Autophagy activation attenuates the neurotoxicity of local anesthetics by decreasing caspase-3 activity in rats / A ativação autofágica atenua a neurotoxicidade dos anestésicos locais ao diminuir a atividade da caspase‐ 3 em ratos

Abstract Background and objectives The mechanisms by which local anesthetics cause neurotoxicity are very complicated. Apoptosis and autophagy are highly coordinated mechanisms that maintain cellular homeostasis against stress. Studies have shown that autophagy activation serves as a protective mechanism in vitro. However, whether it also plays the same role in vivo is unclear. The aim of this study was to explore the role of autophagy in local anesthetic-induced neurotoxicity and to elucidate the mechanism of neurotoxicity in an intrathecally injected rat model. Methods Eighteen healthy adult male Sprague-Dawley rats were randomly divided into three groups. Before receiving an intrathecal injection of 1% bupivacaine, each rat received an intraperitoneal injection of vehicle or rapamycin (1 mg.kg-1) once a day for 3 days. The pathological changes were examined by Haematoxylin and Eosin (HE) staining. Apoptosis was analysed by TdT-mediated dUTP Nick-End Labelling (TUNEL) staining. Caspase-3, Beclin1 and LC3 expression was examined by Immunohistochemical (IHC) staining. Beclin1 and LC3 expression and the LC3-II/LC3-I ratio were detected by western blot analysis. Results After bupivacaine was injected intrathecally, pathological damage occurred in spinal cord neurons, and the levels of apoptosis and caspase-3 increased. Enhancement of autophagy with rapamycin markedly alleviated the pathological changes and decreased the levels of apoptosis and caspase-3 while increasing the expression of LC3 and Beclin1 and the ratio of LC3-II to LC3-I. Conclusions Enhancement of autophagy decreases caspase-3-dependent apoptosis and improves neuronal survivalin vivo. Activation of autophagy may be a potential therapeutic strategy for local anaesthetic-induced neurotoxicity.

Resumo Introdução e objetivos Os mecanismos de neurotoxicidade dos anestésicos locais são complexos. A apoptose e a autofagia são mecanismos altamente organizados que mantêm a homeostase celular durante o estresse. Estudos revelam que a ativação da autofagia atua como mecanismo de proteção in vitro. Não está claro se a autofagia também desempenha essa função in vivo. O objetivo deste estudo foi analisar o papel da autofagia na neurotoxicidade induzida por anestésico local e esclarecer o mecanismo dessa neurotoxicidade utilizando um modelo de injeção intratecal em ratos. Métodos Dezoito ratos Sprague‐Dawley machos adultos saudáveis foram divididos aleatoriamente em três grupos. Antes de receber a injeção intratecal de bupivacaína a 1%, cada rato recebeu injeção intraperitoneal de veículo ou rapamicina (1 mg.kg‐1) uma vez ao dia durante 3 dias. As alterações patológicas foram examinadas por coloração com Hematoxilina e Eosina (HE). A apoptose foi analisada por coloração com o método dUTP Nick‐End Labeling (TUNEL) mediado por TdT. A expressão de caspase‐3, Beclin1 e LC3 foram examinadas por coloração Imunohistoquímica (IHQ). A expressão de Beclin1 e LC3 e a razão LC3‐II/LC3‐I foram detectadas por análise de western blot. Resultados Após a injeção intratecal de bupivacaína, ocorreu lesão patológica nos neurônios da medula espinhal e os níveis de apoptose e caspase‐3 aumentaram. A ativação da autofagia causada pela rapamicina mitigou de forma expressiva as alterações patológicas e diminuiu os níveis de apoptose e caspase‐3, aumentando a expressão de LC3 e Beclin1 e a razão LC3‐II/LC3‐I. Conclusões O aumento da autofagia diminui a apoptose dependente da caspase‐3 e melhora a sobrevivência neuronal in vivo. A ativação da autofagia pode ser uma estratégia terapêutica potencial para a neurotoxicidade induzida por anestésicos locais.

Design, manufacture and initial tests of a drug-eluting coronary stent / Diseño, fabricación y pruebas iniciales de una endoprótesis coronaria liberadora de fármaco

Abstract Introduction: A drug-eluting coronary stent is being developed at the National Institute of Cardiology of Mexico for the treatment of ischemic heart disease. Objective: To establish the best animal model for the tests, to show the advances in the drug-eluting stent prototype, to assess two drugs’ antiproliferative activity and histological results. Method: Smooth muscle cell culture tests were performed in order to assess sirolimus and paclitaxel antiproliferative properties. The drugs were encapsulated inside the polymeric matrix of the stents. Rabbits and pigs were used as animal models. Results: Sirolimus and paclitaxel showed an inhibitory effect, which was higher for the latter. Infrared spectroscopy and light and optical microscopy showed that the drug/polymer layer properly adhered to the stent. At a four-week follow-up, both animal models showed satisfactory clinical evolution and adequate histological response, although the porcine model was shown to be more suitable for future protocols. Conclusions: Preliminary tests of the drug-eluting stent provided bases for the development of a study protocol with an adequate number of pigs and with clinical angiographic and histopathological three-month follow-up.

Resumen Introducción: En el Instituto Nacional de Cardiología de México se desarrolla una endoprótesis (stent) coronaria liberadora de fármacos para el tratamiento de la cardiopatía isquémica. Objetivo: Establecer el mejor modelo animal para las pruebas, mostrar los avances en el prototipo del stent liberador de fármacos, evaluar la actividad antiproliferativa de dos fármacos y los resultados histológicos. Método: Se realizaron cultivos de células de músculo liso para evaluar las propiedades antiproliferativas de sirolimus y paclitaxel. Los fármacos fueron encapsulados en el interior de la matriz polimérica de los stents. Se emplearon conejos y cerdos como modelos animales. Resultados: Sirolimus y paclitaxel mostraron efecto inhibitorio, mayor en el segundo. La espectroscopia infrarroja y la microscopia óptica y electrónica mostraron que la capa del polímero con el fármaco se adhería adecuadamente al stent. A las cuatro semanas de seguimiento, ambos modelos animales mostraron evolución clínica satisfactoria y adecuada respuesta histológica, si bien el modelo porcino resultó más conveniente para protocolos futuros. Conclusiones: Las pruebas preliminares del stent liberador de fármaco brindó bases para desarrollar el protocolo con un número adecuado en cerdos y con seguimiento clínico angiográfico e histopatológico a tres meses.

Síndrome de CLOVES: tratamiento con rapamicina oral: reporte de dos casos / CLOVES syndrome: treatment with oral rapamycin: report of two cases

INTRODUCCIÓN: El síndrome de CLOVES se caracteriza por sobrecrecimiento lipomatoso asociado a malformaciones vasculares, representando un desafío diagnóstico y terapéutico. La rapamicina, un inhibidor de la vía mTOR, ha demostrado ser una buena alternativa terapéutica en un grupo de anomalías vasculares. Reportamos dos casos de síndrome de CLOVES con buena respuesta al tratamiento con rapamicina oral. OBJETIVO: Reportar la experiencia del uso de rapamicina oral en el tratamiento de dos pacientes con síndrome de CLOVES. CASOS CLÍNICOS: Caso 1: preescolar femenino de tres años de edad con sín drome de CLOVES e historia de hospitalizaciones reiteradas por infección severa de malformaciones linfáticas macroquísticas y episodios trombóticos. Evoluciona con mala calidad de vida, múltiples hospitalizaciones, riesgo quirúrgico y progresión de las lesiones, por lo que se indicó rapamicina oral. A los 6 meses de tratamiento se evidenció reducción clínica y radiológica del tamaño de las masas lipomatosas y linfáticas, ausencia de linforrea cutánea y mejoría significativa de la calidad de vida, sin requerir nuevas hospitalizaciones. Caso 2: escolar femenino de diez años de edad, portadora de síndrome de CLOVES, que desarrolló escoliosis y deterioro de su capacidad motora, haciéndose dependiente del uso de silla de ruedas. Se indicó rapamicina oral, evidenciándose a los cuatro meses de tratamiento mejoría en su capacidad física, independencia y autovalencia, con desaparición de la linforrea. CONCLUSIÓN: Proponemos la rapamicina oral para el tratamiento de pacientes con sín drome de CLOVES que presenten complicaciones y deterioro de la calidad de vida producto de su enfermedad.

INTRODUCTION: CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malforma tions, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two ca ses of CLOVES syndrome with good response to oral rapamycin treatment. OBJECTIVE: To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. CLINICAL CASES: Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospita lizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndro me, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and au tonomy, and absence of lymphorrhea after four months of treatment. CONCLUSION: We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.

Resultados iniciais e tardios de pacientes tratados com stent híbrido eluidor desirolimus ou stent eluidor de everolimus / Early and late outcomes of patients treated with hybrid sirolimus-eluting stent or everolimus-eluting stent

Introdução: O stent Orsiro é um stent híbrido que possui revestimentos passivo (carbeto de silício amorfo)e ativo (ácido poli-L-lático, PLLA). O primeiro encapsula as hastes do stent, promovendo menor inflamação local, e o segundo libera o sirolimus por meio de matriz biodegradável. Nosso objetivo foi comparar os resultados das intervenções coronárias percutâneas (ICP) dos stents Orsiro e Xience® V (eluidor de everolimus) na prática clínica diária. Métodos: Estudo observacional em que os pacientes foram alocados em dois grupos: os que e ceberam exclusivamente um ou mais stents Orsiro e os que receberam exclusivamente stents Xience® V. Desfechos iniciais e tardios foram prospectivamente coletados. Resultados: Entre setembro de 2012 e março de 2014, incluímos 92 e 108 pacientes tratados com stent Orsiro e Xience® V, respectivamente. Características clínicas, angiográficas e do procedimento foram, em sua maioria, semelhantes entre os grupos. As taxas de sucesso do procedimento (98,9% vs. 95,4%; p = 0,22), mortalidade (1,1% vs. 0%; p = 0,40) e trombose do stent (0% vs. 0,9%; p = 0,30) hospitalares não diferiram entre os grupos. O tempo de seguimento foi de 434 ± 111 e 477 ± 66 dias (p = 0,23), respectivamente, não sendo observadas diferenças na mortalidade (0,9% vs. 0%; p = 0,30), trombose do stent (0% vs. 0,9%; p = 0,30)e nem na necessidade de revascularização da lesão alvo (0% vs. 0,9%; p = 0,30). Conclusões: Os stents Orsiro e Xience® V apresentaram desempenho semelhante, com baixas taxas de eventos clínicos e angiográficos iniciais e tardios.

Background: The Orsiro is a hybrid stent which has passive (amorphous silicon carbide) and active(poly-L-lactic acid, PLLA) coatings. The first layer encapsulates the stent struts, promoting lower local inflammation, where as the second layer releases sirolimus through a biodegradable matrix. This study’saim was to compare the results of percutaneous coronary interventions (PCI) with Orsiro and Xience™ Vstents (everolimus-eluting stent) in daily clinical practice. Methods: Observational study in which patients were divided into two groups: those who received only one or more Orsiro stents, and those who received only XienceTM V stents. Early and late outcomes were prospectively collected. Results: Between September 2012 and March 2014, this study included 92 and 108 patients treated with Orsiro and Xience™ V stents, respectively. Clinical, angiographic, and procedure characteristics were mostly similar between groups. Rates of procedure success (98.9% vs. 95.4%; p = 0.22), in-hospital mortality (1.1% vs. 0%; p = 0.40) and stent thrombosis (0% vs. 0.9%, p = 0.30) did not differ between groups. Time of follow-up was 434 ± 111 and477 ± 66 days (p = 0.23), respectively, and differences in mortality (0.9% vs. 0%, p = 0.30), stent thrombosis (0% vs.0.9%; p = 0.30), or need for repeat revascularization of the target lesion (0% vs. 0.9%; p = 0.30) were not observed. Conclusions: Orsiro and Xience™ V stents showed similar performance, with low rates of early and late clinical and angiographic events.

Desfechos clínicos tardios de pacientes diabéticos tratados com stents farmacológicos eluidores de sirolimus ou everolimus: uma análise do registro DESIRE / Late clinical outcomes of diabetic patients treated with sirolimus or everolimus drug-eluting stents: an analysis of the DESIRE registry

Stents farmacológicos (SF) de segunda geração demonstraram melhor desempenho clínico que os de primeira geração, sobretudo pela redução nas taxas de trombose, mas ainda não está claro se esse benefício se estende a diabéticos da prática diária. Objetivamos comparar o desempenho de pacientes diabéticos não selecionados tratados com SF eluidores de sirolimus (SES; primeira geração) vs. SF eluidoresde everolimus (SEE; segunda geração).Métodos: Entre 2007 e 2014, 798 diabéticos foram tratados com SES (n = 414) ou SEE (n = 384) e incluídosnesta análise. Seguimento clínico tardio foi obtido em 99,4% da população e os grupos foram comparados quanto à ocorrência de eventos cardíacos adversos maiores (ECAM) e trombose de stent. Resultados: A idade da população foi semelhante, com predomínio do sexo masculino. Em ambas as coortes, a apresentação clínica mais frequente foi a doença coronária estável. Número de vasos tratados (1,50 ± 0,62 vs. 1,52 ± 0,72; p = 0,88) e extensão total de stents (36,1 ± 20,4 mm vs. 37,7 ± 22,2 mm; p = 0,32) foram semelhantes. Os pacientes tratados com SEE apresentaram menores taxas de ECAM (15% vs. 6,8%; p < 0,001), sobretudo à custa de menor mortalidade cardíaca (5,3% vs. 1,3%; p < 0,001). Observou-se também menor ocorrência de trombose de stent definitiva/provável com SF de segunda geração (3,4% vs. 0,5%; p = 0,004).Conclusões: Nesta experiência unicêntrica, o uso de SEE em diabéticos mostrou-se com menor mortalidadecardíaca e trombose da endoprótese. Esse benefício se fez mais evidente no seguimento mais tardio...

Despite the better clinical performance of second-generation drug-eluting stents (DES)when compared to first-generation DES in controlled trials, mainly due to reduction in thrombosis rate, it remains unclear whether this benefit extends to diabetic patients treated in the daily practice. We sought to compare the clinical outcomes of unselected diabetic patients treated with either sirolimus eluting stents - SES (first-generation DES) or everolimus-eluting stents - EES (second-generation DES). Methods: Between January 2007 and October 2014 a total of 798 diabetic patients were treated with SES(n = 414) and EES (n = 384). Long-term clinical follow-up was achieved in 99,4% of the population andthe groups were compared regarding the occurrence of major adverse cardiac events (MACE) and stent thrombosis. Results: In both cohorts age was similar, and most patients were male. Stable coronary disease was the most frequent clinical presentation. The number of treated vessels (1.50 ± 0.62 vs. 1.52 ± 0.72; p = 0.88)and the total stent length (36.1 ± 20.4 vs. 37.7 ± 22.2 mm; p = 0.32) were similar between groups. Patients treated with EES showed lower rates of MACE (15% vs. 6.8%, p < 0.001), mainly due to a lower cardiac death(5.3% vs. 1.3%, p < 0.001). There was also less definitive/ probable thrombosis with the second generation DES (3.4% vs. 0.5%, p = 0.004)...

Everolimo, sirolimo e tacrolimo para imunossupressão em transplante cardíaco / Everolymus, sirolimus and tacrolimus for immunosupression in cardiac transplantation

CONTEXTO: Os transplantes de coração salvam mais de 250 vidas por ano, mas estão entre as trinta terapias mais dispendiosas acessíveis universalmente a toda população brasileira, reembolsadas pelo Sistema Único de Saúde do Brasil, SUS, e há crítica auto-limitação de órgãos disponíveis. Quase a metade deles apresenta episódios de rejeição que pode não responder aos tratamentos disponíveis no SUS. Estima-se que cerca de 1.000 transplantados serão beneficiados mediante resgate com alternativas terapêuticas. EVIDÊNCIAS CIENTÍFICAS: A meta-análise sobre mortalidade dos 10 e 12 estudos controlados randomizados, ECRs, comparando ciclosporina e tacrolimo, bem como de 10 e 06 ECRs respectivamente para o sirolimo e everolimo associados com doses reduzidas de ciclosporina e tacrolimo mostrou pouco ou nenhum impacto na sobrevida. A análise empírica de 348 transplantes cardíacos da coorte do InCor-HC/FMUSP mostrou que a probabilidade de sobrevida foi significativamente superior no 1º. ano do período de seguimento em ambos os grupos etários, adultos e crianças. Na coorte de transplantados que sobreviveram ao primeiro ano, observou-se a perda das diferenças de efeito e menor mortalidade na curva da ciclosporina, refletindo as graves condições de deterioro clínico e complicações que levaram ao switch destes pacientes para estas alternativas terapêuticas. Na meta-análise destes ECRs sobre rejeição, tacrolimo ou ciclosporina não diferiram significativamente. Existe benefício significativo de redução de ocorrência de rejeição de -8,93% e -7,39% com o sirolimo e o everolimo associados com doses reduzidas dos inibidores de calcineurina. O uso de tacrolimo e alternativas com mTORs em adultos e crianças no InCor-HC/FMUSP, de fato, proporcionou eficiente controle de episódios de rejeição em pacientes que se mostraram refratários ou eventos adversos, tais como a recidiva de rejeição, insuficiência renal, alergia ou intolerância. DISCUSSÃO: O uso das alternativas terapêuticas varia com a tolerância dos pacientes e também podem causar eventos adversos. Por isto, observa-se uma dinâmica de trocas entre as alternativas visando superar os episódios de rejeição. Embora a síntese da literatura não mostre taxa diferente de mortalidade entre os esquemas alternativos, estes diversos itinerários terapêuticos permitiram observar uma redução da significativa da mortalidade entre os 348 transplantados no InCor-HCFMUSP, sobretudo no 1º. Ano, resgatando-se + 26% dos casos refratários. Esta experiência é comparável à evolução publicada na análise da base Heart & Lung Transplantation Registry da International Society, onde 69% dos transplantados são mantidos com alternativas. RECOMENDAÇÃO DA CONITEC: Os membros da CONITEC presentes na 35ª reunião da CONITEC, realizada nos dias 6 e 7 de maio de 2015, por unanimidade, deliberaram por recomendar a incorporação dos imunossupressores (everolimo, sirolimo e tacrolimo) em transplantes cardíacos. CONSULTA PÚBLICA: Foram recebidas 4 contribuições durante a consulta pública. Todas as contribuições foram a favor incorporação dos imunossupressores (everolimo, sirolimo e tacrolimo. Não foram apresentadas novas evidências científicas sobre o tema. DELIBERAÇÃO FINAL: Recomendar a incorporação dos imunossupressores (everolimo, sirolimo e tacrolimo em transplante cardíaco, conforme Protocolo Clínico do Ministério da Saúde. Foi assinado o Registro de Deliberação n˚137/2015. DECISÃO: Incorporar everolimo, sirolimo e tacrolimo para imunossupressão em transplante cardíaco no âmbito do Sistema Único de Saúde-SUS. Portaria nº 52 publicada no DOU nº 187, pág. 71, de 30/09/2015.

A 12-Month Single Arm Pilot Study to Evaluate the Efficacy and Safety of Sirolimus in Combination with Tacrolimus in Kidney Transplant Recipients at High Immunologic Risk

The optimal immunosuppressive strategy for renal transplant recipients at high immunologic risk remains a topic of investigation. This prospective single arm pilot study was undertaken to evaluate the safety and efficacy of a combined tacrolimus and sirolimus regimen in recipients at immunological high risk and to compare outcomes with a contemporaneous control group received tacrolimus and mycophenolate mofetil. Patients that received a renal allograft between 2010 and 2011 at high risk (defined as panel reactive antibodies > 50%, 4 or more human leukocyte antigen mismatches, or retransplantation) were enrolled. All patients received basiliximab induction and corticosteroids. A total of 28 recipients treated with tacrolimus and sirolimus were enrolled in this study and 69 recipients were retrospectively reviewed as a control group. The sirolimus group showed a higher, but not statistically significant, incidence of biopsy proven acute rejection and a lower glomerular filtration rate than the control group. Furthermore, sirolimus group was associated with significant increases in BKV infection (P = 0.031), dyslipidemia (P = 0.004), and lymphocele (P = 0.020). The study was terminated prematurely due to a high incidence of adverse events. A de novo tacrolimus/sirolimus combination regimen may not be an ideal choice for recipients at high immunological risk.

Estudo Pré-Clínico de Stent com Polímero Biodegradável e Liberação Abluminal de Sirolimus / Preclinical Study of a Biodegradable Polymer-based Stent with Abluminal Sirolimus Release

Fundamento: Stents recobertos com polímeros bioabsorvíveis e fármacos apenas na face abluminal podem ser mais seguros que stents farmacológicos com polímeros permanentes. Objetivo: Relatar os resultados experimentais com o stent Inspiron(r), um stent recoberto com polímero bioabsorvível e com liberação de sirolimus apenas da face abluminal, recentemente aprovado para uso clínico. Métodos: Foram implantados 45 stents nas artérias coronárias de 15 porcos e, no 28° dia pós-implante, foram obtidos os resultados angiográficos, de ultrassonografia intracoronária e de histomorfologia. Cinco grupos foram avaliados: Grupo I (nove stents sem recobrimento); Grupo II (nove stents com polímero bioabsorvível nas faces luminal e abluminal); Grupo III (oito stents com polímero bioabsorvível na face abluminal); Grupo IV (nove stents com polímero bioabsorvível e sirolimus nas faces luminal e abluminal); e Grupo V (dez stents com polímero bioabsorvível e sirolimus na face abluminal exclusivamente). Resultados: Observamos, para os Grupos I, II, III, IV e V respectivamente: porcentual de estenose de 29 ± 20; 36 ± 14; 33 ± 19; 22 ± 13 e 26 ± 15 (p = 0,443); perda luminal tardia (em mm) de 1,02 ± 0,60; 1,24 ± 0,48; 1,11 ± 0,54; 0,72 ± 0,44 e 0,78 ± 0,39 (p = 0,253); área neointimal (em mm2) de 2,60 ± 1,99; 2,74 ± 1,51; 2,74 ± 1,30; 1,30 ± 1,14 e 0,97 ± 0,84 (p = 0,001; Grupos IV e V versus Grupos I, II e III) e porcentual de área neointimal de 35 ± 25; 38 ± 18; 39 ± 19; 19 ± 18 e 15 ± 12 (p = 0,001; Grupo IV e V versus Grupo I, II e III). Os escores de injúria e inflamação foram baixos e sem diferenças entre os grupos. Conclusão: O stent Inspiron(r) foi seguro e inibiu significativamente a hiperplasia ...

Background: Bioabsorbable polymer stents with drug elution only on the abluminal surface may be safer than durable polymer drug-eluting stents. Objective: To report the experimental findings with the Inspiron(tm) stent - a bioabsorbable polymer-coated stent with sirolimus release from the abluminal surface only, recently approved for clinical use. Methods: 45 stents were implanted in the coronary arteries of 15 pigs. On day 28 after implantation, angiographic, intracoronary ultrasonographic and histomorphological data were collected. Five groups were analyzed: Group I (nine bare-metal stents); Group II (nine coated with bioabsorbable polymer on the luminal and abluminal surfaces); Group III (eight stents coated with bioabsorbable polymer on the abluminal surface); Group IV (nine stents with bioabsorbable polymer and sirolimus on the luminal and abluminal surfaces); and Group V (ten stents with bioabsorbable polymer and sirolimus only on the abluminal surface). Results: The following results were observed for Groups I, II, III, IV and V, respectively: percentage stenosis of 29 ± 20; 36 ± 14; 33 ± 19; 22 ± 13 and 26 ± 15 (p = 0.443); late lumen loss (in mm) of 1.02 ± 0.60; 1.24 ± 0.48; 1.11 ± 0.54; 0.72 ± 0.44 and 0.78 ± 0.39 (p = 0.253); neointimal area (in mm2 )) of 2.60 ± 1.99; 2.74 ± 1.51; 2.74 ± 1.30; 1.30 ± 1.14 and 0.97 ± 0.84 (p = 0.001; Groups IV and V versus Groups I, II and III); and percentage neointimal area of 35 ± 25; 38 ± 18; 39 ± 19; 19 ± 18 and 15 ± 12 (p = 0.001; Groups IV and V versus Groups I, II and III). Injury and inflammation scores were low and with no differences between the groups. Conclusion: The Inspiron(tm) stent proved to be safe and was able to significantly inhibit the neointimal hyperplasia observed on day 28 after implantation in porcine coronary arteries. .

Cost-Effectiveness of Drug-Eluting vs. Bare-Metal Stents in Patients with Coronary Artery Disease from the Korean National Health Insurance Database

PURPOSE: The aim of this study was to evaluate the cost-effectiveness of the use of drug-eluting stents (DESs), as compared with bare-metal stents (BMSs) in Korea. MATERIALS AND METHODS: A retrospective cohort study was conducted between January 2000 and December 2007. Subjects were stent-treated for the first time between 2004 and 2005, with four years of follow-up (2004-2007) (n=43674). The incremental cost-effectiveness ratio (ICER) was used to calculate the costs of DESs compared with BMSs among patients with coronary artery disease (CAD). Cost-effectiveness was assessed with effectiveness defined as a reduction in major adverse cardiac events after six months and after one, two, three, and four years. RESULTS: The total costs of a DESs were 674108 Korean won (KRW) higher than that of a BMSs at the end of the follow-up; 13635 thousand KRW per patient treated with DESs and 12960 thousand KRW per patient treated with BMSs. The ICER was 256315 per KRW/death avoided and 293090 per KRW/re-stenting avoided among the CAD patients at the end of the follow-up. CONCLUSION: The ICER for the high-risk patients was lower than that for the low-risk patients. The use of DESs is clinically more useful than the use of BMSs for CAD and myocardial infarction patients, especially for those considered to be high-risk patients in Korea.

Sirolimus Conversion Efficacy for Graft Function Improvement and Histopathology in Renal Recipients with Mild to Moderate Renal Insufficiency

This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.

Stent farmacológico autoexpansível miniaturizado em coronárias de pequeno calibre: eficácia tardia / Miniaturized self-expanding drug-eluting stent in small coronary arteries: late effectiveness

FUNDAMENTO: Na angioplastia coronária percutânea (ACP), os vasos de fino calibre representam um fator de risco para reestenose. O stent farmacológico (SF) autoexpansível Sparrow®, de perfil menor que os sistemas atuais, nunca foi testado nesse cenário. OBJETIVOS: Avaliar a eficácia tardia do SF Sparrow®, com relação à perda luminal tardia intrastent (PLT intrastent) aos oito meses. MÉTODOS: Estudo prospectivo, randomizado, em P com doença arterial coronária (DAC) sintomática ou com isquemia documentada, submetido à ACP em vasos de calibre < 2,75 mm, dividido em dois grupos quanto ao tipo de stent Sparrow®: grupo 1, SF; grupo 2, stent não farmacológico (SNF). O seguimento clínico foi de 12 meses. De imediato e aos oito meses, avaliação pela angiografia coronária quantitativa (ACQ). Para o cálculo da amostra estimou-se diminuição de mais de 65% de PLT intrastent com o SF. Para análise estatística utilizou-se o programa IBM SPSS Statistics® versão 19 (Chicago, Illinois, EUA). RESULTADOS: Foram incluídos 24 p, 12 em cada grupo. Os grupos SF e SNF foram semelhantes quanto à idade (63,25 ± 10,01 versus 64,58 ± 11,54, p = 0,765), sexo masculino (58,3% versus 33,3%, p = 0,412), fatores de risco e todos os aspectos angiográficos. Os resultados imediatos foram satisfatórios em ambos os grupos. Aos oito meses, a PLT intrastent foi significativamente menor no SF do que no SNF (SF 0,25 ± 0,16 versus SNF 0,97 ± 0,76, p = 0,008). CONCLUSÃO: Em ACP de vasos de calibre < 2,75 mm, o SF Sparrow® determinou significativa redução da PLT intrastent, em comparação ao SNF Sparrow®.

BACKGROUND: Small vessels represent a risk factor for restenosis in percutaneous coronary angioplasty (PCA). The Sparrow® self-expanding drug-eluting stent, which has a lower profile than the current systems, has never been tested in this scenario. OBJECTIVES: To evaluate the late effectiveness of the Sparrow® drug-eluting stent, regarding in-stent late lumen loss (LLL). METHODS: Patients with ischemia, symptomatic or documented, were submitted to PCA in vessels with reference diameter < 2.75 mm, divided into two groups regarding Sparrow® stent type: group 1: Sparrow® drug-eluting stent (DES), group 2: Sparrow® bare metal stent (BMS). Clinical follow-up duration was 12 months. Evaluation using quantitative coronary angiography (QCA) was performed immediately and at 8 months. A decrease of over 65% of in-stent LLL with DES was estimated to calculate sample size. IBM® SPSS software, release 19 (Chicago, Illinois, USA) was used for the statistical analysis. RESULTS: A total of 24 patients were randomized, 12 in each group. The DES and BMS groups were similar in age (63.25 ± 10.01 vs. 64.58 ± 11.54, p = 0.765), male gender (58.3% vs. 33.3%, p = 0.412), risk factors and all angiographs aspects. Immediate results were satisfactory in both groups. At 8 months in-stent late lumen loss was significantly lower in DES than in BMS group (DES vs. BMS 0.25 ± 0.16 0.97 ± 0.76, p = 0.008). CONCLUSION: In small-vessel PCA, the Sparrow® DES determined significant reduction in in-stent LLL, when compared to Sparrow® BMS.

Migration of a sirolimus-eluting stent from the ostium of the left main coronary artery to the right deep femoral artery

No abstract available.

A Prospective, Randomized Comparison of Promus Everolimus-Eluting and TAXUS Liberte Paclitaxel-Eluting Stent Systems in Patients with Coronary Artery Disease Eligible for Percutaneous Coronary Intervention: The PROMISE Study

We aimed comparing two-year clinical outcomes of the Everolimus-Eluting Promus and Paclitaxel-Eluting TAXUS Liberte stents used in routine clinical practice. Patients with objective evidence of ischemia and coronary artery disease eligible for PCI were prospectively randomized to everolimus-eluting stent (EES) or paclitaxel-eluting stent (PES) groups. The primary end-point was ischemia-driven target vessel revascularization (TVR) at 2 yr after intervention, and the secondary end-point was a major adverse cardiac event (MACE), such as death, myocardial infarction (MI), target lesion revascularization (TLR), TVR or stent thrombosis. A total of 850 patients with 1,039 lesions was randomized to the EES (n=425) and PES (n=425) groups. Ischemic-driven TVR at 2 yr was 3.8% in the PES and 1.2% in the EES group (P for non-inferiority=0.021). MACE rates were significantly different; 5.6% in PES and 2.5% in EES (P = 0.027). Rates of MI (0.8% in PES vs 0.2% in EES, P = 0.308), all deaths (1.5% in PES vs 1.2% in EES, P = 0.739) and stent thrombosis (0.3% in PES vs 0.7% in EES, P = 0.325) were similar. The clinical outcomes of EES are superior to PES, mainly due to a reduction in the rate of ischemia-driven TVR.

Avaliação da endotelização de hastes de stents em artérias ilíacas de coelhos / Assessment of stent strut endothelialization in iliac arteries of rabbits

FUNDAMENTO: A rápida endotelização pós-implante de stent é ocorrência desejável por teoricamente reduzir a possibilidade de trombose do stent. OBJETIVO: Avaliar a extensão da endotelização de hastes de stents eluidores de sirolimus (liberados da face luminal e abluminal e abluminal exclusivamente) em artérias ilíacas de coelhos. MÉTODOS: Foram implantados em artérias ilíacas de 10 coelhos quatro stents eluidores de sirolimus na face luminal e abluminal, três stents eluidores de sirolimus na face abluminal, seis stents recobertos com polímero e quatro stents sem recobrimento. Após quatro semanas, foi realizada eutanásia e utilizou-se microscopia eletrônica de varredura para quantificação da área de hastes de stent exposta e da porcentagem de endotelização. RESULTADOS: A área (média ± DP) (mm²) de hastes expostas de stent sem recobrimento, stent recoberto com polímero, stent eluidor de sirolimus na face luminal e abluminal e stent eluidor de sirolimus na face abluminal foi de 0,12 ± 0,08; 0,09 ± 0,12; 0,60 ± 0,67 e 0,05 ± 0,04 respectivamente (p = 0,120). A porcentagem de endotelização (média ± DP) (%) de stent sem recobrimento, stent recoberto com polímero, stent eluidor de sirolimus na face luminal e abluminal e stent eluidor de sirolimus na face abluminal foi de 99 ± 01; 99 ± 0; 97 ± 03 e 99 ± 0 respectivamente (p = 0,133). CONCLUSÃO: Após quatro semanas de implante em artérias ilíacas de coelhos, os stents com liberação de sirolimus tanto da face luminal e abluminal quanto da face abluminal exclusivamente apresentaram taxas de endotelização de hastes de stent semelhantes aos apresentados nos demais tipos de stents sem eluição de medicamento.

BACKGROUND: Fast post-implantation stent endothelialization is desirable for theoretically reducing the possibility of stent thrombosis. OBJECTIVE: To evaluate the extent of sirolimus-eluting stent strut endothelialization (delivered from the luminal and abluminal aspects or abluminal aspect only) in the iliac arteries of rabbits. METHODS: The iliac arteries of 10 rabbits were implanted with four sirolimus-eluting stents in the luminal and abluminal aspects, three sirolimus-eluting stents in the abluminal aspect, six polymer-coated stents, and four uncoated stents. After four weeks, the rabbits were euthanized and scanning electron microscopy was performed to quantify the area of exposed stent strut as well as the percentage of endothelialization. RESULTS: The area (mean ± SD) (mm²) of exposed uncoated stent struts, polymer-coated stents, sirulimus-eluting stent in the abluminal and luminal aspects and sirolimus-eluting stent in the abluminal aspect was 0.12 ± 0.08, 0.09 ± 0.12, 0.60 ± 0.67 and 0.05 ± 0.04, respectively (p = 0.120). The percentage of endothelialization (mean ± SD) (%) of uncoated stents, polymer-coated stents, sirolimus-eluting stents in the luminal and abluminal aspects and sirolimus-eluting stents in the abluminal aspect was 99 ± 01, 99 ± 0. 97 ± 03 and 99 ± 0, respectively (p = 0.133). CONCLUSION: After four weeks of implantation in the iliac arteries of rabbits, both the sirolimus-eluting stents in the luminal plus abluminal aspects and those in the abluminal aspect only showed stent strut endothelialization rates similar to those of the other types of non-drug eluting stents.

Estudo da dose excipiente: fármaco com avaliação da hiperplasia neointimal por tomografia de coerência óptica e histopatologia em artérias coronárias porcinas após o emprego do balão eluidor de sirolimus / Excipient: Drug Dose Finding with Neointimal Hyperplasia Assessed by Optical Coherence Tomography and Histopathology in Porcine Coronary Arteries after Sirolimus-Eluting Balloon Employment

Introdução: Magic TouchTM é um balão recoberto com nanopartículas carreadoras de sirolimus. Objetivamos encontrar a dose excipiente: fármaco com a maior capacidade de inibição da proliferação neointimal 28 dias após o uso desse balão pós-implante de stent não-farmacológico em artérias coronárias porcinas. Métodos: Foram avaliados 14 porcos com implante coronário de stent não-farmacológico seguido por dilatação(60 segundos) com balões com relação excipiente: sirolimus 1:1, 0,5:1, 0,25:1 e 1:0 ou balão controle. Após 28 dias a hiperplasia neointimal foi estudada por tomografia de coerência óptica e histopatologia. Resultados: A hiperplasia neointimal porcentual (%) avaliada pela tomografia de coerência óptica e pela histomorfometria foi de 32,2 e 35,1, 28,1 e 33,4, 17,3 e20,9, 28,6 e 30,2, e 37,9 e 42,3 nos grupos excipiente: sirolimus 0,25:1, 0,5:1, 1:1, 1:0 e balão controle, respectivamente (P = 0,03 para excipiente: sirolimus 1:1 vs. balão controle). A espessura (mm) da neoíntima inter-hastes foi de 0,23, 0,30, 0,16, 0,24 e 0,30 nos grupos excipiente: sirolimus 0,25:1,0,5:1, 1:1, 1:0 e balão controle, respectivamente (P < 0,01para excipiente: sirolimus 1:1 vs. balão controle). Os escores de inflamação, injúria e deposição de fibrina foram baixos e sem diferenças significantes entre os grupos. Conclusões: Ocorreu gradual aumento da eficácia inibitória da proliferação neointimal à medida que a concentração do excipiente aumentou; amenor eficácia ocorreu com a formulação excipiente: sirolimus 0,25:1 e a mais intensa inibição foi observada com a formulação excipiente: sirolimus 1:1, a qual reduziu significantemente a proliferação neointimal em comparação com o grupo controle, com baixos índices de inflamação e injúria.

Impacto dos stents e do sirolimus por via oral na vasomotilidade coronariana dependente e independente do endotelio / Impact of stenting and oral sirolimus on endothelium-dependent and independent coronary vasomotion

FUNDAMENTO: Não há consenso sobre o impacto do implante de stent sobre a função endotelial no longo prazo. Há relatos de disfunção endotelial aumentada com stent com sirolimus quando comparado com o stent metálico convencional (BMS). OBJETIVO: Este estudo visa a avaliar o impacto do BMS e o efeito do sirolimus por via oral sobre a função endotelial. MÉTODOS: Quarenta e cinco pacientes foram randomizados em três grupos: BMS + altas doses de sirolimus oral (dose inicial de 15 mg, seguida de 6 mg/dia durante quatro semanas); BMS + baixa dose de sirolimus (6 mg, seguida de 2 mg por dia durante quatro semanas) e BMS sem sirolimus. Mudanças na vasoconstrição ou vasodilatação, em um segmento de 15 milímetros começando pelo extremo distal do stent em resposta a acetilcolina e nitroglicerina, foram avaliadas por angiografia quantitativa. RESULTADOS: Os grupos apresentaram características angiográficas semelhantes. A variação percentual de diâmetro em resposta a acetilcolina foi semelhante em todos os grupos, nos dois momentos (p = 0,469). Quatro horas após o implante de stent, o segmento alvo apresentou uma disfunção endotelial que se manteve após oito meses em todos os grupos. Em todos os grupos, a vasomotricidade independente de endotélio em resposta a nitroglicerina foi semelhante, às quatro horas e aos oito meses, com diâmetro do segmento alvo aumentado após a infusão de nitroglicerina (p = 0,001). CONCLUSÃO: A disfunção endotelial esteve igualmente presente no segmento distal de 15 milímetros do segmento tratado, às 4 horas e aos 8 meses após implante do stent. O sirolimus administrado por via oral durante quatro semanas para evitar a reestenose não afetou o estado de vasomotricidade endotélio dependente e independente.

BACKGROUND: There is no consensus regarding the impact of stenting on long-term endothelial function. There have been reports of increased endothelial dysfunction with sirolimus-eluting stents as compared to bare metal stenting (BMS). OBJECTIVE: This study aims to assess the impact of BMS and the effect of oral sirolimus on endothelial function. METHODS: Forty-five patients were randomized into three groups: BMS + high-dose oral sirolimus (initial dose of 15 mg, followed by 6 mg/day for four weeks); BMS + low-dose sirolimus (6 mg followed by 2 mg daily for four weeks); and BMS without sirolimus. Changes in vasoconstriction or vasodilation in a 15 mm segment starting at the distal stent end in response to acetylcholine and nitroglycerin were assessed by quantitative angiography. RESULTS: The groups had similar angiographic characteristics. The percent variation in diameter in response to acetylcholine was similar in all groups at the two time points (p = 0.469). Four hours after stenting, the target segment presented an endothelial dysfunction that was maintained after eight months in all groups. In all groups, endothelium-independent vasomotion in response to nitroglycerin was similar at four hours and eight months, with increased target segment diameter after nitroglycerin infusion (p = 0.001). CONCLUSION: The endothelial dysfunction was similarly present at the 15 mm segment distal to the treated segment, at 4 hours and 8 months after stenting. Sirolimus administered orally during 4 weeks to prevent restenosis did not affect the status of endothelium-dependent and independent vasomotion.

Comparison of Drug-Eluting Stents in Acute Myocardial Infarction Patients with Chronic Kidney Disease

BACKGROUND/AIMS: To determine which drug-eluting stents are more effective in acute myocardial infarction (MI) patients with chronic kidney disease (CKD). METHODS: This study included a total of 3,566 acute MI survivors with CKD from the Korea Acute Myocardial Infarction Registry who were treated with stenting and followed up for 12 months: 1,845 patients who received sirolimus-eluting stents (SES), 1,356 who received paclitaxel-eluting stents (PES), and 365 who received zotarolimus-eluting stents (ZES). CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 calculated by the modification of diet in renal disease method. RESULTS: At the 12-month follow-up, patients receiving ZES demonstrated a higher incidence (14.8%) of major adverse cardiac events (MACEs) compared to those receiving SES (10.1%) and PES (12%, p = 0.019). The ZES patients also had a higher incidence (3.9%) of target lesion revascularization (TLR) compared to those receiving SES (1.5%) and PES (2.4%, p = 0.011). After adjusting for confounding factors, ZES was associated with a higher incidence of MACE and TLR than SES (adjusted hazard ratio [HR], 0.623; 95% confidence interval [CI], 0.442 to 0.879; p = 0.007; adjusted HR, 0.350; 95% CI, 0.165 to 0.743; p = 0.006, respectively), and with a higher rate of TLR than PES (adjusted HR, 0.471; 95% CI, 0.223 to 0.997; p = 0.049). CONCLUSIONS: Our findings suggest that ZES is less effective than SES and PES in terms of 12-month TLR, and has a higher incidence of MACE due to a higher TLR rate compared with SES, in acute MI patients with CKD.

Clinical Characteristics of Coronary Drug-Eluting Stent Fracture: Insights from a Two-Center DES Registry

Stent fracture (SF) has been implicated as a risk factor for in-stent restenosis, but its incidence and clinical characteristics are not well established. Therefore we investigated the conditions associated with stent fracture and its clinical presentation and outcome. Between 2004 and 2007, consecutive cases of SF were collected from the Seoul National University Hospital. Clinical characteristics and outcome of patients with fractured stents were compared with a ten-fold cohort of age and gender matched controls (n = 236). A total of 4,845 patients received percutaneous coronary intervention and 3,315 patients (68.4%) underwent angiographic follow-up. Twenty-eight fractured stents were observed in 24 patients. The incidence of SF was 0.89% for sirolimus-eluting stents (SES) and 0.09% for paclitaxel-eluting stents. Chronic kidney disease, stent implantation in the right coronary artery (RCA), and SES use were independent predictors of drug-eluting stent fracture by multivariate analysis. SF was significantly associated with binary restenosis (11.4% vs 41.7%, P < 0.001) and increased risk of target lesion revascularization (8.1% vs 33.3%, P = 0.001). Patients with SF but without significant restenosis showed excellent outcome despite only medical treatment. In conclusion, SF is associated with increased rates of restenosis and repeat revascularization. Significant risk factors include chronic kidney disease, RCA intervention, and SES use.