Pathophysiology of Restenosis: Interaction of Thrombosis, Hyperplasia, and/or Remodeling

doi:10.1016/S0002-9149(98)00191-X

The American Journal of Cardiology

Volume 81, Issue 7, Supplement 1, 9 April 1998, Pages 14E-17E

https://doi.org/10.1016/S0002-9149(98)00191-X Get rights and content

Abstract

In response to arterial injury, a series of intravascular changes take place that lead to restenosis: thrombosis, neointimal hyperplasia, and remodeling of the vessel. Neointima formation involves thrombosis, recruitment (migration), and recruitment/cell proliferation. To determine the source of neointimal cells that accumulate at the site of injury, pig models of stented and catheterized arteries were examined. The phases of neointima formation can each be seen in the pig in which neointimal cells come from nearby arterial tissue. The pig model was also employed to assess the effect of different degrees of force exerted by self-expanding stents on the arterial wall. In this model, the luminal area increased in response to chronic stent force. Slow expansion may help prevent neointimal hyperplasia and maintain luminal patency without causing damage to the artery.

Section snippets

Histologic Phases of Neointima Formation

The process of neointima formation consists of thrombosis, recruitment, and recruitment/proliferation. In the initial thrombotic phase, platelets, fibrin, and red blood cells accumulate at the site of stent injury. Endothelial cells are recruited, mostly monocytes and lymphocytes, causing an inflammatory response with re-endothelialization. In the proliferative phase, myofibroblasts collect over the lesion from the lumen side first, gradually replacing the deeper thrombotic material.

Vessel Remodeling and Restenosis

In addition to thrombosis and proliferation, remodeling is responsible for restenosis after arterial injury. This has been well characterized by Mintz et al[1]using intravascular ultrasound (IVUS). Remodeling can be defined by changes in vessel size. For example, in perfect remodeling, the artery expands to accommodate neointimal formation. This accommodation totally compensates on a volume-for-volume basis, thus preventing luminal narrowing (Fig. 4). In favorable (but not perfect) remodeling,

Remodeling after Stent Placement

How do these findings apply to remodeling after placement of a stent? Technologic innovation has provided us with the self-expanding stent. In the case of the RADIUS stent (SciMED Life Systems, Maple Grove, MN), precise force can be delivered by the stent to the vessel wall. We investigated the effects of 3 different forces (high, moderate, and low) on vessel injury when this type of stent was employed in a pig model. (The pressures were <0.05, 0.05–0.09, and >0.09 lb/m.)

Because the arteries

Conclusions

Restenosis remains a significant problem in interventional cardiology. The persistent inability to prevent restenosis has raised questions about the prevailing concept that medial cell proliferation and neointimal hyperplasia are its principal causes. Over the past decade, it has become clear that the restenotic process itself is substantially more complex than originally understood. Only when the pathophysiology of this process has been elucidated will we be able to address its consequences.

Selected Readings

Berger PB, Holmes DR Jr, Ohman EM, Ma OH, Murphy JG, Schwartz RS, Serruys PW, Faxon DP. Restenosis, reocclusion and adverse cardiovascular events after successful balloon angioplasty of occluded versus nonoccluded coronary arteries. Results from the Multicenter American Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR). J Am Coll Cardiol 1996;27:1–7.

Hoshiga M, Alpers CE, Smith LL, Giachelli CM, Schwartz SM. Alpha-v beta-3

References (1)

GS Mintz et al.
Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses. An intravascular ultrasound study
Circulation
(1997)

Cited by (171)

JCS/CVIT/JCC 2023 guideline focused update on diagnosis and treatment of vasospastic angina (coronary spastic angina) and coronary microvascular dysfunction
2023, Journal of Cardiology
Angioscopic assessments and clinical outcomes one year after polymer-free biolimus A9-coated coronary stent implantation
2021, Journal of Cardiology
Citation Excerpt :
Although we expected a lower rate of angioscopic thrombus adhesion in DCS than in DP-DES patients, the actual incidence was similar. Thrombus adhesion is an initial phase of arterial healing and does not occur where arterial healing is completed [15,22]. Also, thrombus detection power by CAS is superior to OCT [16].
Polymer-free biolimus A9-coated coronary stent (DCS) has novel features which lead to the expectation of better arterial healing. However, comparisons of intravascular status between DCS and drug-eluting stents (DES), and robust real-word clinical assessments of DCS have been lacking to date.
From September 2017 to September 2018, we evaluated the intra-vascular status of 74 DCS implanted in 55 lesions from 43 patients using coronary angioscopy (CAS) approximately one year after implantation from a cohort of 219 lesions in 158 patients. We set 239 second-generation durable-polymer DES (DP-DES) implanted in 211 lesions from 180 patients from a cohort of 2652 lesions in 1914 patients as the control. Angioscopic images were analyzed to determine (1) the dominant degree of neointimal coverage (NIC) over the stent; (2) the heterogeneity of NIC; (3) yellow color grade of the stented segment; and (4) the presence of intra-stent thrombus. The primary outcome was the incidence of thrombus and secondary outcomes were the other CAS findings, and the 1-year clinical outcomes which included target lesion revascularization (TLR) and major adverse cardiac events (MACE). To minimize inter-group differences in baseline characteristics, propensity score matching was performed for clinical outcomes.
Incidence of thrombus adhesion was similar in DCS and DP-DES groups (28.4% versus 22.6%, p = 0.31). However, the dominant NIC grade was significantly higher in DCS (p < 0.001), while NIC was more heterogeneous in DCS than in DP-DES (p = 0.001). Maximum yellow color grade was similar (p = 0.22). After propensity score matching, 202 lesion pairs from 146 patient pairs were retained for analysis. The cumulative incidence of TLR (4.6% versus 3.8%, p = 0.38) and MACE (11.6% versus 11.7%, p = 0.84) was similar for DCS and DP-DES.
DCS showed thrombus adhesion and clinical outcomes at 1 year similar to DP-DES. DCS can thus be used with similar safety and efficacy as DP-DES.
Radial Artery Remodeling following Transradial Percutaneous Coronary Intervention in Men and Women: Insights from Serial Ultrahigh Frequency Ultrasonography
2020, Cardiovascular Revascularization Medicine
Citation Excerpt :
Our study results suggest that there may be similarities in the manner in which the RA heals after TRI and how coronary arteries heal following balloon angioplasty. Restenosis in coronary arteries has been shown to be due to a combination of negative remodeling of the artery (adventitial scarring and reduction in EEL) and neointimal proliferation resulting from extracellular matrix and cellular proliferation [19–21]. Unlike studies of restenosis in coronary arteries, we did not reveal diabetes mellitus as a predictor of IMT Our study suggests that the RA may heal and remodel in a similar fashion, such that there is not only there growth of the neointima, but also negative remodeling in the form of contraction of the RA likely resulting from adventitial scarring.
Remodeling of the radial artery (RA) after transradial percutaneous coronary intervention (TRI) is under studied.
To examine the impact of TRI on RA diameter and intimal-medial thickness (IMT) in men and women using 55 Mhz ultrahigh frequency duplex ultrasound (UHFDU).
We performed UHFDU at 24 h and 90 days after non-emergent TRI in 41 patients (25 men, 16 women). Changes in RA diameter, IMT and RA injury were compared by patient gender. Multivariate linear regression was used to determine the predictors of RA diameter and IMT.
Of the 41 patients, mean age was 66 ± 9.8. Baseline RA diameter was larger in men vs. women (3.1 ± 0.40 mm vs. 2.8 mm ± 0.36, p = 0.02), however there were similar reductions in 90-day diameter (−0.57 ± 0.32 mm vs. -0.64 ± 0.40 mm, respectively; p = 0.48). Baseline IMT was also similar in men and women (0.28 ± 0.04 vs. 0.27 ± 0.06 mm; p = 0.37) and there were 0.073 ± 0.11 mm (26%) and 0.05 ± 0.080 mm (19%) increases in IMT noted, respectively (p < 0.0001 vs. baseline, p = 0.48 for men vs. women). Although UHFDU occasionally detected limited access site intimal tears (12%) at 90 days, frank dissections (2.4%), pseudoaneurysms (2.4%) and total occlusions (4.9%) were infrequent. Female gender correlated with smaller RA diameter at follow-up and there were no predictors of IMT.
Following TRI, there is a 20% reduction in RA diameter and a 20–25% increase in IMT. Only gender predicted RA diameter. As a simple, noninvasive method to accurately depict the RA healing response following TRI, UHFDU may inform future clinical investigation in this area.
Early- and middle-phase arterial repair following bioresorbable- and durable-polymer drug-eluting stent implantation: An angioscopic study
2019, International Journal of Cardiology
Bioresorbable-polymer drug-eluting stent (BP-DES) demonstrates comparable clinical outcomes compared to durable-polymer drug-eluting stent (DP-DES). However, early- and middle-phase arterial repair following deployment of BP-DES and DP-DES has not been elucidated to date.
We extracted coronary angioscopy (CAS) findings covering early phase (4 ± 1 months) or middle phase (10 ± 2 months) between January 2010 and February 2018 from the database of Kansai Rosai Hospital. Neointimal coverage (NIC), yellow color intensity of the stented segment and incidence of thrombus adhesion were compared between BP-DES (Synergy or Ultimaster) and DP-DES (Promus or Resolute or Xience) in early (39 BP-DES of 33 lesions from 24 patients and 83 DP-DES of 74 lesions from 56 patients) and middle (198 BP-DES of 175 lesions from 135 patients and 204 DP-DES of 184 lesions from 149 patients) phases.
In early phase, while NIC was similar in both groups (P = 0.84), the incidence of thrombus adhesion was significantly higher in BP-DES than in DP-DES (67% versus 34%, P = 0.001) even though maximum yellow color was less intense in BP-DES (P = 0.004). In middle phase, while NIC was better in BP-DES (P < 0.001), thrombus adhesion (23% versus 22%, P = 0.81) and maximum yellow color (P = 0.72) were similar in both groups.
Although NIC was similar in the early phase, the incidence of thrombus adhesion was significantly higher in BP-DES than in DP-DES. The incidence of thrombus adhesion reached similar values and NIC improved in BP-DES over that in DP-DES in the middle phase.
Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty
2017, International Journal of Cardiology
Systemic administrations of conventional antithrombotics reduce neointima formation after angioplasty in experimental animals. However, clinical translation of these results has not been successful due to high risk for bleeding.
We sought to determine whether novel annexin-V (ANV)-Kunitz protease inhibitor fusion proteins, TAP-ANV and ANV-6L15, can specifically target to vascular injury site and limit neointima formation without inducing systemic hypo-coagulation in a rat carotid artery balloon angioplasty injury model.
Near infrared imaging was carried out after balloon-injury and injection of fluorescent ANV or ANV-6L15 to examine their bio-distributions. For peri-procedure treatment, TAP-ANV or ANV-6L15 was administered as i.v. boluses 3 times: 30-minutes before balloon-injury, immediate after procedure, and 120-minutes post-balloon-injury. For extended treatment, additional i.v. bolus injection was given on day-2, day-3 and every other day thereafter. Carotid arteries were collected on day-7 and day-14 for analysis. Blood was collected for measurement of clotting parameters.
Near infrared imaging and immunochemistry showed that fluorescent ANV and ANV-6L15 specifically localized to injured carotid artery and significant amount of ANV-6L15 remained bound to the injured artery after 24-h. Peri-procedure injections of TAP-ANV or ANV-6L15 resulted in decrease of intima/media ratio by 56%. Extended injections of both yielded similar results. Both decreased the expression of PCNA on day-7 and increased the expression calponin on day-14 in the intima post-balloon-injury.
TAP-ANV and ANV-6L15 can specifically localize to balloon injured carotid arteries after i.v. bolus injections, resulting in substantial attenuation of intimal hyperplasia without inducing a state of systemic hypo-coagulation.
Neointimal fibrotic lead encapsulation – Clinical challenges and demands for implantable cardiac electronic devices
2017, Journal of Cardiology
Every tenth patient with a cardiac pacemaker or implantable cardioverter-defibrillator implanted is expected to have at least one lead problem in his lifetime. However, transvenous leads are often difficult to remove due to thrombotic obstruction or extensive neointimal fibrotic ingrowth. Despite its clinical significance, knowledge on lead-induced vascular fibrosis and neointimal lead encapsulation is sparse. Although leadless pacemakers are already available, their clinical operating range is limited. Therefore, lead/tissue interactions must be further improved in order to improve lead removals in particular. The published data on the coherences and issues related to lead associated vascular fibrosis and neointimal lead encapsulation are reviewed and discussed in this paper.

View all citing articles on Scopus

View full text

ArticlesPathophysiology of Restenosis: Interaction of Thrombosis, Hyperplasia, and/or Remodeling