Many natural products have been so far tested regarding their potency to inhibit vascular smooth muscle cell proliferation, a process involved in atherosclerosis, pulmonary hypertension and restenosis. Compounds studied in vitro and in vivo as VSMC proliferation inhibitors include, for example indirubin-3'-monoxime, resveratrol, hyperoside, plumericin, pelargonidin, zerumbone and apamin. Moreover, taxol and rapamycin, the most prominent compounds applied in drug-eluting stents to counteract restenosis, are natural products. Numerous studies show that natural products have proven to yield effective inhibitors of vascular smooth muscle cell proliferation and ongoing research effort might result in the discovery of further clinically relevant compounds.

Chronic inflammation of the native vessel wall with infiltration of lipid-laden foamy macrophages through impaired endothelium results in atherosclerosis. Percutaneous coronary intervention, including metallic stent implantation, is now widely utilized for the treatment of atherosclerotic lesions of the coronary artery. Bare-metal stents and the subsequently developed drug-eluting stents seal the atherosclerosis and resolve lumen stenosis or obstruction of the epicardial coronary artery and myocardial ischemia. After stent implantation, neointima proliferates within the stented segment. Chronic inflammation caused by a foreign body reaction to the implanted stent and subsequent neovascularization, which is characterized by the continuous recruitment of macrophages into the vessel, result in the transformation of the usual neointima into an atheromatous neointima. Neointima with an atherosclerotic appearance, such as that caused by thin-cap fibroatheromas, is now recognized as neoatherosclerosis, which can sometimes cause in-stent restenosis and acute thrombotic occlusion originating from the stent segment following disruption of the atheroma. Neoatherosclerosis is emerging as a new coronary stent-associated problem that has not yet been resolved. In this review article, we will discuss possible mechanisms, clinical challenges, and the future outlook of neoatherosclerosis.

Little is known about the very late-phase morphological vessel characteristics within the sirolimus-eluting stent (SES).

We assessed a total of 12 patients with 15 SES implantations who underwent repeat angiographic and angioscopic procedures after 5 and 7 years. The degree of neointimal stent coverage (NSC) was classified as follows: grade 0, uncovered struts; grade 1, visible struts through a thin neointima; or grade 2, invisible struts with complete neointimal coverage. The maximum and minimum NSC grades were evaluated and the existence of in-stent thrombus was also recorded for all patients. The prevalence of a maximum NSC grade of 2 increased and that of a minimum NSC grade of 0 decreased, although there was no significant difference in prevalence between 5 and 7 years. One of four in-stent thrombus identified at 5 years had disappeared from 5 to 7 years and a new thrombus was found in another patient at 7 years. Thus, the incidence of in-stent thrombus did not change from 5 to 7 years. In one case, a thrombus was observed inside the angiographic aneurysmal change, but none of the thrombi were related to adverse events.

This angioscopic study reported gradual arterial repair and continuous delayed healing associated with subclinical thrombus formation 7 years after SES deployment.

The loss-of-function genotype of cytochrome P450 2C19 (CYP2C19) has been proposed as a risk factor for stent thrombosis in patients with drug-eluting stent implantation. The aim of this study was to clarify the clinical features of patients with angioscopically-detected in-stent mural thrombi (ISMT).

Enrolled were 100 stented segments in 55 patients with stable angina (20 bare-metal stents; 39 Cypher sirolimus-eluting stents [SES]; 26 Endeavor zotarolimus-eluting stents [ZES]; 13 Xience V everolimus-eluting stents; and 2 Nobori biolimus-eluting stents). Dual antiplatelet therapy (100 mg aspirin+75 mg clopidogrel once daily) had been continued since stenting. A poor metabolizer (PM) of clopidogrel was defined as a homozygote of CYP2C19 loss-of-function alleles. Coronary angioscopy revealed ISMT in 6 patients (5 SES, 1 ZES). Between the ISMT group and control group (n=49), there were no significant differences with regards to the VerifyNow P2Y12platelet function assay or in-stent endothelial coverage grade. Exact logistic regression analyses with stepwise forward selection at a significance level of 0.10 were performed to reveal predictive variables for ISMT (respectively: odds ratio, 95% confidence interval, P value: CYP2C19 PM genotype (3.28, 0.88-24.80, 0.09), SES implantation (3.37, 0.90-28.09, 0.08), and presence of yellow plaque (3.69, 1.14-25.70, 0.02).

Patients with ISMT were characterized by SES implantation, poor clopidogrel metabolism, and in-stent yellow plaque.