J Cardiol 2007 Jun; 49（6）: 345 – 352

Restenosis Developing Over One
Year After Implantation With a
Sirolimus-Eluting Stent: Two Case
Reports
TakujiNobuhiko

KATAYAMA, MD
OGATA, MD

Yoshio TSURUYA, MD
Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
A 68-year-old man with familial hypercholesterolemia developed effort angina and received a sirolimuseluting stent（SES）to treat 99% stenosis in segment 6 of the left anterior descending coronary artery inJanuary 2005. A further stent was implanted 14 months later to treat 99% restenosis at the proximal stentedge. A 66-year-old man with diabetes developed acute anterior myocardial infarction and underwent SES
implantation to treat 90% stenosis in segment 4 atrioventricular node artery branch of the right coronary
artery in April 2006. Heart failure developed 14 months later. Another stent was implanted to treat 100%
obstructive stenosis of the proximal stent site. Late stent restenosis may occur over 1 year after SES
implantation, so longer follow-up is required compared to bare metal stent.
──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2007 Jun; 49（6）: 345−352

Key Words■ Restenosis■ Stent（sirolimus-eluting）

INTRODUCTION
Randomized, double-blind trials have shown thatsirolimus-eluting stent（SES）implantation markedly
decreases restenosis rates compared with baremetal stent（BMS）1,2）and the beneficial effect persists at mid-term follow-up.3−5）However, late stentrestenosis is a potential risk after implantation of adrug-eluting stent because of the delayed healing
response.6,7）Here we describe two patients withlate stent restenosis 14 months after SES implantation, requiring target lesion revascularization（TLR）.
CASE REPORT
Case 1
A 68-year-old man with familial hypercholesterolemia, hypertension and obesity was referred toour hospital in December 2004 for further examination of frequent chest pain on mild exertion that had■ Coronary artery disease

persisted for 1 month. Atorvastatin（40 mg/day）andcolestimide（1.5 g/day）had been administered forfamilial hypercholesterolemia, but details of his
family history were unknown. Coronary angiography revealed 99% stenosis in segment 6 of the left
anterior descending artery（LAD）. He underwent
percutaneous coronary intervention（PCI）on
January 28, 2005. After pre-dilation with a balloon（Kongou 3.0 × 15 mm, Terumo）, a SES（Cypher
3.5 × 18 mm, Cordis）was deployed initially withan inflation pressure of 12 atm followed by the second dilation up to 18 atm with the same balloon at
a rather proximal site from the stent（Figs. 1−A,
B）. Although follow-up coronary angiography at 8
months after stenting revealed no restenosis, he frequently experienced chest pain on mild exertion
from March 2006. He was admitted to our hospital
under a diagnosis of unstable angina on March 17,
2006.
Physical examination on admission revealed──────────────────────────────────────────────
東京北社会保険病院 循環器科 : 〒 110−3377 東京都北区赤羽台 4−17−56
Division of Cardiology, Tokyo Kita Social Insurance Hospital, Tokyo
Address for correspondence: KATAYAMA T, MD, Division of Cardiology, Tokyo Kita Social Insurance Hospital, Akabanedai 4−
17−56, Kita-ku, Tokyo 110−3377 ; E-mail : taku-iku@fa2.so-net.ne.jp
Manuscript received January 23, 2007 ; revised February 18, 2007 ; accepted February 20, 2007

345

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Katayama, Ogata, Tsuruya

A

B

C

D

Fig. 1 Left coronary angiograms of Case 1
A : Segment 6 of the left anterior descending artery showed 99% stenosis.
B : A sirolimus-eluting stent was implanted for the target lesion.
C : The proximal stent edge developed 99% restenosis 14 months after the first stenting.
D : A sirolimus-eluting stent was implanted to cover the proximal site of the previous stent.

body mass index of 27.6 kg/m2, mildly high bloodpressure of 152/86 mmHg and thick bilateral
Achilles tendons. Lipid profile showed the following : total cholesterol, 194 mg/dl ; high-density
lipoprotein cholesterol, 36 mg/dl ; low-density
lipoprotein cholesterol, 131 mg/dl ; and triglyceride, 127 mg/dl. None of the myocardial enzyme
levels were elevated. Electrocardiography and chest
radiography revealed no unusual findings.
Echocardiography revealed mild hypokinesis in theanteroseptal apex area of the left ventricle.
Coronary angiography showed 99% stenosis in
the proximal stent edge in segment 6 of the LAD

on March 20, 2006. Therefore, ad hoc PCI was performed（Figs. 1−C, D）. After pre-dilation with aballoon（Rosso 2.5 × 15 mm, Kaneka）, a SES（Cypher 3.5 × 18 mm, Cordis）was implanted withan inflation pressure of 18 atm at the proximal siteof the previous stent. Intravascular ultrasound（IVUS）revealed obvious intimal proliferation in
the proximal stent edge with a partial low echoic
area 14 months after stent implantation（Fig. 2）.

Case 2
A 66-year-old male former smoker with untreatJ Cardiol 2007 Jun; 49（6）: 345 – 352

Late Restenosis in Sirolimus-Eluting Stent

A

B

Fig. 2 Intravascular ultrasound and angiography findings in Case 1
A : Left coronary angiogram showing the sites corresponding to the following intravascular ultrasoundframes after the first stenting.
a : Proximal site to the stent. b : Proximal stent edge. c : First culprit lesion.
B : Left coronary angiogram 14 months after the first stenting showing the sites corresponding to the following intravascular ultrasound images.
a : Proximal site to the stent showing intimal proliferation with isoechoic area. b : Proximal stent edge
showing intimal proliferation with partial low echoic area. c : First culprit lesion.

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Katayama, Ogata, Tsuruya

A

B

C

D

Fig. 3 Right coronary angiograms of Case 2
A : Segment 4 atrioventricular node artery branch（AV）of right coronary artery showed 90% stenosis.
B : A sirolimus-eluting stent was implanted for the target lesion.
C : The ostium of segment 4 AV developed 100% obstructive restenosis 14 months after the first stenting.
D : A sirolimus-eluting stent was implanted in the proximal site of the first stent crossing the posterior
descending branch.

ed diabetes was admitted to our hospital to treat anacute anterior myocardial infarction（Killip s classification class 1 ; peak creatine kinase, 8,294 IU/l）on
March 11, 2005. He underwent emergency PCI totreat total occlusion of segment 7 of the LAD, and a
SES（Cypher 3.5 × 23 mm, Cordis）and a BMS（Driver 3.0 × 24 mm, Medtronic）were implanted.
Insulin（30 R of 30 U/day）was administered to treat
diabetes after admission. Additional PCI for stenotic lesions of the right coronary artery was perfomed
before discharge on April 12, 2005, and a BMS（Driver 4.0 × 15 mm, Medtronic）for 75% stenosis
in segment 2 and a SES（Cypher 3.5 × 23 mm,

Cordis）for 90% stenosis in segment 4 atrioventricular node artery branch（AV）were implanted（Figs.
3−A, B）. The SES for segment 4 AV was deployedinitially with an inflation pressure of 12 atm followed by a second dilation up to 18 atm with thesame balloon at a rather proximal site from thestent. Although follow-up coronary angiography
10 months after stenting to the right coronary artery
revealed 75% restenosis for the BMS（distal to thestent in segment 2 and in-stent site in segment 7）,
PCI was not performed. He experienced shortnessof breath on exertion since June 2006. Chest radiography indicated congestive heart failure. He was
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Late Restenosis in Sirolimus-Eluting Stent

admitted to our hospital again on June 16, 2006.
Physical examination on admission showedslightly low blood pressure of 96/58 mmHg andslight pretibial pitting edema in the legs. No significant findings were evident in the chest. Oxygen saturation was normal. Laboratory tests revealed thefollowing : hemoglobin, 11.1 g/dl ; total protein,
6.6 g/dl ; creatine kinase, 364 IU/l ; creatine kinaseMB, 16 IU/l ; C-reactive protein, 2.46 mg/dl ; highdensity lipoprotein cholesterol, 34 mg/dl ; hemoglobin A1c, 6.7% ; and troponin-T, 0.36 ng/ml.
Electrocardiography showed sinus tachycardia
with a heart rate of 100 beats/min, a QS pattern inleads Ⅰ, aⅤL and Ⅴ5, poor R progression in precordial leads and a strain ST-T pattern in leads Ⅴ5
and Ⅴ6. Chest radiography showed a cardiothoracic
ratio of 54%, thickening in the minor fissure anddullness in the bilateral costophrenic angles.
Echocardiography revealed severe hypokinesis in
the inferior wall of the left ventricle in addition toakinesis in the anterior wall, left ventricular enddiastolic diameter of 61 mm and ejection fraction
reduced to 31%.
Coronary angiography revealed 100% obstructive stenosis of Thrombolysis in Myocardial
Infarction（TIMI）grade 1 from the ostium of segment 4 AV with a collateral vessel arising from segment 13 of left circumflex coronary artery on June20, 2006. Therefore, ad hoc PCI was performed（Figs. 3−C, D）. After passing a mildly stiff wire
（Miracle Primo, Asahi Intecc）through the lesion
and dilation with an over-the-wire balloon（Maverick 2.0 × 15 mm, Boston Scientific）, an
SES（Cypher 3.5 × 23 mm, Cordis）was implantedin the proximal site of the previous stent, crossing
the posterior descending branch. IVUS showed
obvious intimal proliferation in the proximal stentedge with a low and heterogeneous echoic area
14 months after implantation（Fig. 4）. In addition,
positive remodeling（external elastic membranecross sectional area enlarged from 18.3 to23.2 mm 2）and incomplete stent apposition were
evident in the previous culprit lesion.
DISCUSSION
The key issue in both of these patients is thatstent restenosis occurred at over 1 year after SES
implantation. The 2-year follow-up outcomes of thelargest randomized double-blind SIRIUS trial 4）
showed that most TLR were performed within 1
year after SES implantation, so the present cases
J Cardiol 2007 Jun; 49（6）: 345 – 352

349

are quite rare. Intimal proliferation occurring in thelate phase after implantation of a drug-eluting stentin an animal model was equivalent to that for a
BMS over the long term, or the late catch up phenomenon.6）Therefore, late restenosis was initiallyinvolved in the clinical application of drug eluting
stent, whereas mid-term follow-up results of a few
SES trials showed that the rate of TLR was significantly smaller in the SES than in the BMS
group.3−5）The RAVEL trial3）included 6 patientswith TLR between 12 and 36 months after SES
implantation, but none in the BMS group. This
result might be the late catch up effect. However,
the risk factors of late stent restenosis were notreported.
The present two patients had some key features
for the mechanism of restenosis. Restenotic lesions
developed in the proximal stent edge and werelocated distally from the bifurcation with the large
branch vessels. In addition, the new lesions weredifferent from the first culprit lesions. The first stent
did not completely cover the region from the proximal site of the stent to the bifurcation and post-dilation was performed rather proximally from the stent
deployment site. Since restenosis in the proximal
stent edge was rather noticeable in the SIRIUS
trial,2）avoiding unnecessary balloon injury and fullcoverage of the plaque beside the culprit lesion
with a longer stent have been recommended for
SES implantation. Balloon injury induced by postdilation might have caused intimal proliferation at
the proximal stent edge in the present two patients.
Hypercholesterolemia or diabetes is commonly
related to vascular endothelial dysfunction,8−11）andour patients probably had worse disease such as
familial hypercholesterolemia or diabetes withinsulin therapy. In fact, vascular endothelial dysfunction is associated with stent restenosis12,13）anddiabetes is widely accepted as a representative factor of stent restenosis.14,15）In the setting of these illnesses, endothelial dysfunction promoted by procedural vascular injury that persists even after the endof sirolimus release from a stent strut might causelate intimal proliferation as in the animal model.
The proposition that the stent thrombosis was
related to obstructive stenosis in the second patient
is difficult to exclude without endoscopic or pathologic evaluation. However, we supposed that themechanism of obstructive stenosis was mainly
restenosis due to intimal proliferation, because theprogress of the lesion was not acute, electrocardio-

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Katayama, Ogata, Tsuruya

A

B

Fig. 4 Intravascular ultrasound and angiography findings in Case 2
A : Right coronary angiogram showing the sites corresponding to the following intravascular ultrasoundframes immediately after the first stenting.
a : Proximal site to the stent. b : Proximal stent edge. c : First culprit lesion with external elastic menbrane2.
cross-sectional area（EEM-CSA）of 18.3 mm（circle）
B : Right coronary angiogram showing the sites corresponding to the following intravascular ultrasoundframes 14 months after the first stenting.
a : Proximal site to the stent showing intimal proliferation with low echoic area. b : Proximal stent edge
showing intimal proliferation with low and heterogenous echoic area. c : First culprit lesion with EEM2
. Positive remodeling and acquired incomplete stent apposition with
CSA enlarged to 23.2 mm（circle）
crescent echo-free space（arrow）had occurred.

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Late Restenosis in Sirolimus-Eluting Stent

graphy showed no significant change in the ST-T
segment, and IVUS revealed increased intimal areain the proximal lesion to the stent. IVUS of thepatient also revealed positive in-stent remodelingand incomplete stent apposition 14 months after
SES implantation. Late incomplete apposition after
SES implantation was not associated with cardiac
events at mid-term follow-up.16, 17）We considered
要351that incomplete stent apposition was not related tostent restenosis in this patient, because the apposition site differed from that of the intimal proliferation.
The present two patients required TLR due tolate stent restenosis that occurred over 1 year after
SES implantation. Longer follow-up is required for
drug-eluting stent than for bare metal stent.
約

シロリムス溶出性ステント留置 1 年以上後に再狭窄をきたした 2 例
片山

卓志

緒方

信彦

鶴谷

善夫

症例 1 は 68 歳，男性，家族性高脂血症あり．2005 年 1 月，労作性狭心症により左前下行枝分節 6の 99% 狭窄にシロリムス溶出性ステントを留置した．14 ヵ月後にステント近位端に 99% 狭窄をき
たし，再度ステント留置した．症例 2 は 66 歳，男性，糖尿病あり．急性前壁心筋梗塞を発症し，2005 年 4 月に残存する右冠動脈分節 4 房室結節動脈枝（AV）の 90% 狭窄に対してシロリムス溶出性
ステントを留置した．14 ヵ月後に心不全となり，4AV のステント近位部が 100 % 閉塞となっていたため，再度ステント留置した．シロリムス溶出性ステント留置例では遅延性再狭窄を生じる可能性があり，通常の金属ステントよりも長期間の経過観察が必要である．

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