Abstracts

Role of interferon-; on smooth muscle cells proliferation and

migration after balloon injury by inhibiting transforming growth

factor-B signal pathway

M Yu, W Guizhao*, H Yonglin*, L Meilin, H Dayi

Cardiovascular Center of Beijing Tongren Hospital, Capital University of

Medical Sciences, Beijing, China

*Department of Cardiology of the 1st Clinical Hospital, Harbin Medical

University, Harbin, China

Background: Restenosis after balloon angioplasty results from abnormal

proliferation of phenotypically modulated vascular smooth muscle cells

(SMCs) that migrate and synthesize large amounts of extracellular matrix.

A variety of growth factors have been shown to play a role in the

development of restenotic lesions including transforming growth factor-b(TGF-b). The expression of TGF-b mRNA and protein in the arterial wall is

increased following balloon injury in rats and over expression of TGF-b by

gene transfer into normal arteries results in neointimal formation. Inter-

feron-g (IFN-g) is shown to prevent neointimal formation after vascular

injury, although the mechanism is unclear.

Objective: To understand the molecular mechanism of vascular thickening,

we examined the effects of IFN-g on SMC proliferation and migration after

balloon injury.

Methods: New Zealand white rabbit right iliac artery was injured with

balloon dilatation, arteries of both sides were collected and analyzed

morphologically 4 days after injury. SMCs derived from injured artery

were maintained in DMEM and 10% heat-inactivated FBS. Cells were

incubated at 37 �C in a humidified atmosphere of 95% O2/5% CO2. Using

this technique, SMCs exhibit typical, spindle-shaped morphology and a

multilayered hill-and-valley growth pattern. Expression of a-actin was

demonstrated by immunohistochemical staining with a smooth muscle-

specific anti-a-actin antibody. Studies were conducted on subconfluent

SMCs (passages 3–5). SMCs were divided into four groups (control, TGF-

b1, IFN-g, TGF-b1 and IFN-g). Cells from each group were treated with

medium or TGF-b1 (10 ng/ml) and/or IFN-g (500 u/ml) for 72 h separately.

At the designated times, cells were trypsinized and quantitated by using a

hemocytometer, and SMCs proliferation inhibiting rate was determined by

MTT, migration of SMCs was also detected 72 h after treatment with

cytokines. The conditioned culture medium was harvested for detection of

matrix metalloproteinase-2 by zymography. Smad7 expression was tested

by Western blot.

Results: Our results showed that, compared with group control

(2.875 ± 0.323�105 cells/ml, 279.9 ± 8.129 mm), TGF-b1 increased cell

count (4.188 ± 0.239�105 cells/ml, P < .01) and migration distance

(365.8±9.686 mm, P < .01), and cell proliferation inhibiting rate of MTT

was�19.4%; whereas IFN-g decreased cell count (1.938 ± 0.249�105 cells/

ml, P< .01) and migration distance (234.4 ± 9.722 mm, P < .01), and cell

proliferation inhibiting rate of MTT was 15.8%; TGF-b1 combined with

IFN-g increased cell count (3.125 ± 0.254�105 cells/ml, P< .01) and migra-

tion distance (323.1 ± 8.481 mm, P < .01), but the value was lower than that

in cells treated by TGF-b1, proliferation inhibiting rate was �9.1%.

Zymography showed that MMP-2 could be detected in all groups, and

pro-MMP-2 could also be detected in cells treated by TGF-b1. Compared

with group control, the relative activity of MMP-2 in cells treated with TGF-

b1, IFN-g and TGF-b1, together with IFN-g, were 143%, 95%, and 109%,

respectively. Western blot showed IFN-g can enhance Smad7 expression.

Conclusion: The results indicate that TGF-b1 can stimulate the proliferation

and migration of SMCs derived from lesions, IFN-g can inhibit SMC

proliferation and migration and reduce the stimulation of TGF-b1 on SMCs.

TGF-b1 can increase pro-MMP-2 and MMP-2 activity, IFN-g can also

decrease MMP-2 activity and lessen the stimulation of TGF-b1 on MMP-2

activity. IFN-g can enhance Smad7 expression in SMCs. IFN-g can

modulate SMCs in various aspects. IFN-g can inhibit TGF-b1 signal

pathway and its effect on SMCs.

Elective percutaneous coronary intervention in a low-volume

community hospital without on-site cardiac surgery

S-U Lee, H-J Myung, S-K Cho, Y-C Ko

Kwangju Christian Hospital, Gwangju, South Korea

Purpose: We studied the safety and efficacy of performing elective

percutaneous coronary intervention (PCI) at a low-volume center without

cardiac surgical capability, which is not recommended in ACC/AHA

guidelines for PCI (2001).

Methods: Kwangju Christian Hospital (KCH) is located 5 min from

Chonnam National University Hospital (CNUH), which is the nearest

tertiary facility with on-site cardiac surgery. Five hundred seventy-eight

cases of coronary angiography (CAG) and 138 cases of PCI were

performed at KCH by one operator from March 2002 to December 2003.

We retrospectively evaluated clinical results from 138 cases of PCI. Sixty-

four cases of stable angina, 42 cases of unstable angina, and 3 cases of acute

myocardial infarction were included.

Results: Procedural success was achieved in 108 (98%) patients with 1

(1%) in-hospital death, and 1 patient required emergent transfer due to

life-threatening access site hematoma. At mean follow-up time of 6.4±3.7

months, one patient died of noncardiac cause. Twenty-five cases of

follow-up CAG were done. Restenosis rate was 24% (six patients). Three

(2.8%) patients had recurrent angina and angiographic restenosis requiring

target vessel revascularization. Ten patients were transferred to CNUH for

bypass surgery.

Conclusion: Percutaneous coronary interventions can be performed with

safety and efficacy in low-volume community hospitals without cardiac

surgical capability in Korea.

Retroperitoneal bleeding following percutaneous coronary intervention:

incidence and a case control study of its risk factors

CL Laham, PB Berger, RJ Lennon, KN Garratt, DR Holmes, Jr

Mayo Clinic and Duke Medical Center

Background: Retroperitoneal bleeding (RPB) following percutaneous

coronary intervention (PCI) via the femoral artery has not been well

studied. We sought to determine the incidence of and risk factors associated

with RPBs.

Methods and results: We retrospectively analyzed the Mayo Clinic PCI

database and identified 55 patients (pts) with a RPB confirmed by

abdominal/pelvic computed tomography or ultrasound between 12/01/93

and 6/30/02. To identify risk factors for RPB, we performed a case control

analysis matching 4 pts without RPB (controls) for each RPB pt based on

1522-1865/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.carrad.2004.03.004

Cardiovascular Radiation Medicine 4 (2003) 205–224

gender, age within 5 years and PCI within 1 year. The incidence of RPB

was 0.44%. Maximal sheath size used during PCI in RPB patients was

7.9 ± 1.2 French versus 7.5 ± 1.1 in controls ( P= .014). Using conditional

logistic regression analysis, prior PCI (relative risk [RR] 3.65 [95%

confidence intervals 1.52, 8.77], P= .004), heparin use after sheath removal

(RR 2.22 [1.11, 4.45], P= .025), maximal sheath size (RR 1.65 [1.10, 2.49],

P= .016) and failure to achieve TIMI-3 grade flow (RR 0.10 [0.03, 0.32],

P < .001) were all associated with RPB.

Conclusions: RPB during PCI from the femoral artery is infrequent.

Administering heparin after sheath removal, larger diameter sheaths, lack

of TIMI-3 grade flow in the treated vessel(s) and prior PCI procedures are

risk factors for its occurrence.

High-risk carotid stenting can still be done safely without protection

device

WY Kadro, A Hamwi, A Othman, Y Al-Kharsa

Golden Interventional Center, Damascus, Syria

Background: Protection device has been recommended for use during

carotid stenting especially in high-risk cases, however, protection devices

are expensive and cannot be afforded in Third World countries. We report

our experience in high-risk carotid stenting without using protection device.

Methods: Fifty consecutive carotid stenting were done at our center over

the past 18 months in 46 patients. All of these patients were turned down

for carotid endartectomy by vascular surgeons because they were consid-

ered high-risk patients for such procedure. All of these cases did not meet

the entry criteria for the NASCET study. Baseline features of the patients

included: age over 80 in 15 (32.6%), concomitant severe coronary disease

in all (100%), left main disease in 20 (43.48%), bilateral significant carotid

stenoses in 7 (15.22%), nonsignificant (< 50%) contralateral carotid stenosis

in 25 (54.35%), contralateral total occlusion in 6 (13.04%), severe stenosis

( > 90%) in 27 (58.69%), subtotal occlusive lesion (string sign) in 12

(26.09%), concomitant vertebral artery disease in 10 (21.74%).

Results: Predilation was done in all cases before implanting the self-

expanding stent, one case required implanting an extra stent with overlap.

Postdilation was done if residual stenosis after stent implantation was

> 25%. Angiographic success was achieved in all cases, no death occurred

in hospital or during the first month following intervention. A neurologist

performed a neurological evaluation before and after intervention. No major

stroke happened during hospital stay or 1 month after intervention. One

transient ischemic attack (TIA) causing motor dysphasia developed in one

case and resolved completely in 2 h and one minor stroke (arm weakness)

that resolved completely within 4 days developed in another case. The TIA

and the minor stroke happened during intervention, there were no further

similar events during hospital stay or 1 month after intervention.

Conclusion: High-risk carotid stenting can still be done safely without

protection device. The cost and the time of the procedure will be less. Good

training and meticulous manipulation of the wires, balloons and stents are

required for those procedures.

Wire arterial stent: choice of material

AG Mrochek, VT Minchenya*, VA Herasevich

The Belarusian Medical Academy of Postgraduate Education, Minsk,

Belarus

*The Belarusian National Technical University, Minsk, Belarus

Background: The problem of restenosis after the implantation of the

arterial stent still remains unresolved. The initial stage of the thrombosis

in a stent gleam is adhesion of the platelets on the material surface from

which the implant is made. The aim of the study was to find out which wire

has the least adhesive properties and could be used in the manufacturing

process of the new arterial stent ‘‘BY-S-Stent.’’

Methods: To conduct the study we use the patented method, which we

recently developed (Patent #5066, Republic of Belarus). The main principle

of the method is as follows: the quantity of the platelets, detained in a

column with a sample of a wire, is determined by passing a certain volume

of blood with a standard speed through the column. Then the formula was

used to calculate the adhesive index, which allows us to compare the given

properties of various wire models. Examples of the wire models inves-

tigated were 316L and 03X18N9T-VI. Research was carried out on 10

samples of each wire model with a surface area of 60 mm2. Polychlorvinyl

tube without a wire sample was used as the control.

Results: The initial amount of platelets measured before the experiment

was on average 232�109/l. The adhesive index the wire 316L calculated

was 9.14 ± 2.41% ( P < .05), whereas the adhesive index of the 03X18N9T-

VI wire was 13.30 ± 2.72% ( P< .05) (Fig.1).

Conclusion: For the manufacturing arterial stents, it is expedient to use a

wire 316L which has a 31% smaller adhesiveness to blood platelets in

comparison to 03X18N9T-VI.

Excessive carotid in-stent neointima formation predicts late

cardiovascular events

M Schillinger, M Exner*, S Sabeti, J Amighi, O Wagner*, R Ahmadi,

E Minar

Departments of Angiology and *Laboratory Medicine, Vienna General

Hospital, Medical School, Austria

Purpose: Critical restenosis (>70%) after carotid artery stenting (CAS)

rarely occurs. However, excessive in-stent neointima formation causing a

subcritical stenosis may indicate enhanced vascular reactivity in response to

injury, thus predicting late cardiovascular events.

Methods: We studied 100 consecutive patients (median age 71 years, 64

males) with high-grade internal carotid artery stenoses (68 asymptomatic,

32 symptomatic) who underwent CAS. High sensitivity C-reactive protein

(hs-CRP) was measured before CAS and patients were followed for median

23 months by duplex ultrasound for excessive in-stent neointima formation

[flow compromising lumen diameter reduction (> 50%), critical restenosis

(>70%), and the occurrence of late major adverse cardiovascular events;

MACE: myocardial infarction (MI), stroke, and death occurring later than

30 days].

Results: We observed excessive neointima formation in 14 patients (14%),

restenosis in 2 patients (2%) and 30 lateMACE in 25 patients (25%) (4MIs, 2

ipsilateral strokes in 2 patients with restenosis, 8 contralateral strokes, 16

cardiovascular deaths). Cumulative MACE-free survival rates at 6, 12, and

24 months were 92%, 84%, and 77%, respectively. Baseline hs-CRP levels

were associated both with neointimal hyperplasia ( P= .024) and MACE

( P= .021). Patients with excessive neointima formation exhibited a signific-

antly increased adjusted risk for MACE (hazard ratio 3.56, P= .010).

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224206

Conclusion: Excessive in-stent neointima formation after CAS indicates an

increased risk for late MACE, potentially reflecting a state of exaggerated

vascular reactivity in response to injury. Inflammation is associated both

with neointimal hyperplasia and MACE, and seems a common character-

istic of different vascular pathologies.

Radiochromic dose map and dose uniformity in the treatment region

for a catheter-based intravascular brachytherapy system

PS Wong

Department of Radiation Oncology and Biophysics, Eastern Virginia

Medical School

Background: The Novoste Beta-Cath System is a catheter-based intra-

vascular brachytherapy (IVBT) delivery device which employs an ingeni-

ous system of hydraulics to deliver the source trains to the catheter tip. The

transfer device serves to transport, hold and deliver the sources during the

procedure. In this study, a quantitative analysis was performed to invest-

igate dose distributions at vessel wall and prescription depths for a reference

lumen diameter (RLD) of 3 mm. The 3.5F 40-mm jacketed radiation source

train (JRST), which consists of a wire-jacketed series of sixteen (16) Sr90/

Y90 sources, was used for the study.

Methods and materials: Stacks of MD-55 radiochromic film strips

(80�15 mm, Fig. I) were sandwiched between b-rail delivery catheter

and solid water slabs. The setup simulates various effective depths from

Sr90/Y90 JRST, ranging from 0.8 to 2.31 mm. 18.4 Gy was delivered to the

prescription depth of 2 mm per Novoste’s protocol. Dose calibration set was

acquired using radiosurgery system with circular applicator of 3 cm

diameter. H & D curve was generated based on exposed doses ranging

from 1 to 60 Gy. Exposed films were scanned using Vidar-16 Dosimetry

Pro scanner. Quantitative analysis was performed using RIT 113 Radiation

Therapy Film Dosimetry. The net optical density (OD) measurements of

each film were converted into 2-D dose map. Longitudinal dose profiles,

which are vertically below source axis, were obtained for each film.

Results: Relative longitudinal dose uniformity within 32 mm of the

therapeutic length (Fig. II) at 0.8 mm, 1.015 mm, 1.23 mm, 1.456 mm

(vessel wall), 1.67 mm, 1.88 mm, 2.095 mm (prescription depth) and 2.31

mm effective depths are within ± 8.9%, ± 5.1%, ± 4.1%, ± 4.3%, ± 4.8%,

± 4.5%, ± 3.8%, and ± 5.5%, respectively (Table 1).

Conclusion: Higher longitudinal dose nonuniformity (± 8.9%) was

observed at 0.8 mm effective depth due to noncontinuity nature of the

JRST. Cold spots between individual sources are visible at this shadow

depth (Fig. Ia). Dose nonuniformity at vessel wall (± 4.3%) and prescription

depth (± 3.8%) verify that intended dose can be delivered to the entire

therapeutic length of 32 mm.

Stenting of significant carotid stenosis improves intracranial frame

count

WY Kadro, D Kadro, N Al-Najjar, R Shehadat

Golden Interventional Center, Damascus, Syria

Background: Carotid stenting (CS) is known to reduce the risk of stroke in

patients with significant carotid stenosis (SCS), however, its effect on

intracranial blood flow (ICBF) is not known. We therefore evaluated the

effect of CS of SCS on ICBF assessed by ICFC.

Methods: ICFC was assessed before and after CS in 17 patients who

received unilateral internal carotid artery (ICA) stenting for SCS. SCS was

defined as stenosis >70% or symptomatic stenosis >50%. All lesions had

TIMI 3 flow before CS. CS was successful in all patients (residual stenosis

<10%). Post-CS TIMI flow was III in all patients. Intracranial cerebral

angiogram before and after CS was done in the AP cranial view at a speed

of 3 frames per second. Frame 1 of ICFC was defined as the first frame that

fills the bifurcation of the ICA into the anterior cerebral (ACA) and middle

cerebral (MCA) arteries after injection. The film was then advanced frame

by frame to the end frame. The end frame of both the ACA and MCA was

assessed. The end frame was defined as the frame that fills the most distal

longitudinal branch of ACA or MCA in the AP cranial view. ICFC was

calculated by counting the frames from Frame 1 to the end frame of both

ACA and MCA.

Results: Mean ICFC for ACAwas 6.14 (range 5–7) frames before CS and

4 (range 3–6) frames after CS ( P= .003). Mean ICFC for MCA was 6.28

(range 5–8) frames before CS and 3.71 (range 3–6) frames after CS

( P= .0007).

Conclusion: CS improves ICBF as assessed by ICFC even when the flow is

excellent (TIMI 3) before stenting. This may reflect improvement in the

cerebral blood flow.

Endovascular gamma radiation therapy inhibits recurrence after

femoropopliteal artery in patients in an older population: the

Vienna experience

RM Wolfram, AC Budinsky, B Pokrajac*, R Potter*, E Minar

Department of Angiology, *Department of Radiotherapy and Radiobiology,

Medical University of Vienna, Vienna, Austria

Background: Endovascular brachytherapy (EBT) utilizing the gamma

emitter 192Ir has shown to efficiently reduce neointimal hyperplasia, the

key factor for restenosis, in patients treated with angioplasty for lesions

in the femoropopliteal arteries. The biological behavior of human cells is

known to change over time as might consequently be their response to

certain treatment modalities. This retrospective analysis was designed to

evaluate potential differences regarding the response to EBT after

femoropopliteal angioplasty according to age, and thus optimize future

treatment strategies.

Methods and results: A total of 199 patients, treated after femoropopliteal

angioplasty with either EBT (n = 100) or placebo (n = 99) within the

prospective randomized trials Vienna 2 and Vienna 3, were analyzed

according to age (median: 72 years). Patients randomized for EBT were

divided into two groups (51 patients =72 years and 49 patients >72 years).

The 12-month outcomes were compared to 99 age-matched patients treated

with angioplasty alone (44 patients =72 years, and 55 patients >72 years).

In patients younger than 72 years, recurrence occurred to a similar extent in

the EBT versus the placebo group at 12 months follow-up (37.3% vs.

56.8%; P= .08). In patients over 72, however, we observed a significant

Dose nonuniformity along the axis of the JRST

Depth0.800mm

1.015mm

1.230mm

1.456mm

1.670mm

1.880mm

2.095mm

2.310mm

Non-uniformity

± 8.9% ± 5.1% ± 4.1% ± 4.3% ± 4.8% ± 4.55% ± 3.8% ± 5.5%

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 207

reduction of restenosis with EBT as compared to angioplasty alone (32.7%

vs. 50.9%; P= .02).

Conclusion: EBT with gamma irradiation significantly reduces restenosis

in an older population after femoropopliteal angioplasty, but does not

improve outcomes in patients <72 years.

Endovascular gamma radiation therapy inhibits recurrence in

restenotic lesions of the femoropopliteal artery: the Vienna experience

R Wolfram, AC Budinsky, B Pokrajac*, R Potter*, E Minar

Department of Angiology, *Department of Radiation Therapy, Medical

University of Vienna, Vienna, Austria

Background: Intracoronary gamma radiation therapy efficiently improves

patency in patients with restenosis. This analysis was designed to

evaluate the efficacy of the gamma emitter 192Ir for the prevention of

recurrent stenosis in the femoropopliteal arteries in patients treated for

restenotic lesions.

Methods and results: A total of 199 patients, treated after femoropopliteal

angioplasty with either radiation (n= 100) or placebo therapy (n = 99)

within the prospective randomized trials Vienna 2 and Vienna 3 were

analyzed according to the stratification criterion of a de novo or recurrent

disease. A total of 66/134 patients with a de novo lesion and 34/65 patients

with a recurrent lesion had been randomized into the brachytherapy (BT)

arm. Outcomes were compared with that of 68 patients with de novo and 31

patients with recurrent lesions treated with placebo. The incidence of

recurrence at 12 months was not significantly different between the BT

and the placebo group for patients with de novo lesions (36.4% and 44.1%,

respectively; P= .32). However, the 12-month recurrence rate was signific-

antly lower in the irradiated group for patients with recurrent lesions

compared with the nonirradiated group (26.5% vs. 71.0%; P= .004).

Conclusion: Endovascular BTwith gamma irradiation significantly reduces

restenosis rate after femoropopliteal angioplasty of recurrent, but not of de

novo lesions.

Vascular brachytherapy with 192-Iridium after femoropopliteal-

stenting in high risk patients—results from the Vienna-5 Trial

RM Wolfram, AC Budinsky, B Pokrajac*, R Potter*, E Minar

Department of Angiology, *Department of Radiotherapy and Radiobiology,

Medical University of Vienna, Vienna, Austria

Objective: To evaluate the efficacy of endovascular brachytherapy (EBT)

for the prevention of restenosis after femoropopliteal stenting in high-risk

patients.

Background: Endovascular brachytherapy with the use of beta and gamma

sources has substantially decreased the restenosis rate after coronary and

peripheral interventions.

Materials and methods: A total of 88 patients with femoropopliteal lesions

(mean treatment length 16.8 ± 7.3 cm) were included into the trial. Patients

underwent PTA and stent implantation and were randomized in a double

blinded fashion to receive either gamma-EBT with a 192-Iridium source

or treatment with nonradioactive seeds. A dose of 14 Gy was prescribed at

2 mm into the arterial wall (target depth = vessel radius + 2 mm). The

primary endpoint of the study was angiographic binary restenosis >50% at

6 months. Secondary endpoint was either percutaneous or surgical TLR

after 6 months.

Results: Revascularization and EBT were successfully accomplished in all

patients. The overall 6-month recurrence rate was 34.8% in the Stent� vs.

33.3% in the Stent+EBT group ( P= .89). Nine (10.2%) patients developed

early reocclusion of the stented segment (two patients [4.3%] in the Stent�and seven [16.7%] in the Stent + EBT group), among those three patients in

the EBT group within the first 24 hours after intervention. Late thrombotic

occlusion (LTO >30 days) was observed in three patients (7.1%) in the

Stent+EBT group.

Conclusion: EBT does not improve 6-month patency after femoropopliteal

stenting in high-risk patients due to a high incidence of early and late

thrombotic occlusion.

Enhanced angiogenesis with autologous bone marrow transplantation

in a porcine non-reperfused myocardial infarction model

R Waksman, J Fournadjiev, R Baffour, R Pakala, D Hellinga, L Leborgne,

H Yazdi, E Cheneau, R Wolfram, R Seabron, K Horton, F Kolodgie*, R

Virmani*, E Rivera*

Washington Hospital Center, Washington, *Armed Forces Institute of

Pathology, Washington, DC

Background: Cell therapy is becoming a viable strategy to improve

revascularization and left ventricular function after myocardial infarction

(MI) injury. This study evaluated the effect of transepicardial bone marrow-

derived mononuclear cell (BMMNC) transplantation on infarct size, blood

vessel formation and myocardial function in a porcine model of non-

reperfused MI.

Methods: Coil implants were positioned in the coronary circulation of 13

domestic swine to produce MI. Twenty-six days later, autologous

BMMNCs were aspirated, labeled with bromdeoxyuridine (BrdU), and

cultured for 48 h. Animals underwent a left thoracotomy and 0.2 ml of BM

(�24�106 cells) were injected at eight sites (1 cm apart) within the

infarcted and border regions of eight swine; five animals injected with

saline served as controls. Animals received systemic BrdU 24 h prior to

euthanasia at 28 days. Regional contractility was assessed by transepicar-

dial echography performed at the time of BMMNC injections and 28 days

after treatment. Collateral growth, angiogenesis, and infarct size were

assessed by angiography, immunohistochemistry, and histomorphometry.

Results: Angiography revealed a trend toward increased collateral growth

in the experimental group. The size of infarct area (mm2) was smaller in the

transplanted BMMNCs group (81.83±10.65) than in the control group

(147.72 ± 23.25, P= .015). BrdU positive cells of treated and control

animals were 51.66% and 29.19%, respectively. Further, a-actin positive

cells were significantly greater in the BMMNC injected animals

(BMMNC=314.8±37.4 vs. saline = 167.1 ± 11.9/0.1 mm2, P= .02) as well

as the number of factor VIII positive endothelial cells (BMMNC=

363.3±28.2 vs. saline = 254.4 ± 28.1 cells/0.1 mm2, P= 0.03). The number

of blood vessels >50 mm was significantly increased in the BMMNC

group=317.9±54.9 vs. 149.12 ± 6.08 (P < .05). Wall motion score index

was similar in the BMMNC injected and saline groups at baseline

(1.63 ± 0.16 vs. 1.25 ± 0.25, P= .21) and at 28 days (1.83 ± 0.22 vs.

1.63 ± 0.38, respectively, P= .62).

Conclusion: Bone marrow-derived mononuclear cell engraftment of

infarcted tissue is feasible with cell viability maintained up to 28 days

and may lead to infarct size reduction. Increased angiogenesis by

BMMNCs transplantation in a model of non-reperfused MI was not

sufficient to support an improvement in left ventricular function.

Endovascular gamma radiation therapy inhibits recurrence after

femoropopliteal artery in patients with diabetes mellitus: the Vienna

experience

RM Wolfram, AC Budinsky, B Pokrajac*, R Potter*, E Minar

Department of Angiology, *Department of Radiotherapy and Radiobiology,

Medical University of Vienna, Vienna, Austria

Background: Endovascular brachytherapy (EBT) has shown to efficiently

improve patency in patients undergoing femoropopliteal angioplasty. This

analysis was designed to evaluate the efficacy of the gamma emitter 192Ir

for the prevention of recurrent stenosis in patients with diabetes mellitus

(DM) treated with percutaneous transluminal angioplasty (PTA) for lesions

in the femoropopliteal arteries.

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224208

Methods and results: A total of 321 patients, treated with either EBT

(n= 176) or placebo (n= 145) after femoropopliteal PTAwithin the prospect-

ive randomized trials Pilot 48, Vienna 2, Vienna 3 and Vienna 5, were

analyzed according to the stratification criteria of DM. Patients with DM

were either randomized to receive EBT (n= 72/176) or angioplasty only

(n= 68/145). Outcomes were compared to those of patients without DM

treated with EBT (n= 104/176) or placebo (n= 77/145). In patients without

DM, recurrence rates at 12monthswere comparable between the EBTand the

placebo group (39.4% vs. 53.2%; P= .065). Twelve months recurrence rates

in patients with DM, however, were significantly lower in the EBT group

versus the group treated with angioplasty only (38.9% vs. 57.4%; P= .029).

Conclusion: EBT with gamma irradiation significantly reduces restenosis

at 12 months after femoropopliteal angioplasty in patients with DM.

Early clinical outcome of drug eluting stents compared to bare metal

stents in patients with acute myocardial infarction

J-H Sung, I-J Hwang, I-J Kim, Y-K Cho, S-W Lim, D-H Cha, D-Y Oh

Department of Cardiology, Pundang CHA Hospital, Sungnam, South Korea

Objective: This pilot study aimed to compare drug eluting stents (DES) with

bare metal stents (BMS) in patients with acute myocardial infarction (AMI).

Background: Routine stent implantation was proven to reduce the risk of

adverse events in patients with AMI. DES has been demonstrated to

virtually abolish in-stent restenosis in elective patients with relatively

simple lesions. However, the safety and clinical impacts of DES for patients

with AMI are currently unknown.

Methods: Primary angioplasty using DES was performed in seven cases and

a control group consisting of 50 patients underwent BMS implantation from

September 2003 to January 2004. In DES cohort, 10 DES were deployed (3

CYPHER and 7 TAXUS) with the average size (diameter = 3.3 ± 0.4 mm,

length = 21.5 ± 0.5 mm). Baseline characteristics were similar between two

groups with no statistically significant differences. Themajor adverse cardiac

events (MACE= death, nonfatal reinfarction, target lesion revascularization)

were observed at admission and during a postangioplasty 30-day clinical

follow-up and the short-term outcomes were evaluated.

Results: There were no in-hospital MACE in the DES group as opposed to

two cases in the BMS group (0% vs. 4%; P= .59). At 30-day MACE, there

was no significant difference between the two groups (DES 0% vs. BMS

12%; P= .33). No significant differences existed in the total MACE

between patients treated with DES and BMS (0% vs. 16%; P= .25) (Table).

Conclusion: DES tends to be safer and more effective than the BMS in

patients with AMI, although there were no statistically significant differ-

ences between the two groups. A larger study can provide better results to

prove the safety and efficiency of DES.

Bivalirudin associated intracoronary thrombosis during gamma

brachytherapy and its experimental validation in acute swine model

P Kuchulakanti, S-W Rha, D Hellinga, R Seabron, R Pakala, LF Satler, WO

Suddath, AD Pichard, KM Kent, R Waksman

Cardiovascular Research Institute, Washington Hospital Center, Washing-

ton DC

Introduction: Intracoronary brachytherapy is an approved method to treat

in-stent restenosis and the anticoagulant requirement is the same as

conventional PTCA and is associated with similar bleeding complications.

Bivalirudin is used as an anticoagulant in patients undergoing percutan-

eous transluminal coronary angioplasty (PTCA) and is replacing heparin

in most cath labs. Few cases of intracoronary thrombosis were observed

during gamma brachytherapy with bivalirudin as an anticoagulant raising

question about the mechanism of this undesirable event.

Methods: To explore the mechanism of intracoronary thrombosis, we

conducted an experiment in acute swine model simulating the clinical

situation by randomizing seven swine to sham radiation+bivalirudin

(Group A; n= 3), gamma radiation+bivalirudin (Group B; n= 2), gamma

radiation and heparin (Group C; n= 2). PTCA with balloon and stent

followed by radiation was conducted in LCX (left circumflex) and LAD

(left anterior descending) arteries with ACT monitoring exactly like in

human cases. Gamma radiation was administered with the commercially

available Checkmate system (Cordis, Miami, FL). The end points were

demonstration of thrombus by angiography and postmortem examination

of the coronaries.

Results: ACT levels were comparable without any significant difference

between the Angiomax group and the Heparin group. Clotting was seen in

entire guide catheter in one animal from Group A and at the tip of the

radiation catheter in one animal from Group B, whereas no clots were seen

in Group C (Table 1). In other animals, we observed that flushing the

guide catheter with saline periodically during the dwell time of radiation

catheter prevented clot formation. The end point of Angiographic or

postmortem demonstration of intracoronary thrombus was not observed in

any of the seven animals.

Conclusion: Thrombus formation with bivalirudin is likely due to pro-

longed dwell time of radiation catheter and stasis of blood in the catheter

which is obviated by periodic saline flushing. We conclude from our study

that intracoronary thrombus occurs as results of propagation from the guide

catheter or from migration during contrast injection and it may not be safe

to use bivalirudin in cases of gamma brachytherapy.

Protective effect of rapamycin against atherosclerosis in Apo-E

knockout mice

R Pakala, E Stabile, AA Finegold, D Hellinga, R Seabron, R Baffour, J

Fournadjiev, PK Kuchulakanti, S-W Rha, R Waksman

Division of Cardiology, Washington Hospital Center, Washington, DC

Background: Rapamycin, a macrolide antibiotic, has been shown to inhibit

in-stent restenosis when delivered locally by drug-eluting stents. In the

current study, we wanted to test the effect of oral rapamycin on athero-

sclerotic plaque progression.

Methods: Eight-week-old Apo-E knockout (ApoE) mice were fed with

normal rat chow containing 0.25% cholesterol diet (Con) or with Con

containing 100 mg/kg rapamycin (Rapa-Diet) for 8 weeks. Mice were

sacrificed, hearts dissected out, flash frozen or fixed in neutral-buffered

formalin, embedded in cryomatrix and sectioned. Formalin fixed sections

were stained with Oil-Red-O and counterstained with Harris modified

hematoxylin. Frozen sections were stained for macrophages/foam cells.

Quantitative analysis of atherosclerosis and lesion area was determined.

Plasma cholesterol, triglyceride and rapamycin levels were measured.

Results: Cholesterol and triglyceride levels were essentially the same in

both groups. No rapamycin could be detected in the Con group, whereas

Rapa-Diet animals had 117 ± 7 pg/ml. In the Con group, atherosclerotic

lesions covered 41% of the aortic arch with a plaque area of 0.96 ± 0.045

Incidence of adverse events at 30 days in patients treated with drug eluting stentsversus patients treated with bare metal stents

DES (n = 7) BMS (n = 50) P

In-hospital MACE (%) 0 (0%) 2 (4%) 0.5930-day MACE (%) 0 (0%) 6 (12%) 0.33Total MACE (%) 0 (0%) 8 (16%) 0.25

Summary of experimental angioplasty results in three groups of animals

Vessel treated

Animal group LCX LAD Thrombus

Group A (Angiomax+sham radiation) stent balloon in the guide catheterstent balloon Nostent balloon No

Group B (Angiomax+gamma radiation) stent balloon over the PTCA wireballoon stent No

Group C (Heparin+gamma radiation) balloon stent Noballoon stent No

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 209

mm2. In contrast, Rapa-Diet animals had only 22% involvement with

0.34 ± 0.024 mm2. Lesions from the control mice encroached on the vessel

lumen with multiple futures of complex atherosclerotic lesions that are

comprised of acellular cores with cholesterol clefts towards the adventitial

side and focal collection of monocytes derived macrophages towards the

luminal side. In contrast, lesions in the Rapa-Diet mice are simple, mainly

composed of monocyte-derived macrophages.

Conclusion: Oral administration of rapamycin is effective in slowing the

progression of atherosclerosis, and may be a cost-effective way for

prevention of in-stent restenosis (Fig.).

The ‘‘real world’’ clinical practice of intracoronary radiation therapy

as compared to investigational trials

S-W Rha, PK Kuchulakanti, R Pakala, AD Pichard, LF Satler, KM Kent, WO

Suddath, E Pinnow, R Torguson, RC Chan, R Deible, J Lindsay, R Waksman

Division of Cardiology, Washington Hospital Center, Washington, DC

Background: Intracoronary radiation therapy (IRT) is well established in

clinical practice as an effective treatment for in-stent restenosis (ISR). We

aimed to determine if the 6-month clinical outcome of patients (pts) treated

postapproval for marketing [commercial radiation (CR)] is equivalent to

those pts enrolled in the Washington Radiation for In-Stent restenosis Trials

[Gamma WRIST and Beta WRIST, Investigational Radiation (IR)].

Methods: The 6-month clinical outcome of 110 consecutive pts with 125

lesions who received IRT [gamma, 192Ir, 15–18 Gy (n= 6); or beta, 32P, 20

Gy (n= 20); or 90Sr/Y, 18.4–23.0 Gy (n= 99)] in CR was compared with the

6-month clinical outcome of 117 pts with 117 lesions who received IRT

[192Ir, 15 Gy (n= 65) in ‘GammaWRIST’ and 90Y, 20.6 Gy (n= 52) in ‘Beta

WRIST’] in IR. Pts in the CR were treated with wider radiation margins. The

CR received antiplatelet therapy for at least 6 months and the IR for 1 month.

Results: The baseline characteristics of both groups were similar. Use of

atheroablation devices was less in CR (15.2% vs. 32.8% in IR, P= .001).

The overall major adverse cardiac events (MACE; death, Q-wave MI and

TVR, 18.2% vs. 29.1% in IR, P= .05) were significantly lower in the CR

when compared with pts in the IR.

Conclusions: The ‘‘real world’’ clinical practice of IRT demonstrates lower

events and better clinical outcomes. This is most likely a result of

implementation of the lessons learned from the clinical trials such as

optimizing the dosimetry by using a higher dose, treating wider margins

to minimize edge effect, and administering prolonged antiplatelet therapy to

abolish late thrombosis.

Impact of major side branch on periprocedural enzyme elevation and

long-term outcome in patients undergoing PCI and brachytherapy for

in-stent restenosis

P Kuchulakanti, S-W Rha, LF Satler, WO Suddath, AD Pichard, KM Kent,

R Pakala, DA Canos, EE Pinnow, R Waksman

Division of Cardiology, Washington Hospital Center, Washington, DC

Background: Major side branch (diameter >1.5 mm, SB) involvement

within the lesion subjected for percutaneous coronary intervention (PCI) is

known to be a contributing factor for periprocedural cardiac enzyme

elevation (CE). We aimed to assess the impact of SB on CE and 6-month

outcome in-patients undergoing brachytherapy for in-stent restenosis (ISR).

Methods: Retrospective analysis of the data of 248 consecutive patients

with a single vessel ISR with SB (Gp1, n= 146) and without SB (Gp2,

n= 102) who underwent brachytherapy using both beta and gamma emitters

was conducted. The procedural complications, CE, in-hospital course and

6-month clinical outcome were compared.

Results: The baseline patient and lesion characteristics were similar among

the groups. Procedural variables were similar except that stent usage was

more in Gp1. Baseline creatine phosphokinase (CPK)-MB levels were

similar, but postprocedure CPK-MB levels were higher in Gp1. In-hospital

complications were similar between the two groups. Six months follow up

revealed higher restenosis andmajor adverse cardiac events (MACE) in Gp1.

Conclusions: Presence of SB within the restenotic segment when treated

with PCI and brachytherapy is associated with higher periprocedural CE

and MACE at 6 months. Special care should be taken when treating ISR

lesions with SB.

Three-year follow-up after intracoronary gamma radiation for in-stent

restenosis in saphenous vein grafts

S-W Rha, PK Kuchulakanti, AE Ajani, R Pakala, E Cheneau, AD Pichard,

LF Satler, KM Kent, E Pinnow, J Lindsay, R Waksman

Division of Cardiology, Washington Hospital Center, Washington, DC

Background: The Washington Radiation for In-Stent Restenosis Trial in

Saphenous Vein Grafts (SVG-WRIST) demonstrated safety and efficacy of

IRT for the treatment of ISR in saphenous vein grafts (SVG) at 12 months.

The purpose of this study was to examine whether the safety and efficacy of

intracoronary gamma radiation (IRT) for in-stent restenosis (ISR) in SVG

reported at 12 months is resilient at 36 months.

Methods: A total 126 patients (pts) with ISR in SVG underwent PTCA,

laser ablation (53% of lesions), rotational atherectomy, and/or additional

stenting (50% of lesions). Pts were randomized to either 192Ir IRT or

placebo, with a prescribed dose of 15 or 18 Gy at 2 mm from the center of

Clinical events at 6 months

Commercial IRT, N (%) Investigational IRT, N (%) P

Death 8/110 (7.3) 5/117 (4.3) .33Any MI 5/110 (4.5) 16/117 (13.7) .02Any revascularization 23/110 (20.9) 42/117 (35.9) .01TLR 9/125 (7.2) 22/117 (18.8) .01TVR 14/125 (11.2) 31/117 (26.5) .002All MACE 20/110 (18.2) 34/117 (29.1) .05Late thrombosis 1/32 (3.1%) 13/94 (13.8%) .12

Comparison of variables in patients with and without major side-branch at therestenotic lesion

With SB(Gp1, n= 146)

Without SB(Gp2, n = 102)

P

value

Usage of stents 47.3% 30.4% .008Baseline CPK-MB normal 96.6% 98.0% .49Postprocedure

CPK-MB�4 15.3% 7.0% .04CPK-MB�5 10.4% 3.0% .029

6 months follow upRestenosis 36.0% 21.5% .031All MACE 29.3% 17.8% .041

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224210

the source. Pts underwent angiography at 6 months and were followed

clinically up to 36 months.

Results: The IRT group had less target lesion [TLR (17% vs. 57%,

P < .001)] and target vessel [TVR (28% vs. 62%, P< .001)] revasculariza-

tion at 12 months and continued to have lower TLR (47% vs.69%, P= .03)

and TLR-MACE rates (53% vs. 74%, P= .03) at 36 months. The Q-wave

MI, non-Q wave MI and death from cardiac causes was similar between the

two groups. TVR-MACE continued to be lower in the IRT group up to 24

months (52% vs. 71%, P= .03) but not at 36 months (69% vs. 80% in the

placebo group, P= .22).

Conclusions: In SVG WRIST, pts with ISR treated with IRT had a marked

reduction in the need for repeat revascularization at 12 months, with

sustained clinical benefit at 3 years.

Effects of contrast media on pig bone marrow derived stem cell and

calf myoblast viability and secretion of VEGF and MCP-1 by bone

marrow derived stem cells in vitro

R Baffour, R Pakala, D Hellinga, R Seabron, J Fournadjiev, R Wolfram, P

Okubagzi, SE Epstein, R Waksman

Division of Cardiology, Washington Hospital Center, Washington, DC

Background: Cell therapy for treating advanced coronary artery disease

represents a tremendous opportunity for developing new therapeutic strat-

egies. Adding contrast media to cell suspension might permit direct

injection of these cells to target area under fluoroscopy guidance. However,

the effect of contrast media on stem cells or myoblast is not well

characterized. We evaluated the effect of various contrast media on pig

bone marrow derived stem cell and calf skeletal myoblast viability and also

on the secretion of growth factors by stem cells.

Methods: Bone marrow was exposed to 10%, 20% or 33% contrast media

(diatrizoate, hypaque, hexabrix or optiray) or no contrast media (controls)

for 1 or 2 h. Bone marrow stem cells were then isolated, and viability

assessed by the trypan blue exclusion. Skeletal myoblasts from gastro-

cnemius were exposed to 10% or 33% contrast media for 15 or 30 min, and

myoblasts viability assessed. In a separate experiment, bone marrow stem

cells were isolated, and cultured in long-term culture medium for 4 weeks

after exposing them to 10% or 33% contrast media. VEGF and MCP-1

levels in the conditioned media from these cultures were assayed by ELISA.

Results: None of the contrast media tested had any effect on the viability of

bone marrow derived stem cells (99–100%). However, incubating myo-

blasts with 10% hypaque for 30 min or with 33% hypaque for 15 or 30 min

increased their viability by 8–10% over the control (control 88%)

( P= .001) (Table 1). Similarly, incubating myoblasts with 33% hexabrix

increased their viability by 8–9% ( P= .001). There were no detectable

levels of VEGF and MCP-1 in the culture medium at Day 0, but the levels

increased significantly to similar values in a time-related manner in the

control, 10% or 33% contrast media. For example, at 4 weeks, VEGF

levels were 2264±169 pg/ml; 2460±77 pg/ml; 2302±104 pg/ml; 2339±163

pg/ml; and 2194±357 pg/ml in the control, 10% diatrizoate, 10% hypaque,

10% hexabrix or 10% optiray, respectively. At 4 weeks, MCP-1 levels were

274±12 pg/ml; 290±11 pg/ml; 305±6 pg/ml; 268±5 pg/ml; 321±14 pg/ml

in the control, 10% diatrizoate, 10% hypaque, 10% hexabrix or 10%

optiray, respectively.

Conclusions: These results demonstrate that exposure of bone marrow stem

cells or skeletal myoblasts to contrast media is not deleterious. These

findings lend support to the concept that stem cell or myoblast suspensions

may be safely mixed with, at least, low concentrations of contrast media

and the mixture directly injected into ischemic myocardium under fluoro-

scopy guidance.

Intracoronary radiation therapy using a novel beta emitter for in-stent

restenosis: Tungsten WRIST

CE Dilcher, RC Chan*, S-W Rha, R Torguson, EE Pinnow, DA Canos, R

Waksman

Division of Cardiology, *Radiation Oncology, Cardiovascular Research

Institute, Washington Hospital Center, Washington, DC

Background: Intracoronary b-radiation therapy reduces in-stent restenosis

(ISR). This study, Tungsten WRIST (Washington Radiation for In-stent

Restenosis Trial), is a safety and feasibility study of intracoronary radiation

therapy (IRT) utilizing tungsten (188W), a beta emitter.

Methods: A total of 30 patients with angiographic evidence of ISR in a

previously treated native coronary artery underwent percutaneous coronary

intervention (balloon angioplasty, ablation by atherectomy, laser angio-

plasty). After the intervention, a noncentered delivery catheter with a side

guide 0.014-in. wire carrying a tungsten (188W) coil with an active length of

33 mm was inserted. Patients were randomized for either radiation with 18,

22 or 25 Gy at 2 mm from the center of the source. Aspirin and Plavix 300

mg loading dose was administered prior to intervention. Plavix 75 mg/day

was prescribed for 6 months after procedure.

Results: At 6 months follow-up, the overall binary angiographic restenosis

rate was 18.8% and the rate for target vessel revascularization (TVR) was

23% and for target lesion revascularization related major adverse cardiac

events (TLR-MACE) was 13.3% without any intergroup differences.

Comparison with the original WRIST radiation cohort utilizing a 192Iri-

dium-source (prescription dose 15 Gy at 2 mm from the source) showed a

similar TVR and TLR-MACE rate of 30% and 18%. TVR and TLR-MACE

rate of the WRIST placebo cohort was 70% and 66%.

Conclusions: Vascular brachytherapy with tungsten (188W) is feasible and

safe. The 6-month clinical outcome is similar to the original WRIST

radiation group.

Dose mapping of coronary arteries in porcine using a fiber

coupled dosimeter

CE Dilcher, RC Chan*, BL Justus**, AL Huston**, DG Hellinga, R

Seabron, R Waksman

Cardiovascular Research Institute, *Radiation Oncology, Washington Hos-

pital Center, **Naval Research Laboratory, Optical Sciences Division,

Washington, DC

Background: The purpose of this study was to measure radiation dosages

to the coronary arteries during intravascular brachytherapy (IVBT) with g-

and b-emitters utilizing, an in vivo dosimeter.

Methods: Domestic pigs were used. In each study catheters were intro-

duced into two different coronary arteries including the left circumflex

(LCX), left anterior descending (LAD), first diagonal (DI), right coronary

Myoblasts viability (% viable, mean±S.D.)

Diatrizoate Hypaque Hexabrix Optiray

Time (min) Control 10% 33% 10% 33% 10% 33% 10% 33%

0 90 ± 7 90 ± 7 90 ± 7 90 ± 7 90 ± 7 90 ± 7 90 ± 7 90 ± 7 90 ± 715 88 ± 6 92 ± 3 93 ± 3 88 ± 6 96 ± 4 88 ± 8 95 ± 4 87 ± 6 92 ± 530 88 ± 4 94 ± 5 91 ± 6 96 ± 4 97 ± 4 92 ± 3 96 ± 3 88 ± 5 87 ± 5Repeated-

measuresANOVAP value

NS .011 NS .001 .001 .048 .026 .027 .019

12- and 36-month clinical outcomes

12 months, N (%) 36 months, N (%)

EventsIr-192(N=54)

Placebo(N=59)

P

valueIr-192(N = 45)

Placebo(N=54)

P

value

Death 4 (7) 4 (7) 1.0 10 (22) 6 (11) .14Q-wave MI 1 (2) 2 (3) 1.0 2 (4) 1 (2) .45TLR 12 (20) 24 (57) <.001 21 (47) 37 (69) .03TVR 19 (32) 37 (62) <.001 29 (64) 40 (74) .30TLR- MACE 14 (23) 36 (60) <.001 24 (53) 40 (74) .03TVR-MACE 19 (32) 38 (63) <.001 31 (69) 43 (80) .22Late thrombosis 2 (4) 4 (7) .67 6 (13) 5 (9) .52

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 211

artery (RCA). A radioactive source (10 seed and 23 seed 192Iridium-/40 mm90Sr/Y-/20 mm 32P-source) and the dosimeter were loaded in each of the

catheters. Measurements were done while pulling back the dosimeter.

Results: Radiation dose is normalized to 100% dose at 2 mm radial

distance from the source. When radiating a branching artery, the dose to

the bifurcation at 5 mm from the source was 35%, 10% and 3% for the192Ir-, 90Sr/Y-, and 32P-source. Using a 23 seed 192Ir-source led to a dose of

40% at 5 mm distance. Radiating the RCA with a 23seed, 192Ir-source did

not result in dose to LAD or LCX.

Conclusions: Dose to adjacent artery segments is less with b- than with g-

emitters. Within a range of 5 mm at bifurcations significant dose exposition

is noted. Prescription doses and safety margins may be adapted in the future.

Intracoronary beta radiation for in-stent restenosis of small coronary

arteries: a dose comparison study

CE Dilcher, RC Chan*, S-W Rha, R Torguson, DA Canos, EE Pinnow,

R Waksman

Cardiovascular Research Institute, *Radiation Oncology, Washington

Hospital Center, Washington DC

Background: Intracoronary b-radiation therapy reduces in-stent restenosis

(ISR) in a dose-dependent manner. This study evaluates dose escalation of

intravascular brachytherapy (IVBT) utilizing a beta-emitter after percutan-

eous coronary intervention (PCI) of small coronary arteries.

Methods: A total of 140 patients with angiographic evidence of ISR in a

previously treated native coronary artery underwent PCI (balloon angio-

plasty, ablation by atherectomy, laser angioplasty). After successful inter-

vention, a noncentered delivery catheter was advanced carrying the active

source train (90Sr/Y) to cover the target site. A total of 90 patients received

18.4 Gy and 50 patients received 23 Gy prescribed to 2 mm radial distance

from the center of the source.

Results: The clinical 6-month follow-up showed a TVR-MACE rate (target

lesion revascularization—major cardiac adverse events) that is similar in

both groups (18.1% vs. 16.3% for 18.4 Gy and 23 Gy groups). All patients

were treated with aspirin and clopidogrel prior to the procedure. At

discharge patients were instructed to continue clopidogrel 75 mg/day for

at least 6 months.

Conclusions: Dose escalation (18.4 Gy vs. 23 Gy) utilizing a 90Sr/Y-source

is feasible, safe and effective in reducing ISR at 6-month follow-up.

IVUS-based dosimetry on patients with repeat radiated coronary art-

eries to the same site

CEDilcher, RC Chan*, P Rai, S-W Rha, R Torguson, DA Canos, RWaksman

Cardiovascular Research Institute, *Radiation Oncology, Washington Hos-

pital Center, Washington DC

Background: Intracoronary radiation reduces recurrent in-stent restenosis

(ISR). Repeat radiation may become necessary due to recurrent ISR. This

study reports outcome-related dose calculations for twice-radiated coronary

artery segments.

Methods: A total of 22 patients with angiographic evidence of ISR in a

previously treated native coronary artery were assigned for repeat percutan-

eous coronary intervention (PCI) and intravascular brachytherapy (IVBT).

IVBT was performed either with a 192Ir-, 90Sr/Y-source (prescription dose:

14–18 and 23 Gy each at 2 mm from the center of the source) or a 32P-

source (20 Gy, 1 mm deep to the vessel wall). Mean time interval between

two IVBT treatments was 394±306 days. For each patient, angiograms and

IVUS cross-sections were reviewed on the basis of anatomical landmarks

matched and the twice-radiated vessel segment was identified. IVUS-based

calculations of maximal and minimal point doses at the endothelium and

the adventitia–media border were performed. The point doses of consec-

utive slices of the twice-radiated vessel segment returned the dose range it

was exposed.

Results: Clinical follow-up at 379±146 days revealed a TVR rate of 18.2%

and a TLR rate of 13.6%. One death was reported. Maximal dose and

average dose at the endothelium was 261 and 124±72.3 Gy and maximal

dose and average dose at the adventitia –media border was 159 and

50.3±29.3 Gy. Fourteen patients had a 1.71 times longer recurrence free

interval compared with the interval between both IVBT treatments.

Conclusions: Repeat IVBT to the same ISR site is safe without any adverse

clinical events at average 12 months follow-up. A second IVBT treatment

led to a prolonged ISR-free survival for the majority of patients. The choice

of isotope did not influence outcome.

Vascular remodeling induced by endothelial cells within gas–plasma

treated scaffolds in aged nude mice

JL Polan, O Munoz, CM Agrawal, SR Bailey

University of Texas Health Science Center at San Antonio: Janey Briscoe

Center for Cardiovascular Research

Purpose: Increased blood vessel remodeling occurs from endothelial-

seeded bioresorbable gas–plasma treated polylactide acid (D,L-PLA) scaf-

folds when implanted into 2-month nude mice (N= 114) up to 72 days. Our

hypothesis is that endothelial-containing gas–plasma treated scaffolds

similarly implanted within 14-month aged nude mice will exhibit reduced

vascular remodeling due to less expression of vascular endothelial growth

factor (VEGF) and basic fibroblast growth factor (bFGF).

Methods: 14-month aged immunological-deficient nude mice were

implanted with nontreated control (n= 7), gas–plasma treated bioresorbable

scaffolds (n= 8) containing human aortic endothelial cells or were proced-

ural shams (n= 2). Scaffolds and peritoneal tissues were evaluated and

statistically compared by in situ quantification of blood vessels (scale 0–4)

at 72 days. VEGF and bFGF indirect immunostainings were prepared on

fixed scaffolds and tissue.

Results: Treated scaffolds induced blood vessel densities near the scaffolds

that were scored 1.83 ± 0.8; whereas, control scaffolds induced 1.47 ± 0.9.

Remodeling after 72 days with gas–plasma treated scaffolds in aged

nude mice.

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224212

Consequently, ANOVA showed no statistical difference ( P= .55). Shams

scored an average of 0 ± 0.0. Both treated ( P= .017) and control ( P= .031)

were significantly different from the shams. Blood vessel densities above

and near the scaffolds were less for 17-month nude mice with treated

scaffolds than for 5-month nude mice ( P= 6.1E�06); whereas, control

scaffolds in the aged and young mice were not significantly different

( P= .450). VEGF and bFGF expression was surprisingly greater in aged

versus young specimens.

Conclusion: 17-month aged nude mice exhibit reduced blood vessel

remodeling despite enhanced angiogenic protein, such as VEGF and bFGF,

production when implanted with either endothelial-containing gas–plasma

and nontreated D,L-PLA scaffolds.

The results of transradial coronary intervention for chronic total

occlusion

T Shiono, S Saito, S Tanaka, Y Miyashita, S Takahashi

Shonan Kamakura General Hospital

Objective: Percutaneous coronary intervention (PCI) for chronic total

occlusion (CTO) is one of the major challenges in interventional cardiology.

The development of a tool like a tapered-tip guidewire improves the

primary success rate of TRI for CTO.

Methods: Between January 2000 and December 2002, 2926 patients

underwent PCI in Shonan Kamakura General Hospital. A total of 2034

patients (69.5%) were treated by TRI, and the others were treated by the

femoral or brachial approach. We analyzed 303 cases (10.6%) of CTO,

which included 196 patients (64.7%) treated by TRI during that. Patients

were carefully distributed to each approach while making diagnostic

coronary angiogram reference. TRI was chosen for the patients expected

to succeed even if it does not image a contralateral coronary angiogram.

We mainly used six French guidings. All procedures were enforced in

accordance with our CTO guideline: (1) successful penetration of a

guidewire <30 min, (2) total procedure time <90 min, (3) total dye

volume <300 ml.

Results: Procedure success was achieved in 145 patients (74.0%) out of

196 TRI for CTO. Among the 51 patients without successful angioplasty,

we have not passed a guidewire in a pathological change part in 35

patients (69%). We could not cross the lesion by a balloon catheter in

only 2 patients and failed to accomplish TIMI-3 flow in 14 patients. There

were no cases of death, emergency bypass surgery or major vascular

complications. In the case of transfemoral approach, four patients required

blood transfusion due to bleeding complication and procedure success rate

was 68.4% during the period. Follow-up angiography was performed in

102 patients (70.3%) and mean follow-up period was 11.2 months.

Among the case of procedure success, 40 patients underwent TLR.

Conclusions: Transradial procedure is a safe and useful method for

treatment of CTO. Various techniques such as a 5 in 6 guiding or an

anchor balloon support TRI for CTO and bring about an equivalent results

compared with conventional approach.

Chronic recovery of endothelium-dependent relaxation in pig coronary

arteries distal to sites of endovascular irradiation after three months

J Li, B Ebato, P Mulkey, NAF Chronos, KA Robinson

American Cardiovascular Research Institute, Norcross, GA

Background: We previously reported that endothelium-dependent relaxa-

tions were impaired in coronary arteries distal to sites of intracoronary

radiation (CADSIR) at 1-month postprocedure. In this study, we investigated

whether vasomotor function in CADSIR remained abnormal at 3 months.

Methods: Pig coronary artery segments 2 cm distal to sites of irradiation

were studied in an organ-chamber apparatus, 3 months after sham (S,

n= 7) or active irradiation (R, n= 8; 20 Gy). There were no fibrotic

adhesions, intramural hemorrhages or enlargement in CADSIR or S

treatment. These morphologies were present at sites of irradiation but

not in sites of sham treatment.

Results: Unlike contractions of target arteries, contractions of CADSIR

to 40 mM KCl (4.44 ± 0.62 vs. 3.85 ± 0.58, NS) and 100 mM KCl

(5.66 ± 0.81 vs. 4.49 ± 0.38, NS) were similar to sham. After NO

synthase inhibition with L-NAME, contraction to 5 mM PGF2a was

significantly higher than contraction to PGF2a before L-NAME

(5.21 ± 0.95 vs. 2.28 ± 0.51, P < .05). Maximal dose relaxation (DRmax;

3 mM) of CADSIR to calcium ionophore A23187 was not different

from S (82.8 ± 0.09% vs. 93.4 ± 0.03%, NS) and was significantly higher

than CADSIR at 1 month (35.7 ± 0.09%, P< .01). DRmax (100 pM) in

CADSIR to substance P was similar to S (41.6 ± 0.06% vs.

44.0 ± 0.07%, NS) and significantly higher than CADSIR at 1 month

(14.7 ± 0.08%, P < .01). Scanning electron microscopy showed confluent

endothelial cells with normal-appearing morphology in both groups.

Morphology of the irradiated site also showed a confluent endothelial

layer, without notable inflammatory cell adherence.

Conclusions: Endothelial function of CADSIR was similar to S at 3 months

post-irradiation and normalized compared to CADSIR at 1 month. This

temporal recovery of distal coronary vasomotor function abnormalities may

relate to angioplasty site healing and resolution of the inflammatory

response. Perfusion of distal myocardium may be affected by upstream

brachytherapy of a site of balloon catheter or stent intervention, but this

effect is expected to resolve over time.

TheraP trial dosimetric characterization of TheraSource (Pd-103)

intravascular brachytherapy source

ME Napolitano, JJ Bergman, KK Millage*, RA Hearn, JJ Rodgers

Radiation Physics, Theragenics Corporation, Buford, GA

*The Millage Group, Flemington, NJ

Purpose: The Monte Carlo Code MCNP4C was used to perform the TG-

60 based dosimetric characterization for TheraSource, a Pd-103 intra-

vascular brachytherapy source. TheraSource was used in the TheraP Trial

(a Phase I safety and feasibility study). In this trial, TheraSource was used

following PTA to deliver 20 Gy to the target tissue in the superficial

femoral and popliteal arteries. The source consists of a 40-mm active

segment of high specific activity Pd-103 coated on a nitinol wire.

Methods: Monte Carlo calculations were used to calculate the dose rate as

well as the axial and radial dose profiles. Dwell times for each step were

calculated based on vessel diameter and a prescription dose of 20 Gy to a

target 2 mm into the vessel wall. The Monte Carlo based dosimetric

characterization was combined with measured activity and compared to

measured thermoluminescent dosimeter (TLD) dose values. Source uni-

formity along the center 2/3 of the source is confirmed using Gafchromic

film. The source was manually stepped to treat interventional treatment

lengths up to 134 mm in four steps with margins of at least 10 mm. To

minimize the possibility of gaps during manual stepping of the source, a 2-

mm overlap was used. A centering balloon, 1 mm smaller than the vessel

inner diameter was used to minimize dose variation at the prescription

point due to noncentering. The dose profile was calculated at the prescrip-

tion depth along the treatment length. A 2-mm overlap was assumed, as

well as realistic permutations due to noncentering and overlap.

Results: The dose based on MCNP4C calculated dose rate combined with

measured source strength compared on average within 10% to TLD dose

measurements over the range of 0.2 to 2.0 cm from the source centerline.

Source uniformity is within ±10% throughout the center 2/3 of the source.

For lesion lengths that require stepping, localized regions in the 2-mm

overlap region receive a 20% increase in dose. In the 2-mm overlap

regions, the worst-case dose variation due to noncentering and a 2-mm

overlap ranges from 17 to 30 Gy.

Conclusions: Good agreement was found between calculated dosimetry

parameters and TLD measurements. The recommendations of TG-60 have

been followed for dosimetric characterization and source uniformity.

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 213

Variation in prescription dose due to overlap required for manual stepping

and noncentering was given careful consideration.

The use of perfusion balloon in stenting of carotid arteries with

contralateral severe stenosis or occlusion

WY Kadro, A Hamo, A Aldebs, I Eid

Golden Interventional Center, Damascus, Syria

Background: Stenting of carotid arteries with contralateral occlusion or

severe contralateral stenosis carries a high risk for seizure or loss of

consciousness during balloon inflation at predilation and postdilation.

The use of perfusion balloon for pre- and postdilation may prevent cerebral

ischemia and reduce the incidence of intolerance to balloon inflation by

preventing total obstruction to the lumen of the artery.

Methods: After having two bad experiences with seizure and loss of

consciousness while intervening on carotid artery with contralateral total

occlusion, we decided to use perfusion balloon for pre- and postdilation.

During the past 2 years, we did 29 cases of carotid artery stenting for

lesions of >70% stenosis with contralateral total occlusion or contrala-

teral severe stenosis. A 3.5-mm perfusion balloon was used for predi-

lation. Postdilation was done with 5–5.5 mm perfusion balloon. All

cases were done without the usage of protection device since it cannot

be afforded in our country due to its high cost.

Results: Procedure success was 100%, angiographic success was 100%,

intolerance to balloon inflation, i.e. seizure or loss of consciousness did not

happen in any case during pre- or postdilation. One episode of transient

facial droop happened in one case during predilation and resolved com-

pletely after balloon deflation and did not recur during postdilation. TIA

happened only in one case after postdilation and resolved completely within

2 h after intervention.

Conclusion: The usage of perfusion balloons for pre- and postdilation is

safe and prevents seizure and loss of consciousness during intervention

on carotid arteries with contralateral total occlusion or contralateral

severe stenosis.

Mobilization of bone marrow stem cells by granulocyte colony

stimulating factor for treatment of patients with severe chronic

ischaemic heart disease

J Kastrup, W Yongzhong, ****K Tagil, RS Ripa, **JC Nilsson, S Carstensen,

E Jørgensen, L Søndergaard, *B Hesse, ***HE Johnsen

Cardiac Catheterization Laboratory, The Heart Centre, *Department of

Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark**Danish Research Centre for Magnetic Resonance, Hvidovre Hospital,***Department of Haematology, Herlev University Hospital, Herlev,

Denmark****Department of Clinical Physiology, Malmo, Sweden

Aim: Granulocyte colony stimulating factor (G-CSF) mobilized bone

marrow stem cells participate in neovasculogenesis in ischaemic myo-

cardium in animal studies. This is the first Phase I safety and efficacy

study with G-CSF treatment of patients with severe ischemic heart

disease (IHD).

Methods and results: Thirteen patients with severe IHD were treated with

subcutaneous injections of 5 mg G-CSF/kg body weight for 6 days. The

treatment was without any deterioration of clinical status or serious adverse

events. However, five patients were ‘‘poor mobilizers’’ to the G-CSF

treatment (max CD34+ cells <12,000/ml blood) with a maximal increase

in CD34+ cells to 8600±1600/ml blood compared to 31,000±5200/ml blood

in ‘‘mobilizers’’ (max CD34+ >12,000/ml blood). At 2 months follow-up,

patients had improved in CCS angina classification from 2.7±0.6 to 1.7±0.6

(mean±S.D., P= .01), a decline in NTG use from 1.5±2.1 to 0.5±1.2 per day

( P< .05) and number of angina pectoris attacks from 1.7±1.7 to 1.0±1.6 per

day ( P< .05). Improvement was mainly seen in the eight patients with a

maximal increase of CD34+ stem cells >12,000/ml blood. However, we

found no accompanying changes in myocardial perfusion and function on a

standard adenosine stress single photon emission computerized tomography

(SPECT), magnetic resonance images or echocardiography.

Conclusion: Treatment by G-CSF in patients with severe IHD seemed

safe without adverse side effects. Improved symptoms of myocardial

ischemia were demonstrated and the effect was related to the degree of

increase in circulating stem cells. Randomized, placebo-controlled studies

are needed to verify whether G-CSF is a new treatment option in ischemic

heart disease.

Combining angiogenesis and cell therapy for improved outcome: the

role of angiogenesis master regulator gene EPAS1

S Iacampo, R Martel, AS Fortin, G Leclerc, L-G Guy

Angiogene Inc., Montreal, Quebec, Canada

Background: Myocardial infarction caused by hypoxia results in cardiac

tissue damage. Cardiac function can be improved by cell transplantation in

the scar. Furthermore, the implanted cells can also be used as vectors for the

production of angiogenic factors to improve perfusion. This study exam-

ined the angiogenic activity of human primary cells modified with the

hypoxia inducible factor EPAS1.

Methods: Human skeletal myoblasts, mesenchymal stem cells, bone

marrow mononuclear cells and fibroblasts were transduced with an

adenovirus expressing EPAS1. VEGF was measured by ELISA and gene

induction profile was documented with microarrays. Human umbilical

vein endothelial cells (HUVECs) proliferation, migration and differenti-

ation was evaluated by colorimetric, modified Boyden chamber and

matrigel tube formation assays after supplementation with conditioned

media from vehicle, myoblasts and EPAS1 modified myoblasts. Vehicle,

myoblasts and EPAS1 modified myoblasts were subcutaneously

implanted in immunodeficient mice and angiogenesis was assessed in

the implants by histology.

Results: In all human primary cell types tested, EPAS1 was found to be

a potent VEGF inducer. Several secreted factors implicated in the

different steps of the angiogenesis process, such as MMP7, PlGF, leptin,

adrenomedullin, IL-8 and LIF, were also found to be induced by EPAS1.

The proliferation, migration and differentiation of endothelial cells were

increased by conditioned media from myoblasts (containing the secreted

factors), but EPAS1 gene transfer in the myoblasts more than doubled

this induction (see Figure). In vivo, EPAS1 transduction into myoblasts

significantly increased angiogenesis activity in subcutaneous implants

compared to myoblasts alone.

Conclusions:Myoblasts secrete several angiogenic factors that stimulate

endothelial cells. EPAS1 gene transfer enhances the production of

these factors and significantly improved the stimulation of cultured

endothelial cells by myoblasts. EPAS1 modification of myoblasts also

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224214

directly improved angiogenesis in vivo. EPAS1 is thus a good

candidate for genetic modification of cells to be transplanted in the

scarred myocardium.

Cell-mediated EPAS1 gene transfer is superior to cell therapy alone for

improving perfusion and cardiac function in infarcted heart

L-G Guy, Y Morimoto*, S Iacampo, AS Fortin, BH Davis*, G Leclerc,

DA Taylor*

Angiogene Inc., Montreal, Quebec, Canada

*Division of Cardiology, Duke University Medical Center, Durham, NC

Background: Successful improvement of cardiac function after transplant-

ing skeletal myoblasts into myocardial scar has moved this treatment into

clinical trials. A major limitation of cellular cardiomyoplasty (CCM) is the

death of cells in the hypoxic infarct milieu. Thus, factors which improve

angiogenesis and cell survival might increase the efficacy of CCM. EPAS1

is a hypoxia inducible factor that regulates genes induced by low oxygen

tension, such as the angiogenic factor vascular endothelial growth factor

(VEGF). The hypothesis of this study is that EPAS1 gene transfer will

improve the angiogenic potential of myoblasts in myocardial scar and thus

the efficacy of the treatment.

Methods: Human skeletal myoblasts were transduced with an adenovirus

expressing EPAS1 and VEGF was measured by ELISA. Microarrays

were used to document the profile of gene induction. Vehicle, myoblasts

and EPAS1 modified myoblasts were implanted into cryoinjured left

ventricle of immunodeficient mice. Cardiac function was assessed at

Days 0 and 28 by magnetic resonance imaging. Fluorescent lectin was

infused in the circulation prior to sacrifice and vessel density in scar was

quantified by histology.

Results: In vitro, there was a 20-fold VEGF induction upon EPAS1 gene

transfer. Other angiogenic genes (PlGF, IL-8, and LIF) and cardioprotec-

tive genes (LIF-R, cardiotrophin 1 and adrenomedullin) were also induced

by EPAS1. Vessel density in the scar was significantly superior in the

EPAS1 modified myoblasts group and lectin staining confirmed that

vessels were functional and connected to the vasculature. LVEF change

after treatment revealed that animals in the vehicle group deteriorated

over time while those treated improved. LVEF improvement more than

doubled in the EPAS1 modified myoblast group compared to the

myoblast alone.

Conclusions: EPAS1 gene transfer increases the expression of angiogenic

and cardioprotective genes and enhances the functional impact of myo-

blasts in scar, presumably by promoting angiogenesis and cell survival.

Age and acute ischemia aremajor determinants of stem cell mobilization

efficacy of granulocyte-colony stimulating factor in patients with

myocardial infarction

H-J Kang, H-J Cho, S-Y Zhang, K-W Park, H-S Kim, B-H Oh, M-M Lee,

Y-B Park

Department of Internal Medicine, Seoul National University College of

Medicine; Cardiovascular Laboratory, Clinical Research Institute, Seoul

National University Hospital, Seoul, Korea

Background: Granulocyte-colony stimulating factor (G-CSF) is one of

the most promising stem cell mobilizer for treatment of ischemic heart

disease. Stem cell mobilizing effects of G-CSF administration were not

evaluated in patients with myocardial infarction. We evaluated stem

cell mobilizing effects of G-CSF in patients with acute and old

myocardial infarction.

Methods and results: Nine patients (60 ± 10 years old, 8 men) underwent

apheresis after 4 days administration of G-CSF with dose of 10 mg/kg/day.Five patients had acute myocardial infarction (AMI: 4 ± 2 days after AMI)

and four patients had old myocardial infarction (OMI: 94 ± 117 days after

AMI). FACS analysis was performed with apheresis products. Apheresis

products from patients with age under 65(n= 6) showed higher proportions

of AC133-positive (0.7 ± 0.6 vs. 0%, P= .04), CD34+ (13.2 ± 11.2 vs.

2.6 ± 1.5%, P= .17) and KDR+ cells (15.4 ± 13.6 vs. 2.1 ± 0.5%, P= .17).

Apheresis yield from both age group were not different (1.4 ± 0.7�109 vs.

1.3 ± 0.3�109 from 1 L of filtered blood, P= 1.0). Although limited

statistical significance, apheresis products from patients with AMI showed

higher numbers of KDR+ cell (3.4 ± 4.0�108 vs. 0.7 ± 1.3�108 from 1 L of

filtered blood, P=.11), CD34+ (2.5 ± 0.3�108 vs. 0.5 ± 0.5�108 from 1 L

of filtered blood, P = .28), and AC133+ cells (1.6 ± 2.6�107 vs.

0.1 ± 0.3�107 from 1 L of filtered blood, P= .55).

Conclusions: Although limited in the number of study population, these

results showed that stem cell mobilizing efficacy of G-CSF was influenced

by age and the presence of acute ischemia in patients with myocardial

infarction. Patients with AMI and younger age had augmented responses to

G-CSF induced stem cell mobilization. These data suggested that higher

doses and longer administration schedule of G-CSF should be considered

for patients with OMI and older age.

The essential role of p21 in radiation-induced cell cycle arrest of vas-

cular smooth muscle cell

H-J Cho, H-S Kim, H-J Cho, J-W Chung, J-S Park, K-W Park, I-H Chae,

M-M Lee

Department of Internal Medicine, Seoul National University College of

Medicine; Cardiovascular Laboratory, Clinical Research Institute, Seoul

National University Hospital, Seoul, Korea

Objective: We investigated the molecular mechanism of radiation-induced

cell cycle arrest in vascular smooth muscle cell (VSMC) and examined

whether p21 knock-out is a cause of radiation failure.

Background: Intravascular radiation therapy is an effective measure to

inhibit restenosis after angioplasty. But it has limitations such as delayed

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 215

catch-up restenosis. The biologic mechanisms for the success and failure of

radiation therapy after angioplasty have not been well studied.

Methods: Using different dosages of gamma radiation, we evaluated the

effect of radiation on VSMC apoptosis and cell cycle progression, and its

action mechanism.

Results: Irradiation significantly retarded the growth of cultured VSMC,

which was not due to induction of apoptosis but mainly due to cell cycle

arrest. Radiation showed remarkable cell cycle arrest at the G1 and G2

phases (G0/G1:S:G2/M phases = 61%:34%:5% with 0 Gy vs. 61%:9%:30%

with 16 Gy, 12 hours after radiation). In immunoblot analysis and kinase

assay, radiation increased the expression of p21 and decreased the

expression and activity of CDK2 and CDK1. In contrast, radiation did

not affect the expression and activity of CDK4 and CDK6, nor the

expression of p27 and p16. When p21 was knocked out, cell cycle of

VSMC was not arrested by radiation, leading to increased proliferation.

Conclusions: Radiation inhibits VSMC proliferation through cell cycle

arrest by enhancing p21 expression and suppressing CDK1 and 2. p21

knockout results in increased proliferation and survival after radiation

suggesting the key role of p21 in radiation-induced cell cycle arrest.

Nitric oxide synthase gene G298 allele: is it a marker for microvascular

angina in hypertensive population?

GEN Elkilany

Cardiology Department, Khalifa Hospital, Ajman, UAE

Background: Nitric oxide (NO) has an important effect on blood pressure,

arterial wall and the basal release of endothelial NO in hypertension. Until

now there are no solid data that revealed the rule of polymorphism of NOS

in patients with hypertension and microvascular angina.

Objectives: The aim of the present study is to investigate the gene of

endothelial nitric oxide synthase (eNOS).As polymorphism of this gene

may be a putative candidate for hypertension and arterial stiffening.

Patients and methods: 60 subjects were recruited for this study, 50

hypertensive patients complaining of chest pain and 10 healthy volunteers

served as control. All patients underwent stress myocardial perfusion

imaging and coronary angiography. Genotyping for all patients and controls

was performed. The linkage between hypertension, microvascular angina

and gene polymorphism was investigated.

Results: Myocardial perfusion imaging and coronary angiography revealed

that 15 patients had chest pain with true ischemia and reversible myocardial

perfusion defects (multiple and mild) but normal epicardial coronary

arteries (microvascular angina) while 15 patients had significant coronary

artery disease (CAD) and 20 hypertensive patients showed normal per-

fusion scan and coronary angiography. The prevalence of the nitric oxide

synthase gene allele was higher in the hypertensive group with micro-

vascular angina (documented by multiple reversible perfusion abnormalities

by SPECT TI-201) than it was among normotensive control subjects

( P< .005). eNOS allele was significantly higher in the hypertensive group

than normotensives, but there was no significant difference in homozygote

mutants among hypertensives, x-syndrome and patients with CAD.

Conclusion: eNOS gene polymorphism proved to be an important etiology

in microvascular angina among hypertensives. In addition, eNOS mutant

gene showed a significant increase in isolated hypertensives and in patients

with CAD.

A novel method for left anterior descending artery ligation in rats with

high success rate

SAS Shariat, MR Movahed

Department of Medicine, Center of Cardiovascular Hormone Research and

Division of Cardiology, University of California, Irvine

Background: Left anterior descending artery (LAD) ligation has been

used commonly in rats to induce left ventricular infarction for research

purposes. However, LAD ligation has been very difficult with at least 50%

mortality in rats. We developed a method of LAD ligation in rats with less

than 5% mortality.

Methods: 36 male Sprague–Dawley male rats weighting 300–350 g were

selected for LAD ligation for induction of ischemic cardiomyopathy. The

surgery was performed under full anesthesia. Left-sided thoracotomy

through cutting of the 5th and 6th ribs was performed. Pericardium was

opened and the heart was exteriorized with a holder consisting of a plastic

loop (1.5�2 cm). The LAD was localized 1–2 mm below the junction of

pulmonary conus and left atrial appendage. A 6.0 silk needle was used to

ligate LAD from the left border of the pulmonary conus to the right border

of the left atrial appendage. The heart was returned back to the chest and

chest wall was closed with presutured lopes of 4.0 silk.

Results: Mid LAD ligation was successful in all rats with less than 5%

mortality. The entire surgery was performed after initial experience in less

than 15 min. Rats survived the procedure without any complication for up

to 3 weeks follow-up.

Conclusions: Mid LAD ligation can safely be performed in rats using

ligation of LAD 1–2 mm below the junction of the pulmonary conus and

the left atrial appendage with very low mortality.

Very high rate of right ventricular infarction after ligation of mid left

anterior descending artery in rats

SAS Shariat, MN Hashemzadeh, MR Movahed

Department of Medicine, Center of Cardiovascular Hormone Research and

Division of Cardiology, University of California, Irvine

Background: The left anterior descending artery (LAD) supplies left

ventricle in human. LAD ligation has been used commonly in rats to

induce left ventricular infarction for research purposes. However, the

myocardial supply territory of LAD is not well established in rats. We

measured the infarction zone in rats after ligation of mid LAD.

Methods: 24 male Sprague–Dawley male rats weighting 300–350 g were

selected for LAD ligation for induction of ischemic cardiomyopathy. The

surgery was performed under full anesthesia. Left-sided thoracotomy was

performed through cuts in 5th and 6th ribs. After opening the pericardium,

LAD was ligated after first diagonal and septal branches. After 24 h, the

hearts were removed and stained with tetrazolium tetrachloride (TTC) for

detection of infarcted area.

Results: Mid LAD ligation induced 100% infarction of mid to apical left

anterior wall and septum involving an average of 45% of LV mass.

Surprisingly, right ventricular infarction was observed in 80% of rats

involving mid to apical right ventricular (RV) wall.

Conclusions: Mid LAD ligation after first septal and diagonal branches

causes substantial left ventricular infarct in rats. However, we find that

80% of the rats had right ventricular infarction. Therefore, hemodynamic

effect of RV infarct should be considered in researches involving LAD

ligation in rats.

Simple and safe method of endotracheal intubation in rats using

straight tip 0.035 wire used for coronary angiography

AS Shariat, PH Wang, MR Movahed*

Department of Medicine, Division of Endocrinology, *Division of Car-

diology, University of California, Irvine Medical Center

Introduction: Endotracheal intubation in rats is a challenging problem.

This is a cumbersome procedure due to narrow oral cavity and difficulty to

visualize vocal cord. It is associated with a high complication rate. We have

developed a very safe and simple method using a straight tip wire as a guide

and smallest pediatric laryngoscope for visualization before intratracheal

intubation of rats.

Method: Seventy Sprague–Dawley rats weighing between 100 and 450 g

were used for endotracheal intubation, using 0.035-in. J-guide wire,

conventional laryngoscope blade Miller Size 0 and conventional cut-down

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224216

18–20 gauge catheter. Rats were anesthetized using mixture of ketamine

(50 mg/kg), zylozine (4 mg/kg) and acepromazine (1 mg/kg). After deep

anesthesia, the animals were laid down in supine position. The upper

insisura were fixed with a rubber band. Using the laryngoscope, the trachea

and vocal cord were visualized with tongue pulled back. Under direct

visualization of the vocal cord, a 0.035-in. straight tip wire was advanced

into the trachea without any difficulty and an 18–20 gauge cut-down

catheter was advanced over the wire into the trachea. The wire was removed

and the catheter was attached to the respirator.

Results: With this method it was not required to use any atropine and we

successfully intubated all 70 rats without any trauma. Successful rate was

100% with no complications or mortality related to intubation. This was

performed within 1 to 2 min after induction of anesthesia. There was no

erroneous intraesophageal or soft tissue intubation or trauma to glottis or

vocal cord.

Conclusion: Using a straight tip wire as a guide and a smallest conven-

tional laryngoscope blade Miller Size 0, we developed a very safe, quick,

and easy method for endotracheal intubation in rats without the usage of

atropine. This method allows researchers to intubate rats with no complica-

tion and makes it possible to study cardiac hemodynamic in rats without the

negative effect of atropine.

Angiogenesis in chronic refractory stable angina induced by autologous

bone marrow: Phase 1

J Vicario, C Campos, J Piva, F Faccio, L Gerardo, C Becker, HH Ortega

Sanatorio Garay, Hospital Iturraspe and U.N.L., Santa Fe, Argentina

Purpose: Based on preclinical studies with unfractionated autologous bone

marrow (UABM) via coronary sinus with transitory occlusion, a clinic

study in patients with chronic stable angina who are not candidates to

percutaneous or surgical revascularization was designed. The objectives

were to evaluate safety, tolerance and feasibility.

Method: A multicenter, prospective study with variable doses and criteria

of inclusion or exclusion defined by an independent clinic committee was

carried out. The treatment was administered to a total of 14 patients (mean

age, 64 years) with two groups: (1) (n= 10) received 60 cc of UABM and

(2) (n= 4) received 120 cc of UABM. Safety was evaluated by ophthalmo-

logic examination (basal and 30 days), laboratory parameters (basal, 24 h

and 30 days), and holter study (basal and 30 days). Tolerance was

evaluated with systemic pressure, coronary sinus pressure, symptoms, time

of hospital stay and clinical events at 180 days. Feasibility was evaluated

with Seattle Angina Questionnaire (SAQ), Canadian Cardiovascular Soci-

ety (CCS) and New York Heart Association (NYHA) angina classification

(basal, 30 days, 90 days and 180 days), myocardial perfusion imaging with

Tc sestamibi under pharmacological stress (basal, 30 days and 90 days)

with independent core lab, and coronary angiography (basal and 30 days).

The expression of CD31 was analyzed in bone marrow biopsies by

immunocytochemistry. A Wilcoxon nonparametric statistic test was used

to evaluate all parameters.

Results: No poblational differences between the doses or changes in the

safety parameters were evidenced at 30 days. No changes in the tolerance

parameters were observed except that only one patient was admitted for

angina at 60 days. Hospital stay was only 23 (± 2) h. Feasibility parameters

showed a mean improvement of 40% in SAQ, and in CCS and NYHA a

significant ( P < .05) improvement was observed. Semiquantitative myo-

cardial perfusion imaging (core lab) showed an improvement in 13/14

patients with a mean improvement of 24% at rest and 33% at stress

( P< .05). Coronary angiography showed more capillary density in 9/14

patients. The immunocytochemical study evidenced a 6.91% (±1.21) of

CD31 (endothelial precursors) positive cells in the biopsies of UABM.

Conclusions: We concluded that UABM via coronary sinus with trans-

itory occlusion is tolerable and safe. An improvement in the myocardial

perfusion at 90 days and in the quality of life at 180 days was observed.

This allows us to design further clinical studies to evaluate their

therapeutic efficacy.

Primary patency of nitinol vs. stainless steel self-expanding stents in the

femoropopliteal artery—a propensity score adjusted analysis

S Sabeti, M Schillinger, J Amighi, C Sherif, W Mlekusch, R Ahmadi, E Minar

Department of Angiology, University of Vienna Medical School,

Vienna, Austria

Purpose: To investigate intermediate-term primary patency rates of nitinol

vs. stainless steel self-expanding stents for treatment of atherosclerotic

lesions in the femoropopliteal artery in a propensity score adjusted analysis.

Methods: We studied 175 consecutive patients with peripheral artery

disease and intermittent claudication (n= 150) or critical limb ischemia

(n= 25) who underwent femoropopliteal stent implantation with either

nitinol (n= 52; Smart n= 28, Dynalink n= 18, Expander n= 6) or stainless

steel (all Wallstents, n= 123) stents in a nonrandomized setting. Stenting

was performed due to a significant residual stenosis (> 30% lumen diameter

reduction) or due to flow limiting dissection after initial balloon angioplasty

of the femoropopliteal artery. Patients were followed for median 9 months

(mean 13 months, range 6 to 66) for the occurrence of a first in-stent

restenosis defined as a >50% lumen diameter reduction indicated by color

coded duplex sonography and confirmed by angiography.

Results: Cumulative patency rates at 6, 12 and 24 months of nitinol vs.

stainless steel stents were 85%, 75% and 69% vs. 78%, 54% and 34%,

respectively ( P= .008 by Log Rank), without statistically significant

differences between the three different nitinol stents ( P= 0.72 by Log

Rank). Multivariate Cox proportional hazard analysis showed a statist-

ically significant reduced risk for restenosis of nitinol compared to the

stainless steel stents (adjusted hazard ratio 0.44, 95% confidence

interval 0.22 to 0.85, P= .014) including the propensity of receiving

a nitinol stent.

Conclusion: Nitinol stents exhibit substantially improved primary patency

rates in the femoropopliteal artery compared to stainless steel stents.

Randomized controlled trials are warranted to confirm these results.

Beta-brachytherapy with a liquid Rhenium-188 filled balloon for

treatment of in-stent restenosis

M Hoher, BJ Krause*, T Nusser, T Habig, OC Grebe, SN Reske*, V

Hombach, M Kochs, J Wohrle

Department of Cardiology, *Department of Nuclear Medicine, University

of Ulm, Ulm, Germany

Background: Coronary beta-brachytherapy with a liquid Rhenium-188

filled balloon offers a self-centering irradiation technique providing homo-

geneous dose delivery, and does not require costly additional lead shielding

in the cath lab. In de novo lesions, Rhenium-188 brachytherapy resulted in

a 6% restenosis rate at the target lesion and a 13% restenosis rate of the

total vessel, comparable with drug-eluting stents. In this study, we

evaluated the efficacy of Rhenium-188 brachytherapy for treatment of

restenotic lesions.

Methods: In 218 restenotic lesions (88% in-stent restenosis, 32% second or

third restenosis), coronary angioplasty and Rhenium-188 brachytherapy

were performed. The prescribed irradiation dose of 22.5 Gy in 0.5-mm

tissue depth was successfully delivered in all patients. The dose was the

same as previously used in our de novo trial. The diameter of the irradiation

balloon ranged between 2.0 and 4.0 mm. The length of the irradiated

segment was 74±48 mm and was chosen at least 10 mm longer than the

vessel segment traumatized by angioplasty. Combined antiplatelet therapy

was prescribed for 12 months. Patients received angiographic follow-up

after 6 and 12 months clinical control.

Results: Lesions were located in native coronary arteries (90%) or venous

bypass grafts (10%). Patients had diabetes mellitus in 32%. Pre-interven-

tional reference diameter (RD) was 2.67 ± 0.60 mm and minimal lumen

diameter (MLD) was 0.61 ± 0.36 mm. A new stent was implanted in only

8%. At follow-up, RD was 2.77 ± 0.50 mm and MLD was 2.05 ± 0.77 mm.

Late loss and late loss index at the target lesion were 0.31 ± 0.67 mm and

0.17 ± 0.39 and in the total vessel segment including edge effects 0.37± 0.71

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 217

mm and 0.21 ± 0.44, respectively. Binary restenosis rate (>50% diameter

stenosis) at the target lesion was 15% and for the total segment including

edge stenosis 21%. Target vessel revascularization rate (re-angioplasty,

CABG) was 18%.

Conclusion: In this large patient series with restenosis and in-stent

restenosis, beta-brachytherapy with a Rhenium-188 filled balloon catheter

showed a low restenosis rate and target vessel revascularization rate after 6

months. With the current technique, the occurrence of edge-stenosis is low

and does not differ between de novo or restenotic lesions.

Brachytherapy in the real world for in-stent restenosis: immediate

results, clinical and angiographic follow-up. A prospective registry in

two French centers

M Bedossa, MJ Alibelli-Chemarin, I Latorzeff, E Le Prise, D Carrie,

H Le Breton

University Hospital from Rennes and Toulouse, France

Background: Restenosis remains a major limitation of coronary angio-

plasty with bare metallic stents. The only validated treatment for diffuse in-

stent restenosis is brachytherapy. Regarding the legal difficulties to develop

this technique in France, only a few centers were allowed to perform

coronary brachytherapy in 2001.

Aim: The goal of this prospective registry was to evaluate the Novoste

system in the treatment of in-stent restenosis in French centers with a high

activity (>900 PCI each year). Two centers included patients in this

prospective registry. A systematic angiographic follow-up was scheduled

at 6 months.

Methods: Patients with a clinical and angiographic in-stent restenosis were

included. One hundred patients were included in 2 years (2, 5% of patients

during this period) with a majority of male (80%), a mean age of 66±2 years

and 26% of diabetics. The clinical status was stable angina, unstable angina

and silent ischemia in 38%, 35% and 27% of cases, respectively.

Results: 112 lesions were treated with a majority of LAD (40%). The

angiographic diameter before procedure was 2.96±0.44 mm (4.04 mm on

IVUS) and the length of lesion was19.2±9 mm. In 92% of cases, it was a

diffuse in-stent restenosis (only 8% of focal restenosis). The dose of beta

irradiation was 21±2.1 Gr. In 4% of patients, a new stent was implanted

because of vessel wall dissection. The primary success was 96% (4 patients

were treated by balloon angioplasty alone because of failure to advance the

catheter due to calcifications or tortuosity of the vessel). No in-hospital

complications occurred in successfully treated patients. At 6 months, 92%

of patients were free of symptoms. A coronary angiogram was performed in

82% of cases. The angiographic restenosis rate (>50%) was 15% and the

aspect of this restenosis was focal in six patients, diffuse in four patients and

an edge effect in three patients. The restenosis was treated by balloon

angioplasty in 10 patients, by CABG in 2 patients and medically in 1

patient. The follow-up at 1 year is ongoing.

Conclusion: When restenosis occurs after stent implantation, brachyther-

apy is safe and associated with excellent clinical and angiographic results.

This technique could keep indications despite the increasing used of drug

eluting stents. In the treatment of in-stent restenosis, randomized trials

comparing brachytherapy to drug eluting stents are necessary.

Intracoronary thermography in stable and unstable angina using a

blood flow occluding thermal system

LT Padilla, J Belardi, P Perez Balino, F Cura, O Mendiz, J Korotko,

W O’Neill

Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina; Wm

Beaumont Hospital, Michigan, USA; Fundacion Favaloro, Buenos

Aires, Argentina

Background: Temperature measurement of coronary lesions may provide

lesion assessment beyond what is possible with conventional angiography

and ultrasound methods. It holds the potential to be a predictor of future

clinical events. However, temperature measurement studies reported thus

far have not addressed the effect that blood flow through the artery has on

a measurement. Clinical measurements have been made with a novel

thermal sensing catheter (TSC) that temporarily occludes blood flow

during the measurement.

Methods: Principal inclusion criteria were patients undergoing elective

coronary intervention for stable or unstable angina. A thermal sensing

catheter (Accumed Systems, Ann Arbor, MI) was used to make temperature

measurements in the coronary artery. The catheter temporarily occludes

flow through the artery while the temperature measurement was made. The

system takes a baseline reading of blood temperature flowing through the

artery and then surface temperature of the lesion while blood flow is

temporarily occluded. The measurement is the difference between these two

readings. We performed a 6-month follow-up.

Results: Temperature measurements were made in 15 lesions from 11

patients. Measurements were made in all three major vessels, RCA, LAD

and LCX. Five of the 11 patients had one lesion with a temperature

elevation of at least 0.3 �C over baseline, 4 of them with unstable angina

and 1 with stable angina. The system and method were found to be safe for

clinical use.

At 6 months follow-up there was one event (intrastent restenosis) in a

patient with a hot lesion and no events in patients without hot lesions.

Conclusions: Blood flow through an artery interferes with the ability to

measure lesion temperature. This occluding thermal sensing catheter was

found to be a safe and feasible method to accurately measure plaque

temperature while occluding coronary blood flow. Patients with unstable or

stable angina could have both cold and hot lesions. Larger, controlled

clinical trials would significantly increase the value of being able to assess

lesion temperature to guide decisions regarding treatment and follow-up.

NF-kB inhibition potentiates antiproliferative effects of radiation on

vascular smooth muscle cells

K-W Park , H-J Cho, S Oh, J-S Park, J-W Chung, Y-S Cho, H-S Kim, M-M

Lee, Y-B Park

Department of Internal Medicine, Seoul National University College of

Medicine; Cardiovascular Laboratory, Clinical Research Institute, Seoul

National University Hospital, Seoul, Korea

Introduction: NF-kB promotes cell survival against external stress such as

radiation. We examined whether NF-kB inhibition enhances the antiproli-

ferative effects of radiation on vascular smooth muscle cells (VSMCs).

Methods and results: To evaluate the effects of NF-kB inhibition, NF-kB

decoy oligonucleotides were transfected to VSMCs. The extent of cellular

viability and proliferation was determined by MTT assay after gamma-ray

irradiation using 137-Cs. Irradiation induced activation or nuclear trans-

location of NF-kB p65 in vascular smooth muscle cell which was

significantly blocked by NF-kB decoy transfection. RT-PCR and Western

blotting showed reduced transcription and translation of ICAM, iNOS, and

TNF-a, confirming the inactivation of NF-kB. NF-kB decoy potentiated

antiproliferative effects of radiation so that the effect of 2- and 8-Gy

radiation combined with NF-kB decoy transfection (48 h after irradiation:

1.43 ± 0.21 and 1.50 ± 0.31, respectively) was similar to that of 16-Gy

radiation without NF-kB inhibition (1.63 ± 0.35). In addition, apoptosis was

increased after NF-kB decoy transfection in irradiated VSMCs (apoptosis

fraction: 13.33 ± 2.08% vs. 26.29 ± 7.43%, for radiation only vs. radia-

tion+NF-kB decoy transfection, P < .05). However, NF-kB inhibition did

not show any additive effects on the cell cycle of irradiated VSMCs as

measured by flow cytometry analysis.

Conclusion: NF-kB inhibition reduces proliferation and survival of irradi-

ated VSMCs and this seems to be through increased apoptosis rather than

additive cell cycle arrest. Our data suggest the possibility of adjunctive gene

therapy using NF-kB decoy to improve efficacy and to decrease the adverse

effects of intracoronary radiation therapy.

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224218

Combined treatment with percutaneous intramyocardial VEGF gene

therapy and cytokine-induced endothelial progenitor cell mobili-

zation: assessment of efficacy with electromechanical mapping and

echocardiography

LJ Diaz-Sandoval, S Patel, A Kawamoto, K Kusano, J-I Yamaguchi, H

Nishimura, Y-S Yoon, T Murayama, M Kearney, T Asahara, JM Isner, DW

Losordo

St. Elizabeth’s Medical Center of Boston, Tufts University School of

Medicine

Background: NOGA left ventricular electromechanical mapping (EMM)

has been previously used to assess strategies of catheter-based intramyo-

cardial gene and cell therapy. Echocardiography is well established in the

assessment of myocardial ischemia. Whether these modalities are useful to

assess a combined approach using both catheter-based intramyocardial

(IM) gene transfer of vascular endothelial growth factor-2 (VEGF-2) and

subcutaneous (SC) administration of cytokines such as stem cell factor and

granulocyte-colony stimulating factor is unknown. Therefore, we inves-

tigated the hypothesis that the use of a combination strategy with local

intramyocardial gene transfer of VEGF-2 and cytokine-induced mobiliza-

tion of endothelial progenitor cells would be more effective than the use of

either modality alone, and that the efficacy of this strategy could be better

assessed by using both EMM and echocardiography.

Methods: Myocardial ischemia was induced in 28 pigs by surgical

placement of an ameroid constrictor around the left circumflex artery. On

Week 5, animals underwent echo, coronary angiography and EMM. The

ischemic area was identified by EMM and the pigs were randomized to

receive: (A) IM empty plasmid+SC saline (n= 6); (B) IM empty plas-

mid+SC cytokines (n= 6); (C) IM VEGF-2+SC saline (n= 8); (D) IM

VEGF-2+SC cytokines (n= 8). IM injections were performed with the

NOGA catheter. Statistical data are presented as mean±standard deviation.

Groups were compared with ANOVA and the correlation between echo and

EMM was determined with the Pearson correlation coefficient (r).

Results: On Week 9, Group D showed the greatest improvement in

ischemic area versus Groups C, B and A (�30.4 vs. �12.7, 6.4, and

4.5%, P < .01) as well as in linear local shortening index (LLSI) by EMM

(6.8 vs. 3.2, 1.7 and 0.2, P < .01). Group D also had the greatest

improvement in fractional shortening (5.4 vs. 1.3, �0.3 and �1.1,

P < .01) and wall motion score by echo (�3.9 vs. �1.2, 0.2 and 1.2,

P < .005). EMM and echo findings had an excellent correlation (r = .97).

Conclusions: Our results illustrate that both EMM and echo are effective in

assessing the effects of combination therapy on myocardial ischemia. EMM

catheters have the advantage of serving both as a diagnostic and therapeutic

tool. Our findings support that a strategy using combination therapy with

EMM-guided catheter-based IM gene transfer of VEGF-2 in conjunction

with systemic administration of stem cell factor and granulocyte-colony

stimulating factor to increase the number of circulating endothelial progen-

itor cells which will home to the area of ischemia, is more effective than

either modality alone in the treatment of chronic myocardial ischemia.

Modified Mayo Clinic risk score with inclusion of elevated cardiac

biomarkers accurately predicts complications following percutaneous

coronary interventions

M Singh, CS Rihal, RJ Lennon, KN Garratt, V Mathew, DR Holmes, Jr.

Mayo Clinic, Rochester, MN

Background: Accurate risk assessment of patient-specific risk is necessary

for patient counseling and recommendation of percutaneous coronary

angioplasty (PCI). Previous studies lack post-PCI elevation of cardiac

biomarkers as a potential complication.

Objective: The goals were to identify major clinical and angiographic

risk factors associated with in-hospital cardiovascular complications

(death, Q-myocardial infarction, post-PCI CK-MB 30ULN, emergent

CABG, and/or TIA or stroke). Based on these risk factors, we con-

structed a simple risk score.

Methods and results: First PCI on 4572 patients performed between

August 2000 and October 2003 were included. Complications were

observed in 1114 (24%), 952 (85%) enzyme elevation, 37 (3%) mortality.

Bootstrap data reduction was used to choose the final model out of 27

candidate variables. Logistic regression was used to fit the final model.

The Hosmer–Lemeshow test was used to test the adequacy of the model

fit to the data. The c-index was used to assess the discriminatory ability of

the model. The integers for the scoring system were chosen to be roughly

proportional to the estimated continuous coefficients from the logistic

model. The final integer system was selected based on a high correlation

with the original parameter estimates and a reasonable range of values.

Logistic regression with the integer score of the study sample was used to

estimate the expected risk for each score. Five hundred separate bootstrap

samples were used to internally validate the simplified scoring system. The

model was applied to the samples and the c-index and observed and

expected event rates were recorded. Nine variables were selected for the

final prediction model (Fig): MI within 24 h prior to PCI, pre-procedural

shock, thrombus in any lesion, MI 1 to 7 days prior to PCI, left main

stenosis 70%, emergency PCI, ACC/AHA type-C lesion, prior bypass

surgery, and age. The model adequately fits the data (Hosmer–Lemeshow

test statistic = 8.51 on 8 df, P= .39). The model discriminated well between

event and nonevent patients (c= 0.853). In the 500 bootstrap samples for

internal validation, the mean c-index was 0.852 ± 0.007, indicating good

discriminatory ability. The average number of observed events was

1112.2 ± 28.7 compared to 1113.8 ± 18.0 expected events, for an average

of difference of 1.6 ± 23.1.

Conclusions: Nine variables were combined into a convenient risk scoring

system that accurately predicts cardiovascular complications after PCI.

Intravascular brachytherapy for renal arteries with gamma and

beta sources

N-C Yang, R Chan

Radiation Oncology, and Cardiovascular Research Institute, Washington

Hospital Center, Washington, DC

Purpose: This investigation was undertaken to study the dosimetry of the

renal arteries for the in-stent restenosis with gamma and beta sources.

Methods: The renal arteries were modeled with diameters between 4 and 6

mm. The Monte Carlo program MCNP4B was used to calculate the doses at

the bisector of the source axis at 2.0, 2.5, 3.0, 3.5 and 4.0 mm. For the

Cordis Ir-192 source, 10 seed ribbons were used. For the Novoste Sr/Y-90

system, 40 mm source was used. For the Guidant P-32 system, Galileo3 20

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 219

mm source was used. Five and one million histories were computed for the

gamma and beta sources, respectively.

Results: For a renal artery of 4 mm diameter and with prescription dose 18

Gy at 2 mm, the doses at 2.5 mm were 13.9, 12.1, and 10.5 Gy for Cordis,

Novoste, and Guidant, respectively. The doses at 3.0 mm were 11.3, 8.2,

and 6.0 Gy, respectively. The doses at 3.5 mm were 9.5, 5.7, and 3.2 Gy,

respectively. The doses at 4.0 mm were 8.2, 3.8, and 1.7 Gy, respectively.

For a renal artery of 5 mm diameter and with prescription dose 18 Gy at 2.5

mm, the doses at 3.0 mm were 14.7, 12.2, and 10.3 Gy, respectively. The

doses at 3.5 mm were 12.4, 8.5 and 5.6 Gy, respectively. The doses at 4.0

mm were 10.6, 5.6, and 2.8 Gy, respectively. For a renal artery of 6 mm

diameter and with prescription dose 18 Gy at 3.0 mm, the doses at 3.5 mm

were 15.2, 12.5, and 9.8 Gy, respectively. The doses at 4.0 mm were 13.0,

8.3, and 5.0 Gy, respectively.

Conclusions: With prescription dose 18 Gy at the intima layer. The Cordis

Ir-192 gamma source delivered enough doses to the media and adventitia

areas of the renal arteries. If a centering catheter was available, the Novoste

Sr/Y-90 system could be used, too. The depth dose of the Guidant P-32

source fell off too rapidly and could not do the job to treat renal arteries.

Heterologous transplantation of endothelial progenitor cells transfected

with human telomerase reverse transcriptase leads to myocardial

salvage and enhanced functional recovery in murine model of

myocardial infarction

LJ Diaz-Sandoval, P von Samson, C Luedemann, K Kusano, A Hanley, M

Gavin, H Ma, S Murasawa, DW Losordo

Caritas St. Elizabeth’s Medical Center of Boston, Tufts University School

of Medicine

Objectives: Transplantation of bone marrow-derived circulating endothelial

progenitor cells (EPCs) is a novel and beneficial therapeutic approach to

myocardial ischemia. However, the very low number of these cells in

peripheral blood limits the efficacy of this strategy. Human telomerase

reverse transcriptase (hTERT) extends lifespan and improves physiologic

properties of endothelial cells, increasing the availability and quality of

these cells. Therefore, we evaluated the hypothesis that a gene therapy

strategy based on transfection of EPCs with hTERT could enhance their

therapeutic potential in a murine model of acute myocardial infarction.

Methods: Total peripheral blood mononuclear cells were isolated from

five healthy human volunteers (age 34±4) by density-gradient centrifu-

gation and cultured on EBM-2 media. Day 7 cultured EPCs were trans-

fected with 500 multiples of infection of Ad/hTERT. After inducing

myocardial infarction by surgical ligation of the LAD, two groups of

male Hsd: Rhnu athymic nude rats received an intravenous injection of:

(A) 5�105 EPCs (n= 8), and (B) 5�105 transfected EPCs (hTERT group,

n= 5). LV function was assessed by echocardiography and Millar catheter

at baseline and on Day 28 when the tissue sections were taken. Nitrate

content of the cell culture media was measured after 14 days to evaluate

nitric oxide (NO) production.

Results: LV function was significantly better after 28 days in the hTERT

group (fractional shortening29.17 ± 1.18%vs. 21.75 ± 1.55%;P < .001; dP/dt

max 4344 ± 624 vs. 3150 ± 137; P< .05; dP/dt min: NS). Capillary density

was also increased (325 ± 27.5 vs. 290 ± 18.8/mm2; P < .001), and the LV-

fibrotic area was significantly reduced (4.05 ± 2.26% vs. 20.23 ± 11.09%;

P < .001). NO content in cell culture media after 14 days was higher in the

hTERT group (2.37 ± 0.41 mM/ml vs. 1.79 ± 0.17 mM/ml; P < .05).

Conclusions: Our findings suggest that telomerase transfection signific-

antly augments the therapeutic neovascularization induced by endothelial

progenitor cells, leading to enhanced capillary density, NO production, left

ventricular functional recovery (as demonstrated by improved fractional

shortening and maximal dP/dt) and myocardial salvage (as shown by the

reduction in infarct size). These data support that the use of hTERT gene

transfer enhances the therapeutic neovascularization achieved by EPC

transplantation, leading to improvements in functional recovery and myo-

cardial salvage after myocardial infarction.

Endothelial cell macromolecular barrier function but not platelet

reactivity is abnormal six months after endovascular brachytherapy

in balloon-injured pig coronary arteries

J Li, B Ebato, J Rios, J Cui, NAF Chronos, KA Robinson

American Cardiovascular Research Institute, Norcross, GA

Background: Endovascular brachytherapy limits restenosis after coronary

interventions but may have undesirable side effects such as late thrombosis,

under certain circumstances. We previously demonstrated that one month

after brachytherapy and balloon angioplasty, re-endothelialization was

inhibited by brachytherapy and platelet recruitment was augmented. The

purpose of the present study was to assess whether endothelial restitution

was complete at a later time point of 6 months postangioplasty, and to

determine whether platelet deposition was affected.

Methods: Balloon angioplasty was performed with a balloon/artery ratio of

1.3:1, in two coronary arteries of eight adult Yucatan miniature pigs. One

vessel then received intracoronary irradiation (RAD; n= 8; 20Gy b) and the

other sham treatment (S; n= 8). Six months later, platelet recruitment on the

coronary arteries was determined using autologous 111In platelet labeling.

Endothelial macromolecular barrier function was assessed using the Evans

blue dye technique and planimetric macroscopy. Histology and electron

microscopy were performed to determine endothelial and overall coronary

artery morphology.

Results: Platelet recruitment in RAD vessels was not different from sham

(429 ± 70�103 pl/vessel in RAD vs. 347 ± 67�103 pl/vessel in S, P=NS).

Coronary artery surface area with positive Evans blue staining in RAD was

significantly higher than sham (42.2 ± 7.7% vs. 9.1 ± 5.7%, P < .01). Extens-

ive perivascular fibrosis with diffuse inflammatory cell infiltration was

present in RAD but not in S; neointima in RAD but not in S occasionally

showed fibrinoid material. SEM showed confluent endothelium in both RAD

and S; however, individual endothelial cells showed circular figures sug-

gestive of cytoplasmic inclusions that were not present in S.

Conclusions: Six months after 20 Gy irradiation at the site of balloon

angioplasty, coronary artery endothelium showed abnormally high macro-

molecular permeability. However, platelet reactivity of the vessel surface

was equivalent to control. The presence of inflammatory cells and fibrosis

in the adventitia may influence these phenomena, but the mechanisms

remain to be established.

Endothelium-dependent vasomotor function of coronary arteries

remains abnormal six months after endovascular brachytherapy

J Li, B Ebato, J Cui, NAF Chronos, KA Robinson

American Cardiovascular Research Institute, Norcross, GA

Background: We previously found that endothelium-dependent relaxation

of pig coronary arteries was nearly abolished 1 month after vascular

brachytherapy. More recently, we reported partial recovery of endothe-

lium-dependent relaxation at 3 months postirradiation. The purpose of this

study was to extend the prior observations and establish the time course of

endothelium-dependent vasomotor functional recovery.

Methods: Vascular responses of isolated segments of pig coronary arteries

were studied were studied in an organ chamber apparatus. Endothelium-

dependent and -independent relaxations as well as contractile responses

were investigated 6 months after active irradiation (RAD; n= 12; 20 Gy b

radiation at 0.5 mm tissue depth from the luminal surface); or sham

treatment (S; n= 8; placement of delivery catheter with inactive wire) and

in naive controls (C; n= 8). Endothelial and overall vascular microscopic

morphology and phenotype was studied by scanning electron microscopy

(SEM), histology, and immunohistochemistry.

Results: Macroscopically, irradiated coronary arteries appeared enlarged

and were surrounded by abundant tough connective tissue. Relaxation to a

maximal dose of calcium ionophore A23187 (3 mM) was decreased in

RAD (29.8 ± 9.4% vs. 86.0 ± 7.0% in S and 90.2 ± 11.0% in C; P< .01).

Relaxation to a maximal dose of substance P (0.1 nM) was also less for

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224220

RAD (29.7 ± 5.4% vs. 65.0 ± 3.9% in S and 67.4 ± 6.8% in C; P< .01).

Contractile responses to both KCl and PGF2a in the presence of nitric oxide

synthase (eNOS) blockade using N-nitro-L-arginine methyl ester (L-

NAME) were significantly decreased and endothelium-independent relaxa-

tion to SNP was potentiated in irradiated vessels. Scanning electron

microscopy showed confluency of the endothelial cell layer in irradiated

coronary arteries; some ultrastructural abnormalities including surface

microvilli and apparent cytoplasmic inclusions were present occasionally

in RAD but not as frequently in S. Immunohistochemistry showed positive

eNOS staining in the arterial endothelium of both RAD and S.

Conclusions: Endothelial-dependent relaxation responses remained abnor-

mal 6 months after endovascular brachytherapy but were partially restored

in comparison to 1 month (data not shown; from previous work). However,

a progressive increase in recovery of normal vascular function, when

considering 3-month responses (data not shown), was not demonstrated.

Since morphology and eNOS content appeared similar, as yet unidentified

factors appear to be responsible for chronically abnormal vasomotor

function in irradiated coronary vessels and determination of the source of

these mechanisms warrants further investigations.

Transplantation of autologous bone marrow mononuclear cells

does not alter arrhythmia threshold in adult swine with chronic

myocardial ischemia

F Tondato, A Yegin, J Cui, M Ebato, B Ebato, S Frohwein, J Rios, K

Robinson, N Peters, J Sanzo, T Goodchild, M Ungs, N Chronos

American Cardiovascular Research Institute, Norcross, GA

Background: Bone marrow-derived mononuclear cells (BM-MNCs) can

give rise to endothelial progenitor cells. Localized transplantation of

autologous BM-MNCs into ischemic myocardium may augment neovascu-

larization and treat heart failure. However, little is known regarding the

arrhythmogenic potential of BM-MNCs after intramyocardial transplant.

The goal of this study was to evaluate the threshold for ventricular

arrhythmia induction with conventional electrophysiologic study (EPS)

with programmed stimulation in pigs with chronic myocardial ischemia

treated with autologous BM-MNCs.

Methods: Adult Yucatan miniature pigs underwent left circumflex (LCX)

ameroid constrictor placement. At 4 weeks, animals were randomized to

receive either BM-MNCs (n= 8) or DMEM culture medium as control

(n= 8). Bone marrow (30–50 ml) was aspirated from the sternum and, if

necessary, from the iliac crest. Mononuclear cells were isolated using

density gradient centrifugation. Catheter-based (Boston Scientific Stiletto)

intramyocardial injections were performed guided by combined biplane

fluoroscopy and intracardiac echocardiography (ICE). The treatment

group received a total of 1�108 BM-MNCs at 10 sites, 5 in the

ischemic (LCX), and 5 in the nonischemic (LAD) region. Four weeks

after intramyocardial injection, global wall motion score index (GWMSI)

was evaluated by dobutamine stress echocardiography. Subsequently,

electrophysiologic study was performed with right ventricle stimulation

at apex and outflow tract, using a basic cycle length of 500 and 400 ms

and 1–3 extra stimuli.

Results: There was no between-groups difference in the total number of

cases with inducible arrhythmias between the BM-MNC and control

groups: three out of eight animals (38%) in the BM-MNC group (two

polymorphic VT and one VF) and three out of eight animals (38%) in the

control group (one monomorphic VT and two VF). There was also no

difference in global wall motion (GWMSI = 1.03 in BM-MNCs; 1.17 in

sham, P= .38) and there was no correlation between GWMSI and

ventricular arrhythmia induction (1.29 for induced pigs; 1.01 for non-

induced, P= .09).

Conclusion: Transplantation of autologous BM-MNCs into the left

ventricle of pigs with induced chronic myocardial ischemia did not affect

the threshold for ventricular arrhythmia. From an electrophysiologic

standpoint, intramyocardial injection of autologous BM-MNCs appears

to be safe.

Cost-effectiveness of the TAXUS paclitaxel-eluting coronary stent

system vs. bare stent implantation: the TAXUS IV Trial

DJ Cohen, E Mahoney, TA Lavelle, C Shi, B Justason, M Clark, M Lacey, S

Ellis, G Stone on behalf of the TAXUS IV Investigators

Harvard Clinical Research Institute, Boston, MA

Background: Previous studies have demonstrated that TAXUS paclitaxel

drug-eluting stents (DES) dramatically reduce angiographic and clinical

restenosis compared with conventional stenting. Initial hospital costs, long-

term costs, and the overall cost-effectiveness (C/E) of TAXUS compared

with bare metal stenting are unknown.

Methods: We prospectively measured medical resource use for 1314 PCI

patients randomized to either TAXUS (DES) or bare stents (BS) as part of

the TAXUS IV Trial. Costs in the cath lab were computed using the

measured resource use and unit cost estimates. Unit costs of BS and DES

were estimated at US$900 and US$2800 (current market average) per

stent, respectively. Hospital bills for all initial and subsequent hospital-

izations were collected for 460 randomly selected patients. These bills

were used to impute other inpatient and ancillary costs using a regression

model for the remaining patients. Costs were assessed from the US

societal perspective.

Results: Resource use and 1-year cost data are displayed below (see

Table). DES significantly reduced target vessel revascularizations and

rehospitalizations by 64% ( P< .001) and 31% ( P < 0.001), respectively

and follow-up costs by US$1456/pt ( P < .001). Although the initial

procedure costs per DES patient were US$2028 higher than BS, costs

were reduced to US$571 over the course of 1 year. This difference in 1-

year costs was not statistically significant ( P= .31). The incremental C/E

ratio for DES compared with BS was US$4678 per repeat revasculari-

zation avoided. The cost per quality adjusted life-year gained ($/QALY)

was US$47,798.

Conclusions: In the TAXUS IV Trial, use of paclitaxel-eluting stents led to

substantial reductions in the need for repeat revascularizations and rehospi-

talizations at net cost to the healthcare system of US$571 per patient. The

resulting C/E ratios compare favorably with other commonly accepted

medical treatments in the US which are considered cost-effective. These

findings were robust across a wide range of patient subgroups.

Autologous fibroblast transplantation into myocardial infarcts in pigs:

effects on arrhythmogenesis and arrhythmic threshold

F Tondato, K Robinson, J Cui, J Sanzo, T Goodchild, M Fowlkes, R Lee, M

Maciejevski, N Chronos, N Peters

American Cardiovascular Research Institute, Norcross, GA

Background: Myocardial infarction is often associated with lethal arrhyth-

mias, secondary to nonuniformity of myocardial electrophysiology with an

abnormal pattern of signal conduction. Autologous cell transplant used to

repair or favorably remodel infarcted myocardium has the potential to

either worsen or suppress arrhythmic tendency, dependent on effects on

electrophysiological heterogeneity. Autologous fibroblasts (Afbr) are a

realistic option for cell therapy, being readily available, easily cultured,

and resistant to hypoxia. Afbr may modify arrhythmic tendency by

TAXUS stent Bare stent P value

Procedure time (min) 51 51 NSNumber of study

stents/patient1.05 ± 0.3 1.05 ± 0.3 .81

Cath lab cost US$6324 ± 2187 US$4336 ± 2426 <.001Initial hospital cost US$11,095 ± 3195 US$9067 ± 3387 <.0011-year outcomesRepeat revascularization

(target vessel)6.9/100 patients 19.1/100 patients <.001

Rehospitalization 26.4/100 patients 38.0/100 patients <.001F/U cost US$3487 ± 7489 US$4943 ± 10,916 <.0011-year total cost US$14,582±8174 US$14,011 ± 9540 .31

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 221

creating conduction block in infarcted regions, and can readily be trans-

duced to modify phenotype and membrane channel expression. The

purpose of this study was to test whether Afbr transplant to infarcted

myocardium modifies arrhythmogenesis.

Methods: Eight pigs underwent myocardial infarction by coronary occlu-

sion with embolized microspheres. A skin sample was harvested for

dermal Afbr isolation, culture and tagging with BrdU. At 3 weeks,

animals (randomized) received epicardial injections of either tagged

dermal Afbr or medium alone via thoracotomy. A total of 2.5 ± 1 ml

(68 ± 43�106 cells/ml) of solution was injected, before which electro-

physiologic study (EPS) with programmed stimulation (two RV sites,

drive cycle length = 500, 400 and 350 ms, up to three extra stimuli) was

performed, and a subcutaneous wireless ECG-telemetry system was

implanted. Continuous ECG was recorded for 4 weeks, after which repeat

EPS was performed and animals were sacrificed for evaluation of infarcts

by histopathology and BrdU immunostaining.

Results: Immunostaining revealed engraftment of tagged cells within the

infarction scar. ECG analysis showed reduction in number of spontaneous

episodes of nonsustained VT (0.07 ± 0.37 vs. 30.6 ± 148.2 episodes/day;

P < .01) and a reduced total number of beats of nonsustained VT (0.7 ± 3.3

vs. 199.8 ± 976.8; P< .01) in the Afbr group compared with sham. At

4-week EPS, two control and none of the Afbr animals were more inducible

of VT than at baseline.

Conclusions: Dermal Afbr engraft in ischemic myocardium and are

associated with a reduction in arrhythmic episodes and arrhythmogenicity.

These initial findings indicating antiarrhythmic properties of Afbr trans-

plantation warrant further investigation.

Myocardial repair with a tissue-engineered extracellular matrix

scaffold

KA Robinson, J Li, A Redkar, M Mathison, SF Badylak, RG Matheny

American Cardiovascular Research Institute, Norcross, GA; McGowan

Institute for Regenerative Medicine, Pittsburgh, PA

Background: Synthetic or glutaraldehyde-crosslinked patch materials are

used in cardiac surgery to repair congenital defects and damaged or

diseased myocardium. However, such materials are inert and are thus

incapable of fostering functional recovery of the myocardial tissue. The

present study was undertaken to investigate the use of peracetic acid-

treated, buffer-washed, vacuum-pressed porcine urinary bladder matrix

(UBM) as an extracellular matrix scaffold for the repair of infarcted

myocardium in surgical ventriculoplasty. This and similar materials have

been used for a variety of tissue engineering applications. These include

current clinical uses in cystoplasty and hernia repair, and numerous

veterinary tissue repair procedures.

Methods: Pigs underwent myocardial infarction by catheter-based coronary

embolization. At 6 weeks, a full-thickness region of the infarcted ventricu-

lar myocardium was excised under cardiopulmonary bypass and replaced

with either 4-ply UBM or single-ply ePTFE. Samples were harvested after 1

month, examined macroscopically, and pieces were prepared for flow

cytometry, histology, and immunohistochemistry.

Results: Patched regions from both UBM and ePTFE showed pearly white

as well as brown and gray regions of tissue; however, ePTFE showed a

distinct rim of white tissue surrounding the implant, whereas in UBM, the

implant was not distinct and the extent of pearly white tissue appeared

diminished. Histology revealed an intense granulomatous and foreign-body

giant cell and fibrocellular encapsulation response to ePTFE, whereas there

were only mild and diffuse infiltrates associated with the UBM implants

with little surrounding fibrosis. Occasional cell invasion of the UBM

material was seen, whereas this was absent in ePTFE. Rare cells in UBM

were of round shape and immunoreactive for CD45 antibody staining;

numerous regions showed spindle-shaped and stellate cells that were

smooth muscle alpha-actin positive. Using flow cytometry, the cellular

populations of normal myocardium and UBM were quantified. In UBM,

19 ± 11% of cells were CD45+ (monocytes and granulocytes); 35% were

alpha-actin+ (smooth muscle cells and myofibroblasts); 11 ± 2% were

CD31+ (endothelial cells); and 49±2% were positive for cardiac myosin.

The proportions in normal myocardium were 13 ± 2% CD45+, 17% alpha-

actin+, 28 ± 6% CD31+, and 68±0% cardiac myosin+.

Conclusions: UBM implanted as a patch replacement for infarcted myo-

cardium undergoes an early phase of cellular recruitment involving a

variety of cell types found in normal myocardium, and appears favorable

in comparison to the encapsulization response to ePTFE. Ongoing studies

will investigate the long-term and functional outcomes of UBM patching as

well as investigate the mechanisms of cellular recruitment.

This study was supported in part by r21 grant #HL-072209 from the

National Heart, Lung, and Blood Institute (K.A.R.).

Oral Rapamycin to inhibit restenosis after stenting of de novo coronary

lesions: the ORBIT Study

R Waksman, AE Ajani*, AD Pichard, R Torguson, E Pinnow, D Canos, LF

Satler, KM Kent, P Kuchulakanti, C Pappas, L Gambone, N Weissman, MC

Abbott, J Lindsay

Cardiovascular Research Institute, Washington Hospital Center, Washing-

ton DC; *Royal Melbourne Hospital and NHMRC Centre of Clinical

Research Excellence in Therapeutics, Department of Epidemiology and

Preventive Medicine, Monash University, Melbourne, Australia

Objective: The aim of this pilot study was to establish safety and feasibility

of oral Rapamycin at two dosing strategies (2 and 5 mg) in achieving low

rates of repeat target vessel revascularization in de novo native coronary

artery lesions.

Background: Drug-eluting stents (utilizing antiproliferative agents such as

Rapamycin) have shown the ability to limit restenosis. Oral Rapamycin is

an alternative delivery strategy that can target multiple coronary lesions that

are targets for catheter-based revascularization with any approved metal

stent and with potentially lower cost.

Methods: Oral Rapamune to Inhibit Restenosis (ORBIT) is an open-label

study of 60 patients with de novo coronary artery stenosis treated with stent

implantation in up to two vessels. The first 30 patients received Rapamycin

2 mg/day for 30 days, and the second 30 patients received Rapamycin 5

mg/day for 30 days (loading dose being 5 mg for both groups). Patients

underwent 6-month angiographic, intravascular ultrasound (IVUS), and

clinical follow-up.

Results: Baseline clinical and procedural characteristics were similar. Side

effects including rash, mouth ulcers, diarrhea, and fatigue (with the

majority of these remitting with cessation of medication), which resulted

in Rapamycin discontinuation, were higher in the 5-mg group. At 6-month

follow-up, both cohorts had similar rates of late loss (0.6 ± 0.5 vs. 0.7 ± 0.5

mm, P=NS), in-stent binary restenosis (7.1% vs. 6.9%, P=NS), in-stent %

volume obstruction by IVUS (29% vs. 24%, P=NS), and angiographically

driven target lesion revascularization (14.3% vs. 5.4%, P=NS), (2 vs.

5 mg, respectively).

Conclusions: Oral Rapamycin as adjunct therapy to intracoronary stenting

for the prevention of restenosis is safe, feasible and associated with low

rates of repeat revascularization and may be considered for patients under-

going multivessel percutaneous coronary intervention (PCI) if proven in

larger randomized studies.

Early clinical outcomes of the first 849 patients treated with Sirolimus-

eluting stent—a single-center postmarketing surveillance study

S-W Rha, PK Kuchulakanti, R Pakala, E Cheneau, A GebreEyesus, G

Aggrey, EE Pinnow, R Torguson, AD Pichard, LF Satler, KM Kent, J

Lindsay, R Waksman

Washington Hospital Center, Washington, DC

Background: The Sirolimus-eluting stent (SES, Cypher) is currently being

used in patients (pts) undergoing percutaneous coronary intervention (PCI).

We report our initial results from a postmarketing surveillance experience

with use of SES in everyday ‘‘real world’’ clinical practice.

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224222

Methods: Data of the first 849 pts (1377 lesions) treated with the SES since

its approval were collected and analyzed. All pts were discharged with

antiplatelet therapy for 3 to 12 months. Pts are followed at 30 days and 3

months from the date of SES implantation.

Results: Our cath lab utilizes SES during PCI in 45% of procedures. The

mean age of the pts was 64 ± 37 years, males 63.8% and diabetics 34.7%.

The SES was implanted in complex lesions (type B2/C lesion) 85.0%, in-

stent restenosis (ISR) 6.8%, total occlusion 3.5% and saphenous vein grafts

3.8%. The overall number of SES utilized per procedure was 1.14 ± 0.6.

The mean SES length was 21.7 ± 6.4 mm and 234 lesions (25.7%) were

implanted with long SES (> 25 mm). The mean SES diameter was

2.98 ± 0.4 mm and 225 lesions (24.4%) received a small SES (2.5 mm).

IVUS-guided PCI was performed in 76.7% of cases. The procedural

success rate was 97.2%. In-hospital, 30-day and 90-day clinical outcomes

were shown in the table.

Conclusion: In daily clinical practice of using the SES, the overall clinical

event rates up to 3 months were comparable with other previous reports.

Long-term follow-up results of this cohort are needed to prove the efficacy

and safety of SES in ‘‘real world’’ clinical practice.

Effect of ionizing radiation on the stability and performance of TAXUS

Express paclitaxel eluting stent

C Dilcher, R Chan, D Hellinga, R Seabron, R Pakala, PK Kuchulakanti,

S-W Rha, R Richard*, K Chan*, S Zhong*, JJ Barry*, R Waksman

Cardiovascular Research Institute, *Boston Scientific Corporation, Wash-

ington DC

Background: Recently, there are some reports that in some patients drug

eluting stents have failed to prevent in-stent restenosis. Vascular brachy-

therapy is an ideal option for treatment of this class of patients. However,

since ionizing radiation is known to change the chemical structure of many

polymers and drugs, we wanted to assess the effect of radiation on the

stability of the Translute polymer carrier and paclitaxel, and paclitaxel

kinetic drug release (KDR) in TAXUS Express paclitaxel eluting stents

(TAXUS stents).

Methods: Using a custom fixture designed to simulate an artery, TAXUS

stents were exposed to different doses of gamma (18 and 36 Gy) and beta

radiation (23 and 46 Gy). A control group of TAXUS stents underwent the

same procedure, but was not exposed to radiation. Before and after exposure,

Translute molecular weight was determined by gel permeation chromato-

graphy and polydispersity indices were calculated to assess Translute

stability. Stability of the paclitaxel was evaluated by determining the level

of degradants within the polymer by HPLC. Finally, paclitaxel KDR was

determined by high-performance liquid chromatography (HPLC) at various

time points as an added assessment of stability of the coating with radiation.

Results: There were no statistical differences in the molecular weights or

the polydispersity indices (ratio of weight to number average molecular

weight) of the TAXUS control stents and beta or gamma radiation-treated

TAXUS stents. Similarly, there was no difference in the amount of

paclitaxel degradants detected in the control and beta or gamma radi-

ation-treated stents. Furthermore, there was also no statistical difference in

paclitaxel KDR between the control, beta or gamma radiation treated stents.

Conclusion: Beta and gamma radiation doses typically used in vascular

brachytherapy had no significant effect on the Translute polymer carrier,

paclitaxel degradation, or paclitaxel release in this in vitro model. These

data are encouraging and support further evaluation of the use of intra-

vascular brachytherapy in the treatment of in-stent restenosis in the

presence of drug eluting stents

Angiomax versus heparin as an antithrombotic agent in patients

undergoing percutaneous coronary intervention in saphenous vein

bypass grafts

S-W Rha, PK Kuchulakanti, R Pakala, E Cheneau, G Aggrey, A GebreEye-

sus, R Torguson, M Nandalur, EE Pinnow, J Lindsay, R Waksman

Washington Hospital Center, Washington, DC

Background: Bivalirudin (Angiomax) is a thrombin-specific anticoagulant

approved for use in percutaneous coronary intervention (PCI). This study

aimed to compare the efficacy and safety of bivalirudin with heparin in

patients (pts) undergoing PCI in saphenous vein bypass grafts (SVG).

Methods: All patients were treated with bivalirudin (0.75 mg/kg bolus and

1.75 mg/kg/h infusion) or heparin as the antithrombotic agent during

standard PCI in SVGs. All pts received aspirin and clopidogrel and were

recommended to continue for at least 1 year. Periprocedural complications

and in-hospital events of both groups were compared.

Results: Overall 93 pts (131 lesions) in the Angiomax group and 1890 pts

(2718 lesions) in the heparin group were included in the study. Baseline

clinical characteristics were similar in both groups. Procedural and in-

hospital events were similar except that vascular complications were

significantly higher in the heparin group.

Conclusion: Angiomax as a single antithrombotic agent in pts undergoing

standard PCI in SVGs is clinically safe and is associated with significantly

low vascular complications as compared to heparin.

Angiomax versus heparin as an antithrombotic agent in patients

treated with sirolimus-eluting stent

S-W Rha, PK Kuchulakanti, R Pakala, E Cheneau, A GebreEyesus, G

Aggrey, EE Pinnow, R Torguson, AD Pichard, LF Satler, KM Kent, J

Lindsay, R Waksman

Washington Hospital Center, Washington, DC

In-hospital, 30-day and 90-day clinical outcomes

In-hospital 30 days 90 days

Death, % 0.2 0.7 2.0Q-wave myocardial infarction (MI), % 0.2 1.3 2.0Target lesion revascularization (TLR), % 0.1 1.3 1.6Target vessel revascularization (TVR), % 0.1 2.0 2.4TVR MACE, % 0.2 3.3 4.5Thrombosis, % 0.0 1.3 1.6

Polydispersity Index (PDI) and paclitaxel degradants in ionizing radiationtreated TAXUS Express paclitaxel eluting stent

Group PDI

Non-TaxaneDegrad(area%)

7-epi,10-DeActaxol (area%)

10-DeAcTaxol(area%)

7-Epitaxol(area%)

Totalarea%Impurity

Control 1 1.33 ± 0.01 0.23 0.31 0.28 0.42 1.24Control 2 1.33 ± 0.01 0.20 0.31 0.28 0.37 1.16Beta 23 Gy 1.34 ± 0.01 0.26 0.27 0.25 0.37 1.15Beta 46 Gy 1.34 ± 0.01 0.11 0.26 0.24 0.43 1.04Gamma

18 Gy1.35 ± 0.01 0.12 0.26 0.22 0.43 1.03

Gamma36 Gy

1.34 ± 0.01 0.10 0.25 0.27 0.44 1.06

In-hospital clinical outcomes of angiomax vs. heparin in SVG intervention

Clinical Events

Angiomax(N=93 pts/131 lesions)

Heparin(N=1890 pts/2718 lesions) P value

Bleeding complications (%)Major hematoma 0.0 1.1 .350Major bleeding 2.2 3.3 .551Hematocrit drop �15 1.2 2.5 .438Transfusion 6.5 6.1 .893

Vascular complications (%) 0.0 4.9 .028In-hospital TVR-MACE

(death, Q-MI, TVR, %)2.2 1.7 .768

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224 223

Background: Angiomax (Bivalirudin) is increasingly used as a substitute

for heparin in a variety of percutaneous coronary interventions (PCI). This

study aimed to compare the clinical efficacy and safety of Angiomax, as

compared to heparin, as an antithrombotic regimen in patients (pts) treated

with sirolimus-eluting stents (SES, Cypher).

Methods: A total 881 pts with 1426 lesions underwent standard PCI with

SES for various coronary artery lesions. Patients were treated with

Angiomax (0.75 mg/kg bolus and 1.75 mg/kg/h infusion, n= 591) or

with heparin alone (80 U/kg bolus, n=290) during PCI. We compared

procedural, in-hospital and 30-day clinical outcomes in both groups.

Results: Baseline clinical and angiographic parameters were similar

between both groups. Major bleeding complications and vascular compli-

cations were similar between both groups. However, CKMB rise �5�normal, in-hospital repeat PTCA and overall in-hospital complications were

lower in the Angiomax group. At 30 days, non-Q wave MI was lower in the

Angiomax group but death, Q-wave MI, TLR, TVR and MACE were

similar between both groups.

Conclusions: Angiomax, as a single antithrombotic agent in pts undergoing

PCI with SES, is clinically safe and feasible without significant bleeding

and vascular complications as compared to heparin. Thirty-day clinical

follow-up results showed that the use of Angiomax was related to less

periprocedural and early ischemic events compared to heparin.

Clinical outcomes of angiomax vs. heparin

VariablesAngiomax(N = 591 pts)

Heparin(N = 290 pts) P value

In-hospital complications (%)CKMB 5� normal 3.9 9.3 .001Repeat PTCA 0.3 2.4 .004Overall in-hospital complications 0.5 3.1 .002

Major bleeding* 2.4 2.8 .727Vascular complications** (%) 2.7 2.8 .96830-day clinical outcomes (%)Death 0.9 1.1 .859Non Q-wave myocardial infarction 16.0 28.1 .008All MACE 1.3 1.1 1.0

* Major bleeding: major hematoma, hematocrit drop �15 or gastrointestinalbleeding.

** Vascular complication: AV fistula, pseudoaneurysm, surgical repair, retroper-itoneal bleeding or major hematoma.

Abstracts / Cardiovascular Radiation Medicine 4 (2003) 205–224224