Treatment of In-Stent Restenosis by Excimer Laser Coronary Atherectomy and Drug-Coated Balloon: Serial Assessment with Optical Coherence Tomography.

OBJECTIVES: We aimed to compare the results of neointimal modification before drug-coated balloon (DCB) treatment with excimer laser coronary atherectomy (ELCA) plus scoring balloon predilation versus scoring balloon alone in patients presenting with in-stent restenosis (ISR). BACKGROUND: Treatment of ISR with ELCA typically results in superior acute gain by neointima debulking. However, the efficacy of combination therapy of ELCA and DCB remains unknown. METHODS: A total of 42 patients (44 ISR lesions) undergoing DCB treatment with ELCA plus scoring balloon (ELCA group, n = 18) or scoring balloon alone (non-ELCA group, n = 24) were evaluated via serial assessment by optical coherence tomography (OCT) performed before, after intervention, and at 6 months. RESULTS: Although there was significantly greater frequency of diffuse restenosis and percent diameter stenosis (%DS) after intervention in the ELCA group, comparable result was shown in %DS, late lumen loss, and binary angiographic restenosis at follow-up. On OCT analysis, a decreased tendency in the minimum lumen area and a significant decrease in the minimum stent area were observed in the ELCA group between 6-month follow-up and after intervention (-0.89 ± 1.36 mm2 vs. -0.09 ± 1.25 mm2, p = 0.05, -0.49 ± 1.48 mm2 vs. 0.28 ± 0.78 mm2, p = 0.03, respectively). The changes in the neointimal area were similar between the groups, and target lesion revascularization showed comparable rates at 1 year (11.1% vs. 11.4%, p = 0.85). CONCLUSIONS: Despite greater %DS after intervention, ELCA before DCB had possible benefit for late angiographic and clinical outcome.

Optical coherence tomography and histopathological assessment of delayed arterial healing after drug-eluting stent implant in a pig coronary model.

BACKGROUND: Delayed healing, such as persistent inflammation and fibrin deposition, and vascular dysfunction after drug-eluting stent has been reported. Histological validation of coronary optical coherence tomography (OCT) morphology has not yet been done. METHODS: Sirolimus eluting stents (SES, n=8) and bare metal stents (BMS n=8) were implanted in pig coronary arteries. One month after implantation, an acetylcholine challenge test and OCT were performed. The OCT texture pattern of the neointima was classified into one of the three categories; Layered type, Homo type, and Hetero type. Hearts were harvested for histopathological scoring of inflammation and intramural thrombus. RESULTS: Inflammation and intramural thrombus scores were higher in the Hetero type than in the Layered type and Homo type. OCT intensity of the Homo type was higher than that of the Layered type and Hetero type. Most SES were of the Hetero type. Conversely, most BMS were of the Homo type. SES exhibited higher inflammation and intramural thrombus than BMS (1.72 ± 0.89 vs 1.00 ± 0.00, P=0.0003, 2.39 ± 0.70 vs 0.92 ± 0.28, P<0.001 respectively). After acetylcholine injection, the diameter change was 4.31 ± 4.80% for SES versus -3.68 ± 6.81% for BMS (P=0.024). CONCLUSIONS: The Hetero type texture pattern in OCT images was associated with histological inflammation and intramural thrombus predominantly found in SES, and is related to endothelial dysfunction.

In stent restenosis and thrombosis assessment after EP224283 injection in a rat model.

OBJECTIVE: After stent implantation, platelet aggregation and thrombus formation are thought to play a key role in the early phase of in-stent restenosis (ISR). Drug-eluting stents have reduced ISR, but are associated with healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. EP224283 is a new dual-action antithrombotic molecule combining a GPIIbIIIa antagonist and a factor Xa inhibitor. We investigated its efficacy on restenosis in a rat model of ISR and on platelet adhesion. METHODS AND RESULTS: Rat aortas were stented and the animals received either EP224283 or vehicle subcutaneously every 48 h. At day 7 and day 28 after surgery, the stented aortas were removed and processed for morphometric analysis or protein analysis. At day 28, EP224283 significantly reduced neointima growth (in the range of 20%). Protein analysis revealed that EP224283 reduced cell proliferation pathways: ERK1/2 and Akt were down-regulated and p38 up-regulated. Expression of Ki67 was also reduced. In vitro assessment depicted a reduction of platelet activation and platelet adhesion among treated rats. CONCLUSION: These results show a beneficial effect of EP224283 on in-stent restenosis and on stent thrombogenicity that may improve results after stent implantation. Further investigations are required to assess the efficacy of a local delivery of EP224283 on both acute thrombosis and ISR.

Cre8™ coronary stent: preclinical in vivo assessment of a new generation polymer-free DES with Amphilimus™ formulation.

AIMS: This new generation of DES has attempted to improve clinical safety by avoiding the presence of polymers. The present preclinical in vivo study was designed to investigate the safety profile of Cre8™ stent. This is a new coronary stent based on Amphilimus™, a sirolimus formulated with a polymer-free amphiphilic carrier released from reservoirs machined onto the abluminal stent surface. METHODS AND RESULTS: Cre8™ stents were compared with two controls: R3 (the same platform only loaded with an amphiphilic carrier) and the Cypher Select Plus® stent (Cordis, Johnson & Johnson, Warren, NJ, USA). All devices (48 stents) were implanted in porcine coronary arteries with subsequent histological and morphometric evaluations at seven, 30 and 90 days. Early endothelisation at seven days was almost complete in all stents. Vessel wall histology at 30 days demonstrated a mild inflammation score in all groups (an inflammation score lower than 1 was observed in 100% of Cre8 stent, 71.5% for R3 and 66.7% for Cypher; p=n.s.) while morphometry showed a significantly smaller neointimal area in Cre8™ (Cre8 0.93±0.43 mm2; R3 1.49±0.67 mm2; Cypher 1.81±0.94 mm2; Cre8 vs. Cypher p<0.05); this difference was maintained after 90 days (inflammation score lower than 1 in 100% of Cre8 stent, 100% for R3 and 66.7% for Cypher; p=n.s. Neointimal area was 1.27±0.56 mm2 for Cre8, 1.74±0.60 mm2 for R3 and 2.79±1.14 mm2 for Cypher; Cre8 and R3 vs. Cypher p<0.05 while neointimal thickness was 0.15±0.07 mm for Cre8, 0.21±0.12 mm for R3 and 0.31±0.15 mm for Cypher; Cre8 vs. Cypher p<0.05). CONCLUSIONS: The most significant experimental evidence appears to be the absence of chronic inflammatory response in Cre8™ stent. This is expressed by a reduced neointimal thickness and inflammatory score at all follow-ups. Such an outcome positively compares with the other DES where a trend to neointimal growth and increased cell infiltration was observed.

Rosiglitazona e lesão vascular em coelhos hipercolesterolêmicos: avaliação da formação neointimal / Rosiglitazone and vascular injury in hypercholesterolemic rabbits: neointimal formation assessment / Rosiglitazona y lesión vascular en conejos hipercolesterolémicos

FUNDAMENTO: O uso da rosiglitazona tem sido o objeto de extensas discussões. OBJETIVO: Avaliar os efeitos da rosiglitazona nas artérias ilíacas, no local da injúria e na artéria contralateral, de coelhos hipercolesterolêmicos submetidos à lesão por cateter-balão. MÉTODOS: Coelhos brancos machos receberam uma dieta hipercolesterolêmica através de gavagem oral por 6 semanas e foram divididos em 2 grupos: grupo rosiglitazona (GR - 14 coelhos tratados com rosiglitazona por 6 semanas) e grupo controle (GC - 18 coelhos sem rosiglitazona). Os animais foram submetidos a lesão por cateter-balão na artéria ilíaca direita no 14º dia. RESULTADOS: Na artéria ilíaca contralateral, não houve diferença significante na razão entre as áreas intimal e medial (RIM) entre os grupos GR e GC. A rosiglitazona não reduziu a probabilidade de lesões tipo I, II ou III (72,73 por cento vs 92,31 por cento; p=0,30) e lesões tipo IV ou V (27,27 por cento vs 7,69 por cento; p=0,30). Na artéria ilíaca homolateral, a área intimal era significantemente menor no GR quando comparado ao GC (p = 0,024). A área luminal era maior no GR quando comparado ao GC (p < 0,0001). Houve uma redução significante de 65 por cento na IMR no GR quando comparado ao GC (p = 0,021). Nenhum dos critérios histológicos para lesões ateroscleróticas tipos I a V (American Heart Association) foram encontrados na artéria ilíaca homolateral. CONCLUSÃO: Esses achados demonstram que a administração de rosiglitazona por 6 semanas impede a aterogênese no local da lesão, mas não em um vaso distante do sítio da lesão.

BACKGROUND: Rosiglitazone has been the focus of extensive discussion. OBJECTIVE: To evaluate the effects of rosiglitazone on iliac arteries, both at the injury site and the contralateral artery, of hypercholesterolemic rabbits undergoing balloon catheter injury. METHODS: White male rabbits were fed a hypercholesterolemic diet by oral gavage for 6 weeks and divided into two groups as follows: rosiglitazone group (14 rabbits treated with rosiglitazone during 6 weeks) and the control group (18 rabbits without rosiglitazone). Animals underwent balloon catheter injury of the right iliac artery on the 14th day. RESULTS: In the contralateral iliac artery, there was no significant difference in the intima/media layer area ratio (IMR) between the control and rosiglitazone groups. Rosiglitazone did not reduce the probability of type I, II, or III lesions (72.73 percent vs 92.31 percent; p=0.30) and type IV or V lesions (27.27 percent vs 7.69 percent; p=0.30). As for the homolateral iliac artery, the intimal area was significantly lower in the rosiglitazone group, as compared to the control group (p = 0.024). The luminal layer area was higher in the rosiglitazone group vs. the control group (p < 0.0001). There was a significant reduction of 65 percent in the IMR in the rosiglitazone group vs the control group (p = 0.021). None of the histological criteria for type I-V atherosclerotic lesions (American Heart Association) were found in the homolateral iliac artery. CONCLUSION: These findings demonstrate that rosiglitazone given for 6 weeks prevents atherogenesis at the injury site, but not in a vessel distant from the injury site.

FUNDAMENTO: El uso de rosiglitazona ha estado siendo el objeto de extensas discusiones. OBJETIVO: Evaluar los efectos de la rosiglitazona en las arterias ilíacas, en el local de la injuria y en la arteria contralateral, de conejos hipercolesterolémicos sometidos a la lesión por catéter-balón. MÉTODOS: Conejos blancos machos recibieron una dieta hipercolesterolémica a través de gavage oral por 6 semanas y se los dividieron en 2 grupos: grupo rosiglitazona (GR - 14 conejos tratados con rosiglitazona por 6 semanas) y grupo control (GC - 18 conejos sin rosiglitazona). Los animales se sometieron a lesión por catéter-balón en la arteria ilíaca derecha en el 14º día. RESULTADOS: En la arteria ilíaca contralateral, no hubo diferencia significativa en la razón entre las áreas íntima y media (RIM) entre los grupos GR y GC. La rosiglitazona no redujo la probabilidad de lesiones tipo I, II ó III (72,73 por ciento vs 92,31 por ciento; p=0,30) y lesiones tipo IV ó V (27,27 por ciento vs 7,69 por ciento; p=0,30). En la arteria ilíaca homolateral, el área intima era significantemente menor en el GR cuando comparado al GC (p = 0,024). El área luminal era mayor en el GR cuando comparado al GC (p < 0,0001). Hubo una reducción significante del 65 por ciento en la IMR en el GR cuando comparado al GC (p = 0,021). Ningún de los criterios histológicos para lesiones ateroscleróticas tipos I a V (American Heart Association) se encontraron en la arteria ilíaca homolateral. CONCLUSIÓN: Estos hallazgos demuestran que la administración de rosiglitazona por 6 semanas impide la aterogénesis en el local de la lesión, pero no en un vaso distante del sitio de la lesión.

Rosiglitazone and vascular injury in hypercholesterolemic rabbits: neointimal formation assessment.

BACKGROUND: Rosiglitazone has been the focus of extensive discussion. OBJECTIVE: To evaluate the effects of rosiglitazone on iliac arteries, both at the injury site and the contralateral artery, of hypercholesterolemic rabbits undergoing balloon catheter injury. METHODS: White male rabbits were fed a hypercholesterolemic diet by oral gavage for 6 weeks and divided into two groups as follows: rosiglitazone group (14 rabbits treated with rosiglitazone during 6 weeks) and the control group (18 rabbits without rosiglitazone). Animals underwent balloon catheter injury of the right iliac artery on the 14th day. RESULTS: In the contralateral iliac artery, there was no significant difference in the intima/media layer area ratio (IMR) between the control and rosiglitazone groups. Rosiglitazone did not reduce the probability of type I, II, or III lesions (72.73% vs 92.31%; p=0.30) and type IV or V lesions (27.27% vs 7.69%; p=0.30). As for the homolateral iliac artery, the intimal area was significantly lower in the rosiglitazone group, as compared to the control group (p = 0.024). The luminal layer area was higher in the rosiglitazone group vs. the control group (p < 0.0001). There was a significant reduction of 65% in the IMR in the rosiglitazone group vs the control group (p = 0.021). None of the histological criteria for type I-V atherosclerotic lesions (American Heart Association) were found in the homolateral iliac artery. CONCLUSION: These findings demonstrate that rosiglitazone given for 6 weeks prevents atherogenesis at the injury site, but not in a vessel distant from the injury site.