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Serial Intravascular Ultrasound Findings After Treatment of Chronic Total Occlusions Using Drug-Eluting Stents
Serial Intravascular Ultrasound Findings After Treatment of Chronic Total Occlusions Using Drug-Eluting Stents Shigeo Saito, MDa,b,c, Akiko Maehara, MDb,c,*, Tadayuki Yakushiji, MDa, Tomotaka Dohi, MD, PhDb,c,d, Nobuaki Kobayashi, MD, PhDb,c,e, Lei Song, MDb,c,f, Gary S. Mintz, MDb, and Masahiko Ochiai, MD, PhDa Morphologic changes after chronic total occlusion (CTO) treatment with drug-eluting stents (DESs) have not been assessed in detail. Our aim was to use both baseline and follow-up intravascular ultrasound studies to evaluate the morphologic changes and, especially, the changes in distal vessel size and the effect of subintimal stenting after treatment of CTOs with DES. We analyzed serial follow-up intravascular ultrasound (baseline and follow-up at 9 – 2 months) after DES implantation into 40 CTOs. Overall, 33 CTOs were treated by the anterograde approach; and 7 were treated by the retrograde approach. Minimum lumen cross-sectional area (CSA) trended toward a decrease from baseline to follow-up (4.8 – 1.7 vs 4.5 – 1.7 mm2, p [ 0.10), although the minimum stent CSA (4.8 – 1.7 vs 4.9 – 1.7 mm2, p [ 0.26) did not change. The distal reference, but not the proximal reference lumen CSA, increased significantly at follow-up (3.8 – 2.0 to 5.1 – 2.3 mm2, p [ 0.0004). Late-acquired stent malapposition was seen in 17 patients (42.5%). In 8 CTOs (20%), a part of the stent was implanted into a subintimal space; in these 8 patients, maximum percent neointimal hyperplasia and minimum lumen area was similar in the subintimal segment compared with the adjacent intraplaque segment. The frequency of late-acquired stent malapposition was similar. In conclusion, after CTO treatment with DES, distal vessel enlargement was detected. Subintimal stenting after recanalization of CTO was not inferior compared with stenting within the plaque in terms of long-term morphologic impact. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;117:727e734) Previous studies have reported that successful percutaneous revascularization of a chronic total occlusion (CTO) is associated with better long-term mortality compared with patients in whom the procedure was not successful.1,2 Current success rates have improved because of the development of techniques such as controlled antegrade and retrograde tracking (CART), reverse CART, and subintimal tracking and reentry (STAR)2e8; however, morphologic changes after successful CTO recanalization, especially after drug-eluting stent (DES) implantation, have not been assessed in detail including whether subintimal stenting is deleterious and what is the appropriate stent sizing when the distal segment may be smaller than expected due to longterm reduced flow and negative remodeling. The aims of this study were to examine both baseline and follow-up intravascular ultrasound (IVUS) studies after successful
a Division of Cardiology and Cardiac Catheterization Laboratories, Showa University Northern Yokohama Hospital, Yokohama, Japan; b Clinical Trials Center, Cardiovascular Research Foundation, New York, New York; cCenter for Interventional Vascular Therapy, Division of Cardiology, Columbia University Medical Center, New York, New York; d Department of Cardiovascular Medicine, Juntendo University School of Medicine, Tokyo, Japan; eDivision of Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan; and fDepartment of Cardiology, Fuwai Hospital, Bejing, China. Manuscript received November 23, 2015; revised manuscript received and accepted November 29, 2015. See page 732 for disclosure information. *Corresponding author: Tel: (646) 434-4569; fax: (646) 434-4464. E-mail address: [email protected] (A. Maehara).
0002-9149/15/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.11.055
treatment of CTO lesions with DES implantation to evaluate long-term morphologic changes—especially the effect of subintimal stenting and changes of vessel size that occur with increased anterograde flow. Methods We analyzed 40 serial IVUS studies (baseline and follow-up at 9 2 months) after DES implantation into de novo (not previously stented) CTOs. All lesions were treated by a single interventional cardiologist (MO) at the Showa University Northern Yokohama Hospital (Yokohama, Japan) from November 2004 to March 2012. The indications for follow-up IVUS studies were clinical symptoms or at the operator’s discretion. A CTO was defined as an obstruction of a native coronary artery with no luminal continuity and with Thrombolysis In Myocardial Infarction 0 for >3 months. Patients treated using baremetal stents, lesions that represented reocclusion, or a total occlusion related to an acute coronary syndrome were excluded. Patient demographics were confirmed by hospital review. Coronary risk factors included diabetes mellitus (diet controlled, oral agent, or insulin treated), hypertension (medication-treated only), hypercholesterolemia (medication treated or total cholesterol >240 mg/dl), cigarette smoking, and family history of coronary artery disease. Baseline and follow-up cine angiograms were analyzed with a computer-assisted, automated edge-detection algorithm (QCA-CMS; Medis medical imaging systems bv, www.ajconline.org
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Leiden, the Netherlands) by independent experienced observers (TD and NK) blinded to clinical and IVUS data. The length of the occlusion was measured during simultaneous anterograde and retrograde injection of contrast or only anterograde injection of contrast after guidewire crossing and predilation. Collateral flow was graded according to Rentrop classification. Angiographic analysis included Thrombolysis In Myocardial Infarction flow, minimum lumen diameter, reference vessel diameter, and diameter stenosis and was done using conventional methods.9 Restenosis patterns were categorized as gap, margin, focal, multifocal, diffuse, proliferative, and total occlusion.10 Moderate calcification was defined as densities noted only with cardiac motion before contrast injection; severe calcification was defined as radioopacities noted without cardiac motion before contrast.9 IVUS was performed after recanalization with a guidewire or after predilation using commercially available IVUS systems (Boston Scientific Corp., Natick, Massachusetts; Volcano Therapeutics Inc., Rancho Cordova, California). The IVUS catheter was advanced at least 5 mm beyond the CTO segment, and an imaging run was performed using either automatic pullback at a speed of 0.5 or 1.0 mm/s (n ¼ 18) or using manual pullback. IVUS images were recorded onto digital media for offline analysis. All baseline and follow-up studies were reviewed side-by-side. Qualitative and quantitative IVUS analyses were performed by independent experienced observers (SS and AM) according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement, and Reporting of Intravascular Ultrasound studies.11 Using planimetry software (echoPlaque; INDEC Systems Inc., Santa Clara, California), quantitative IVUS analysis was performed within the CTO and the proximal and distal 5 mm reference segments every 1 mm to include: external elastic membrane (EEM), lumen, plaque and media (EEM minus lumen), and stent cross-sectional area (CSA); plaque burden (plaque and media divided by EEM); and neointimal hyperplasia CSA. Maximum plaque thickness at the distal reference was analyzed; significant thickening was defined as a maximum plaque thickness 0.5 mm.12 Lengths were calculated from the pullback speed and duration. Volumes were calculated using Simpson’s rule and reported as total and normalized volumes (volume divided by analysis length). Malapposition was defined as a separation of stent struts from the luminal border with the presence of blood between the struts and the plaque. Late-acquired stent malapposition (LASM) was present at follow-up but was not present at baseline, and persistent malapposition was visible both at baseline and at follow-up (Figure 1). Stent fracture was defined as an absence of struts >120 within the stent. Tissue protrusion was defined as visible tissue on the luminal side of the stent and adherent to the stent struts after implantation and considered persistent if it remained at followup. A subintimal space was an echo-free space outside the intima without a 3-layer appearance (Figure 2). Statistical analysis was performed with StatView 5.0 (SAS Institute Inc., Cary, North Carolina). Continuous data were reported as mean SD and compared using paired t tests if normally distributed. Otherwise, nonparametric data were reported as median and interquartile range and
compared with the ManneWhitney U test and Wilcoxon signed-rank test. Multivariate linear regression was performed to identify the independent predictors for changes of lumen CSA from baseline to follow-up at distal reference. A p value of <0.05 was considered statistically significant. Results There were 40 CTO lesions in 40 patients. Patient and procedural characteristics are listed in Table 1. Overall, 90% of the patients were men, 83% of lesions were treated through an anterograde approach, and 50% of the CTO occlusion duration was <12 months. Nine sirolimus-eluting stents, 8 paclitaxel-eluting stents, and 23 everolimus-eluting stents were used. Two patients (5%) had a failed previous CTO attempt. Nineteen lesions were in the right coronary artery (RCA), 10 lesions were in the left anterior descending coronary artery (LAD), and 11 lesions were in the left circumflex coronary artery (Table 2). The occlusion length measured 17.0 14.6 mm. Only 2 (5%) had severe calcification. The minimum lumen diameter decreased from poststent implantation to follow-up (2.25 0.48 vs 1.80 0.70 mm, p <0.0001). At follow-up, although the distal reference vessel diameter increased from baseline to follow-up (from 1.91 0.66 to 2.14 0.67 mm, p ¼ 0.02), the proximal reference vessel diameter decreased (from 3.30 0.79 to 3.01 0.75 mm, p ¼ 0.02). Overall, 27.5% (11 of 40) developed angiographic restenosis defined as diameter stenosis 50%; 27.3% (3 of 11) were focal in the body, 18.2% (2 of 11) were multifocal, 18.2% (2 of 11) were focal at the margin, 18.2% (2 of 11) were focal at a gap, 1 was proliferative, and 1 was a total occlusion. Minimum lumen CSA trended toward a decrease from baseline to follow-up (4.8 1.7 vs 4.5 1.7 mm2, p ¼ 0.10), although there was no change in minimum stent CSA from baseline to follow-up (Table 3). At follow-up, minimum lumen CSA sites were located at the minimum stent area site in 53%. Stent segments were divided into proximal, middle, and distal subsegments (Figure 3). The EEM CSA in the proximal stent subsegment showed no change from baseline to follow-up, but the EEM CSA in the mid and distal stent subsegments increased from baseline to follow-up. There were 20 (50%) stent malappositions at follow-up. Seventeen of 20 malappositions (85%) were LASM (Figure 1), and 3 (15%) were persistent. Of the 17 LASM, 35.3% (6 of 17) were located in the proximal part of the stent, 35.3% (6 of 17) were located in the mid part of the stent, and 29.4% (5 of 17) were located in the distal part of stent; all 5 LASM in the distal part of stent were observed in non-LAD lesions. Four stent fractures (in 3 lesions, 7.5%) and 2 persistent tissue protrusions (5%) were seen at follow-up. Postprocedural IVUS showed that stents were implanted into a subintimal space in 8 patients (20%); in 3 of them, the true lumen could still be identified behind the stent at follow-up. In the 8 lesions with subintimal stenting, subintimal segments were located at the proximal edge of the CTO in 37%, at the distal edge in 25%, and in the body of the CTO in 38%. The incidence of LASM, the changes in EEM CSA, and maximum percent neointimal hyperplasia did not differ in between subintimal stented subsegments
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Figure 1. An example of distal vessel enlargement and LASM at the distal stent edge after DES implantation into an RCA CTO lesion. (A, C) Baseline and follow-up angiogram. Arrows indicate the site of the distal stent edge; (B, D) identical sequences of IVUS images from distal stent edge into the distal reference are compared between baseline and follow-up. The stent CSA in the middle frame measured 2.7 mm2 at baseline and 2.8 mm2 at follow-up indicating no stent recoil. At the distal stent edge (middle frames) baseline EEM CSA increased from 8.7 to 10.4 mm2 resulting stent strut malapposition (double-headed arrow) without change of plaque CSA (5.6 to 5.4 mm2). Baseline plaque thickness measured 1.2 mm at the distal reference where the EEM CSA increased from 9.0at baseline to 11.6 mm2 at follow-up indicating positive remodeling that was associated with an increase in distal reference lumen CSA (2.3 mm2 at baseline to 6.3 mm2 at follow-up).
Figure 2. Examples of subintimal wiring and intraplaque (non subintimal) wiring after stent implantation. Upper and lower panels show the IVUS images of after wiring and poststent in a case with subintimal wiring and a case with intraplaque wiring, respectively. White arrows indicate true lumen which was pushed by the wire or stent in the subintimal space.
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Table 1 Patient and procedural characteristics in 40 lesions in 40 patients
Table 2 Angiographic findings in 40 lesions
Variable
Variable
Age (years) Men Hypertension Diabetes Hypercholesterolemia Cigarette smoking Family history of coronary artery disease Prior percutaneous coronary intervention Prior coronary artery bypass grafting Canadian Cardiovascular Society angina class II Medication Aspirin continued until follow-up Thienopyridine continued until follow-up Statin use at the time of discharge of procedure Expected occlusion duration <12 months 12 months Unknown Reattempt for chronic total occlusion treatment Antegrade approach Type of drug-eluting stent implanted Paclitaxel-eluting stent Sirolimus-eluting stent Everolimus-eluting stent
62 8 36 (90%) 20 (50%) 13 (32.5%) 18 (45%) 15 (38%) 17 (43%) 22 (55%) 2 (5%) 13 (33%) 39 (98%) 38 (95%) 18 (45%) 20 6 14 2 33
(50%) (15%) (35%) (5%) (83%)
8 (20%) 9 (22%) 23 (58%)
Values are presented as mean SD or number of observations (%).
and adjacent segments in which the stent was located within the plaque (Table 4). We had 12 paired IVUS images of the proximal reference and 24 paired IVUS images of the distal reference. There were no statistically significant changes from baseline to follow-up within the proximal reference segment in either the planar or volumetric analyses (Table 3); however, from baseline to follow-up, the smallest distal reference lumen area within 5 mm of the distal stent edge increased from 3.8 2.0 to 5.1 2.3 mm2, p ¼ 0.0004, along with an increase in the EEM CSA (from 8.4 5.7 to 9.3 5.2 mm2, p ¼ 0.005). Similar results were identified in the volumetric analysis (Table 3). Changes in lumen and EEM CSA were similar when comparing stents with versus without LASM (change in lumen CSA measured 35.0% [14.7 to 73.9] vs 28.7% [14.2 to 48.9], p ¼ 0.31; change in EEM CSA measured 16.8% [0.8 to 26.8] vs 4.4% [-4.5 to 23.3], p ¼ 0.54). Distal reference lumen CSAs were compared between baseline and follow-up in the following 3 subgroups: (1) LAD versus non-LAD, (2) lesions with distal reference maximum plaque thickness <0.5 mm versus 0.5 mm (Figure 4), and (3) 1st versus 2nd generation DES. Distal reference lumen CSA at follow-up significantly increased from baseline in non-LAD but not in LAD lesions. At baseline, CTO lesions with a distal reference maximum plaque thickness 0.5 mm had larger lumen CSAs (4.3 [3.4 to 6.2] vs 3.5 mm2 [2.9 to 4.0], p ¼ 0.20); EEM CSAs (10. [8.5 to 14.2] vs 5.4 mm2 [4.0 to 5.9], p ¼ 0.0004); and plaque burden (56.7% [52.7 to 63.8] vs 30.0% [27.4 to 35.4], p <0.0001) compared with the distal reference with a maximum plaque thickness <0.5 mm at baseline. Distal
Baseline
Follow-up
p Value
Coronary location of chronic total occlusion Right 19 (48%) Left anterior descending 10 (25%) Left circumflex 11 (28%) Occlusion length (mm) 17.0 14.6 Rentrop’s grade classification of collaterals 1 3 (7.5%) 2 2 (5%) 3 34 (85%) Not evaluable 1 (2.5%) Calcium Moderate 9 (23%) Severe 2 (5%) Stump morphology Abrupt 9 (23%) Tapered 31 (77%) Side brunch arising from stump 16 (40%) Quantitative coronary angiography findings baseline final and follow-up Thrombolysis in Myocardial 39 (98%) 40 (100%) 0.32 Infarction flow 3 Proximal reference vessel 3.30 0.79 3.01 0.75 0.02 diameter (mm) Distal reference vessel 1.91 0.66 2.14 0.67 0.02 diameter (mm) Minimum lumen diameter in 2.25 0.48 1.80 0.70 <0.0001 stent (mm) Diameter stenosis in stent (%) 16.3 9.5 35.2 22.9 <0.0001 Binary restenosis 18 (45%) Values are presented as mean SD or number of observations (%).
reference lumen CSA at follow-up significantly increased in lesions associated with a distal reference maximum plaque thickness 0.5 mm versus <0.5 mm. These findings are shown in Figure 4. When we evaluated IVUS findings between 1st and 2nd generation stent groups separately, the increase of EEM CSA in the distal reference was similar in both 1st and 2nd generation stents. Figure 5 shows the correlation between the percent change in lumen CSA versus percent change in EEM CSA and percent change in lumen CSA versus percent changes in plaque CSA at the distal reference segment. Percent change in lumen CSA had a strong correlation with percent change in EEM CSA (r ¼ 0.78, p <0.0001), but percent change in lumen CSA did not correlate with percent change in plaque CSA (p ¼ 0.99). Overall, there were 9 repeat revascularizations during the follow-up period, none in lesions with subintimal stent implantation. Discussion The main findings of this study were as follows: (1) there was distal but not proximal reference segment lumen and vessel enlargement that extended distally beginning from the middle of stent. Distal reference lumen enlargement correlated with distal reference EEM enlargement, but not with any change in plaque area, consistent with a positive remodeling effect, and (2) Subintimal stent implantation did
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Table 3 Serial planar and volumetric quantitative intravascular ultrasound findings Variable Planar analysis in 40 lesions Minimum lumen CSA (mm2) Minimum stent CSA (mm2) EEM CSA at MLA site (mm2) Maximum NIH CSA (%) Proximal reference Smallest lumen (mm2) EEM CSA at the smallest lumen (mm2) PþM CSA at the smallest lumen (mm2) Maximum lumen CSA (mm2) Distal reference Smallest lumen (mm2) EEM CSA at the smallest lumen (mm2) PþM CSA at the smallest lumen (mm2) Maximum lumen CSA (mm2) Volumetric analysis in 18 lesions Stent segment Stent length (mm) Mean lumen CSA (mm3/mm) Mean stent CSA (mm3/mm) Mean EEM CSA (mm3/mm) NIH (%) Proximal reference Mean lumen CSA (mm3/mm) Mean EEM CSA (mm3/mm) Mean PþM CSA (mm3/mm) Distal reference Mean lumen CSA (mm3/mm) Mean EEM CSA (mm3/mm) Mean PþM CSA (mm3/mm)
Baseline
Follow-up
4.8 1.7 4.8 1.7 11.6 6.4
4.9 4.9 12.4 26.0
6.5 3.0 15.3 4.2
6.1 2.7 15.2 6.2
0.63 0.28
8.8 3.0
9.4 5.4
0.58
9.4 3.8
8.9 3.6
0.59
3.8 2.0 8.4 5.7
5.1 2.3 9.3 5.2
0.0004 0.005
4.5 4.1
4.2 3.4
0.79
5.0 2.2
6.8 3.1
0.001
40.5 6.4 6.3 13.5
p Value
1.9 0.13 1.7 0.26 6.6 0.01 19.0
21.4 40.2 21.6 1.8 6.3 2.2 1.8 6.5 2.0 4.1 14.5 4.8 6.5 13.0
0.21 0.76 0.10 0.01
7.2 2.5 15.4 4.1 8.2 2.8
7.5 3.2 15.6 4.1 8.1 3.5
0.60 0.66 0.95
4.4 1.8 8.7 4.0 4.4 2.9
5.8 2.6 10.3 5.0 4.4 2.7
0.009 0.06 0.84
Values are presented as mean SD. CSA ¼ cross-sectional area; EEM ¼ external elastic membrane; MLA ¼ minimum lumen cross-sectional area; NIH ¼ neointimal hyperplasia; P þ M ¼ plaque þ media.
not appear to be deleterious in terms of LASM or neointimal hyperplasia compared with stenting the true lumen. In the present study, vessel enlargement was identified from the middle of stent to the distal reference. Lumen increase was seen in 83% (20 of 24) of distal references with a median increase in lumen diameter of 0.3 mm. Although the number of lesions in each subgroup was small, distal reference lumen enlargement was greater in vessels with a baseline maximum plaque thickness 0.5 mm (vs <0.5 mm) or nonLAD lesions (vs LAD lesions). Park et al13 reported a significant increase in mean distal reference lumen diameter of 0.21 mm (10.4 19.9%) and in mean EEM diameter of 0.13 mm (5.8 14.9%), in that of Gomez-Lara’s14 study was 0.29 mm and 0.19 mm, respectively, similar to the present study. Their clinical predictors of lumen CSA increase included an occluded duration of >3 months, poor collateral flow, and statin use. Cessation of forward blood flow in the setting of a CTO seems to result in distal vessel shrinkage. After recanalization of a CTO, vessel enlargement occurs by a recovery of blood flow. One animal study supported this
Figure 3. Comparison of EEM CSA in each segment between baseline and follow-up. In the 36 patients with available baseline and follow-up IVUS images, the percent changes in EEM CSA from baseline to follow-up are shown for each stent subsegment and the proximal and distal reference segments. There was an increase in EEM CSA from the middle stent subsegment that extended distally.
hypothesis.15 After 2 weeks, a 70% reduction in the rate of blood flow through a ligated carotid artery of rabbits caused a 21% decrease in arterial diameter. In addition, Galassi et al16 and Brugaletta et al17 showed impaired vasomotion function after recanalization of CTO and that this resistance improved over time, which seems to be one explanation of enlargement of distal reference of CTO. Because LAD has greater vessel tapering compared with non-LAD,18 the greater increase of distal reference lumen enlargement in non-LAD could be explained. Kawano et al19 showed that the intima þ media thickening of coronary artery correlated with worse flowmediated endothelial function. Therefore, the higher degree of intima thickness (>0.5 mm) may show more severe or longer decreased blood flow and vosomoter response caused by CTO. Correspondingly, the recovery of vasomotor function could be more notable in these lesions. With the advancement of CTO techniques such as CART, reverse CART, and STAR, subintimal stenting is common. Godino et al20 reported clinical outcomes after CTO recanalization using the contrast-guided STAR technique, but there are few data regarding subintimal stented segments as evaluated by IVUS. Tsujita et al21 reported a case of LASM after subintimal DES implantation due to vessel remodeling; however, in the present study, there were no differences in qualitative or quantitative IVUS between subintimal stented subsegments versus stents located in an adjacent intraplaque segment including the frequency of LASM, although the number of subintimal stented segments was small. In this present study, LASM occurred in 42.5% (17 of 40), 35.3% (6 of 17) were located in the proximal part of the stent, 35.3% (6 of 17) were located in the mid part of the stent, and 29.4% (5 of 17) were located in the distal part of stent. Previous studies in non-CTO lesions showed LASM in 7.6% to 33.7%, mostly within the body of the stent.22e24 Ako et al22 analyzed 141 patients (80 sirolimus-eluting stents and 61 bare-metal stents); 22% had LASM at follow-up, all in
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Table 4 Comparison of IVUS findings between subintimal and adjacent true lumen stented segments Variable Location of subintimal segment Proximal edge of the chronic total occlusion Distal edge of the chronic total occlusion Body of the chronic total occlusion Late-acquired stent malapposition (n) Maximum malapposition CSA (mm2) Baseline minimum lumen CSA (mm2) Follow-up minimum lumen CSA (mm2) Baseline maximum EEM CSA (mm2) Follow-up maximum EEM CSA (mm2) Change of EEM CSA at follow-up maximum EEM site (%) Maximum neointimal hyperplasia (%)
Subintimal Segment 3 2 3 3 3.2 6.4 6.9 18.4 18.5 4.4 12.9
(37%) (25%) (37%) (37.5%) (2.1, 4.5) (5.5, 6.8) (4.9, 7.7) (13.2, 20.3) (14.2, 20.8) (2.6, 7.4) (8.2, 17.7)
True Lumen Segment
3 2.0 4.9 4.6 17.5 17.6 10.9 17.8
(37.5%) (1.6, 2.0) (4.2, 6.1) (4.2, 6.6) (15.5, 18.9) (16.5, 22.3) (2.8, 23.7) (13.6, 23.8)
p Value
0.99 0.51 0.16 0.13 0.99 0.75 0.21 0.44
Values are presented as median (1st and 3rd quartiles) or number of observations (%). CSA ¼ cross-sectional area; EEM ¼ external elastic membrane.
Figure 4. Lumen measurements at the distal reference between baseline and follow-up. Comparison of baseline and follow-up distal reference lumen CSA overall and in LAD, non-LAD, maximum plaque thickness <0.5 mm, and maximum plaque thickness 0.5 mm (Panel A) accompanied by the percent change in lumen CSA (Panel B).
sirolimus-eluting stents at the stent edge. Guo et al23 studied 241 patients (184 paclitaxel-eluting stents and 57 bare-metal stents); 25% had LASM at follow-up (62 paclitaxel-eluting stents and 5 bare-metal stents) primarily at a stent edge. In the present study, there was vessel enlargement from the middle stent sub-egment to the distal reference at follow-up to explain the mechanism of LASM. In the present study, 4 stent fractures were seen in 3 lesions, a frequency of 7.5%. Canan et al25 reviewed previous reports; the frequency of stent fracture using DES was 0.8% to 7.7%, and the risk factors of stent fracture were overlapping stents, longer stents, RCA lesion location, and tortuosity or angulation of the vessel. Although a CTO was not reported to be a primary anatomic factor related to stent fracture, a CTO lesion is usually long, frequently in the RCA, and often treated with overlapping stents as was seen in the present study and in previous reports of DES fracture. Consistent with this, 1 study26 which reviewed 430 lesions in 382 patients who underwent follow-up angiography after
implantation of sirolimus-eluting stents reported that the frequency of stent fracture was 7.7% (33 of 430) in all lesions and 17.6% (3 of 14) in CTO lesions. This study has a number of limitations. The duration of IVUS and angiographic follow-up was only 9 months. A longer observation period with more patients is necessary to clarify the current findings and their impact on clinical events such as very late stent thrombosis. Only 8 patients had subintimal stenting, and only 24 patients had imaging of the distal vessel. In only half of patients (45%), IVUS were imaged using automatic pullback. Owing to retrospective nature of this study, current population has a selection bias, which may explain the higher incidence of restenosis. Disclosures Dr. Maehara receives grant support from Boston Scientific; is a consultant for Boston Scientific, ACIST; and receives speaker fee from St. Jude Medical. Dr. Mintz receives
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Figure 5. Scatter plot of intravascular ultrasound measurements obtained at baseline and at follow-up at the site of the distal reference maximum lumen CSA. (A) Relation between change in EEM and lumen CSA. Percent change in lumen CSA had a strong correlation with that of EEM CSA (r ¼ 0.78, p <0.0001); (B) relation between percent change in lumen CSA and plaque CSA. There was no significant correlation (p ¼ 0.99).
grant support from Volcano and is a consultant for Volcano, Boston Scientific, InfraReDx. Dr. Ochiai receives Speakers bureau from Boston Scientific. All other authors have no conflicts of interest to disclose. 1. Valenti R, Migliorini A, Signorini U, Vergara R, Parodi G, Carrabba N, Cerisano G, Antoniucci D. Impact of complete revascularization with percutaneous coronary intervention on survival in patients with at least one chronic total occlusion. Eur Heart J 2008;29:2336e2342. 2. Suero JA, Marso SP, Jones PG, Laster SB, Huber KC, Giorgi LV, Johnson WL, Rutherford BD. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience. J Am Coll Cardiol 2001;38:409e414. 3. Jones DA, Weerackody R, Rathod K, Behar J, Gallagher S, Knight CJ, Kapur A, Jain AK, Rothman MT, Thompson CA, Mathur A, Wragg A, Smith EJ. Successful recanalization of chronic total occlusions is associated with improved long-term survival. JACC Cardiovasc Interv 2012;5:380e388. 4. Olivari Z, Rubartelli P, Piscione F, Ettori F, Fontanelli A, Salemme L, Giachero C, Di Mario C, Gabrielli G, Spedicato L, Bedogni F. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions. J Am Coll Cardiol 2003;41:1672e1678. 5. Hoye A, van Domburg RT, Sonnenschein K, Serruys PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992-2002. Eur Heart J 2005;26:2630e2636. 6. Kimura M, Katoh O, Tsuchikane E, Nasu K, Kinoshita Y, Ehara M, Terashima M, Matsuo H, Matsubara T, Asakura K, Asakura Y, Nakamura S, Oida A, Takase S, Reifart N, Di Mario C, Suzuki T. The efficacy of a bilateral approach for treating lesions with chronic total occlusions the CART (controlled antegrade and retrograde subintimal tracking) registry. JACC Cardiovasc Interv 2009;2:1135e1141. 7. Colombo A, Mikhail GW, Michev I, Iakovou I, Airoldi F, Chieffo A, Rogacka R, Carlino M, Montorfano M, Sangiorgi GM, Corvaja N, Stankovic G. Treating chronic total occlusions using subintimal tracking and reentry: the STAR technique. Catheter Cardiovasc Interv 2005;64:407e411; discussion 412. 8. Sumitsuji S, Inoue K, Ochiai M, Tsuchikane E, Ikeno F. Fundamental wire technique and current standard strategy of percutaneous intervention for chronic total occlusion with histopathological insights. JACC Cardiovasc Interv 2011;4:941e951. 9. Pompa J, Almonacid A, Burke D. Qualitative and quantitative coronary angiography. In: Topol EJ, Teirstein PS, eds. Textbook of Interventional Cardiology. 6th ed. Philadelphia, PA: Saunders, 2011:757e775. 10. Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, Pichard AD, Kent KM, Stone GW, Leon MB. Angiographic patterns of
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in-stent restenosis : classification and implications for long-term outcome. Circulation 1999;100:1872e1878. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478e1492. Kapadia SR, Nissen SE, Ziada KM, Guetta V, Crowe TD, Hobbs RE, Starling RC, Young JB, Tuzcu EM. Development of transplantation vasculopathy and progression of donor-transmitted atherosclerosis : comparison by serial intravascular ultrasound imaging. Circulation 1998;98:2672e2678. Park JJ, Chae IH, Cho YS, Kim SW, Yang HM, Seo JB, Kim SY, Oh IY, Yoon CH, Suh JW, Park KW, Chung WY, Youn TJ, Choi DJ, Kim HS. The recanalization of chronic total occlusion leads to lumen area increase in distal reference segments in selected patients: an intravascular ultrasound study. JACC Cardiovasc Interv 2012;5:827e836. Gomez-Lara J, Teruel L, Homs S, Ferreiro JL, Romaguera R, Roura G, Sanchez-Elvira G, Jara F, Brugaletta S, Gomez-Hospital JA, Cequier A. Lumen enlargement of the coronary segments located distal to chronic total occlusions successfully treated with drug-eluting stents at follow-up. EuroIntervention 2014;9:1181e1188. Langille BL, O’Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 1986;231:405e407. Galassi AR, Tomasello SD, Crea F, Costanzo L, Campisano MB, Marza F, Tamburino C. Transient impairment of vasomotion function after successful chronic total occlusion recanalization. J Am Coll Cardiol 2012;59:711e718. Brugaletta S, Martin-Yuste V, Padro T, Alvarez-Contreras L, GomezLara J, Garcia-Garcia HM, Cola C, Liuzzo G, Masotti M, Crea F, Badimon L, Serruys PW, Sabate M. Endothelial and smooth muscle cells dysfunction distal to recanalized chronic total coronary occlusions and the relationship with the collateral connection grade. JACC Cardiovasc Interv 2012;5:170e178. Javier SP, Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Leon MB. Intravascular ultrasound assessment of the magnitude and mechanism of coronary artery and lumen tapering. Am J Cardiol 1995;75:177e180. Kawano H, Yoshida T, Miyao Y, Hokamaki J, Miyamoto S, Miyazaki Y, Nagayoshi Y, Yamabe H, Ogawa H. The relationship between endothelial function in the brachial artery and intima plus media thickening of the coronary arteries in patients with chest pain syndrome. Atherosclerosis 2007;195:361e366. Godino C, Latib A, Economou FI, Al-Lamee R, Ielasi A, Bassanelli G, Figini F, Chieffo A, Montorfano M, Colombo A, Carlino M. Coronary
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chronic total occlusions: mid-term comparison of clinical outcome following the use of the guided-STAR technique and conventional anterograde approaches. Catheter Cardiovasc Interv 2012;79:20e27. 21. Tsujita K, Maehara A, Mintz GS, Poon M, Maiolino G, Sugaya T, Igarashi K, Ochiai M. Cross-sectional and longitudinal positive remodeling after subintimal drug-eluting stent implantation: multiple late coronary aneurysms, stent fractures, and a newly formed stent gap between previously overlapped stents. JACC Cardiovasc Interv 2009;2:156e158. 22. Ako J, Morino Y, Honda Y, Hassan A, Sonoda S, Yock PG, Leon MB, Moses JW, Bonneau HN, Fitzgerald PJ. Late incomplete stent apposition after sirolimus-eluting stent implantation: a serial intravascular ultrasound analysis. J Am Coll Cardiol 2005;46:1002e1005. 23. Guo N, Maehara A, Mintz GS, He Y, Xu K, Wu X, Lansky AJ, Witzenbichler B, Guagliumi G, Brodie B, Kellett MA Jr, Dressler O, Parise H, Mehran R, Stone GW. Incidence, mechanisms, predictors,
and clinical impact of acute and late stent malapposition after primary intervention in patients with acute myocardial infarction: an intravascular ultrasound substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONSAMI) trial. Circulation 2010;122:1077e1084. 24. Kang SJ, Mintz GS, Park DW, Lee SW, Kim YH, Lee CW, Han KH, Kim JJ, Park SW, Park SJ. Late and very late drug-eluting stent malapposition: serial 2-year quantitative IVUS analysis. Circ Cardiovasc Interv 2010;3:335e340. 25. Canan T, Lee MS. Drug-eluting stent fracture: incidence, contributing factors, and clinical implications. Catheter Cardiovasc Interv 2010;75: 237e245. 26. Umeda H, Gochi T, Iwase M, Izawa H, Shimizu T, Ishiki R, Inagaki H, Toyama J, Yokota M, Murohara T. Frequency, predictors and outcome of stent fracture after sirolimus-eluting stent implantation. Int J Cardiol 2009;133:321e326.
a Division of Cardiology and Cardiac Catheterization Laboratories, Showa University Northern Yokohama Hospital, Yokohama, Japan; b Clinical Trials Center, Cardiovascular Research Foundation, New York, New York; cCenter for Interventional Vascular Therapy, Division of Cardiology, Columbia University Medical Center, New York, New York; d Department of Cardiovascular Medicine, Juntendo University School of Medicine, Tokyo, Japan; eDivision of Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan; and fDepartment of Cardiology, Fuwai Hospital, Bejing, China. Manuscript received November 23, 2015; revised manuscript received and accepted November 29, 2015. See page 732 for disclosure information. *Corresponding author: Tel: (646) 434-4569; fax: (646) 434-4464. E-mail address: [email protected] (A. Maehara).
0002-9149/15/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.11.055
treatment of CTO lesions with DES implantation to evaluate long-term morphologic changes—especially the effect of subintimal stenting and changes of vessel size that occur with increased anterograde flow. Methods We analyzed 40 serial IVUS studies (baseline and follow-up at 9 2 months) after DES implantation into de novo (not previously stented) CTOs. All lesions were treated by a single interventional cardiologist (MO) at the Showa University Northern Yokohama Hospital (Yokohama, Japan) from November 2004 to March 2012. The indications for follow-up IVUS studies were clinical symptoms or at the operator’s discretion. A CTO was defined as an obstruction of a native coronary artery with no luminal continuity and with Thrombolysis In Myocardial Infarction 0 for >3 months. Patients treated using baremetal stents, lesions that represented reocclusion, or a total occlusion related to an acute coronary syndrome were excluded. Patient demographics were confirmed by hospital review. Coronary risk factors included diabetes mellitus (diet controlled, oral agent, or insulin treated), hypertension (medication-treated only), hypercholesterolemia (medication treated or total cholesterol >240 mg/dl), cigarette smoking, and family history of coronary artery disease. Baseline and follow-up cine angiograms were analyzed with a computer-assisted, automated edge-detection algorithm (QCA-CMS; Medis medical imaging systems bv, www.ajconline.org
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Leiden, the Netherlands) by independent experienced observers (TD and NK) blinded to clinical and IVUS data. The length of the occlusion was measured during simultaneous anterograde and retrograde injection of contrast or only anterograde injection of contrast after guidewire crossing and predilation. Collateral flow was graded according to Rentrop classification. Angiographic analysis included Thrombolysis In Myocardial Infarction flow, minimum lumen diameter, reference vessel diameter, and diameter stenosis and was done using conventional methods.9 Restenosis patterns were categorized as gap, margin, focal, multifocal, diffuse, proliferative, and total occlusion.10 Moderate calcification was defined as densities noted only with cardiac motion before contrast injection; severe calcification was defined as radioopacities noted without cardiac motion before contrast.9 IVUS was performed after recanalization with a guidewire or after predilation using commercially available IVUS systems (Boston Scientific Corp., Natick, Massachusetts; Volcano Therapeutics Inc., Rancho Cordova, California). The IVUS catheter was advanced at least 5 mm beyond the CTO segment, and an imaging run was performed using either automatic pullback at a speed of 0.5 or 1.0 mm/s (n ¼ 18) or using manual pullback. IVUS images were recorded onto digital media for offline analysis. All baseline and follow-up studies were reviewed side-by-side. Qualitative and quantitative IVUS analyses were performed by independent experienced observers (SS and AM) according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement, and Reporting of Intravascular Ultrasound studies.11 Using planimetry software (echoPlaque; INDEC Systems Inc., Santa Clara, California), quantitative IVUS analysis was performed within the CTO and the proximal and distal 5 mm reference segments every 1 mm to include: external elastic membrane (EEM), lumen, plaque and media (EEM minus lumen), and stent cross-sectional area (CSA); plaque burden (plaque and media divided by EEM); and neointimal hyperplasia CSA. Maximum plaque thickness at the distal reference was analyzed; significant thickening was defined as a maximum plaque thickness 0.5 mm.12 Lengths were calculated from the pullback speed and duration. Volumes were calculated using Simpson’s rule and reported as total and normalized volumes (volume divided by analysis length). Malapposition was defined as a separation of stent struts from the luminal border with the presence of blood between the struts and the plaque. Late-acquired stent malapposition (LASM) was present at follow-up but was not present at baseline, and persistent malapposition was visible both at baseline and at follow-up (Figure 1). Stent fracture was defined as an absence of struts >120 within the stent. Tissue protrusion was defined as visible tissue on the luminal side of the stent and adherent to the stent struts after implantation and considered persistent if it remained at followup. A subintimal space was an echo-free space outside the intima without a 3-layer appearance (Figure 2). Statistical analysis was performed with StatView 5.0 (SAS Institute Inc., Cary, North Carolina). Continuous data were reported as mean SD and compared using paired t tests if normally distributed. Otherwise, nonparametric data were reported as median and interquartile range and
compared with the ManneWhitney U test and Wilcoxon signed-rank test. Multivariate linear regression was performed to identify the independent predictors for changes of lumen CSA from baseline to follow-up at distal reference. A p value of <0.05 was considered statistically significant. Results There were 40 CTO lesions in 40 patients. Patient and procedural characteristics are listed in Table 1. Overall, 90% of the patients were men, 83% of lesions were treated through an anterograde approach, and 50% of the CTO occlusion duration was <12 months. Nine sirolimus-eluting stents, 8 paclitaxel-eluting stents, and 23 everolimus-eluting stents were used. Two patients (5%) had a failed previous CTO attempt. Nineteen lesions were in the right coronary artery (RCA), 10 lesions were in the left anterior descending coronary artery (LAD), and 11 lesions were in the left circumflex coronary artery (Table 2). The occlusion length measured 17.0 14.6 mm. Only 2 (5%) had severe calcification. The minimum lumen diameter decreased from poststent implantation to follow-up (2.25 0.48 vs 1.80 0.70 mm, p <0.0001). At follow-up, although the distal reference vessel diameter increased from baseline to follow-up (from 1.91 0.66 to 2.14 0.67 mm, p ¼ 0.02), the proximal reference vessel diameter decreased (from 3.30 0.79 to 3.01 0.75 mm, p ¼ 0.02). Overall, 27.5% (11 of 40) developed angiographic restenosis defined as diameter stenosis 50%; 27.3% (3 of 11) were focal in the body, 18.2% (2 of 11) were multifocal, 18.2% (2 of 11) were focal at the margin, 18.2% (2 of 11) were focal at a gap, 1 was proliferative, and 1 was a total occlusion. Minimum lumen CSA trended toward a decrease from baseline to follow-up (4.8 1.7 vs 4.5 1.7 mm2, p ¼ 0.10), although there was no change in minimum stent CSA from baseline to follow-up (Table 3). At follow-up, minimum lumen CSA sites were located at the minimum stent area site in 53%. Stent segments were divided into proximal, middle, and distal subsegments (Figure 3). The EEM CSA in the proximal stent subsegment showed no change from baseline to follow-up, but the EEM CSA in the mid and distal stent subsegments increased from baseline to follow-up. There were 20 (50%) stent malappositions at follow-up. Seventeen of 20 malappositions (85%) were LASM (Figure 1), and 3 (15%) were persistent. Of the 17 LASM, 35.3% (6 of 17) were located in the proximal part of the stent, 35.3% (6 of 17) were located in the mid part of the stent, and 29.4% (5 of 17) were located in the distal part of stent; all 5 LASM in the distal part of stent were observed in non-LAD lesions. Four stent fractures (in 3 lesions, 7.5%) and 2 persistent tissue protrusions (5%) were seen at follow-up. Postprocedural IVUS showed that stents were implanted into a subintimal space in 8 patients (20%); in 3 of them, the true lumen could still be identified behind the stent at follow-up. In the 8 lesions with subintimal stenting, subintimal segments were located at the proximal edge of the CTO in 37%, at the distal edge in 25%, and in the body of the CTO in 38%. The incidence of LASM, the changes in EEM CSA, and maximum percent neointimal hyperplasia did not differ in between subintimal stented subsegments
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Figure 1. An example of distal vessel enlargement and LASM at the distal stent edge after DES implantation into an RCA CTO lesion. (A, C) Baseline and follow-up angiogram. Arrows indicate the site of the distal stent edge; (B, D) identical sequences of IVUS images from distal stent edge into the distal reference are compared between baseline and follow-up. The stent CSA in the middle frame measured 2.7 mm2 at baseline and 2.8 mm2 at follow-up indicating no stent recoil. At the distal stent edge (middle frames) baseline EEM CSA increased from 8.7 to 10.4 mm2 resulting stent strut malapposition (double-headed arrow) without change of plaque CSA (5.6 to 5.4 mm2). Baseline plaque thickness measured 1.2 mm at the distal reference where the EEM CSA increased from 9.0at baseline to 11.6 mm2 at follow-up indicating positive remodeling that was associated with an increase in distal reference lumen CSA (2.3 mm2 at baseline to 6.3 mm2 at follow-up).
Figure 2. Examples of subintimal wiring and intraplaque (non subintimal) wiring after stent implantation. Upper and lower panels show the IVUS images of after wiring and poststent in a case with subintimal wiring and a case with intraplaque wiring, respectively. White arrows indicate true lumen which was pushed by the wire or stent in the subintimal space.
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Table 1 Patient and procedural characteristics in 40 lesions in 40 patients
Table 2 Angiographic findings in 40 lesions
Variable
Variable
Age (years) Men Hypertension Diabetes Hypercholesterolemia Cigarette smoking Family history of coronary artery disease Prior percutaneous coronary intervention Prior coronary artery bypass grafting Canadian Cardiovascular Society angina class II Medication Aspirin continued until follow-up Thienopyridine continued until follow-up Statin use at the time of discharge of procedure Expected occlusion duration <12 months 12 months Unknown Reattempt for chronic total occlusion treatment Antegrade approach Type of drug-eluting stent implanted Paclitaxel-eluting stent Sirolimus-eluting stent Everolimus-eluting stent
62 8 36 (90%) 20 (50%) 13 (32.5%) 18 (45%) 15 (38%) 17 (43%) 22 (55%) 2 (5%) 13 (33%) 39 (98%) 38 (95%) 18 (45%) 20 6 14 2 33
(50%) (15%) (35%) (5%) (83%)
8 (20%) 9 (22%) 23 (58%)
Values are presented as mean SD or number of observations (%).
and adjacent segments in which the stent was located within the plaque (Table 4). We had 12 paired IVUS images of the proximal reference and 24 paired IVUS images of the distal reference. There were no statistically significant changes from baseline to follow-up within the proximal reference segment in either the planar or volumetric analyses (Table 3); however, from baseline to follow-up, the smallest distal reference lumen area within 5 mm of the distal stent edge increased from 3.8 2.0 to 5.1 2.3 mm2, p ¼ 0.0004, along with an increase in the EEM CSA (from 8.4 5.7 to 9.3 5.2 mm2, p ¼ 0.005). Similar results were identified in the volumetric analysis (Table 3). Changes in lumen and EEM CSA were similar when comparing stents with versus without LASM (change in lumen CSA measured 35.0% [14.7 to 73.9] vs 28.7% [14.2 to 48.9], p ¼ 0.31; change in EEM CSA measured 16.8% [0.8 to 26.8] vs 4.4% [-4.5 to 23.3], p ¼ 0.54). Distal reference lumen CSAs were compared between baseline and follow-up in the following 3 subgroups: (1) LAD versus non-LAD, (2) lesions with distal reference maximum plaque thickness <0.5 mm versus 0.5 mm (Figure 4), and (3) 1st versus 2nd generation DES. Distal reference lumen CSA at follow-up significantly increased from baseline in non-LAD but not in LAD lesions. At baseline, CTO lesions with a distal reference maximum plaque thickness 0.5 mm had larger lumen CSAs (4.3 [3.4 to 6.2] vs 3.5 mm2 [2.9 to 4.0], p ¼ 0.20); EEM CSAs (10. [8.5 to 14.2] vs 5.4 mm2 [4.0 to 5.9], p ¼ 0.0004); and plaque burden (56.7% [52.7 to 63.8] vs 30.0% [27.4 to 35.4], p <0.0001) compared with the distal reference with a maximum plaque thickness <0.5 mm at baseline. Distal
Baseline
Follow-up
p Value
Coronary location of chronic total occlusion Right 19 (48%) Left anterior descending 10 (25%) Left circumflex 11 (28%) Occlusion length (mm) 17.0 14.6 Rentrop’s grade classification of collaterals 1 3 (7.5%) 2 2 (5%) 3 34 (85%) Not evaluable 1 (2.5%) Calcium Moderate 9 (23%) Severe 2 (5%) Stump morphology Abrupt 9 (23%) Tapered 31 (77%) Side brunch arising from stump 16 (40%) Quantitative coronary angiography findings baseline final and follow-up Thrombolysis in Myocardial 39 (98%) 40 (100%) 0.32 Infarction flow 3 Proximal reference vessel 3.30 0.79 3.01 0.75 0.02 diameter (mm) Distal reference vessel 1.91 0.66 2.14 0.67 0.02 diameter (mm) Minimum lumen diameter in 2.25 0.48 1.80 0.70 <0.0001 stent (mm) Diameter stenosis in stent (%) 16.3 9.5 35.2 22.9 <0.0001 Binary restenosis 18 (45%) Values are presented as mean SD or number of observations (%).
reference lumen CSA at follow-up significantly increased in lesions associated with a distal reference maximum plaque thickness 0.5 mm versus <0.5 mm. These findings are shown in Figure 4. When we evaluated IVUS findings between 1st and 2nd generation stent groups separately, the increase of EEM CSA in the distal reference was similar in both 1st and 2nd generation stents. Figure 5 shows the correlation between the percent change in lumen CSA versus percent change in EEM CSA and percent change in lumen CSA versus percent changes in plaque CSA at the distal reference segment. Percent change in lumen CSA had a strong correlation with percent change in EEM CSA (r ¼ 0.78, p <0.0001), but percent change in lumen CSA did not correlate with percent change in plaque CSA (p ¼ 0.99). Overall, there were 9 repeat revascularizations during the follow-up period, none in lesions with subintimal stent implantation. Discussion The main findings of this study were as follows: (1) there was distal but not proximal reference segment lumen and vessel enlargement that extended distally beginning from the middle of stent. Distal reference lumen enlargement correlated with distal reference EEM enlargement, but not with any change in plaque area, consistent with a positive remodeling effect, and (2) Subintimal stent implantation did
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Table 3 Serial planar and volumetric quantitative intravascular ultrasound findings Variable Planar analysis in 40 lesions Minimum lumen CSA (mm2) Minimum stent CSA (mm2) EEM CSA at MLA site (mm2) Maximum NIH CSA (%) Proximal reference Smallest lumen (mm2) EEM CSA at the smallest lumen (mm2) PþM CSA at the smallest lumen (mm2) Maximum lumen CSA (mm2) Distal reference Smallest lumen (mm2) EEM CSA at the smallest lumen (mm2) PþM CSA at the smallest lumen (mm2) Maximum lumen CSA (mm2) Volumetric analysis in 18 lesions Stent segment Stent length (mm) Mean lumen CSA (mm3/mm) Mean stent CSA (mm3/mm) Mean EEM CSA (mm3/mm) NIH (%) Proximal reference Mean lumen CSA (mm3/mm) Mean EEM CSA (mm3/mm) Mean PþM CSA (mm3/mm) Distal reference Mean lumen CSA (mm3/mm) Mean EEM CSA (mm3/mm) Mean PþM CSA (mm3/mm)
Baseline
Follow-up
4.8 1.7 4.8 1.7 11.6 6.4
4.9 4.9 12.4 26.0
6.5 3.0 15.3 4.2
6.1 2.7 15.2 6.2
0.63 0.28
8.8 3.0
9.4 5.4
0.58
9.4 3.8
8.9 3.6
0.59
3.8 2.0 8.4 5.7
5.1 2.3 9.3 5.2
0.0004 0.005
4.5 4.1
4.2 3.4
0.79
5.0 2.2
6.8 3.1
0.001
40.5 6.4 6.3 13.5
p Value
1.9 0.13 1.7 0.26 6.6 0.01 19.0
21.4 40.2 21.6 1.8 6.3 2.2 1.8 6.5 2.0 4.1 14.5 4.8 6.5 13.0
0.21 0.76 0.10 0.01
7.2 2.5 15.4 4.1 8.2 2.8
7.5 3.2 15.6 4.1 8.1 3.5
0.60 0.66 0.95
4.4 1.8 8.7 4.0 4.4 2.9
5.8 2.6 10.3 5.0 4.4 2.7
0.009 0.06 0.84
Values are presented as mean SD. CSA ¼ cross-sectional area; EEM ¼ external elastic membrane; MLA ¼ minimum lumen cross-sectional area; NIH ¼ neointimal hyperplasia; P þ M ¼ plaque þ media.
not appear to be deleterious in terms of LASM or neointimal hyperplasia compared with stenting the true lumen. In the present study, vessel enlargement was identified from the middle of stent to the distal reference. Lumen increase was seen in 83% (20 of 24) of distal references with a median increase in lumen diameter of 0.3 mm. Although the number of lesions in each subgroup was small, distal reference lumen enlargement was greater in vessels with a baseline maximum plaque thickness 0.5 mm (vs <0.5 mm) or nonLAD lesions (vs LAD lesions). Park et al13 reported a significant increase in mean distal reference lumen diameter of 0.21 mm (10.4 19.9%) and in mean EEM diameter of 0.13 mm (5.8 14.9%), in that of Gomez-Lara’s14 study was 0.29 mm and 0.19 mm, respectively, similar to the present study. Their clinical predictors of lumen CSA increase included an occluded duration of >3 months, poor collateral flow, and statin use. Cessation of forward blood flow in the setting of a CTO seems to result in distal vessel shrinkage. After recanalization of a CTO, vessel enlargement occurs by a recovery of blood flow. One animal study supported this
Figure 3. Comparison of EEM CSA in each segment between baseline and follow-up. In the 36 patients with available baseline and follow-up IVUS images, the percent changes in EEM CSA from baseline to follow-up are shown for each stent subsegment and the proximal and distal reference segments. There was an increase in EEM CSA from the middle stent subsegment that extended distally.
hypothesis.15 After 2 weeks, a 70% reduction in the rate of blood flow through a ligated carotid artery of rabbits caused a 21% decrease in arterial diameter. In addition, Galassi et al16 and Brugaletta et al17 showed impaired vasomotion function after recanalization of CTO and that this resistance improved over time, which seems to be one explanation of enlargement of distal reference of CTO. Because LAD has greater vessel tapering compared with non-LAD,18 the greater increase of distal reference lumen enlargement in non-LAD could be explained. Kawano et al19 showed that the intima þ media thickening of coronary artery correlated with worse flowmediated endothelial function. Therefore, the higher degree of intima thickness (>0.5 mm) may show more severe or longer decreased blood flow and vosomoter response caused by CTO. Correspondingly, the recovery of vasomotor function could be more notable in these lesions. With the advancement of CTO techniques such as CART, reverse CART, and STAR, subintimal stenting is common. Godino et al20 reported clinical outcomes after CTO recanalization using the contrast-guided STAR technique, but there are few data regarding subintimal stented segments as evaluated by IVUS. Tsujita et al21 reported a case of LASM after subintimal DES implantation due to vessel remodeling; however, in the present study, there were no differences in qualitative or quantitative IVUS between subintimal stented subsegments versus stents located in an adjacent intraplaque segment including the frequency of LASM, although the number of subintimal stented segments was small. In this present study, LASM occurred in 42.5% (17 of 40), 35.3% (6 of 17) were located in the proximal part of the stent, 35.3% (6 of 17) were located in the mid part of the stent, and 29.4% (5 of 17) were located in the distal part of stent. Previous studies in non-CTO lesions showed LASM in 7.6% to 33.7%, mostly within the body of the stent.22e24 Ako et al22 analyzed 141 patients (80 sirolimus-eluting stents and 61 bare-metal stents); 22% had LASM at follow-up, all in
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Table 4 Comparison of IVUS findings between subintimal and adjacent true lumen stented segments Variable Location of subintimal segment Proximal edge of the chronic total occlusion Distal edge of the chronic total occlusion Body of the chronic total occlusion Late-acquired stent malapposition (n) Maximum malapposition CSA (mm2) Baseline minimum lumen CSA (mm2) Follow-up minimum lumen CSA (mm2) Baseline maximum EEM CSA (mm2) Follow-up maximum EEM CSA (mm2) Change of EEM CSA at follow-up maximum EEM site (%) Maximum neointimal hyperplasia (%)
Subintimal Segment 3 2 3 3 3.2 6.4 6.9 18.4 18.5 4.4 12.9
(37%) (25%) (37%) (37.5%) (2.1, 4.5) (5.5, 6.8) (4.9, 7.7) (13.2, 20.3) (14.2, 20.8) (2.6, 7.4) (8.2, 17.7)
True Lumen Segment
3 2.0 4.9 4.6 17.5 17.6 10.9 17.8
(37.5%) (1.6, 2.0) (4.2, 6.1) (4.2, 6.6) (15.5, 18.9) (16.5, 22.3) (2.8, 23.7) (13.6, 23.8)
p Value
0.99 0.51 0.16 0.13 0.99 0.75 0.21 0.44
Values are presented as median (1st and 3rd quartiles) or number of observations (%). CSA ¼ cross-sectional area; EEM ¼ external elastic membrane.
Figure 4. Lumen measurements at the distal reference between baseline and follow-up. Comparison of baseline and follow-up distal reference lumen CSA overall and in LAD, non-LAD, maximum plaque thickness <0.5 mm, and maximum plaque thickness 0.5 mm (Panel A) accompanied by the percent change in lumen CSA (Panel B).
sirolimus-eluting stents at the stent edge. Guo et al23 studied 241 patients (184 paclitaxel-eluting stents and 57 bare-metal stents); 25% had LASM at follow-up (62 paclitaxel-eluting stents and 5 bare-metal stents) primarily at a stent edge. In the present study, there was vessel enlargement from the middle stent sub-egment to the distal reference at follow-up to explain the mechanism of LASM. In the present study, 4 stent fractures were seen in 3 lesions, a frequency of 7.5%. Canan et al25 reviewed previous reports; the frequency of stent fracture using DES was 0.8% to 7.7%, and the risk factors of stent fracture were overlapping stents, longer stents, RCA lesion location, and tortuosity or angulation of the vessel. Although a CTO was not reported to be a primary anatomic factor related to stent fracture, a CTO lesion is usually long, frequently in the RCA, and often treated with overlapping stents as was seen in the present study and in previous reports of DES fracture. Consistent with this, 1 study26 which reviewed 430 lesions in 382 patients who underwent follow-up angiography after
implantation of sirolimus-eluting stents reported that the frequency of stent fracture was 7.7% (33 of 430) in all lesions and 17.6% (3 of 14) in CTO lesions. This study has a number of limitations. The duration of IVUS and angiographic follow-up was only 9 months. A longer observation period with more patients is necessary to clarify the current findings and their impact on clinical events such as very late stent thrombosis. Only 8 patients had subintimal stenting, and only 24 patients had imaging of the distal vessel. In only half of patients (45%), IVUS were imaged using automatic pullback. Owing to retrospective nature of this study, current population has a selection bias, which may explain the higher incidence of restenosis. Disclosures Dr. Maehara receives grant support from Boston Scientific; is a consultant for Boston Scientific, ACIST; and receives speaker fee from St. Jude Medical. Dr. Mintz receives
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Figure 5. Scatter plot of intravascular ultrasound measurements obtained at baseline and at follow-up at the site of the distal reference maximum lumen CSA. (A) Relation between change in EEM and lumen CSA. Percent change in lumen CSA had a strong correlation with that of EEM CSA (r ¼ 0.78, p <0.0001); (B) relation between percent change in lumen CSA and plaque CSA. There was no significant correlation (p ¼ 0.99).
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