Scientific Session 1: Arterial Intervention 1

Sunday, March 21, 1999 8:00 am-9:30 am

PURPOSE To report a single unit experience managing coarctation of the aorta in adults using endovascular techniques.

Scientific Session 1 Arterial Intervention 1 Moderator: Timothy Murphy, MD 8:00 am

Abstract No.1

Obstructive Lesions in the Aorta Caused by Nonspecific Aortitis: Results of Treatment by Percutaneous Transluminal Angioplasty Sanjiv Sharma, MD, New Delhi, India. Manoranjan Mamapatra, MD. Anita Saxena, DM. Shyam S. Kothari, DM. Rajneesh juneja, DM. Mira Rajani, MD PURPOSE To evaluate the results of percutaneous angioplasty in treating aortic stenosis caused by nonspecific aortitis. MATERIALS AND METHODS: The results of 47 consecutive patients were studied. The indications included severe hypertension (n = 43) or lower limb claudication (n = 4) in the presence of >70% stenosis, >20 mm Hg gradient, and inactive disease. RESULTS: Forty-eight lesions were treated, located in the descending thoracic aorta (34) and the abdominal aorta (14). The stenosis decreased from 81 ::':: 7 to 19 ::':: 19%, pressure gradient decreased from 76 ::':: 19 to 26 ::':: 11 mm Hg, blood pressure improved from 185 ::':: 20/112 ::':: 12 mm Hg to 146 ::':: 12/90 ::':: 7 mm Hg, and drug requirement decreased from 4 ::':: 1 to 1.3 ::':: 0.9 (P < 0.00l). Obstructive dissection occurred in six patients, five of whom were successfully treated by stent placement. One patient underwent surgery because of nonavailability of stent. Long stenosis, eccentric location, and presence of abnormal adjacent segments adversely affected the immediate outcome of angioplasty (P < 0.00l). At 19 ::':: 13 months follow-up, restenosis was seen in two patients. In addition, two patients developed an aneurysm at the angioplasty site. CONCLUSION Symptomatic stenosis caused by nonspecific aortitis can be treated by percutaneous angioplasty with excellent results. An eccentric, long stenosis with abnormal adjacent segments predisposes to an adverse immediate outcome; however, remodelling with late clinical improvement still occurs in most cases. Stents are useful in the treatment of obstmctive dissection after angioplasty. 8:15 am

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Abstract No.2

The Endovascular Management of Adult Aortic Coarctation Peter Gaines, MRCP, FRCR, Sheffield, United Kingdom. Trevor Cleveland, FRCS, FRCR. julian Gunn, MRCP

MATERlALSANDMETHODS: Between 1991 and 1998, 15 unselected patients (M = 11, F = 4) aged 9-49 years (average, 25 years) with coarctation of the aorta and hypertension were treated on 16 occasions in the Radiology Department under general anesthesia. From 1991 to 1996, 10 patients were treated by either a kissing balloon technique or a single balloon. Since 1996, six patients were considered for stent placement (6 de novo, I restenosis). Palmaz stents were placed in four patients. Two patients were considered unsuitable for stent placement because of acute angulation of the aorta or proximity to the left subclavian artery. Follow-up evaluation was clinical and by MRA or helical CT. RESULTS: There were no deaths or complications. The mean translesion gradient was reduced from 34 mm Hg to 2 mm Hg. The mean systolic blood pressure decreased by 30 mm Hg. There were three recurrences out of the 10 patients treated by the kissing balloon technique. There were no recurrences in the patients treated with either a single balloon or stenL. CONCLUSION Single balloon dilatation and stent placement have been successful and safe forms of treatment in these patients. Kissing balloons have a high recurrence rate. 8:30 am

Abstract No. 3

FEATURED ABSTRACT Commentator: Macke Consignv, PhD Prevention of Restenosis After Balloon Angioplasty: Experimental Results with Local Application of the ACE Inhibitor Ramipril in ew Zealand White Rabbits Gunrlm' Tepe, MD, Tltbingen, Germany. Marc Kalinowski, ""W. Andrea Schieber. MD. Jakob lViskirchen. ,\lID. Claus D. Clau wm, MD. Stephan H Duda,.MD

PURPO E: To evaluate the effect of high-dose, local application of an ACE Inhibitor with a microporous balloon catheter to prevent ncointima formation after halloon angiopla ty. MATERIALS AND METHODS: eointima formation wa induced in n = 29 New Z aland White Rabbits by balloon denudation followed by 0.5% cholesterol diet. DirecLly aft r denudation local application of 1.8 mg ramipriJat (n = 7) or saline (n = 7) with a O1i roporOll' balloon catheter at a pressure of 3 atm was ped"ormed. Both group additionally receivedven ani~ systemic ramipJiI application (l mg/dD. mals were treated with syStemic ramipril appliCation alone. The control group was fed a cholesterol diet

exclusively (n = 8). The animals were sacrificed 6 weeks after intervention, and histology and morphometry wasperfOimed.

RESULTS: Systemic application of ramipril resulted in a significant reduction of plaque area (66%, P< 0.05). The combination of a systemic and local application ofth ACE inhibirorwa foUowed bya non ignificanr reduction of the neointima.l area (17%). Local application of saline with systemic application of ramipril was combined ,"vith an increase in neointima formation (280%, P < 0.05). CONCLUSION: 111e possible benefit of local ramipril application was diminished by the inherent vessel trauma. Sy teOlic ramipril application r ulted in a significant reduction of neointimal proliferation.

8:45 am

Abstract No.4

Does I88-Rhenium Have the Potential to Inhibit Cell Growth of Human Aortic Smooth Muscle Cells in Order to Prevent Restenosis After Transluminal Angioplasty? jakub Wiskirchen, MD, Tubingen, Germany. Helmut Dittmann, MD • jens Vogel-Claussen. Regina Gebert. Bernhard M. Dobmen, MD • Stephan H. Duda, MD PURPOSE: Effects of the beta/gamma-emitter 188-Rhenium 88 Re) on overall cell growth and cJonogenic activity of human aortic smooth muscle cells were examined in a cell culture model to establish a dose-response relationship.

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MATERIALS AND METHODS: Smooth muscJe cells were subcultivated for analysis of proliferation kinetics. Two days after plating, the cells were incubated with 188Re (beta Emax 2.12 MeV, tissue range max ~10 rom, Tl/2 17 hours) for 5 days. The activity administered to the cells ranged from 0.4 MBq (total dose approximately 0.4 Gray) to 16 MBq (total dose approximately.16 Gray) within 5 days. The absolute cell numbers were calculated for the following 15 days. Colony formation assays were performed to analyze the cJonogenic activity of the cells and to detect a possible regeneration of the cells after removal of the radionucJide. RESULTS: The 0.4 MBq group did not show any significant differences of the total cell numbers compared with the control group. A slight reduction of the c1onogenic activity did not prove to be statistically relevant. The 2 MBq, 8 MBq, and 16 MBq groups presented a dosedependent growth inhibition with a biologic growth arrest in the 16 MBq group. The 2 MBq, however, and partly the 8 MBq group showed signs of regeneration after the removal of 188Re . The cJonogenic activity of the 16 MBq group was clearly suppressed compared with the control group even after a 10 day-incubation period with nonradioactive culture medium.

CONCLUSION: Smooth muscle cell proliferation can be suppressed effectively with 188Re depending on the dose administered. I88Re may serve as a valuable radionuclide to inhibit restenosis after arterial angioplasty. 9:00 am

Abstract No. 5

Monocyte Chemoattractant Protein 1 Gene Expression After Balloon Angioplasty Aziz Merchant, Philadelphia, PA • Amy 1. Simon, MS. Ellen D. Dillavou, MD. Pamela A. Cup, BS. Nicholas j. Vitali, BS. Paul M. Consigny, PhD, et al PURPOSE: Previous studies have documented that monocyte chemoattractant protein-1 (MCP-I) gene expression is increased shortly after Fogarty balloon denudation of the rabbit aorta and porcine iliac artery. The purpose of this study was to characterize MCP-1 gene expression after balloon angioplasty of rabbit arteries. MA TERIALS AND METHODS: Balloon angioplasty was performed on the external iliac arteries of New Zealand White rabbits. The arteries were removed 1 hour (n = 2), 4 hours (n = 2), 18 hours (n = 2), and 24 hours (n = 2) later, and the RNA was extracted from the dilated and control (n = 6) arteries. RNA (2 /-Lg) from each altelY was reverse transcribed to cDNA, and the cDNA products were amplified by polymerase chain reaction using primers for MCP-1 and a reporter gene, gJyceraldehyde3-phosphate dehydrogenase (G3PDH). The PCR products were separated by agarose gel electrophoresis, and the amounts of MCP-] and G3PDH were quantified using ultraviolet densitometry. The result for each artelY was expressed as a ratio (MCP-1/G3PDH). RESULTS: The MCP-1/G3PDH ratios (mean ::t: SEM) averaged 0.82 ::t: 0.17 for the control arteries. The ratios in the dilated arteries were not markedly different from the control arteries, averaging 0.92 ::t: 0.37, 0.42 ::t: 0.1, 1.26 ::t: 0.1, and 0.83 ::t: 0.2 for arteries removed 1 hour, 4 hours, 18 hours, and 24 hours after angioplasty, respectively. CONCLUSION: We conclude that, unlike Fogarty baJJoon denudation, balloon angioplasty does nol increase MCP-1 gene expression up to 24 hours after angioplasty.

9:15 am

Abstract No. 6

Vivo Vascular Tissue Engineering Michael D. Kuo, MD, Stanford, CA. jacob M. Waugh, MD • Eser Yuksel, MD. Michael D. Dake, MD

In

PURPOSE: To examine and define the potential feasibility of an entirely new approach to molecular medicine, in vivo tissue engineering, for the treatment of vascular thrombosis.

MATERIALS AND METHODS: Rabbit femoral veins were transfected in situ with either a previously characterized adenoviral-tissue plasminogen activator construct (adenoviraJ tPA) or a viral (adenoviral (3-galactosidase) or nonviral (Buffer) control and then immediately har-

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vested and used as an interposition vein graft in the ipsilateral common femoral artery. Thrombus formation then was induced in the immediate downstream recipienl artery utilizing a previously characterized complex stimulus for thrombus formation. Vein graft and downstream artery segment then were harvested 6 days later and examined by defined anatomic zones for thrombus. Transfection efficiency and vein graft smooth muscle cell content also were evaluated as parameters of our therapy. RESULTS: The engineered vein graft demonstrated a sig-

nificant reduction in thrombus formation 04.6% :±: 4.9%) both within the grafl as well as in the downstream artery relative to nonviral (60.9% :±: 5.6%) and viral (46.3% :±: 5.1%) controls. Greater than 90% underlying endothelial cell transfection was demonstrated. A 2.4-fold and 10fold increase in the smooth muscle a-actin positive cells in the engineered vein graft relative to nonviral and viral controls, respectively, were observed. CONCLUSION [n vivo tissue engineering for the treatment of vascular thrombosis represents a new paradigm in molecular medicine that potentially avoids many of the inherent limitations of current gene therapy and tissue engineering strategies.

Sunday, March 21, 1999 8:00 am-9:30 am

Moderator: Karen T. Brown, MD

liver in DNA dose of 1 mg, 3 mg, and 10 mg were found to induce expression of transferred human WT p53 RNA and protein and to presence of lacZ in rabbit liver and/or lung in a dose-dependent manner. In contrast, liver tissues of rabbits of group 1 thal were administered with normal saline did not show expression of human WT p53 or presence of lacZ. In addition, there were no significant differences in laboratory findings and histology of vital organs between each group. CONCLUSION Transalterial cationic polyliposome-mediated p53 gene administration could effectively transfer human WT p53 gene into normal rabbit liver without Significant toxicity in DNA doses of up to 4 mg/kg.

8:15 am

Abstract No.8

; FEATURED ABSTRACT Commentator: John W. Thomas, MD

Abstract No. 7

An Experimental Study on Transarterial Cationic Polyliposome-Mediated p53 Gene Therapy in Rabbit Liver: Gene Expression and Safety

PURPOSE: To evaluate the antitumor efficacy of transarterial cationic polyliposome-mediated p53 gene therapy OI'l VX2 Clucinoma model of rabbit liv r.

Byung K. Kwak, MD, Seoul, Korea. Hyung j. Shim, MD. Woo-Chul Moon, MD. Song j. Yang, MD. Sang H. Kim, MD. Chang j. Lee, MD

MA TERMIS AND METHODS: We constructed a com-

PURPOSE: To evaluate the gene transfer efficacy and safety of transarterial cationic polyliposome-mediated p53 gene administration into normal rabbit liver.

MATERIALS AND METHODS: We constructed a complex

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RESULTS: Transarterial administration of HV1 to rabbit

An Experimental Stndy on Transarterial Cationic Polyliposome-Mediated p53 Gene Therapy in Rabbit Liver: Antitumor Efficacy on VX2 Carcinoma Hyz,mgj. Sb'im, i1tJD, Seoul, KOrea. Byung K. Kwak, MD. Woo-Cbu/ Moon, J1IlD. ong.f. Yang, MD. Sang H. Kim, MD. Cbang j. Lee, MD

Scientific Session 2 Cancer Therapy 1 8:00 am

transfer efficacy were evaluated by DNA-polymerase chain reaction (PCR) and Southern blot for plasmid vector DNA sequence (lacZ), reverse transcription (Rn-PCR and Southern blot, Western blot for p53 protein, and safety by histologic analysis of vital organs as well as laboratory studies (CBC, urinalysis, and serum multiple analysis-12), respectively.

of plasmid carrying cDNA of human wild type (WT) p53 and novel cationic polyliposome, DDL (in weight ratio of 1:3.375), and named it Hepatovectin-1 (HV1). HV1 was produced and prepared in sterile and endotoxin-free status depending on FDA guidelines. Forty New Zealand white rabbits weighing a mean of 2.5 kg were divided into four groups (n = 10 in each group) and administered the follOWing: normal saline in Group 1, HVl in DNA dose of 1 mg in Group 2, 3 mg in Group 3, and 10 mg in Group 4, respectively, all through the hepatic artely by femoral artery catheterization using a microcatheter. Animals were sacrificed 1 week later, gene

plex of plasmid carrying cDNA of human wild type WT) p53 and novel cationic polyliposome, DDt (in wight ratio of 1:3.375) and named it H parovectin-l (HV1). INl was produced and prepared in sterile and endotoxin-free st.'1nJS depending on FDA guidelilles.. VX2 carCinOllYd was demonstrated by D A eqllencing to carry a missense pOint mutation of p53. Thi"rty New Zealand white rabbits weighing mean of 2.5 kg were implant d by VX2 carcinoma cells (l X 107 lis) into left lobe of the liver and were divided into three groups (n = 10 in each group). Two weeks after implantation of VX2 cells, CT and angiography revealed growth of liver tumor. Animals were divided into three group (n = 8 or 9 in each group) and the followiug W f admini tered twice weekly from 2 weeks after tumor implanration with normal saline (group 1), a complex of plasmid v CIOf carrying betagalactosidase marker gene in a D A dose of 3 mg