First in human evaluation of a novel Sirolimus-eluting ultra-high molecular weight bioresorbable scaffold: 9-, 24-and 36-months imaging and clinical results from the multi-center RENASCENT study.

BACKGROUND: RENASCENT is a prospective, multi-center first-in-human clinical study to evaluate the clinical performance of the novel sirolimus-eluting 150-µm strut thickness FORTITUDE® BRS for percutaneous coronary intervention of single de novo coronary lesions. METHODS: FORTITUDE® BRS was tested in a prospective study in Italy and Colombia. Study objectives were in-scaffold angiographic late lumen loss (LLL) measured by quantitative coronary angiography and target vessel failure (TVF) defined as the composite rate of cardiac death, target vessel myocardial infarction or ischemia driven target lesion revascularization (TLR) at 9- and 24-months with clinical results up to 36-months. RESULTS: A total of 63 patients were enrolled. All patients underwent lesion pre-dilatation and 22 patients (34.9%) underwent post-dilatation. Clinical device and procedural success was 98.4% (62/63 patients) and 96.8% (61/63 patients) respectively. At 9-months, TVF occurred in 3/61 (4.9%) of the patients including 2 peri-procedural MI and one ischemia-driven TLR. Between 9- to 24-months, ischemia-driven TLR occurred in 3 additional patients (4.9%) including 1 patient who presented with very late ST after stopping all medications. There were no further TVF between 24- and 36-months. CONCLUSIONS: In this multi-center prospective study, the FORTITUDE® BRS was shown to be safe and effective in the treatment of single coronary lesions with low levels of TVF and LLL at 9- and 24-months. It was shown to be clinically safe upto 36-months follow-up.

Effects of Rosuvastatin on Apolipoprotein J in Balloon-Injured Carotid Artery in Rats.

BACKGROUND: Restenosis after percutaneous coronary intervention in coronary heart disease remains an unsolved problem. Clusterin (CLU) (or Apolipoprotein [Apo] J) levels have been reported to be elevated during the progression of postangioplasty restenosis and atherosclerosis. However, its role in neointimal hyperplasia is still controversial. OBJECTIVE: To elucidate the role Apo J in neointimal hyperplasia in a rat carotid artery model in vivo with or without rosuvastatin administration. METHODS: Male Wistar rats were randomly divided into three groups: the control group (n = 20), the model group (n = 20) and the statin intervention group (n = 32). The rats in the intervention group were given 10mg /kg dose of rosuvastatin. A 2F Fogarty catheter was introduced to induce vascular injury. Neointima formation was analyzed 1, 2, 3 and 4 weeks after balloon injury. The level of Apo J was measured by real-time PCR, immunohistochemistry and western blotting. RESULTS: Intimal/medial area ratio (intimal/medial, I/M) was increased after balloon-injury and reached the maximum value at 4weeks in the model group; I/M was slightly increased at 2 weeks and stopped increasing after rosuvastatin administration. The mRNA and protein levels of Apo J in carotid arteries were significantly upregulated after rosuvastatin administration as compared with the model group, and reached maximum values at 2 weeks, which was earlier than in the model group (3 weeks). CONCLUSION: Apo J served as an acute phase reactant after balloon injury in rat carotid arteries. Rosuvastatin may reduce the neointima formation through up-regulation of Apo J. Our results suggest that Apo J exerts a protective role in the restenosis after balloon-injury in rats.

Effects of Rosuvastatin on Apolipoprotein J in Balloon-Injured Carotid Artery in Rats / Efeitos da Rosuvastatina sobre Apolipoproteína J em Artérias de Ratos Lesionadas com Balão

Abstract Background: Restenosis after percutaneous coronary intervention in coronary heart disease remains an unsolved problem. Clusterin (CLU) (or Apolipoprotein [Apo] J) levels have been reported to be elevated during the progression of postangioplasty restenosis and atherosclerosis. However, its role in neointimal hyperplasia is still controversial. Objective: To elucidate the role Apo J in neointimal hyperplasia in a rat carotid artery model in vivo with or without rosuvastatin administration. Methods: Male Wistar rats were randomly divided into three groups: the control group (n = 20), the model group (n = 20) and the statin intervention group (n = 32). The rats in the intervention group were given 10mg /kg dose of rosuvastatin. A 2F Fogarty catheter was introduced to induce vascular injury. Neointima formation was analyzed 1, 2, 3 and 4 weeks after balloon injury. The level of Apo J was measured by real-time PCR, immunohistochemistry and western blotting. Results: Intimal/medial area ratio (intimal/medial, I/M) was increased after balloon-injury and reached the maximum value at 4weeks in the model group; I/M was slightly increased at 2 weeks and stopped increasing after rosuvastatin administration. The mRNA and protein levels of Apo J in carotid arteries were significantly upregulated after rosuvastatin administration as compared with the model group, and reached maximum values at 2 weeks, which was earlier than in the model group (3 weeks). Conclusion: Apo J served as an acute phase reactant after balloon injury in rat carotid arteries. Rosuvastatin may reduce the neointima formation through up-regulation of Apo J. Our results suggest that Apo J exerts a protective role in the restenosis after balloon-injury in rats.

Resumo Fundamento: A reestenose após intervenção coronária percutânea (ICP) após doença coronariana continua um problema não solucionado. Estudos relataram que os níveis de clusterina (CLU), também chamada de apolipoproteína (Apo) J, encontram-se elevados na progressão da reestenose pós-angioplastia e na aterosclerose. Contudo, seu papel na hihperplasia neointimal ainda é controverso. Objetivo: Elucidar o papel da Apo J na hiperplasia neointimal na artéria carótida utilizando um modelo experimental com ratos in vivo, com e sem intervenção com rosuvastatina. Métodos: ratos Wistar machos foram divididos aleatoriamente em três grupos - grupo controle (n = 20), grupo modelo (n = 20), e grupo intervenção com estatina (n = 32). Os ratos no grupo intervenção receberam 10 mg/kg de rosuvastatina. Um cateter Fogarty 2 F foi introduzido para induzir lesão vascular. A formação de neoíntima foi analisada 1, 2, 3 e 4 semanas após lesão com balão. Concentrações de Apo J foram medidas por PCR em tempo real, imuno-histoquímica e western blotting. Resultados: A razão área íntima/média (I/M) aumentou após a lesão com balão e atingiu o valor máximo 4 semanas pós-lesão no grupo modelo; observou-se um pequeno aumento na I/M na semana 2, que cessou após a administração de rosuvastatina. Os níveis de mRNA e proteína da Apo J nas artérias carótidas aumentaram significativamente após administração de rosuvastatina em comparação ao grupo modelo, atingindo o máximo na semana 2, mais cedo em comparação ao grupo modelo (semana 3). Conclusão: A Apo J atuou como reagente de fase aguda após lesão com balão nas artérias carótidas de ratos. A rosuvastatina pode reduzir a formação de neoíntoma por aumento de Apo J. Nossos resultados sugerem que a Apo J exerce um papel protetor na reestenose após lesão com balão em ratos.

Technical difficulty in stenting Supralimus in radial artery graft.

Woman, 67 years old, with unstable angina and history of myocardial revascularization: left internal thoracic artery to anterior descending artery and graft with radial artery (RA) to right coronary artery branches. Coronariography showed stenosis of 90% in the RA graft, treated with conventional stent. After two months, the patient developed unstable angina related to in-stent restenosis, treated with sirolimus-eluting stent. In the follow-up, six months after implantation, the patient was asymptomatic and maintening the outcome of the implant. This case report demonstrates the technical difficulties of percutaneous intervention in RA grafts and treatment outcome of in-stent restenosis with sirolimus stent.

In vitro evaluation of the safe margin, antithrombotic and antiproliferative actions for the treatment of restenosis: Nitric oxide donor and polymers.

Drug-eluting stents (DES) were developed to combat the problem of in-stent restenosis, and evaluating the biological activity from DES systems is critical for its safety and efficacy. To test the cytotoxicity of nitric oxide (NO) donor-containing polymers for their potential use in DES applications, S-nitrosoglutathione (GSNO) or in combination with poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) in an aqueous polymeric solution (PVA/PVP/GSNO) was investigated using Balb/c 3T3 and Rabbit arterial smooth muscle (RASM) cells. The sensitivity of 3T3 cells to the cytotoxicity effects induced by GSNO was higher than that of RASM cells, while RASM cells were more susceptible to alterations in membrane permeability. Cell growth assays showed that GSNO and PVA/PVP/GSNO induced antiproliferative effects in RASM cells. Moreover, the presence of polymers can reduce the cytotoxicity and enhance the antiproliferative effects of GSNO. Dose-dependent inhibition of platelet aggregation was similar for both PVA/PVP/GSNO (EC50 of 3.4 ± 2.3 µM) and GSNO (EC50 of 2.8 ± 1.1 µM) solutions. Platelet adhesion assays showed that the inhibition caused by GSNO (EC50 of 5.0 mM) was dependent on the presence of plasma. These results demonstrate that the methodology adopted here is suitable to establish safety margins and evaluate the antithrombotic potential and antiproliferative effects of NO-eluting biomaterials and polymeric solutions for the new cardiovascular devices, and also to emphasize the importance of using more specific cell lines in these evaluations.

Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients.

OBJECTIVE: To describe the clinical, laboratory, and radiographic manifestations of Takayasu arteritis (TA) in a cohort from the US, evaluate the response to interventions, remission and relapse rates, and disease progression, and compare these observations with those from other cohorts in the US, Japan, India, Italy, and Mexico. METHODS: Seventy-five patients were retrospectively studied using a uniform database that included clinical, laboratory, and imaging data. Vascular imaging studies were performed at least yearly to monitor disease progression. RESULTS: Common manifestations at disease onset included loss or asymmetry of pulses (57%), limb blood pressure discrepancy (53%), and bruits (53%). Eleven percent of patients were asymptomatic prior to disease diagnosis. Initial angiographic studies showed aortic abnormalities in 79% of patients and frequent involvement of the subclavian (65%) and carotid (43%) arteries.Ninety-three percent of longitudinally followed patients attained disease remission of any duration, but only 28% sustained remission of at least 6 months' duration after prednisone was tapered to <10 mg daily. Both angioplasty and vascular surgery were initially successful, but recurrent stenosis occurred in 78% of angioplasty and 36% of bypass/reconstruction procedures. More than two-thirds of patients had difficulty performing routine daily activities and approximately one-fourth of all patients were unable to work. Our cohort was similar to the National Institutes of Health, Italian, Japanese, and Mexican cohorts in terms of the predominance of female subjects and disease manifestations, but differed from the Indian cohort in that the latter group had a higher frequency of male subjects, abdominal aorta and renal artery involvement, and hypertension. CONCLUSION: Although improvement of symptoms in TA usually follows glucocorticoid therapy, relapses usually occur with dosage reduction. Attempts to restore vascular patency are often initially successful, but restenosis occurs frequently. Chronic morbidity and disability occur in most patients with TA in the US.

Oral rapamycin after coronary bare-metal stent implantation to prevent restenosis: the Prospective, Randomized Oral Rapamycin in Argentina (ORAR II) Study.

OBJECTIVES: The purpose of this study was to assess the role of oral rapamycin in decreased restenosis after bare metal stent implantation. BACKGROUND: Small observational studies suggest that the administration of oral rapamycin reduces angiographic restenosis after bare metal stent implantation. METHODS: Between September 2003 and September 2004, 100 patients were randomized to either oral rapamycin (6-mg loading dose given 2.7 h before intervention followed by 3 mg/day for 14 days) plus diltiazem 180 mg/day or no therapy after the implantation of a coronary bare metal stent design. The primary study end point was incidence of angiographic binary restenosis and late loss at nine months. The secondary end points were target lesion revascularization, target vessel revascularization, and incidence of major adverse cardiovascular events at 1 year. RESULTS: Angiographic follow-up was completed in 87% of patients. In the rapamycin group, the drug was well tolerated (26% minor side effects) and was maintained in 96% of patients. At 9 months, the in-segment binary restenosis was reduced by 72% (11.6% rapamycin vs. 42.8% no-therapy group, p = 0.001) and the in-stent binary restenosis was reduced by 65% (12% rapamycin vs. 34.6% no-therapy group, p = 0.009). The in-segment late loss was also significantly reduced with oral therapy (0.66 vs. 1.13 mm, respectively; 43% reduction, p < 0.001). At 1 year, patients in the oral rapamycin group also showed a significantly lower incidence of target vessel revascularization (8.3% vs. 38%, respectively, p < 0.001), target lesion revascularization (7.6% vs. 37.2%, respectively, p < 0.001), and major adverse cardiovascular events (20% vs. 44%, respectively, p = 0.018). CONCLUSIONS: This randomized, controlled, and unblinded study showed that the administration of oral rapamycin during 14 days after stent implantation significantly reduces angiographic and clinical parameters of restenosis.

Four-year angiographic and intravascular ultrasound follow-up of patients treated with sirolimus-eluting stents

Background—Despite the proven superiority of sirolimus-eluting stents (SES) compared with bare stents in the first year after implantation, long-term outcomes of patients treated with these novel devices remain unknown. Our goal was to evaluate the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with SESs 4 years after implantation.Methods and Results—The study included 30 patients treated with sirolimus-eluting Bx Velocity stenting (slow release [SR; n 15] and fast release [FR; n 15]). Twenty-six patients underwent 4-year angiographic and IVUS follow-up and had matched assessments at all time points (index and 4-, 12-, 24-, and 48-month follow-up). One death occurred during the study period in a patient with a patent SES. There were no target-vessel revascularizations or thromboses between 2- and 4-year follow-up examinations. There was no stent thrombosis, target-lesion revascularization, death, or myocardial infarction in the SR group up to 4 years. Cumulative event-free survival rate was 87% for the totalpopulation (80% in the FR group and 93% in the SR group). In-stent late loss was slightly greater in the FR group(0.41 0.49 mm) than the SR group (0.09 0.23) after 4 years. One patient in the FR group had a 52% in-stent restenosis lesion. Percent neointimal hyperplasia volume, as detected by IVUS, remained minimal after 4 years (FR 9.1% and SR 5.7%).Conclusions—This study confirms the longevity of the optimal outcomes observed in patients treated with sirolimuseluting Bx Velocity stents 4 years after implantation. In-stent lumen dimensions remained essentially unchanged at 4-year follow-up, particularly in the population treated with the currently available SES (SR formulation).

Efficacy and safety of oral sirolimus to inhibit in-stent intimal hyperplasia.

Sirolimus systemic administration has shown marked inhibition of neointimal hyperplasia (NIH) after balloon angioplasty in porcine models. In this pilot study, we tested the hypothesis that oral sirolimus is safe and effective to inhibit in-stent NIH and therefore to prevent and treat in-stent restenosis (ISR). Twelve patients (18 lesions) with high risk for ISR, including 8 ISR lesions, were admitted. One day before the procedure, patients were given a 15 mg loading dose of oral sirolimus, followed by 5 mg daily for 28 days, with weekly whole blood level measurements. The daily dose was adjusted to keep the concentration at 10-15 ng/ml. Sirolimus was well tolerated by all patients but one, who died at the end of the third week of treatment. The 4- and 8-month follow-up revealed an angiographic late loss of 0.40 +/- 0.24 and 0.67 +/- 0.45 mm (P < 0.01), respectively. At the same time points, the intravascular ultrasound in in-stent relative volumetric obstruction was 14.4% +/- 9.1% and 23.2% +/- 10.1% (P < 0.01), respectively. At 24-month clinical follow-up, adverse events were one (8.3%) death, two (11.1%) target lesion, and four (22.2%) target vessel revascularizations. In conclusion, in this small group of high-risk ISR patients, oral sirolimus inhibited NIH and therefore may be an effective strategy for the prevention and treatment of ISR.

Intravascular ultrasound study of effects of overlapping sirolimus-eluting stents.

Drug-eluting stents have been investigated as a treatment option for in-stent restenosis after bare metal stenting. However, it remains unclear whether overlapping drug-eluting stents have a toxic effect on the vessel wall. The aim of this study was to analyze the 1-year intravascular ultrasound findings after 2 overlapping sirolimus-eluting stent implantations in patients with in-stent restenosis lesions. Eight patients required 2 sirolimus-eluting stents, 18 mm in length, for full lesion coverage; these stents were implanted with >1-mm overlap. At 1-year follow-up, there were no significant quantitative changes in intravascular ultrasound measurements within the overlapped segment.

Sirolimus-eluting stents inhibit neointimal hyperplasia in diabetic patients. Insights from the RAVEL Trial

Patients with diabetes mellitus have less favourable outcomes after percutaneous coronary intervention (PCI) than non-diabetics. We performed a subgroup analysis of the multicentre RAVEL trial to examine the impact of the sirolimus-eluting stent (SES) on outcomes in diabetic patients. The RAVEL study randomized 238 patients to treatment with either sirolimus-eluting or bare metal stents. Forty-four patients were diabetic; 19 received sirolimus-eluting stents and 25 were treated with bare metal stents. The differences in outcomes between diabetic and non-diabetic patients treated with SES (n=101) were also assessed. Follow-up angiography was performed at 6 months. Major adverse cardiac events (MACE) defined as death, myocardial infarction (MI), or target lesion revascularization (TLR) were analysed at 12-month follow-up. Six-month in-stent late lumen loss was significantly lower for the diabetic SES than the bare stent group (0.07+/-0.2 vs 0.82+/-0.5mm; P<0.001) and similar to that in non-diabetics treated with SES (-0.03+/-0.27mm). There was zero restenosis in the SES groups (diabetic and non-diabetic) compared to a 42%r ate in the diabetic population assigned to bare metal stents (P=0.001) After 12 months, there was one non-Q-wave MI and one non-cardiac death in the diabetic SES group, while 12 patients in the bare metal stent group had MACE (one death, two MI, nine TLR) (P=0.01)-an event-free survival rate of 90% vs 52%, respectively (P<0.01). There were no TLRs in both SES groups compared to 36% rate in the diabetic bare metal stent group (P=0.007)...

Pilot study of oral rapamycin to prevent restenosis in patients undergoing coronary stent therapy: Argentina Single-Center Study (ORAR Trial).

Rapamycin-coated stents are associated with low restenosis rates, but the ability of oral rapamycin to prevent restenosis is unknown. From December 2001 through February 2002, thirty-four patients with 49 lesions were treated with oral rapamycin for 1 month following percutaneous coronary intervention (PCI) with bare stents. Patients received a loading dose of 6 mg rapamycin followed by a daily dose of 2 mg. Rapamycin blood levels were measured in all patients during the third week of treatment. Cholesterol and triglycerides were evaluated before and 1 month after treatment. A 6-month follow-up angiogram was performed in all patients. Angiographic binary restenosis (> 50%), target lesion revascularization (TLR), late loss, treatment compliance and major adverse cardiac events were analyzed independent of rapamycin levels. Baseline characteristics included a history of diabetes in 35% of patients and the presence of in-stent restenosis in 24.5% of lesions (12/49). The rapamycin was well tolerated and only 1 patient discontinued the therapy due to mild side effects. Angiographic restenosis and TLR at 6 months was present in 26.5% of lesions (13/49). Restenosis in de novo lesions was 18.9% (7/37) compared to 50% of in-stent restenotic lesions (6/12; p = 0.08). Restenosis in de novo lesions in patients with rapamycin levels > 8 ng/ml was 0% (0/12), whereas it was 24% (6/25) when the rapamycin levels were < 8 ng/ml (p = 0.07). Late loss was significantly lower when rapamycin levels were > 8 ng/ml (0.3 mm versus 0.9 mm, respectively; p = 0.04). Thus, in this observational study, oral rapamycin administered for 1 month after PCI with bare stenting was safe and well tolerated. Higher therapeutic rapamycin blood levels were associated with a lower late loss and a trend toward a lower restenosis rate in de novo lesions.

Sirolimus-eluting stent for the treatment of in-stent restenosis: a quantitative coronary angiography and three-dimensional intravascular ultrasound study.

BACKGROUND: We have previously reported the safety and effectiveness of sirolimus-eluting stents for the treatment of de novo coronary lesions. The present investigation explored the potential of this technology to treat in-stent restenosis. METHODS AND RESULTS: Twenty-five patients with in-stent restenosis were successfully treated with the implantation of 1 or 2 sirolimus-eluting Bx VELOCITY stents in São Paulo, Brazil. Nine patients received 2 stents (1.4 stents per lesion). Angiographic and volumetric intravascular ultrasound (IVUS) images were obtained after the procedure and at 4 and 12 months. All vessels were patent at the time of 12-month angiography. Angiographic late loss averaged 0.07+/-0.2 mm in-stent and -0.05+/-0.3 mm in-lesion at 4 months, and 0.36+/-0.46 mm in-stent and 0.16+/-0.42 mm in-lesion after 12 months. No patient had in-stent or stent margin restenosis at 4 months, and only one patient developed in-stent restenosis at 1-year follow-up. Intimal hyperplasia by 3-dimensional IVUS was 0.92+/-1.9 mm(3) at 4 months and 2.55+/-4.9 mm(3) after 1 year. Percent volume obstruction was 0.81+/-1.7% and 1.76+/-3.4% at the 4- and 12-month follow-up, respectively. There was no evidence of stent malapposition either acutely or in the follow-up IVUS images, and there were no deaths, stent thromboses, or repeat revascularizations. CONCLUSION: This study demonstrates the safety and the potential utility of sirolimus-eluting Bx VELOCITY stents for the treatment of in-stent restenosis.