Fig. 14.1
Schematic presentation of time sequence after BMS implantation to coronary artery. Initially, platelet deposition and activation occur at the injury site, leading to activate inflammatory cells that secrete molecules that bind to specific receptors on smooth muscle cells. Migration and proliferation of smooth muscle cells increase the cellular mass in the neointima (Ref. [1])
Comparative preclinical histologic studies remain the most effective method for assessing the healing characteristics of vascular stents. Porcine coronary models have been widely used for the evaluation of newly developed stent devices including drug-eluting stent (DES) [2]. Figure 14.2 demonstrated the hematoxylin-eosin staining histopathological cross sections in porcine coronary model at different time points following BMS implantation. As was shown in Fig. 14.1, initial thrombus formation at 2 days was followed by inflammatory cell infiltration and smooth muscle cell proliferation at 4–10 days. Finally, matured thick fibrocellular neointima was observed at 30 days.
Fig. 14.2
Histopathological cross sections in porcine coronary model at different time points following BMS implantation. Initial thrombus formation at 2 days was followed by inflammatory cell infiltration and smooth muscle cell proliferation at 4–10 days. Finally, matured thick fibrocellular neointima was observed at 30 days
We have evaluated angioscopic appearance of coronary arteries with BMS in parallel with assessment of arterial wall histological characteristics in nine porcine models at 30 days. It has been generally recognized that vascular response to stent implantation at 1 month in porcine is equivalent to 3–6 months in humans. So, this observation mimicked the midterm (6 months) follow-up angioscopy in human. Macroscopic images of vascular luminal surfaces of coronary segments showed BMS developed opaque white neointima, with virtual strut invisibility. Angioscopic finding was consistent with macroscopic images, and most of the stent strut embedded in the neointima was not visible at 30 days in porcine (Fig. 14.3) [3]. When angioscopic grading for neointimal coverage was classified into 4 semiquantitative grading categories, grade 0 = fully visible struts (similar to immediate post-implant); grade 1 = struts covered, but protruding into lumen, and transparently visible; grade 2 = struts embedded by neointima, but still translucent; and grade 3 = struts fully embedded and invisible, 93 % of BMS neointimal coverage was angioscopic grade 3, with invisible struts and overlying coverage of white, opaque neointima. 7 % and 0 % of BMS met criteria for grades 2 and 1, respectively (Fig. 14.4) [4]. Microscopic images of BMS segment exhibited well-healed, thick fibrocellular neointima, completely covered with endothelial cells. Only minute deposits of inspissated thrombus and fibrin deposits were observed (Fig. 14.3).
Fig. 14.3
Macroscopic images of vascular luminal surfaces of coronary segments implanted with BMS. BMS developed opaque white neointima, with virtual strut invisibility. Most of the stent struts embedded in the neointima were not visible by angioscopy. Movat pentachrome staining (20×) and hematoxylin-eosin staining (200×) showed BMS segment exhibited well-healed, thick fibrocellular neointima, completely covered with endothelial cells. Only minute deposits of inspissated thrombus and fibrin deposits were observed (Ref. [3])
Fig. 14.4
(a) Strut coverage grade by angioscopy. Grade 0 was defined as stent struts that were fully visible, similar to immediately after implantation. Grade 1 was defined as stent struts that bulged into the lumen and, although covered, were still transparently visible. Grade 2 was defined as stent struts that were visible, but not clearly seen. Grade 3 was defined as stent struts that were not visible by angioscopy. (b) Proportion of neointimal coverage grade at BMS-implanted segment at 1 month in porcine coronary model. Most of the segments developed grade 3 coverage
14.3 Time Course of Neointimal Growth After BMS Implantation in Human
The timing of healing response to stent placement may be difficult to translate from animal models to human; however, it has been suggested that the stages of healing are remarkably similar. Histological investigations using human autopsy samples have reported that migration of smooth muscle cells is identified around 2 weeks after BMS implantation and complete neointimal growth and endothelial coverage is achieved at 12 weeks [5, 6]. Angioscopy has been used to evaluate the time course of neointimal coverage of stents in human. According to the serial angioscopic study, no neointimal coverage was found angioscopically at 8–18 days post-implant [7]. Approximately 3 months were required for the completion of neointimal stent coverage after BMS implantation [7, 8]. Angioscopic study has shown complete neointimal coverage was observed in all of the BMS segments at 6 months [4]. Figure 14.5 demonstrates the angioscopic image of BMS-implanted segment at 6-month follow-up.
Fig. 14.5
Representative angiography and angioscopy images at 6 months after BMS implantation to stable coronary disease in human. Complete neointimal coverage was observed by angioscopy
BMS have a plaque-healing/stabilizing effect. With BMS treatment, the unstable yellow plaque containing protruding mixed thrombus in infarction-related lesion changes to stable white plaque during 6-month follow-up [9]. Figure 14.6 shows the serial changes of angioscopic images at pre- and post-balloon inflation, post-stent placement, and 6-month follow-up after BMS implantation in patients with acute myocardial infarction (AMI). It is noteworthy that neointimal proliferation provides surface passivation of unstable plaques as well as the disappearance of early intra-stent thrombus [8]. Interestingly, plaque morphology on angioscopy may affect the artery healing process after BMS implantation. A serial angioscopic study of patients with AMI has demonstrated that the grade of neointimal stent coverage at 1-month follow-up is lower in the ruptured segment of infarct-related lesions than in the adjacent non-ruptured segment. Also the yellow grade of plaque color in ruptured segment was higher than that of non-ruptured segment immediately after stenting and at 1-month follow-up. Neointimal stent coverage and plaque color eventually became equivalent at 6 months [10]. These observations may in part support the rationale of recent guidelines regarding the duration of dual antiplatelet therapy after the onset of acute coronary syndrome [11].
Fig. 14.6
Serial angioscopic images. (a) At baseline, a protruding mixed thrombus was seen. (b) Immediately after balloon angioplasty, a protruding thrombus and intimal flap were seen. (c) Immediately after stenting. (d) At 1-month follow-up, a lining thrombus was seen. (e) At 1-month follow-up, there was partial neointimal coverage. (f) At 6-month follow-up, there was smooth and white plaque without thrombus. F intimal flap, GW guide wire, L lumen, Y yellow plaque, T thrombus. (Ref. [9])
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