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Translational Research: Migrating Therapeutic Discoveries From Bench to Bedside (oral 95-98)
Monday, October 25, 2006, 8:15 am - 12:30 Pm
Translational Research: Migrating Therapeutic Discoveries from Bench to Bedside
O R A L A B S T R AC T S
Room 152 AB Wednesday, October 25, 2006, 8:15 am – 12:30 pm (Abstract Nos. 95-98) TCT-95 Adventitial Delivery of Liposomes Containing Complex Lipids and Human Derived Oxidized LDL Induces the Formation of Coronary Atherosclerotic Lesions with Abundant Neovascularization and Macrophage Infiltration Juan F. Granada, David Wallace-Bradley, Carlos Alviar, Angela Builes, Eli I. Lev, Daryl G. Schulz, Albert E. Raizner, Greg L. Kaluza The Methodist Hospital Research Institute, Houston, TX Background: We aim to develop a porcine model of complex coronary lesions through the endovascular adventitial delivery of a liposome-based solution of cholesterol esters and human oxidized LDL. Methods: One hundred coronary arterial segments injected with lipids were compared with 55 non-injected coronary segments in 8 pigs maintained up to 8.3 ± 1.8 weeks. Histology was performed to analyze lesion significance and for the presence of macrophages (myeloperoxidase-labeled streptavidinbiotin method) and adventitial neovessels (anti-factor VIII antibody). Results: There was no evidence of vascular lesion formation in non-injected segments. In the injected segments, the mean plaque area (0.99 ± 0.59 mm2 versus 0.05 ± 0.03 mm2, p<0.01) and the mean percentage of plaque area (58.9% ± 14% versus 7.5% ± 4.9%, p<0.01) were significantly different compared to non-injected segments. All lesions were classified as eccentric and comprising less than a half of the vessel circumference and were mainly composed of fibro-lipidic material (SMCs 41.1% ± 14%, ECM and collagen 46% ± 14.2% and lipid clefts 12.9% ± 5.5% of the plaque area). The presence of lipid deposits colocalized with the presence of tissue macrophages (mean macrophage count 32.7 ± 13.4 in the injected sites versus 12.7 ± 10.5 in the control group, p<0.01). The mean count of adventitial neovessels was also increased in the injected segments compared to controls (33.1 ± 12.8 versus 17.4 ± 8.7, p=0.05). There was no evidence of necrotic core formation, intraplaque hemorrhage or calcium deposits in any of the lesions. Conclusions: After 10 weeks, the adventitial delivery of lipid-rich liposomes induces fibro-lipidic lesions that contain abundant macrophages and demonstrate adventitial neovascularization. Longer follow up is needed to determine if the lesions induced in this fashion can develop hallmarks of more complex atherosclerosis: necrotic core and calcification. TCT-96 Mobilization of CXCR4+ Stem Cells in Acute Myocardial Infarction is Correlated with Left Ventricular Ejection Fraction and Myocardial Perfusion Assessed by MRI in 1 year follow-up (REGENT Trial) Wojciech Wojakowski1, Magdalena Kucia2, Andrzej Ochala1, Pawel Buszman3, Marek Krol1, Rafal Wyderka1, Katarzyna Maslankiewicz1, Aleksander Zurakowski3, Mariusz Z. Ratajczak2, Michal Tendera1 1 3rd Division of Cardiology, Katowice, Poland2Stem Cell Biology Program, Louisville, KY;3Acute Coronary Care Unit, Katowice, Poland Background: Stem cells are mobilized into blood in acute myocardial infarction (AMI). In patients with low left ventricular ejection fraction (LVEF) in acute phase of AMI the mobilization of stem cells is significantly impaired, however there is no data regarding the long-term MRI follow-up. AIM of the study was to correlate the mobilization of CD34/CXCR4+ stem cells and the number of circulating cells after 1 year in patients with AMI treated with primary PCI with LVEF, left ventricular remodeling, late enhancement and adenosine first pass myocardial perfusion after 1 year
46M
http://www.attendeeinteractive.com/shows/tct0601
follow-up. Methods: 48 patients were enrolled during index AMI and 15 patients underwent control MRI scan after 12-14 months. Stem cells number was measured on admission, after 24 hours, 7 days and 1 year. MRI study was performed using 1.5 T scanner. First pass study (Turbo-FLASH, 3 slices, short axis view) was performed first in stress conditions (adenosine 140 ug/min/kg, 4 min) and after 15 min in rest conditions. Delayed contrast enhancement study was performed in 3,6,9,15 min after second contrast injection by using inversion recovery segmented 3D turbo FLASH. Results: In patients with baseline LVEF <40% the number of mobilized stem cells on admission was significantly lower in comparison to patients with LVEF >40% (p<0.03). Patients with LVEF <40% after 1 year had lower baseline CXCR4+ cell counts than patients with LVEF >40% on follow-up visit (p<0.03). Baseline number of CD34/CXCR4+cells was positively correlated with LVEF after 1 year (r=0.51; p<0.02), and negatively with parameters of LV remodeling: LVEDV (r=-0.31; p<0.03) and LVESV (r=-0.34; p<0.04). The peak number of mobilized CD34/CXCR4+ cells early in AMI was also significantly negatively correlated with the mean delayed enhancement after 1 year (r=-0.30; p<0.03). In patients with low number of circulating CD34/ CXCR4+ cells the number of segments displaying impaired adenosine first pass perfusion was significantly higher (p<0.05) than in patients with higer number of circiulating cells. Conclusions: In AMI the number of circulating CXCR4 cells is significantly correlated with LVEF, left ventricular remodeling and myocardial perfusion measured using MRI after 1 year follow-up. TCT-97 Impact of Double Dose Sirolimus-Eluting Stents on Neointimal Hyperplasia in Diabetic Patients: A Serial (6-month and 2-year) Intravascular Ultrasound Analysis from the Double Dose Diabetes (3D) Study Seung-Ho Hur1, Yoshihisa Shimada1, Ichizo Tsushino1, Junya Ako1, Ali H M Hassan1, Alexandre Abizaid2, J. Eduardo M R Sousa2, Basil S Lewis3, Giulio Guagliumi4, Paul G Yock1, Peter J Fitzgerald1, Yasuhiro Honda1 1 Stanford University, Stanford, CA;2Institute Dante Pazzanese, San Paulo, Brazil3Lady Davis Carmel Medical Center, Haifa, Israel4Ospedali Riuniti di Bergamo, Bergamo, Italy Background: Although sirolimus-eluting stents (SES) markedly reduced neointimal hyperplasia (NIH) in de novo coronary lesion, diabetes still remains a risk factor of restenosis after stenting. The aim of this study was to evaluate the efficacy of increased drug dose in SES on neointimal hyperplasia (NIH) in diabetic patients. Methods: A total of 39 patients available with serial volumetric analyses (baseline, 6-month, 2-year) were enrolled from the Double Dose Diabetes study (13 single dose: 140μg/cm2; 19 double dose: 280μg/cm2). Each volume index was calculated as volume divided by stent length. Percent neointimal volume (%NIV) was calculated as (neointimal volume/stent volume)*100. To evaluate axial NIH distribution, NIH volume index was obtained every 1 mm in 32 patients who treated with a 23 mm single SES. Results: In the 2 stent groups, volumetric IVUS results were similar at each time point (P=NS for all). Serial comparison showed minimal increase in NIH index and %NIV between 6 months and 2 years (P<0.05 for all). There was no late-acquired incomplete stent apposition in either group (Table). At 2-year follow-up, mild accumulation of NIH at both edges was observed in both stent groups (P<0.05). However, NIH amount in each subsegment was not different between the groups (P=NS).
The American Journal of Cardiology® | October 22-27, 2006 | TCT Abstracts/Oral
http://www.attendeeinteractive.com/shows/tct0601
Monday, October 25, 2006, 8:15 am - 12:30 Pm
O R A L A B S T R AC T S
Conclusions: In diabetic patients, reduced NIH by SES was well maintained with similar axial NIH distribution from 6 months to 2 years. Compared to single dose SES, double dose SES did not confer further NIH suppression during 2 years. TCT-98 Human Embryonic Stem Cells Improve Diastolic Function in Rats With Acute Myocardial Infarction Malin Lorentzon, Truls Råmunddal, Entela Bollano, Elmir Omerovic Department of Cardiology, Gothenburg, Sweden Background: Human embryonic stem cells (hES) have emerged as an attractive therapeutic approach for treatment of heart diseases. The aim of this study was to evaluate in rats with acute myocardial infarction (MI): 1) effects of myocardial transplantation of undifferentiated hES on left ventricular (LV) function and morphology and 2) to determine whether improvement in LV function requires the presence of hES in the myocardium. Methods: Male Sprague-Dawley rats ~ 200 g were used. MI was induced by cryo-injury (protocol 1) and by ligation of left coronary artery (protocol 2). These procedures resulted in anterior MI engaging ~ 30 - 40 % of left ventricle (LV). In the protocol 1, the rats were randomized into two groups: rats with MI treated with vehicle (n = 8) and rats with MI treated with 1 million hES cells (n = 8). Rats treated with hES cells received cyclosporine (5 mg/kg/d). The hES cells were transplanted by intramyocardial injection into the viable myocardium close to the infracted area directly after cryo-injury. The rats were followed for 1 week. In order to evaluate hypothetical paracrine effects of hES, in the protocol 2, the rats were randomised into three groups: rats with MI treated with vehicle (n = 4), rats with MI treated with cell medium (n = 6) and rats with MI treated with supernatant extracted from hES cell culture (n = 6). The animals received i.p. injections 3 times/week during 4 weeks. All animals were investigated with transthoracal echocardiography, continuous ECG and LV catheterization. Post-mortem, the hearts were evaluated histologically. Results: In the protocol 1 neither deaths nor arrhythmias occurred in the hES treated rats. dP/dT was similar in both groups. There were no signs of abnormal tissue growth at the site of hES cell engraftment. There was no difference in the indices of LV systolic function while diastolic function was significantly improved in the hES rats (p < 0.05). In the protocol 2, no difference was found between the groups in indices of LV function and morphology after 4 weeks of treatment. Conclusions: Transplantation of undifferentiated hES cells have positive effect on LV diastolic function in the rat model of acute MI. This effect requires the presence of hES in the tissue.
The American Journal of Cardiology® | October 22-27, 2006 | TCT Abstracts/Oral
47M
Translational Research: Migrating Therapeutic Discoveries from Bench to Bedside
O R A L A B S T R AC T S
Room 152 AB Wednesday, October 25, 2006, 8:15 am – 12:30 pm (Abstract Nos. 95-98) TCT-95 Adventitial Delivery of Liposomes Containing Complex Lipids and Human Derived Oxidized LDL Induces the Formation of Coronary Atherosclerotic Lesions with Abundant Neovascularization and Macrophage Infiltration Juan F. Granada, David Wallace-Bradley, Carlos Alviar, Angela Builes, Eli I. Lev, Daryl G. Schulz, Albert E. Raizner, Greg L. Kaluza The Methodist Hospital Research Institute, Houston, TX Background: We aim to develop a porcine model of complex coronary lesions through the endovascular adventitial delivery of a liposome-based solution of cholesterol esters and human oxidized LDL. Methods: One hundred coronary arterial segments injected with lipids were compared with 55 non-injected coronary segments in 8 pigs maintained up to 8.3 ± 1.8 weeks. Histology was performed to analyze lesion significance and for the presence of macrophages (myeloperoxidase-labeled streptavidinbiotin method) and adventitial neovessels (anti-factor VIII antibody). Results: There was no evidence of vascular lesion formation in non-injected segments. In the injected segments, the mean plaque area (0.99 ± 0.59 mm2 versus 0.05 ± 0.03 mm2, p<0.01) and the mean percentage of plaque area (58.9% ± 14% versus 7.5% ± 4.9%, p<0.01) were significantly different compared to non-injected segments. All lesions were classified as eccentric and comprising less than a half of the vessel circumference and were mainly composed of fibro-lipidic material (SMCs 41.1% ± 14%, ECM and collagen 46% ± 14.2% and lipid clefts 12.9% ± 5.5% of the plaque area). The presence of lipid deposits colocalized with the presence of tissue macrophages (mean macrophage count 32.7 ± 13.4 in the injected sites versus 12.7 ± 10.5 in the control group, p<0.01). The mean count of adventitial neovessels was also increased in the injected segments compared to controls (33.1 ± 12.8 versus 17.4 ± 8.7, p=0.05). There was no evidence of necrotic core formation, intraplaque hemorrhage or calcium deposits in any of the lesions. Conclusions: After 10 weeks, the adventitial delivery of lipid-rich liposomes induces fibro-lipidic lesions that contain abundant macrophages and demonstrate adventitial neovascularization. Longer follow up is needed to determine if the lesions induced in this fashion can develop hallmarks of more complex atherosclerosis: necrotic core and calcification. TCT-96 Mobilization of CXCR4+ Stem Cells in Acute Myocardial Infarction is Correlated with Left Ventricular Ejection Fraction and Myocardial Perfusion Assessed by MRI in 1 year follow-up (REGENT Trial) Wojciech Wojakowski1, Magdalena Kucia2, Andrzej Ochala1, Pawel Buszman3, Marek Krol1, Rafal Wyderka1, Katarzyna Maslankiewicz1, Aleksander Zurakowski3, Mariusz Z. Ratajczak2, Michal Tendera1 1 3rd Division of Cardiology, Katowice, Poland2Stem Cell Biology Program, Louisville, KY;3Acute Coronary Care Unit, Katowice, Poland Background: Stem cells are mobilized into blood in acute myocardial infarction (AMI). In patients with low left ventricular ejection fraction (LVEF) in acute phase of AMI the mobilization of stem cells is significantly impaired, however there is no data regarding the long-term MRI follow-up. AIM of the study was to correlate the mobilization of CD34/CXCR4+ stem cells and the number of circulating cells after 1 year in patients with AMI treated with primary PCI with LVEF, left ventricular remodeling, late enhancement and adenosine first pass myocardial perfusion after 1 year
46M
http://www.attendeeinteractive.com/shows/tct0601
follow-up. Methods: 48 patients were enrolled during index AMI and 15 patients underwent control MRI scan after 12-14 months. Stem cells number was measured on admission, after 24 hours, 7 days and 1 year. MRI study was performed using 1.5 T scanner. First pass study (Turbo-FLASH, 3 slices, short axis view) was performed first in stress conditions (adenosine 140 ug/min/kg, 4 min) and after 15 min in rest conditions. Delayed contrast enhancement study was performed in 3,6,9,15 min after second contrast injection by using inversion recovery segmented 3D turbo FLASH. Results: In patients with baseline LVEF <40% the number of mobilized stem cells on admission was significantly lower in comparison to patients with LVEF >40% (p<0.03). Patients with LVEF <40% after 1 year had lower baseline CXCR4+ cell counts than patients with LVEF >40% on follow-up visit (p<0.03). Baseline number of CD34/CXCR4+cells was positively correlated with LVEF after 1 year (r=0.51; p<0.02), and negatively with parameters of LV remodeling: LVEDV (r=-0.31; p<0.03) and LVESV (r=-0.34; p<0.04). The peak number of mobilized CD34/CXCR4+ cells early in AMI was also significantly negatively correlated with the mean delayed enhancement after 1 year (r=-0.30; p<0.03). In patients with low number of circulating CD34/ CXCR4+ cells the number of segments displaying impaired adenosine first pass perfusion was significantly higher (p<0.05) than in patients with higer number of circiulating cells. Conclusions: In AMI the number of circulating CXCR4 cells is significantly correlated with LVEF, left ventricular remodeling and myocardial perfusion measured using MRI after 1 year follow-up. TCT-97 Impact of Double Dose Sirolimus-Eluting Stents on Neointimal Hyperplasia in Diabetic Patients: A Serial (6-month and 2-year) Intravascular Ultrasound Analysis from the Double Dose Diabetes (3D) Study Seung-Ho Hur1, Yoshihisa Shimada1, Ichizo Tsushino1, Junya Ako1, Ali H M Hassan1, Alexandre Abizaid2, J. Eduardo M R Sousa2, Basil S Lewis3, Giulio Guagliumi4, Paul G Yock1, Peter J Fitzgerald1, Yasuhiro Honda1 1 Stanford University, Stanford, CA;2Institute Dante Pazzanese, San Paulo, Brazil3Lady Davis Carmel Medical Center, Haifa, Israel4Ospedali Riuniti di Bergamo, Bergamo, Italy Background: Although sirolimus-eluting stents (SES) markedly reduced neointimal hyperplasia (NIH) in de novo coronary lesion, diabetes still remains a risk factor of restenosis after stenting. The aim of this study was to evaluate the efficacy of increased drug dose in SES on neointimal hyperplasia (NIH) in diabetic patients. Methods: A total of 39 patients available with serial volumetric analyses (baseline, 6-month, 2-year) were enrolled from the Double Dose Diabetes study (13 single dose: 140μg/cm2; 19 double dose: 280μg/cm2). Each volume index was calculated as volume divided by stent length. Percent neointimal volume (%NIV) was calculated as (neointimal volume/stent volume)*100. To evaluate axial NIH distribution, NIH volume index was obtained every 1 mm in 32 patients who treated with a 23 mm single SES. Results: In the 2 stent groups, volumetric IVUS results were similar at each time point (P=NS for all). Serial comparison showed minimal increase in NIH index and %NIV between 6 months and 2 years (P<0.05 for all). There was no late-acquired incomplete stent apposition in either group (Table). At 2-year follow-up, mild accumulation of NIH at both edges was observed in both stent groups (P<0.05). However, NIH amount in each subsegment was not different between the groups (P=NS).
The American Journal of Cardiology® | October 22-27, 2006 | TCT Abstracts/Oral
http://www.attendeeinteractive.com/shows/tct0601
Monday, October 25, 2006, 8:15 am - 12:30 Pm
O R A L A B S T R AC T S
Conclusions: In diabetic patients, reduced NIH by SES was well maintained with similar axial NIH distribution from 6 months to 2 years. Compared to single dose SES, double dose SES did not confer further NIH suppression during 2 years. TCT-98 Human Embryonic Stem Cells Improve Diastolic Function in Rats With Acute Myocardial Infarction Malin Lorentzon, Truls Råmunddal, Entela Bollano, Elmir Omerovic Department of Cardiology, Gothenburg, Sweden Background: Human embryonic stem cells (hES) have emerged as an attractive therapeutic approach for treatment of heart diseases. The aim of this study was to evaluate in rats with acute myocardial infarction (MI): 1) effects of myocardial transplantation of undifferentiated hES on left ventricular (LV) function and morphology and 2) to determine whether improvement in LV function requires the presence of hES in the myocardium. Methods: Male Sprague-Dawley rats ~ 200 g were used. MI was induced by cryo-injury (protocol 1) and by ligation of left coronary artery (protocol 2). These procedures resulted in anterior MI engaging ~ 30 - 40 % of left ventricle (LV). In the protocol 1, the rats were randomized into two groups: rats with MI treated with vehicle (n = 8) and rats with MI treated with 1 million hES cells (n = 8). Rats treated with hES cells received cyclosporine (5 mg/kg/d). The hES cells were transplanted by intramyocardial injection into the viable myocardium close to the infracted area directly after cryo-injury. The rats were followed for 1 week. In order to evaluate hypothetical paracrine effects of hES, in the protocol 2, the rats were randomised into three groups: rats with MI treated with vehicle (n = 4), rats with MI treated with cell medium (n = 6) and rats with MI treated with supernatant extracted from hES cell culture (n = 6). The animals received i.p. injections 3 times/week during 4 weeks. All animals were investigated with transthoracal echocardiography, continuous ECG and LV catheterization. Post-mortem, the hearts were evaluated histologically. Results: In the protocol 1 neither deaths nor arrhythmias occurred in the hES treated rats. dP/dT was similar in both groups. There were no signs of abnormal tissue growth at the site of hES cell engraftment. There was no difference in the indices of LV systolic function while diastolic function was significantly improved in the hES rats (p < 0.05). In the protocol 2, no difference was found between the groups in indices of LV function and morphology after 4 weeks of treatment. Conclusions: Transplantation of undifferentiated hES cells have positive effect on LV diastolic function in the rat model of acute MI. This effect requires the presence of hES in the tissue.
The American Journal of Cardiology® | October 22-27, 2006 | TCT Abstracts/Oral
47M