Fig. 9.1
Changes in vessel diameter in response to Ach and NTG infusion expressed as percentage of changes versus the baseline diameter in comparison between the SES and the PES. Ach acetylcholine, NTG nitroglycerin, SES sirolimus-eluting stent, PES paclitaxel-eluting stent
Fig. 9.2
A representative case with SES. In this case, SES was implanted in the LAD. At 9 months follow-up, restenosis was not found. Severe vasoconstriction to Ach distal to the stent was observed, while vasodilation to NTG was preserved. In angioscopic evaluation, poor neointimal coverage and yellow plaque between the strut were observed in the SES. SES sirolimus-eluting stent, LAD left anterior descending artery, NTG nitroglycerin
Fig. 9.3
A representative case with PES. PES was implanted in the LAD. At 9 months follow-up, severe vasoconstriction to Ach distal to the stent was observed, while vasodilation to NTG was preserved. The poor neointimal coverage and red thrombus formation were observed in the PES by angioscopy. PES paclitaxel-eluting stent, LAD left anterior descending artery, NTG nitroglycerin
Fig. 9.4
Changes in vessel diameter in response to Ach and NTG infusion expressed as percentage of changes versus the baseline diameter in comparison between the poor-coverage group and the good-coverage group. p values indicate difference between the poor-coverage group and the good-coverage group. Ach acetylcholine, NTG nitroglycerin
Fig. 9.5
Angioscopic findings in comparison between the poor-coverage group and the good-coverage group
9.3.2 Possible Mechanisms of Endothelial Dysfunction with First-Generation DES
Previous studies have reported some potential mechanisms of abnormal endothelial function with DES. Re-endothelialization is nearly completed after BMS implantation [34], but not after DES implantation [28, 29]. Accordingly, reduced NO production attributable to delayed re-endothelialization and/or endothelial dysfunction at the stented site could be associated with endothelial dysfunction at areas adjacent to the DES. Sahler LG, et al. showed that antiproliferative drugs may have locally diffused through the vaso vasorum to the non-stented distal segments, leading to impaired endothelial function distal to the DES [35]. Pendyala LK, et al. reported polymer incompatibility and potentiation of superoxide activity may be a culprit of endothelial dysfunction with PES [36]. We have previously reported that thrombi release several vasoactive substances which are shed into the distal site and would impair distal endothelial function in the canine model of acute coronary syndromes [37, 38] and endothelial dysfunction distal to the stent is strongly associated with existence of thrombus inside the first-generation DES implantation in the clinical setting [27]. Thus, poor re-endothelialization and thrombus at the stent site might work together to aggravate endothelial function adjacent to the first-generation DES.
9.3.3 Endothelial Dysfunction and Delayed Healing with First-Generation DES Persist for a Long-Term?
Some angioscopic studies revealed delayed arterial healing associated with first-generation DES is still observed at 2–5 years after PCI [31, 33]. However, there are few investigations that evaluated how long endothelial dysfunction persists after DES implantation. Kitahara et al. showed endothelial dysfunction at >12 months after SES implantation was smaller than that at <12 months [26]. However, in their study, only low-dose Ach infusion was used, and additionally serial change in endothelial function was not examined. We examined serial changes in endothelial function and intra-stent condition by angioscopy in comparison between 9 months and over 24 months after PES implantation. In that study, endothelial dysfunction distal to the PES and delayed healing improved slightly as time passed; however, those findings were still observed over 24 months after stent implantation (Figs. 9.6, 9.7, and 9.8) [39]. Thus, the restoration of coronary endothelial function and arterial healing associated with first-generation DES might be significantly delayed.
Fig. 9.6
A representative case with PES (2). In this case, PES was implanted in the LAD. At 9 months follow-up, restenosis was not found. Severe vasoconstriction to Ach distal to the stent was observed. At 24 months follow-up, vasoconstriction to Ach was still observed at the distal segment to the stent. In angioscopic evaluation, the maximum neointimal coverage site was grade 3 coverage. In contrast, many uncovered struts and red thrombus were found at both 9 and 24 months follow-up, similarly in the minimum neointimal coverage site. PES paclitaxel-eluting stent, LAD left anterior descending artery
Fig. 9.7
Changes in vascular response to Ach and NTG distal to PES in comparison between 9 months and over 24 months. Ach acetylcholine, NTG nitroglycerin, PES paclitaxel-eluting stent
Fig. 9.8
Angioscopic findings at minimum coverage site in PES in comparison between 9 months and over 24 months
9.3.4 Endothelial Function and Arterial Healing in Newer-Generation DES
Several newer-generation DESs have been developed with different drugs, polymers, drug release kinetics, and stent designs. Zotarolimus-eluting stent (ZES) (EndeavorTM, Medtronic Inc., Santa Rosa, California) and everolimus-eluting stent (EES) (XienceTM, Abbott Vascular, Santa Clara, California) are newly developed DES. Both ZES and EES showed better outcomes compared with first-generation DES in real-world patients [40, 41].
In our study, ZES and EES demonstrated better endothelial function and arterial healing than first-generation DES at 9 months after PCI (Figs. 9.8, 9.9, 9.10, 9.11, and 9.12) [42], similar to other reports [43–46].
Fig. 9.9
A representative case with EES. EES was implanted in the LAD. At 9 months follow- up, vascular response to Ach was very small, and vasodilation to NTG was preserved. In angioscopic observation, relatively good neointimal coverage was observed, and there was no thrombus in the EES. EES everolimus-eluting stent, LAD left anterior descending artery, NTG nitroglycerin
Fig. 9.10
A representative case with ZES. EES was implanted in the LAD. At 9 months follow-up, vascular response to Ach and NTG was preserved. In angioscopic observation, complete neointimal coverage was obtained, and there was no thrombus in the ZES. ZES zotarolimus-eluting stent, LAD left anterior descending artery, NTG nitroglycerin
Fig. 9.11
Changes in vessel diameter in response to Ach and NTG infusion expressed as percentage of changes versus the baseline diameter in comparison between the first-generation DES and the second-generation DES. Ach acetylcholine, NTG nitroglycerin, DES drug-eluting stent, SES sirolimus-eluting stent, PES paclitaxel-eluting stent, EES everolimus-eluting stent, ZES zotarolimus-eluting stent
Fig. 9.12
Angioscopic findings in comparison between the first-generation DES and the second-generation DES. DES drug-eluting stent, SES sirolimus-eluting stent, PES paclitaxel-eluting stent, EES everolimus-eluting stent, ZES zotarolimus-eluting stent
9.4 Conclusion
To evaluate endothelial function using intravascular imaging modalities in human coronary arteries would be challenging. However, in patients with DES, assessment of intra-stent condition by imaging modalities, especially angioscopy which enables to visually inspect the macroscopic pathology, could be a surrogate for endothelial function with DES.
