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.

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.

Erectile dysfunction and coronary artery disease: an association of higher risk in younger men.

INTRODUCTION: The association between erectile dysfunction (ED) and coronary artery disease (CAD) has been described in various settings, but it is unclear if there is an independent interaction with age. AIM: To investigate the interaction of age in the association between ED and CAD. METHODS: This case-control study was conducted among 242 patients referred for elective coronary angiography. One hundred fourteen patients with significant CAD were identified as cases and 128 controls without significant CAD. ED was evaluated by the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire, determined by a score ≤ 25 points. MAIN OUTCOME MEASURES: Significant CAD was based on stenosis of 50% or greater in the diameter in at least one of the major epicardial vessels or their branches. The analysis was conducted in the whole sample and according to the age strata, controlling for the effects of cardiovascular risk factors, testosterone, and C-reactive protein. Results. Patients had on average 58.3 ± 8.9 years. CAD and ED were associated exclusively in patients younger than 60 years (ED in 68.8% of patients with CAD vs. 46.7% of patients without CAD, P = 0.009). The association was independent of cardiovascular risk factors, testosterone and C-reactive protein (risk ratio 2.3, 95% confidence interval from 1.04 to 5.19). Severity of CAD was higher in patients younger than 60 years with ED. CONCLUSIONS: Men with less than 60 years of age who report ED presented a higher risk of having chronic CAD and more severe disease diagnosed by coronary angiography.

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.

Modelo experimental de reestenose intrastent em artérias coronárias de suínos: efeito do implante de stent sobredimensionado / Experimental model of in-stent restenosis in swine coronary arteries: effect of oversized stent deployment

INTRODUÇÃO: Há múltiplos modelos experimentais em animais, entretanto o modelo suíno é o que apresenta características anatômicas e funcionais mais próximas às humanas. Assim sendo, esse trabalho foi realizado com o objetivo de desenvolverr e implementar um protocolo experimental de indução de hiperproliferação neointimal em suínos, visando à criação de técnicasw de lesão vascular simulando a reestenose. Método: De agosto de 2006 a março de 2009, 69 suínos jovens da raça Large White foram submetidos a cinecoronariografia seguida de lesão vascular com implante de 102 stents sobredimensionados, guiados por ultrassom intracoronário. Em 28 dias foi realizado reestudo com nova cinecoronariografia e ultrassom intracoronário. Resultados: O diâmetro luminal mínimo e a área luminal mínima imediatamente após o implante de stent no grupo stent sobredimensionado foram maiores em comparação ao grupo controle...

BACKGROUND: There are several experimental animal models, but, the swine model is the most similar to human anatomic and physiologic characteristics. Therefore, this study was carried out to develop and implement an experimental protocol of vascular neointimal hyperplasia induction in swine, aiming at creating vascular injury techniques simulating restenosis. METHOD: From August 2006 to March 2009, 69 young Large White swine underwent coronary angiography followed by vascular injury and implantation of 102 oversized stents guided by intravascular ultrasound. After 28 days a new coronary angiography and intravascular ultrasound was performed. RESULTS: The minimal luminal diameter and the minimal luminal area immediately after the stent deployment in the group treated with an oversized stent were significantly higher when compared to the control group (3.5 ± 0.3 mm vs. 3 ± 0.2 mm, P < 0.0001 and 40.7 ± 0.3 mm² vs. 30.2 ± 0.2 mm², P < 0.0001). The binary restenosis rate in the group treated with an oversized stent was 92% (69/75 stents), whereas it was 12% (3/25 stents) in the control group, with a statistically significant difference (P < 0.0001). The neointimal hyperplasia volume was significantly higher in the group treated with an oversized stent in comparison to the control group (5.9 ± 0.8 mm³/stent mm vs. 1.8 ± 0.7 mm³/stent mm, P < 0.0001). CONCLUSION: The proposed experimental model of neointimal proliferation induction in swine is effective in inducing instent hyperplasia, and therefore it may be used for the study of the pathophysiologic mechanisms of in-stent restenosis as well as for therapeutic purposes, such as the evaluations of new drugs, new devices and new drug-eluting stents for the prevention and treatment of in-stent 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.

Plasma endothelin-1 levels after coronary stenting in humans.

Endothelin (ET)-1 levels were analyzed in patients who underwent elective coronary stenting. There was a significant increase in systemic ET-1 levels immediately after the procedure, which is probably a marker of endothelial dysfunction that is associated with arterial injury. However, there was no association between ET-1 levels and in-stent restenosis in humans.

Behavior of inflammatory markers of myocardial injury in cardiac surgery: laboratory correlation with the clinical picture of postpericardiotomy syndrome.

OBJECTIVE: To verify the association of serum markers of myocardial injury, such as troponin I, creatinine kinase, and creatinine kinase isoenzyme MB, and inflammatory markers, such as tumor necrosis factor alpha (TNF-alpha), C-reactive protein, and the erythrocyte sedimentation rate in the perioperative period of cardiac surgery, with the occurrence of possible postpericardiotomy syndrome. METHODS: This was a cohort study with 96 patients undergoing cardiac surgery assessed at the following 4 different time periods: the day before surgery (D0); the 3rd postoperative day (D3); between the 7th and 10th postoperative days (D7-10); and the 30th postoperative day (D30). During each period, we evaluated demographic variables (sex and age), surgical variables (type and duration, extracorporeal circulation), and serum dosages of the markers of myocardial injury and inflammatory response. RESULTS: Of all patients, 12 (12.5%) met the clinical criteria for a diagnosis of postpericardiotomy syndrome, and their mean age was 10.3 years lower than the age of the others (P=0.02). The results of the serum markers for tissue injury and inflammatory response were not significantly different between the 2 assessed groups. No significant difference existed regarding either surgery duration or extracorporeal circulation. CONCLUSION: The patients who met the clinical criteria for postpericardiotomy syndrome were significantly younger than the others were. Serum markers for tissue injury and inflammatory response were not different in the clinically affected group, and did not correlate with the different types and duration of surgery or with extracorporeal circulation.

Common variants in the lipoprotein lipase gene in Brazil: association with lipids and angiographically assessed coronary atherosclerosis.

Lipoprotein lipase is the rate-limiting enzyme in the lipolysis of plasma triglyceride-rich lipoproteins. We studied six variants (T-93G, D9N, N291S, PvuII, HindIII and S447X) in the lipoprotein lipase (LPL) gene in 309 non-diabetic patients with angiographically assessed coronary artery disease and in 197 controls in a southern Brazilian population of European descent. The HindIII H-allele was associated with lower triglycerides (p < 0.01) and higher high-density lipoprotein cholesterol (p = 0.03) levels, and the S447X mutation was associated with lower triglyceride levels (p < 0.01) in males, but not females. No other significant lipid associations were observed. Haplotypes were derived from these two sites (HindIII/S447X), and carriers of H-S and H-X haplotypes showed lower triglycerides (p < 0.01) and increased high-density lipoprotein cholesterol (p = 0.01) levels when compared to the H+S haplotype in males. In this gender, the H-X haplotype was associated with a protective effect (OR = 0.36, 95%CI = 0.13-0.97) for significant disease (> or = 60% of luminal coronary stenosis), even controlling for other classical risk factors.

Hemodynamic effects of sildenafil in patients with stable ischemic heart disease.

BACKGROUND: Recently the new specific phosphodiesterase-5 inhibitor sildenafil was introduced into therapy for erectile dysfunction. The hemodynamic effects of sildenafil may be potentially hazardous for patients with cardiac disease. Sildenafil has been reported to augment the hypotensive effects of nitrates. There is sparse information regarding the systemic and pulmonary hemodynamic effects of a single oral dose of sildenafil in patients with stable angina. METHODS: Male patients referred for coronary angiography with diagnosis of chronic stable angina were enrolled in this study to assess the acute hemodynamic effects of sildenafil. Patients receiving long-acting or sublingual nitrates for the last 6 h before the study were excluded. Hemodynamic measurement were taken during right and left heart catheterization in the basal state and 60 min after 50 mg of oral sildenafil. RESULTS: Twelve patients (age 53+/-7 years) were studied. All had stable angina CCS class II or III. Four had previous myocardial infarction. By coronary angiography, seven patients had at least one coronary artery with >70% stenosis, four had at least one with 50-70% stenosis, and one had only intimal irregularities. There were no significant effects of sildenafil on systemic or pulmonary arterial pressure, left ventricle end diastolic pressure, cardiac output, and systemic or pulmonary vascular resistance (P>0.05 for all). No adverse events were observed. CONCLUSION: A single oral dose of sildenafil had no significant hemodynamic effect in supine patients with stable angina. Isolated administration of sildenafil does not appear to be associated to adverse cardiovascular effects.

Comportamento dos marcadores inflamatórios e de injúria miocárdica na cirurgia cardíaca: correlaçäo laboratorial com quadro clínico de síndrome pós-pericardiotomia / Behavior of inflammatory markers of myocardial injury in cardiac surgery: laboratory correlation with the clinical picture of postpericardiotomy syndrome

OBJECTIVE: To verify the association of serum markers of myocardial injury, such as troponin I, creatinine kinase, and creatinine kinase isoenzyme MB, and inflammatory markers, such as tumor necrosis factor alpha (TNF-alpha), C-reactive protein, and the erythrocyte sedimentation rate in the perioperative period of cardiac surgery, with the occurrence of possible postpericardiotomy syndrome. METHODS: This was a cohort study with 96 patients undergoing cardiac surgery assessed at the following 4 different time periods: the day before surgery (D0); the 3rd postoperative day (D3); between the 7th and 10th postoperative days (D7-10); and the 30th postoperative day (D30). During each period, we evaluated demographic variables (sex and age), surgical variables (type and duration , extracorporeal circulation), and serum dosages of the markers of myocardial injury and inflammatory response. RESULTS: Of all patients, 12 (12.5 percent) met the clinical criteria for a diagnosis of postpericardiotomy syndrome, and their mean age was 10.3 years lower than the age of the others (P=0.02). The results of the serum markers for tissue injury and inflammatory response were not significantly different between the 2 assessed groups. No significant difference existed regarding either surgery duration or extracorporeal circulation. CONCLUSION: The patients who met the clinical criteria for postpericardiotomy syndrome were significantly younger than the others were. Serum markers for tissue injury and inflammatory response were not different in the clinically affected group, and did not correlate with the different types and duration of surgery or with extracorporeal circulation

Estudo comparativo das estimulações ventricular direita e biventricular no pós-operatório de revascularização miocárdica / Comparative study of right ventricular and biventricular stimulations in post-operative of myocardial revascularization

OBJETIVO: Nos anos recentes, a ressincronização entricular tem sido proposta como adjuvante no tratamento da insuficiência cardíaca congestiva. O objetivo deste estudo é comparar as alterações eletrocardiográficas e o efeito hemodinâmico imediato das estimulações ventricular direita (EVD) e biventricular (EBV), no pós-operatório de operação de revascularização miocárdica (CRM) com circulação extracorpórea (CEC). CASUÍSTICA E MÉTODOS: Em um ensaio clínico cruzado, 13 pacientes com doença coronária multiarterial, e fração de ejeção inferior a 50por cento, foram submetidos a estimulação epicárdica temporária univentricular direita e biventricular, no quinto dia de pós-operatório. As variáveis analisadas foram duração do complexo QRS, dimensões do átrio esquerdo (AE) e ventrículo esquerdo (VE), fração de encurtamento do VE (delta D) e fração de ejeção do VE. Os grupos foram comparados através do teste de t de Student para amostras pareadas, considerando-se nível de significância de 0,05. RESULTADOS: A duração média do complexo QRS foi de 185±26 ms durante a EVD, e de 126±37 ms com a EBV (p<0,001). Odiâmetro médio do AE com a EVD foi de 40±4 mm, e de 35±4 mm na EBV (p<0,001). As médias dos diâmetros diastólico e sistólico finais do VE foram, respectivamente, de 49±13 mm e 59±11 mm com a EVD, e de 42±12 mm e 52±10 mm durante a EBV (p<0,001). A delta D média do VE determinada pela EVD foi de 18±7por cento, e de 22±8por cento com a EBV (p=0,017). A fração de ejeção média do VE com a EVD foi de 33±14por cento, e de 46±17por cento durante a EBV (p<0,001). CONCLUSÃO: No modelo estudado, a estimulação biventricular temporária determinou melhora significativa do desempenho hemodinâmico, em comparação à estimulação ventricular direita, e um complexo QRS com duração próxima à fisiológica

Valvuloplastia mitral por cateter-balä0, suas indicaçöes e comparaçäo com procedimentos cirúrgicos / Percutaneous valvuloplasty as compared to surgical procedures: its indications

A estenose mitral é a valvulopatia reumática mais comum e acomete principalmente indivíduos jovens. A fase assintomática da doença dura vários anos até o surgimento das primeiras manifestaçöes clínicas, quando entäo a doença adquire um caráter progressivo. A ecocardiografia tem um papel crucial no acompanhamento destes pacientes, permitindo uma adequada avaliaçäo do diagnóstico, severidade e progressäo da doença. O alívio dos sintomas é obtido através do tratamento intervencionista, que consiste no alívio da obstruçäo mecânica. Até alguns anos atrás, as abordagens cirúrgicas eram as únicas opçöes terapêuticas. Recentemente a valvuloplastia percutânea por cateter baläo tem mostrado resultados semelhantes quando comparado com as técnicas cirúrgicas em paciente com anatomia valvular favorável, com custos estimados menores, principalmente com a reutilizaçäo do cateter e taxas de complicaçöes comparáveis . Assim sendo, o tratamento de escolha para pacientes com estenose mitral severa com anatomia valvular favorável parece ser a valvuloplastia percutânea por cateter baläo, sendo reservado o tratamento cirúrgico para aqueles com morfologia valvular inadequada ou contra- indicaçöes ao procedimento percutâneo