DISCUSSION

Although the published incidence of stent-associated CAA after DES implantation ranges from 0.3% to 6%, the true overall incidence of CAA or PSS in the real world practice remains unknown because of insufficient data and study design (Aoki et al., 2008). In our study, CAAs were rarely detected (1.5% per lesion, 2.1% per patient) during the angiographic follow-up. There is a concern that CAAs develop more commonly after DES compared to BMS implantation, available data including that from our review show that there is significantly frequent CAA/PSS formation in DES lesions compared to BMS lesions (Bavry et al., 2007; Aoki et al., 2008; Paulista et al., 2008; James et al., 2009). Especially patients undergoing PCI with sirolimus-eluting stent had dominantly CAA or PSS(Stabile et al., 2004; Virmani et al., 2004). CAA/PSS lesions could be regarded as representing an abnormal vessel wall response and PSS could be regarded as a continuum of pathological process in vessel wall at the site of DES implantation (Rab et al., 1991; Bell et al., 1992;

Nebeker et al., 2006). The title the larger, the better in the BMS era might have caused more vascular injury due to the high-pressure balloon(Hill et al., 1983; Bell et al., 1992; Aoki et al., 2008); however, in the DES era, the high-pressure balloon was not routinely applied and it may have the effect of less vascular injury compared to the previous stent even though DES have the other factors such as polymeric and drug-related reactions (Köster et al., 2000;

Stabile et al., 2004; Hong et al., 2006; Bavry et al., 2007; Alfonso et al., 2009).

Several mechanisms of CAA/PSS formation after DES implantation have been proposed, yet remained to be shown as relevant in most cases. Previous studies have shown that coronary arteries might be damaged by the toxic effects of drugs and polymers in DES(Rab et al.,

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1991; Bell et al., 1992; Slota et al., 1997; Cook et al., 2009). Virmani et al reported some cases in which late thrombosis with malapposition and aneurysmal change occurs, especially in association with a hypersensitivity reaction to SESs(Virmani et al., 2004). Based on the fact that sirolimus is eluted from the stent struts for only 6 weeks (with a half life in the tissue of 60 hours), it seems unlikely that sirolimus itself can induce long-term alterations of the vessel wall(Köster et al., 2000; Hillen et al., 2002; Hong et al., 2006; James et al., 2009).

There might be different mechanism for occurrence of CAA/PSS, the reason why CAA/PSS developed in younger and non-diabetic patients compared than non-CAA/PSS group.

Procedural factors such as longer stent length might be related with lesion complexity as well as more “stent” effect on vessel wall. In the TAXUS VI trial, involving long and complex lesions, in 1.4% of patients in the paclitaxel-eluting stent arm late acquired aneurysms developed compared with patients in bare-metal stent arm (Dawkins et al., 2005;

Nebeker et al., 2006).

Survival analysis showed significant difference in event free survival between CAA/PSS and non-CAA/PSS groups. The major cardiovascular adverse events including instent restenosis were significantly increased in CAA/PSS group compared with non-CAA/PSS group. Previous IVUS studies showed that CAA after DES implantation may be associated with DES restenosis and DES thrombosis (Hong et al., 2006; Alfonso et al., 2009).

In current analysis, DES restenosis was more increased in CAA/PSS group but all cause mortality was not increased compared with patients in non-CAA/PSS group. Several reports about clinical outcome of CAA revealed that asymptomatic patients with CAA had benign course under continued dual antiplatelet therapy and did not experience life-threatening

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problems, as our data revealed that no cardiac mortality related with CAA/PSS (Alfonso et al., 2009; Ahn et al., 2010).

In the current analysis, we used the PSS definition proposed by previous study which could be a transit phenomenon in the progression to CAA (Imai et al., 2011). There are several cases which showed progression from PSS to CAA during follow-up of angiography.

Therefore the incidences of instent restenosis or target lesion revascularization tended to be higher in lesions with CAA than in lesions with PSS, suggesting that possible inflammatory reactions underlying CAA/PSS formation might be milder in PSS than CAA, which involved in the restenosis process of DES(Rab et al., 1991; Virmani et al., 2004). Also, cumulative incidence of stent thrombosis (ST) in lesions with CAA/PSS was numerically higher than ordinary post PCI results (Hong et al., 2006). Therefore, it would be reasonable to regard patients with CAA/PSS as being at high risk for subsequent ST. These observations might suggest that common mechanisms such as chronic inflammation might be operative for both VLST and restenosis requiring TLR(Aoki et al., 2008).

There are several important limitations in this study. First, this was a retrospective observational analysis of registry data from a single center with insufficient procedural information such as ballooning or stenting pressure to investigate the relationship of barotraumas to CAA/PSS occurrence. However, because of large volume center, the number of patients enrolled was not small and all patients who came into the cardiovascular center and underwent follow up angiography were included; therefore we could minimize selection bias. Second, the number of patients with PSS as well as CAA was relatively small to evaluate a possible correlation between morphological classification and risk of VLST. Also,

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risk stratification for VLST according to the status of antiplatelet therapy could not be conducted because of the small number of patients with CAA/PSS. At last, most importantly, the number of patients with VLST after diagnosis of CAA/PSS, as well as in the non-CAA/PSS group, was very small, rendering the estimation of the incidences of VLST relatively inaccurate. The real incidences and risk factors of VLST and myocardial infarction after CAA/PSS diagnosis should be evaluated in a larger number of patients with scheduled follow-up.

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