Impact of Neointimal Calcifications on Acute Stent Performance during the Treatment of In-Stent Restenosis

Abstract

Optical coherence tomography (OCT) has become the invasive imaging modality of choice for coronary stent assessment due to its unmatched spatial resolution. Neointimal calcification (NC) is a rare finding, observed in 5-10% of in-stent restenosis (ISR) neointima. The impact of NC on percutaneous coronary intervention of ISR is unknown. We therefore present the outcome of six unique cases of ISR and NC in which OCT was used to evaluate the impact of NC on the quality of stent-in-stent deployment for the treatment of ISR. This series demonstrates for the first time the impact of NC on stent expansion, a finding which might help guiding percutaneous coronary intervention for ISR with NC.

Keywords
Optical coherence tomography; in-stent restenosis; neointimal calcification; percutaneous coronary intervention; drug eluting stents

Resumo

A Tomografia de coerência óptica (TCO) tornou-se a modalidade de imagem invasiva de escolha para avaliação de stent coronário, devido à sua resolução espacial inigualável. A calcificação da neoíntima (CN) é um achado raro, observado em 5-10% de casos de reestenose intra-stent (RIS) da neoíntima. O impacto da CN na intervenção coronária percutânea da RIS é desconhecida. Por conseguinte, apresentamos o resultado de seis casos únicos de RIS e CN nos quais TCO foi utilizada para avaliar o impacto da CN na qualidade de implante de stent-in-stent, para o tratamento da RIS. Esta série demonstra pela primeira vez o impacto da CN na expansão de stent, uma descoberta que pode ajudar a guiar a intervenção coronária percutânea para RIS com CN.

Palavras-chave
Cardiomiopatias; Calcinose; Stent; Oclusão de Enxerto Vascular

Brief Communication

Neoatherosclerosis, defined as the presence of neointimal calcification (NC) or lipid-laden neointima,¹ has been reported as an important mechanism of late stent failure.² Intravascular imaging modalities enabled further elucidation of neoatherosclerosis´ pathophysiology in vivo.³ Neointimal calcification is observed in 5-10% of in-stent restenosis (ISR),⁴ but its impact on the acute performance of stents implanted in-stent for the treatment of ISR is unknown. Intravascular optical coherence tomography (OCT) enables precise assessment of calcified plaques, while dramatically reducing imaging artifacts compared with intravascular ultrasound.⁵ We therefore used OCT to evaluate the impact of NC on the quality of stent-in-stent deployment for the treatment of ISR.

Herewith we present 6 cases of ISR and NC from our institution's OCT registry. OCT (C7-XR OCT Intravascular Imaging System; St.Jude Medical, St. Paul, Minnesota) images were acquired pre- and post-stent-in-stent procedure using the integrated automated pullback device at 20 mm/s (frame interval of 0.2 mm). Neointimal calcification was defined as an area of low attenuation, low backscattering and clear borders within the stent neointima (Figure 1). Areas and diameters for the old (outer) and newly implanted (inner) stents were obtained; in addition, the mean distance and area between the stents were automatically obtained by 360° chords (Figure 1). Stent eccentricity was defined as minimum stent diameter/maximum stent diameter, while stent expansion was defined as the average stent area at the NC zone divided by the average stent reference [(average proximal reference + average distal reference)/2]. OCT analysis was undertaken offline by a Core Laboratory blinded to the procedure´s characteristics using commercially available software (Version C.0.4, St Jude Medical, St. Paul, MN). Analyses were concentrated in 3 consecutive frames at 3 different locations (i.e. 9 frames per OCT pullback): 1) NC region, 2) proximal and 3) distal to NC region (Figure 1).

Figure 1
OCT images of in-stent restenosis case with neointimal calcification (red arrow) before (A) and after (B) stent-in-stent implantation. Panel C: schematic representation of the effect of neointimal calcification (NC) on stent expansion. D: stent diameter; d: distance between stents.

Stent areas, diameters and stent eccentricity were similar between the frames with NC and the frames distal to the NC (Table 1). When comparing the NC area to the ISR region proximal to the NC, there was a trend for smaller area (difference = 0.9 mm², p = 0.09), and diameter (difference = 0.2mm, p = 0.09) of the inner (newly implanted) stent and bigger stent area (difference = 1.2 mm², p = 0.06), and diameter (difference = 0.2mm, p = 0.06) of the external (older) stent at the location of NC compared to the proximal non-calcified ISR analyzed frames (Table 1).

Table 1
Quantitative effect of neointimal calcification on stent implantation

	Difference			Difference
	Proximal – NC	t	p-value	Distal – NC	t	p-value
Stent 1 Area	0.90	2.11	0.09	0.58	1.52	0.19
Stent 2 Area	-1.20	-2.49	0.06	-0.76	-1.35	0.23
Minimum d	0.03	1.61	0.17	0.02	0.83	0.45
Mean d	0.21	3.90	0.01	0.13	3.21	0.02
Maximum d	0.43	8.30	0.01	0.27	2.06	0.09
Minimum D1	0.17	1.92	0.11	0.09	0.95	0.38
Mean D1	0.20	2.12	0.09	0.12	1.43	0.21
Maximum D1	0.24	2.32	0.07	0.15	1.51	0.19
SE D1	0.02	0.95	0.39	0.02	1.31	0.25
Minimum D2	-0.20	-2.43	0.06	-0.14	-1.31	0.25
Mean D2	-0.20	-2.35	0.06	-0.14	-1.31	0.25
Maximum D2	-0.22	-2.68	0.04	-0.15	-1.45	0.21
SE D2	-0.01	-0.88	0.42	-0.004	-0.38	0.72

• Stent 1: inner (newly implanted stent); stent 2: outer (older stent; d: distance between stents; D: diameter of stent; SE: stent eccentricity (minD/MaxD); NC: neointimal calcification.

The mean distance between the stents was always longer at the area of calcification: difference between the NC area and the distal area was 0.13mm (p = 0.02) and the NC area and the proximal ISR region as 0.21 (p = 0.01). The average stent expansion at the area of calcified neointima was 81.4%.

Stent underexpansion has been linked to clinical adverse events, notably stent thrombosis and restenosis.^6,7 We were able to demonstrate that the presence of NC led to underexpansion of the newly implanted stent compared with adjacent segments. Further investigation is required to determine whether these findings have an impact on clinical events.

The mechanisms leading to stent ISR have been divided into technical (barotrauma outside stented segment, stent gap, residual uncovered atherosclerotic plaques), mechanical (stent underexpansion, non-uniform stent strut distribution, stent fracture, non-uniform drug elution/ deposition, polymer peeling) and biological (drug resistance, hypersensitivity).⁸ The advancement of intravascular imaging, notably OCT, is expected to allow a better understanding of the ISR process and will likely influence the therapeutic strategies (i.e., customized therapy) utilized in this scenario. While current alternatives for ISR therapy (i.e., plain balloon angioplasty, drug-eluting balloon, in-stent DES) are mostly based on the type of restenosis (focal in-stent, focal at stent edge, diffuse in-stent, proliferative),⁹ they do not take neointimal qualitative assessment into account. We believe information provided by OCT imaging could, therefore, further improve therapeutic decisions in ISR. For example, in cases of ISR with NC as herewith described, more aggressive in-stent pre-dilations or use of debulking devices could potentially help improve the expansion of the newly implanted stent. The effect of neointimal atherosclerosis characterization on therapeutic choices for ISR therapy and its effect on clinical outcomes are yet to be determined in future prospective studies.

• Sources of Funding
  There were no external funding sources for this study.
• Study Association
  This study is not associated with any thesis or dissertation work.

References

• ¹
  Tian J, Ren X, Uemura S, Dauerman H, Prasad A, Toma C, et al. Spatial heterogeneity of neoatherosclerosis and its relationship with neovascularization and adjacent plaque characteristics: optical coherence tomography study. Am Heart J. 2014;167(6):884-92.e2.
• ²
  Park SJ, Kang SJ, Virmani R, Nakano M, Ueda Y. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol. 2012;59(23):2051-7.
• ³
  Kang SJ, Mintz GS, Akasaka T, Park DW, Lee JY, Kim WJ, et al. Optical coherence tomographic analysis of in-stent neoatherosclerosis after drug-eluting stent implantation. Circulation. 2011;123(25):2954-63.
• ⁴
  Nakazawa G, Otsuka F, Nakano M, Vorpahl M, Yazdani SK, Ladich E, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 2011;57(11):1314-22.
• ⁵
  Bezerra HG, Attizzani GF, Sirbu V, Musumeci G, Lortkipanidze N, Fujino Y, et al. Optical coherence tomography versus intravascular ultrasound to evaluate coronary artery disease and percutaneous coronary intervention. JACC Cardiovasc Interv. 2013;6(3):228-36.
• ⁶
  Liu X, Doi H, Maehara A, Mintz GS, Costa Jde R Jr, Sano K, et al. A volumetric intravascular ultrasound comparison of early drug-eluting stent thrombosis versus restenosis. JACC Cardiovasc Interv. 2009;2(5):428-34.
• ⁷
  Parodi G, La Manna A, Di Vito L, Valgimigli M, Fineschi M, Bellandi B, et al. Stent-related defects in patients presenting with stent thrombosis: differences at optical coherence tomography between subacute and late/very late thrombosis in the Mechanism Of Stent Thrombosis (MOST) study. EuroIntervention. 2013;9(8):936-44.
• ⁸
  Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol. 2010;56(23):1897-907.
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Publication Dates

• Publication in this collection
  May 2016

History

• Received
  29 Nov 2015
• Reviewed
  21 Jan 2016
• Accepted
  11 Feb 2016