Plaque burden is associated with minimal intimal coverage following drug-eluting stent implantation in an adult familial hypercholesterolemia swine model

Abstract

Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients' responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES.

Figure 1

Histological verification of coronary atherosclerotic plaque type by OCT. Different types of plaques were selected by evaluation of OCT, which showed arteries without plaque (NP, a = e = h, green outline), with disease-free arcs (asterisk) and fibrous plaque (non-circumferential plaque) (IT/IX, b = f = i, blue outline) and with lipid-rich circumferential plaque (PIT/FCA, c = g = j, orange outline). The graph shows the distribution of plaque burden as evaluated by OCT (d). H&E (e–g) and ORO (h–j) staining of an artery without atherosclerotic plaque (e,h), with non-circumferential plaque (f,i) and with circumferential plaque (g,j). In ORO staining the lipids are stained in red (j); the asterisks indicate the plaque-free wall and the arrows indicate the lipid-rich regions. NP no plaque, IT/IX intimal thickening/intimal xanthoma, PIT/FCA pathological intimal thickening/fibrous cap atheroma.

Figure 2

Relation between pre-existing plaque burden and strut coverage at follow-up as evaluated by OCT. Top: OCT frames showing an artery with low pre-implant plaque burden (a) and the same artery at follow-up (b), showing fibrotic neointima (NI) (close-up in c). Middle: OCT frames showing an artery with higher pre-implant plaque burden (d) and the same artery at follow-up (e), showing uncovered and poorly-covered struts (close-up in f). Bottom: Quantitative relations between pre-existing plaque burden and NI burden (g) and the percentage uncovered struts (h) at follow-up. The red rimmed dots designate the arteries shown in (a) and (d). While we present the data as a single data set based on non significant differences between the two stent types, full data including stent type are presented in Supplementary Fig. S3 for completeness.

Figure 3

Relation between pre-existing plaque burden and pattern of strut coverage at follow-up as evaluated by OCT. Top: OCT frames showing an artery with low pre-implant plaque burden (a) and the same artery at follow-up (b), showing a homogeneous neointima (NI) (close-up in c). Middle: OCT frames showing an artery with higher pre-implant plaque burden (d) and the same artery at follow-up (e), showing crenellated NI (close-up in f). Bottom: quantitative relation between pre-existing plaque burden and percentage crenellated NI at follow-up (g). The red rimmed dots designate the arteries shown in (a) and (d). While we present the data as a single data set based on insignificant differences between the two stent types, full data including stent type are presented in Supplementary Fig. S3 for completeness.

Figure 4

Contribution of tissue classification and pattern of coverage to the relation between pre-existing plaque burden and neointima (NI) burden at follow-up as evaluated by OCT. Top: plaque tissue was divided into lipid-rich (a, arrow), fibrotic (b), healthy (a, asterisk and c, asterisks) and intima presenting irregularity (c, arrow). Bottom: quantitative relation between pre-existing plaque burden and NI burden with the addition of tissue composition in the form of pie charts (d). Each pie chart indicates the percentage of tissue type for each stented artery (orange = lipid-rich, light blue = fibrous, grey = no plaque, blue = intima irregularity, yellow = artefact). The outer ring indicates the type of pattern of coverage (green = homogeneous NI, red = crenellated NI). The percentages of in-stent tissue composition pre-implant and the pattern of coverage at follow-up for each point shown in the figure are given in Supplementary Table S5. Scale bar: 1 mm.