Stent Edge Restenosis　― An Inevitable Drawback of Stenting? ―

Percutaneous coronary intervention with stent implantation is currently the gold standard treatment for patients with coronary artery disease (CAD). This technique, which involves implanting a relatively rigid metallic foreign material into the beating heart, has improved prognosis in patients with CAD in terms of preventing acute stent thrombosis and in-stent restenosis. On the other hand, once implanted, the stent and implanted vessel are exposed to various external stresses, reportedly leading to several unfavorable phenomena related to stent implantation.

Article p ????

Stent edge-related restenosis (SER) first emerged as a prominent clinical problem in the era of brachytherapy. Although SER did not feature in the bare metal stent (BMS) era, several reports mentioned that SER can occur after BMS implantation as well as after drug-eluting stent (DES) implantation, which suggests that the implantation itself of a coronary stent into a curved or tortuous coronary artery in the beating heart can be a major contributor to SER.

In contrast, it has been reported that the incidence of SER can vary according to various factors (Table).^1–5 Although the detailed mechanisms of SER remain uncertain, Hoffmann et al reported that BMS SER was a combination of stent-induced intimal hyperplasia and progressively increased negative remodeling at the stent’s edges.⁶ In the subgroup analysis of the SIRIUS trial, Sakurai et al clarified that a larger stent edge plaque burden and the step-up index predicted SER after Cypher sirolimus-eluting stent (SES) implantation.¹

Table. Studies of Stent Edge-Related Restenosis

Authors (Ref. no.)	Stent type and sample size	Incidence of SER	Associated factors of SER
Sakurai et al1 IVUS cohort of SIRIUS trial	BMS: n=149 Cypher SES: n=168	BMS: 8.1% Cypher SES: 3.5%	• Larger reference %plaque area • Larger edge stent area/reference minimum lumen (step-up index)
Liu et al2 Integrated TAXUS IV, V, and VI IVUS analysis	BMS: n=255 Taxus PES: n=276	BMS 　Proximal: 2.5% 　Distal: 2.4% Taxus PES 　Proximal: 5.2% 　Distal: 0.4	• Edge plaque burden 　BMS: cutoff=47.7% 　Taxus PES: cutoff=47.1%
Kang et al3 Asan Medical Center retrospective registry	Endeavor-ZES: n=236 Resolute-ZES: n=246 EES: n=505	Endeavor-ZES: 2.1% Resolute-ZES: 2.4% EES: 3.4%	• Reference segment plaque burden ≥55% • Reference segment minimum lumen area=5.7 mm2
Kim et al4 Seoul National University single-center retrospective registry	Cypher SES: n=753 Taxus PES: n=834 Endeavor-ZES: n=633	Cypher SES: 4.5% Taxus PES: n=7.6% ZES: n=10.1%	• Severe angulation at the stent edge segment • Stiff stent such as Cypher SES
Ino et al5 Single-center retrospective registry	EES: n=319	EES: n=10.3%	• Lipid-rich plaque by OCT • Minimum lumen area in the stent edge segments

BMS, bare metal stents; EES, everolimus-eluting stents; IVUS, intravascular ultrasound; OCT, optical coherence tomography; PES, paclitaxel-eluting stent; SER, stent edge-related restenosis; SES, sirolimus-eluting stent; ZES, zotarolimus-eluting stent.

In this issue of the Journal, Jimba et al⁷ demonstrate that the hinge angle after stent implantation was significantly larger in the SER group than in the restenosis or no-restenosis groups. In the per-edge analysis, hinge angle measured after stent implantation and residual plaque burden were independent predictors of SER. Ino et al have previously demonstrated that pre-stent target vessel hinge motion was an independent predictor of in-stent restenosis for the Cypher SES.⁸ Thus, Jimba et al provide new insights into the relationship between post-stent hinge motion and future SER in the era of newer-generation DES.⁷

Although the detailed mechanism of the relationship between high post-stent hinge motion and SER remains uncertain due to limited number of cases available for serial intravascular imaging analysis (39 out of 584 edge segments: 6.7% of enrolled segments), several investigators have suggested the following. Stent implantation straightens a tortuous coronary artery and consequently enhances the hinge motion by shifting the hinge point to the proximal or distal edge of the stent. As a result, stent edge struts can cause continuous mechanical stress on the vessel wall during the cardiac cycle, accelerating local injury or inflammation and thereby leading to plaque and/or neointimal growth.⁴ Because the local drug dose delivered to the vessel wall at the stent edge is generally lower than that within the stented segment, it may be insufficient for the suppression of neointimal hyperplasia.^4,5 In the present study, Jimba et al report that hinge angle and residual plaque burden are independent predictors of SER, and the coexistence of excessive hinge motion and residual plaque burden has an amplified effect on stenotic progression in their quantitative angiographic analysis of follow-up angiography.⁷

Many studies have shown a clear relationship between hinge motion and stent fracture.^9–11 Therefore, stent fracture may be another potential contributor. The incidence of stent fracture in the present study was only 0.5% (2 out of 426 lesions), which is lower than previously reported. The incidence of stent fracture in newer-generation DES such as Cobalt chrome–everolimus-eluting stents, biolimus-eluting stents, and Platinum chrome–everolimus-eluting stents was 2.9%,⁹ 4.1%,¹⁰ and 1.7%¹¹ of the lesions, respectively. On the other hand, a serial IVUS analysis reported a high incidence of axial stent deformation in cases of SER (10 out of 13 SER cases). The stent area was significantly reduced at the SER edges, with a decrease in the asymmetry index, whereas no significant change was observed at the non-SER edges. Although previous reports consistently demonstrate a relationship between hinge motion and stent fracture,^9–11 some newer-generation DES have improved design in terms of longitudinal integrity, flexibility, and conformability, resulting in resistance to stent fracture. With these improvements, it is reasonable to assume that even if high hinge motion does not result in stent fracture, chronic stent recoil or axial stent deformation might occur, especially in lesions with high hinge motion or tortuosity because the repetitive and continuous cardiac contraction exposes the stent to compression, torsion, elongation, and bending until the heart becomes inactive.

The final interesting finding of the present study is that cleaved calcification and its protrusion were visualized in 2 SER lesions on follow-up IVUS. Recently, the association between coronary hinge motion, severely calcified lesions, and the occurrence of calcified nodules (CN) has been frequently reported. Lee et al demonstrated that CN were located more frequently in the ostial or mid-right coronary artery, where torsion stress is maximal.¹² Although the mechanism of CN development is unknown, a potential hypothetical mechanism involves mechanical stress that fragments calcium sheets, resulting in small nodules surrounded by fibrin that eventually erupt through the plaque surface into the coronary lumen. Considering that hinge motion is a common risk factor for the progression of CN, stent fracture, and SER, the progression of CN could be considered an important contributor to the occurrence of SER in calcified tortuous lesions.

Interestingly, a statistically significant correlation was found between pre-stent vessel factors (pre-stent hinge angle and vessel curvature index) and post-stent hinge motion, but the relevance was extremely weak. These data suggest that not only pre-stent vessel factors but also other factors such as lesion location, position of stent landing, and type of stent used might affect the post-stent hinge motion. In a way, SER due to hinge motion is an inevitable drawback of placing a metallic foreign material into the beating heart but a multilateral approach to lesion evaluation and treatment strategy might reduce the incidence of this phenomenon. A future prospective study is warranted to confirm this hypothetical and wishful speculation.

Disclosures / Conflicts of Interest

H.O. received research funds and lecture fees from Abbott Vascular Japan.

Acknowledgment

None.

References

• 1.   Sakurai R, Ako J, Morino Y, Sonoda S, Kaneda H, Terashima M, et al. Predictors of edge stenosis following sirolimus-eluting stent deployment (a quantitative intravascular ultrasound analysis from the SIRIUS trial). Am J Cardiol 2005; 96: 1251–1253.
• 2.   Liu J, Maehara A, Mintz GS, Weissman NJ, Yu A, Wang H, et al. An integrated TAXUS IV, V, and VI intravascular ultrasound analysis of the predictors of edge restenosis after bare metal or paclitaxel-eluting stents. Am J Cardiol 2009; 103: 501–506.
• 3.   Kang SJ, Cho YR, Park GM, Ahn JM, Kim WJ, Lee JY, et al. Intravascular ultrasound predictors for edge restenosis after newer generation drug-eluting stent implantation. Am J Cardiol 2013; 111: 1408–1414.
• 4.   Kim YG, Oh IY, Kwon YW, Han JK, Yang HM, Park KW, et al. Mechanism of edge restenosis after drug-eluting stent implantation: Angulation at the edge and mechanical properties of the stent. Circ J 2013; 77: 2928–2935.
• 5.   Ino Y, Kubo T, Matsuo Y, Yamaguchi T, Shiono Y, Shimamura K, et al. Optical coherence tomography predictors for edge restenosis after everolimus-eluting stent implantation. Circ Cardiovasc Interv 2016; 9: e004231.
• 6.   Hoffmann R, Mintz GS, Kent KM, Satler LF, Pichard AD, Popma JJ, et al. Serial intravascular ultrasound predictors of restenosis at the margins of Palmaz-Schatz stents. Am J Cardiol 1997; 79: 951–953.
• 7.   Jimba T, Ikutomi M, Tsukamoto A, Matsushita M, Yamasaki M. Effect of hinge motion on stent edge-related restenosis after right coronary artery treatment in the current drug-eluting stent era. Circ J, doi:10.1253/circj.CJ-21-0196.
• 8.   Ino Y, Kubo T, Kitabata H, Shimamura K, Shiono Y, Orii M, et al. Impact of hinge motion on in-stent restenosis after sirolimus-eluting stent implantation. Circ J 2011; 75: 1878–1884.
• 9.   Kuramitsu S, Iwabuchi M, Haraguchi T, Domei T, Nagae A, Hyodo M, et al. Incidence and clinical impact of stent fracture after everolimus-eluting stent implantation. Circ Cardiovasc Interv 2012; 5: 663–671.
• 10.   Kuramitsu S, Iwabuchi M, Yokoi H, Domei T, Sonoda S, Hiromasa T, et al. Incidence and clinical impact of stent fracture after the Nobori biolimus-eluting stent implantation. J Am Heart Assoc 2014; 3: e000703.
• 11.   Kuramitsu S, Hiromasa T, Enomoto S, Shinozaki T, Iwabuchi M, Mazaki T, et al. Incidence and clinical impact of stent fracture after PROMUS element platinum chromium everolimus-eluting stent implantation. JACC Cardiovasc Interv 2015; 8: 1180–1188.
• 12.   Lee T, Mintz GS, Matsumura M, Zhang W, Cao Y, Usui E, et al. Prevalence, predictors, and clinical presentation of a calcified nodule as assessed by optical coherence tomography. JACC Cardiovasc Imaging 2017; 10: 883–891.