Intracoronary Optical Coherence Tomography and Histology of Overlapping Everolimus-Eluting Bioresorbable Vascular Scaffolds in a Porcine Coronary Artery Model

OBJECTIVES: This study sought to assess the vascular response of overlapping Absorb stents compared with overlapping newer-generation everolimus-eluting metallic platform stents (Xience V [XV]) in a porcine coronary artery model. BACKGROUND: The everolimus-eluting bioresorbable vascular scaffold (Absorb) is a novel approach to treating coronary lesions. A persistent inflammatory response, fibrin deposition, and delayed endothelialization have been reported with overlapping first-generation drug-eluting stents. METHODS: Forty-one overlapping Absorb and overlapping Xience V (XV) devices (3.0 × 12 mm) were implanted in the main coronary arteries of 17 nonatherosclerotic pigs with 10% overstretch. Implanted coronary arteries were evaluated by optical coherence tomography (OCT) at 28 days (Absorb n = 11, XV n = 7) and 90 days (Absorb n = 11, XV n = 8), with immediate histological evaluation following euthanasia at the same time points. One animal from each time point was evaluated with scanning electron microscopy alone. A total of 1,407 cross sections were analyzed by OCT and 148 cross sections analyzed histologically. RESULTS: At 28 days in the overlap, OCT analyses indicated 80.1% of Absorb struts and 99.4% of XV struts to be covered (p < 0.0001), corresponding to histological observations of struts with cellular coverage of 75.4% and 99.6%, respectively (p < 0.001). Uncovered struts were almost exclusively related to the presence of "stacked" Absorb struts, that is, with a direct overlay configuration. At 90 days, overlapping Absorb and overlapping XV struts demonstrated >99% strut coverage by OCT and histology, with no evidence of a significant inflammatory process, and comparable % volume obstructions. CONCLUSIONS: In porcine coronary arteries implanted with overlapping Absorb or overlapping XV struts, strut coverage is delayed at 28 days in overlapping Absorb, dependent on the overlay configuration of the thicker Absorb struts. At 90 days, both overlapping Absorb and overlapping XV have comparable strut coverage. The implications of increased strut thickness may have important clinical and design considerations for bioresorbable platforms.

MASP-1 Induced Clotting--The First Model of Prothrombin Activation by MASP-1.

Mannan-binding lectin-associated serine protease-1 (MASP-1), a protein of the complement lectin pathway, resembles thrombin in terms of structural features and substrate specificity. Due to its interplay with several coagulation factors, it has the ability to induce fibrin clot formation independent of the usual coagulation activation pathways. We have recently shown that MASP-1 activates prothrombin and identified arginine (R) 155, R271, and R393 as potential cleavage sites. FXa cleaves R320 instead of R393, and thrombin cleaves R155 and R284 in prothrombin. Here we have used three arginine-to-glutamine mutants of prothrombin, R271Q, R320Q, R393Q and the serine-to-alanine active site mutant S525A to investigate in detail the mechanism of MASP-1 mediated prothrombin activation. Prothrombin wildtype and mutants were digested with MASP-1 and the cleavage products were analysed by SDS-PAGE and N-terminal sequencing. A functional clotting assay was performed by thrombelastography. We have found that MASP-1 activates prothrombin via two simultaneous pathways, either cleaving at R271 or R393 first. Both pathways result in the formation of several active alternative thrombin species. Functional studies confirmed that both R393 and R320 are required for prothrombin activation by MASP-1, whereas R155 is not considered to be an important cleavage site in this process. In conclusion, we have described for the first time a detailed model of prothrombin activation by MASP-1.