques. The search for positive arterial remodeling may be a useful strategy for detecting vulnerable plaques before rupture.

Local delivery of sirolimus nanoparticles for the treatment of in-stent restenosis.

OBJECTIVES: To test the local delivery of sirolimus nanoparticles following percutaneous transluminal coronary angioplasty (PTCA) to treat in-stent restenosis (ISR) in a swine model. BACKGROUND: Coronary bare-metal stent (BMS) implantation reduces major adverse cardiac events when compared with PTCA; however, ISR rates remain high. METHODS: Eighteen swine underwent BMS deployment guided by intravascular ultrasound (IVUS). Of these, 16 developed ISR (1 stent/swine) and underwent angioplasty with a noncompliant balloon (PTCA-NC). The animals were then randomized into four groups for local infusion of sirolimus nanoparticles through a porous balloon catheter, as follows: (1) PTCA-NC alone (control); (2) PTCA-NC + (polylactic acid)-based nanoparticle formulation (anionic 1); (3) PTCA-NC + (polylactic-co-glycolic acid)-based nanoparticle formulation (anionic 2); and (4) PTCA-NC + Eudragit RS nanoparticle formulation (cationic). Coronary angiography and IVUS follow-up were performed 28 days after ISR treatment. RESULTS: There was one episode of acute coronary occlusion with the cationic formulation. Late area loss was similar in all groups at 28 days according to IVUS. However, luminal volume loss (control = 20.7%, anionic 1 = 4.0%, anionic 2 = 6.7%, cationic = 9.6%; P = 0.01) and neointimal volume gain (control = 68.7%, anionic 1 = 17.4%, anionic 2 = 29.5%, cationic = 31.2%; P = 0.019) were significantly reduced in all treatment groups, especially in anionic 1. CONCLUSIONS: PTCA-NC followed by local infusion of sirolimus nanoparticles was safe and efficacious to reduce neointima in this model, and this strategy may be a promising treatment for BMS ISR. Further studies are required to validate this method in humans.

Friable but treatable: coronary artery dissections in Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome is a rare connective tissue disorder associated with arterial dissection or rupture. Percutaneous coronary intervention (PCI) is often critical in patients with this syndrome because their coronary arteries are prone to dissection, enhancing the risk of stent borders dissection when conventional stent deployment pressures are used. Coronary artery bypass graft (CABG) treatment for these patients may also raise concerns because the left internal mammary artery is probably friable. Therefore, coronary artery revascularization in vascular Ehlers-Danlos syndrome either using PCI or CABG is challenging due to the arteries friability. A small number of cases have been published describing the friability of the vessels and associated complications; nevertheless, the optimum treatment remains unclear. We report the case of a 54-year-old woman treated successfully with PCI and CABG in two different acute coronary syndrome episodes, in which specific technical issues related to both procedures were decisive.

Identificação de genes envolvidos na síntese de proteínas de células musculares lisas com expressão aumentada em placas ateromatosas associados a hiperplasia neointimal após implante de stents não-farmacológicos: estudo GENESIS-R / Identification of genes involved in smooth muscle cell protein synthesis with increased expression in atheromathous plaques associated to neointim al hyperplasia after bare-metal stenting: GENESISI-R Study

Introdução: A reestenose coronária é um fenômeno pouco compreendidoe que permanece como um desafio mesmo na era dos stents farmacológicos. Este estudo tem como objetivo identificar genes envolvidos na síntese de proteínas estruturais e funcionais de células musculares lisas com expressão aumentada em placas ateromatosas de humanos associadosa hiperplasia neointimal após o implante de stents não-farmacológicos. Métodos: Placas ateromatosas foram obtidasmediante aterectomia direcionada, previamente ao implante do stent. A análise da expressão dos genes foi realizada utilizando-se o sistema Affymetrix GeneChip. Os pacientes foramsubmetidos a ultrassom intracoronário 6 meses após o procedimento para análise volumétrica intrastent. Foi avaliada a correlação entre a expressão gênica de placas ateromatosas e o porcentual de hiperplasia intimal intrastent. Resultados: A maioria dos pacientes era do sexo masculino (85,7%), com60,2 ± 11,4 anos de idade, 35,7% eram diabéticos e o porcentual de hiperplasia intimal intrastent foi de 29,9 ± 18,7%.Não houve variação do porcentual de hiperplasia intimal intrastent entre os pacientes com ou sem diabetes (29,5% vs. 30,7%; P = 0,89). Não houve correlação entre a extensão do stent e o porcentual de hiperplasia intimal intrastent (r = -0,26; P = 0,26) ou entre o diâmetro do stent e o porcentual dehiperplasia intimal intrastent (r = 0,14; P = 0,56). Oito genes envolvidos na síntese de proteínas estruturais e funcionais de células musculares lisas apresentaram correlação positiva como porcentual de hiperplasia intimal intrastent. Conclusões: As lesões coronárias de novo apresentam expressão aumentada de genes relacionados com a síntese de proteínas estruturais e funcionais de células musculares lisas associados a futurahiperplasia neointimal intrastent significativa, surgindo como novos alvos terapêuticos.

First-in-man study of simvastatin-eluting stent in de novo coronary lesions: the SIMVASTENT study.

BACKGROUND: Statins have anti-inflammatory and antiproliferative properties irrespective of their cholesterol-lowering effects. The aim of the present study was to evaluate a simvastatin-eluting stent (SimvES) in the treatment of de novo coronary lesions. METHODS AND RESULTS: Forty-two patients with de novo coronary artery lesions were assigned to SimvES, bare-metal stent (BMS) or everolimus-eluting stent (EES) implantation followed by intravascular ultrasound (IVUS) for neointimal quantitative analysis. Six months later, quantitative coronary angiography (QCA) and IVUS were repeated. QCA showed no binary restenosis, a mean in-stent late loss of 1.05 ± 0.25 mm (BMS, 1.12 ± 0.48 mm; EES, 0.20 ± 0.16 mm) and a diameter stenosis of 33.5 ± 7.1% (BMS, 35.5 ± 15.30%; EES, 7.2 ± 3.12%). Control IVUS showed a mean in-stent obstruction of 18.3 ± 9.4% (BMS, 32.8 ± 19.1%; EES, 9.8 ± 2.4%) and a neointimal volume index of 1.58 ± 0.75 mm(3)/mm (BMS, 2.93 ± 1.76 mm(3)/mm; EES, 0.80 ± 0.16 mm(3)/mm). Thrombus, late incomplete apposition and major adverse cardiac events were not observed. CONCLUSIONS: In this sample of patients with de novo coronary lesions, the use of a SimvES was not related to major adverse cardiac events, but it was associated with a higher level of neointimal proliferation than expected.

Endovascular approach to treat ascending aortic pseudoaneurysm in a patient with previous CABG and very high surgical risk.

Pseudoaneurysm of the ascending aorta is an uncommon pathology and a challenge in high-risk patients who undergo conventional surgery because of high operative morbidity and mortality. Endovascular exclusion of an aortic pseudoaneurysm using an endoprosthesis is a less invasive approach, but few such cases have been reported. Moreover, the use of this approach poses unique therapeutic challenges because there is no specific endoprosthesis for ascending aortic repair, particularly to treat patients with previous coronary artery bypass graft (CABG). We describe the case of a 74-year-old patient who had undergone CABG and later presented with an iatrogenic ascending aortic pseudoaneurysm that occurred during an angiography. This patient was at very high risk for surgical treatment and, therefore, an endovascular approach was adopted: percutaneous coronary intervention for the left main coronary artery, left anterior descending and left circumflex native coronary arteries followed by endovascular endoprosthesis deployment in the ascending aorta to exclude the pseudoaneurysm. Both procedures were successfully performed, and the patient was discharged without complications 4 days later. At 5 months' clinical follow-up, his clinical condition was good and he had no complications.

The importance of the interaction between leukocyte integrin Mac-1 and platelet glycoprotein Ib-a for leukocyte recruitment by platelets and for the inflammatory response to vascular injury.

OBJECTIVE: To assess the importance of the interaction between leukocyte integrin Mac-1 (a Mb 2) and platelet glycoprotein (GP) Ib-a for leukocyte recruitment after vascular injury and the effect of the neutralization of the Mac-1-GPIba interaction on cell proliferation and the neointimal hyperplasia triggered by the vascular injury. METHODS: A peptide called M2 or anti-M2 antibody was developed to block the Mac-1-GPIba interaction. This peptide was injected and compared to a control-peptide in C57B1/6J mice submitted to vascular injury of the femoral artery with a guide wire. One, five or 28 days after the vascular injury, the femoral arteries were removed for morphometric and immunohistochemical analyses. RESULTS: The blocking of the Mac-1-GPIba interaction promoted a statistically significant reduction in the number of leukocytes in the neointimal layer on the first day after the vascular injury (control: 7.9+/-5.0% of the cell total versus anti-M2: 2.0+/-1.6%, p=0.021), as well as determined a statistically significant decrease in leukocyte accumulation in the neointimal layer on days 5 and 28 (control: 42.3+/-12.9% versus anti-M2: 24.6+/-10.8%, p=0.047 and control: 7.9+/-3.0% versus anti-M2: 3.3+/-1.3%, p=0.012; respectively). Cell proliferation in the neointimal layer of the vessel five days post-injury was reduced with the blocking of the Mac-1-GPIba interaction (control: 5.0+/-2.9% of the cell total versus anti-M2: 1.8+/-0.5%; p=0.043), along with a significant decrease in cell proliferation in the vessel neointimal layer 28 days post-injury (control: 3.8+/-1.7% versus anti-M2: 2.0+/-1.2%; p=0.047). The blocking of the Mac-1-GPIba interaction also determined a statistically significant decrease of the intimal thickening 28 days post-injury (control: 10,395+/-3,549 microm(2) versus anti-M2: 4,561+/-4,915 microm(2); p=0.012). CONCLUSION: Leukocyte recruitment after a vascular injury depends on the Mac-1-GPIba interaction and the neutralization of this interaction inhibits cell proliferation and neointimal formation.

The importance of the interaction between leukocyte integrin Mac-1 and platelet glycoprotein Ib-a for leukocyte recruitment by platelets and for the inflammatory response to vascular injury / Importância da interação entre a integrina Mac-1 dos leucócitos e a glicoproteína Iba das plaquetas para o recrutamento de leucócitos pelas plaquetas e para a resposta inflamatória à lesão vascular

OBJETIVO: Avaliar a importância da interação entre a integrina Mac-1 dos leucócitos (a Mb 2) e a glicoproteína (GP) Iba das plaquetas para o recrutamento de leucócitos após a lesão vascular e o efeito da neutralização da interação Mac-1-GPIba sobre a proliferação celular e a hiperplasia neointimal desencadeadas por lesão vascular. MÉTODOS: Um peptídeo denominado M2 ou anticorpo anti-M2 foi desenvolvido para bloquear a interação Mac-1-GPIba . Esse peptídeo foi injetado e comparado com anticorpo-controle em camundongos C57B1/6J submetidos a lesão vascular da artéria femoral com corda-guia. Um, cinco ou 28 dias após a lesão vascular, as artérias femorais foram retiradas para a realização de morfometria e imuno-histoquímica. RESULTADOS: O bloqueio da interação Mac-1-GPIba promoveu uma redução estatisticamente significativa do número de leucócitos na camada média no primeiro dia após a lesão vascular (controle: 7,9±5,0 por cento do total de células versus anti-M2: 2,0±1,6 por cento, p=0,021), bem como determinou uma diminuição estatisticamente significativa do acúmulo de leucócitos na neoíntima em cinco e 28 dias (controle: 42,3±12,9 por cento versus anti-M2: 24,6±10,8 por cento, p=0,047 e controle: 7,9±3,0 por cento versus anti-M2: 3,3±1,3 por cento, p=0,012; respectivamente). A proliferação celular na camada média do vaso em cinco dias pós-lesão foi reduzida com o bloqueio da interação Mac-1-GPIba (controle: 5,0±2,9 por cento do total de células versus anti-M2: 1,8±0,5 por cento; p=0,043), assim como houve diminuição significativa da proliferação celular na camada íntima do vaso em 28 dias (controle: 3,8±1,7 por cento versus anti-M2: 2,0±1,2 por cento; p=0,047). O bloqueio da interação Mac-1-GPIba também determinou uma redução estatisticamente significativa do espessamento intimal em 28 dias pós-lesão (controle: 10.395±3.549 µm² versus anti-M2: 4.561±4.915 ...

OBJECTIVE: To assess the importance of the interaction between leukocyte integrin Mac-1 (a Mb 2) and platelet glycoprotein (GP) Ib-a for leukocyte recruitment after vascular injury and the effect of the neutralization of the Mac-1-GPIba interaction on cell proliferation and the neointimal hyperplasia triggered by the vascular injury. METHODS: A peptide called M2 or anti-M2 antibody was developed to block the Mac-1-GPIba interaction. This peptide was injected and compared to a control-peptide in C57B1/6J mice submitted to vascular injury of the femoral artery with a guide wire. One, five or 28 days after the vascular injury, the femoral arteries were removed for morphometric and immunohistochemical analyses. RESULTS: The blocking of the Mac-1-GPIba interaction promoted a statistically significant reduction in the number of leukocytes in the neointimal layer on the first day after the vascular injury (control: 7.9±5.0 percent of the cell total versus anti-M2: 2.0±1.6 percent, p=0.021), as well as determined a statistically significant decrease in leukocyte accumulation in the neointimal layer on days 5 and 28 (control: 42.3±12.9 percent versus anti-M2: 24.6±10.8 percent, p=0.047 and control: 7.9±3.0 percent versus anti-M2: 3.3±1.3 percent, p=0.012; respectively). Cell proliferation in the neointimal layer of the vessel five days post-injury was reduced with the blocking of the Mac-1-GPIba interaction (control: 5.0±2.9 percent of the cell total versus anti-M2: 1.8±0.5 percent; p=0.043), along with a significant decrease in cell proliferation in the vessel neointimal layer 28 days post-injury (control: 3.8±1.7 percent versus anti-M2: 2.0±1.2 percent; p=0.047). The blocking of the Mac-1-GPIba interaction also determined a statistically significant decrease of the intimal thickening 28 days post-injury (control: 10,395±3,549 µm² versus anti-M2: 4,561±4,915 µm²; ...

Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events.

BACKGROUND: Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. METHODS AND RESULTS: We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, P=0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 microg/mL, P<0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (Ptrend<0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). Risks were independent of standard risk factors and C-reactive protein. CONCLUSIONS: The platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before STEMI, and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.

Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury.

BACKGROUND: Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (alphaMbeta2, CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise alphaMbeta2 counterligand responsible for mediating adhesion-strengthening interactions between neutrophils and platelets in vivo has not previously been identified. METHODS AND RESULTS: Our previous studies have established the P201-K217 sequence in the alphaMI domain as the binding site for platelet glycoprotein (GP) Ibalpha. Here we report that antibody targeting of alphaM(P201-K217) reduced alphaMbeta2-dependent adhesion to GP Ibalpha but not other alphaMbeta2 ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-alphaM(P201-K217) inhibited the firm adhesion of both human and murine leukocytes to adherent platelets under laminar flow conditions. In a mouse femoral artery wire injury model, antibody targeting of alphaM(P201-K217) reduced leukocyte accumulation after injury that was accompanied by inhibition of cellular proliferation and neointimal thickening. CONCLUSIONS: This study demonstrates that GP Ibalpha is a physiologically relevant ligand for alphaMbeta2 and that integrin engagement of GP Ibalpha is critical to leukocyte function and the biological response to vascular injury. These observations establish a molecular target for selectively disrupting leukocyte-platelet complexes that promote inflammation in thrombosis and restenosis.

O polimorfismo 894G>T do gene da óxido nítrico sintase endotelial e sua associação com doença coronária / The 894G>T polymorphism of the endothelial constitutive nitric oxide synthase gene and its association with coronary artery disease

O endotélio cumpre um papel fundamental na vasodilatação fisiológica e na proteção da parede arterial frente aos processos de trombose e aterosclerose, assim como na resposta à lesão provocada pela angioplastia ou implante de stent intracoronário. Essa função protetora é exercida, entre outros mecanismos, através da síntese e liberação de óxido nítrico (NO) pela célula endotelial. O NO inibe a adesão e a agregação plaquetária, assim como provoca a desagregação de agregado plaquetário. Inibe também a mitogênese e a proliferação de células de músculo liso vascular, assim como a quimiotaxia e a adesão de polimorfonucleares neutrófilos ao endotélio. O NO é sintetizado na célula endotelial, a partir da L-Arginina, pela NO sintase endotelial constitutiva (NOSec), uma enzima constitutiva codificada por um gene localizado no cromossomo 7q35-36, contendo 26 éxons que ocupam 21 quilobases. Foram descritos alguns polimorfismos deste gene, entre os quais, o polimorfismo 894G>T, presente no éxon 7 do gene da NOSec. Este polimorfismo consiste na substituição de uma base guanina por uma timina no nucleotídeo 894 do gene; esta mutação resulta na substituição de um aminoácido glutamato por aspartato na posição 298 da NOSec (Glu298Asp). Nesta revisão, descreve-se a possível associação desse polimorfismo com a doença coronária, destacando algumas contribuições de nosso grupo de pesquisa.

The endothelium plays a major role in the physiological vasodilatation, in the protection of the arterial wall against atherosclerotic and thrombotic process, as well as in the response to vessel injury after coronary angioplasty and stenting. This protective function is mediated, among others, by the synthesis and release of nitric oxide (NO) by endothelial cells. The NO has been shown to inhibit platelet adhesion and aggregation, and also to stimulate disaggregation of preformed platelet aggregates. It also inhibits mitogenesis and the proliferation of vascular smooth muscle cells, as well as polymorphonuclear adhesion and chemotaxis. The NO is synthesized in the endothelial cell from L-arginine, by endothelial constitutive nitric oxide synthase (ecNOS), which is a constitutive enzyme codified by a gene located in locus 7q35-36, containing 26 exons that occupy 21 kilobases. Some polymorphisms in this gene have been described. Among these, the 894G>T polymorphism present in the exon 7 of the ecNOS gene. This polymorphism consists of the substitution of a guanine base by a thymine at nucleotide 894 of the gene; this mutation results in the substitution of the glutamate amino acid by aspartate at the 298th position of the ecNOS protein (Glu298Asp). In this review, we describe the possible association of this polymorphism with coronary artery disease and the contributions of our research group.

Evidence for a role of macrophage migration inhibitory factor in vascular disease.

OBJECTIVE: Inflammation plays an essential role in atherosclerosis and restenosis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is widely expressed in vascular cells. However, there is no in vivo evidence that MIF participates directly in vascular injury and repair. Therefore, we investigated the effect of MIF blockade on the response to experimental angioplasty in atherosclerosis-susceptible mice. METHODS AND RESULTS: Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDL receptor-deficient mice treated with a neutralizing anti-MIF or isotype control monoclonal antibody. After 7 days and 28 days, intimal and medial sizes were measured and intima/media area ratio (I/M) was calculated. Intimal thickening and I/M were reduced significantly by anti-MIF compared with control antibody. Vascular injury was accompanied by progressive vessel enlargement or "positive remodeling" that was comparable in both treatment groups. MIF blockade was associated with reduced inflammation and cellular proliferation and increased apoptosis after injury. CONCLUSIONS: Neutralizing MIF bioactivity after experimental angioplasty in atherosclerosis-susceptible mice reduces vascular inflammation, cellular proliferation, and neointimal thickening. Although the molecular mechanisms responsible for these effects are not yet established, these data prompt further research directed at understanding the role of MIF in vascular disease and suggest novel therapeutic interventions for preventing atherosclerosis and restenosis.

Simvastatin reduces neointimal thickening in low-density lipoprotein receptor-deficient mice after experimental angioplasty without changing plasma lipids.

BACKGROUND: Statins exert antiinflammatory and antiproliferative actions independent of cholesterol lowering. To determine whether these actions might affect neointimal formation, we investigated the effect of simvastatin on the response to experimental angioplasty in LDL receptor-deficient (LDLR-/-) mice, a model of hypercholesterolemia in which changes in plasma lipids are not observed in response to simvastatin. METHODS AND RESULTS: Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDLR-/- mice treated with low-dose (2 mg/kg) or high-dose (20 mg/kg) simvastatin or vehicle subcutaneously 72 hours before and then daily after injury. After 7 and 28 days, intimal and medial sizes were measured and the intima to media area ratio (I:M) was calculated. Total plasma cholesterol and triglyceride levels were similar in simvastatin- and vehicle-treated mice. Intimal thickening and I:M were reduced significantly by low- and high-dose simvastatin compared with vehicle alone. Simvastatin treatment was associated with reduced cellular proliferation (BrdU), leukocyte accumulation (CD45), and platelet-derived growth factor-induced phosphorylation of the survival factor Akt and increased apoptosis after injury. CONCLUSIONS: Simvastatin modulates vascular repair after injury in the absence of lipid-lowering effects. Although the mechanisms are not yet established, additional research may lead to new understanding of the actions of statins and novel therapeutic interventions for preventing restenosis.