- Email: [email protected]
195 Uterine stem cells are recruited to the infarcted myocardium for cardiac regeneration
S130
Canadian Journal of Cardiology Volume 27 2011
lative rate of MI was 6.1% with rates at 1, 2 and 3 years were 4.0%, 1.4% and 0.6%, respectively. All cause mortality was 2.8%, 2.4% and 0.6%, whereas cardiac mortality was 1.6%, 1.8 % and 0.6% at 1, 2 and 3 year followup, respectively. CONCLUSIONS: The rates of the clinical outcomes of TVR and TLR in this study were relatively low and were similar to those reported in earlier randomized studies, despite use of the Endeavor stent in an unrestricted population. Our results do not suggest an increased rate of late stent thrombosis.
RHS allows complete revascularization equivalent to conventional bypass. The significant lower MBB-level on the arterial side of ECC may lead to a potential reduction of neurocognitive impairment after CABG.
CONCLUSIONS:
194 THREE YEAR CLINICAL OUTCOMES ASSOCIATED WITH THE USE OF THE ZOTAROLIMUS-ELUTING STENT IN AN UNRESTRICTED CONTEMPORARY PRACTICE L Drzymala, K Giles, M Armstrong, A Ha, D So, C Glover Ottawa, Ontario BACKGROUND: Drug eluting stents (DES) have improved clinical outcomes by reducing the need for target vessel revascularization. However, the randomized trials from which this data originated included only patients with single, non-complex lesions and excluded patients with acute coronary syndromes. There has been a suggestion in the literature that DES may be associated with late (⬎1 year) stent thrombosis. The objective of this study was to evaluate clinical outcomes associated with the use of the Endeavor stent in a single center unrestricted clinical practice over a three-year period. METHODS: Percutaneous coronary intervention was performed at the discretion of the Interventional Cardiologist. Telephone follow-up and review of hospital and clinic records were conducted 2 years post procedure. At three years, hospital and clinic records were re-reviewed and patients living outside the immediate Ottawa area were re-contacted by telephone. The primary outcome was clinically driven target vessel revascularization (TVR), target lesion revascularization (TLR) and stent thrombosis (ST) at one, two and three years. Secondary endpoints included acute myocardial infarction (MI), cardiac death and non-cardiac death. RESULTS: Four hundred ninety four consecutive patients treated with Endeavor stents from June 2005 to Feb 2007 were followed. 717 stents were used to treat 625 lesions. Clinicallydriven TLR rates were 6.2%, 1.1% and 0.3% at 1, 2 and 3 years respectively. TVR rates were 8.1%, 2.4% and 0.5% for the same time periods. The cumulative rates of TLR and TVR for the three-year period were 7.7% and 11.0%, respectively. There were 4 cases of ARC definite stent thrombosis involving 3 patients and 1 case of ARC probable stent thrombosis, all occurring within 12 months, with a rate of 0.7%. The cumu-
195 UTERINE STEM CELLS ARE RECRUITED TO THE INFARCTED MYOCARDIUM FOR CARDIAC REGENERATION K Hatta, M Xaymardan, Z Sun, M Tsukashita, F Konecny, RD Weisel, R Li Toronto, Ontario BACKGROUND: Pre-menopausal women have fewer cardiovascular complications than age-matched men. The mechanisms responsible for this protection have not been conclusively identified. We evaluated the hypothesis that uterine stem cells may home to the injured myocardium and improve outcomes. METHODS/RESULTS: (1) Hysterectomy (Hx) was performed in young female rats (leaving the ovaries intact), and 7 days later the left coronary artery was occluded to produce a myocardial infarction (MI). Young female and male rats also underwent coronary occlusion as controls. Cardiac function in all groups at 28 days after MI was measured using echocardiography. Fractional shortening was best in non-Hx females and lower in both Hx females and males (n ⫽ 10/group, P ⬍ 0.05). (2) To investigate the homing of uterine stem cells to infarcted myocardium, uteri were removed from GFP rats and heterotopically transplanted into the abdomen of non-GFP recipients (n ⫽ 12). Seven days later, the uterine transplant recipients underwent coronary occlusion. GFP⫹ uterine cells were found in the recipient hearts 7 days after MI (n ⫽ 6) and persisted for 6 months (n ⫽ 6). Confocal analysis showed that most homed uterine stem cells were located around blood vessels, suggesting their involvement in neovascularization by paracrine mechanisms. (3) Since the uterine stem cells can home to infarcted
S131
Abstracts
myocardium, we evaluated uterine cell transplantation for cardiac regeneration. GFP⫹ uterine cells were injected intravenously immediately after inducing an MI in female mice 7 days post-Hx. At 28 days after cell transplantation, GFP⫹ cells were found to home to the injured myocardium, stimulate angiogenesis, and improve function and survival (n ⫽ 6/group, P ⬍ 0.01) in comparison to Hx mice without cell implantation. CONCLUSION: Uterine stem cells can home to the injured myocardium, enhance tissue repair, and prevent cardiac dysfunction. Uterine stem cells may play a role in the prevention of cardiovascular complications in young females. Canadian Institutes of Health Research (CIHR) 196 INJECTABLE MATRIX ACTIVATES MYOGENIC DIFFERENTIATION IN EMBRYONIC STEM CELLS AND REGENERATES MUSCLE IN ISCHEMIC TISSUE D Kuraitis, D Ebadi, P Zhang, B Vulesevic, A Al-Madhoun, T Sofrenovic, TG Mesana, I Skerjanc, M Ruel, EJ Suuronen Ottawa, Ontario BACKGROUND: Previously, we demonstrated that an injectable collagen-based matrix containing sialyl LewisX (sLeX) applied to ischemic tissue amplified the endogenous progenitor cell response and increased vascular regeneration and perfusion, with evidence of enhanced myogenesis. In this study, we further explored the myogenic effects of this material. METHODS/RESULTS: The ability of collagen and sLeX-collagen matrices to promote the myogenic process was evaluated in vitro using mouse embryonic stem (mES) cell-matrix cultures. Q-PCR analysis showed higher expression of the skeletal muscle precursor markers Pax3 and Pax7 in cells differentiating on matrix compared to control tissue culture plates (P ⬍ 0.05), indicative of enhanced myogenic progenitor formation. Furthermore, expression of myogenic regulatory factors, Myf5 and myogenin, and of the final differentiation marker MHC3 was greater on matrices (P ⬍ 0.05), suggesting enhanced myoblast/ myotube formation. For evaluation in vivo, C57BL/6J mice were irradiated and received marrow transplantation from GFP⫹ donor mice. After marrow reconstitution (6-wk), injury was induced by femoral artery ligation followed by an intramuscular injection of: 1) PBS; 2) collagen matrix; or 3) sLeXcollagen matrix. By day 14, the sLeX-matrix group demonstrated increased arteriole density (P ⬍ 0.03), the greatest arteriole diameter (3-fold greater than PBS; P ⬍ 0.0002), and the greatest improvement in perfusion (P ⬍ 0.04). Immunohistochemical analysis revealed increases in GFP⫹ marrow-derived cells (by 5.5-fold) and CXCR4⫹ cells (by 3.8-fold) in sLeXtreated hindlimbs (P ⬍ 0.03) and a 70% decrease in apoptotic cells, compared to PBS (P ⫽ 0.02). GFP⫹ cells were not observed to differentiate into, or integrate into vasculature or myocytes. The frequency of regenerating myocytes, indicated by centralized nuclei, increased 6.7-fold with sLeX-matrix treatment (P ⫽ 0.02). Using a non-marrow transplant model, there were no differences in myogenic transcripts or regenerating myocytes at day 3 post-treatment. At 10 days, there were
4.2-fold more new myocytes with sLeX-matrix treatment (P ⫽ 0.01), combined with increases in local transcripts of Six1, M-Cadherin, Myf5, myogenin (P ⬍ 0.05), Pax7 and MyoD (P ⬍ 0.1), as measured by Q-PCR. CONCLUSION: In vitro, the matrix was able to enhance myogenesis in mES cells, suggesting its suitability for generating therapeutic muscle precursors for transplantation. In vivo, the sLeX-collagen matrix restores perfusion to ischemic tissue, associated with the formation of more arterioles of greater size, in addition to reducing local levels of apoptosis and improving muscle regeneration. Together, these results suggest that the application of sLeX-collagen matrix is a promising novel therapeutic option for the treatment of ischemic muscle, enhancing both the vasculogenic and myogenic repair processes without stem cell transplantation.
197 LONG-TERM OUTCOMES AFTER PERCUTANEOUS INTERVENTION OF THE INTERNAL THORACIC ARTERY ANASTOMOSIS: THE USE OF DRUG-ELUTING STENTS IS ASSOCIATED WITH A HIGHER REPEAT REVASCULARIZATION RATE X Freixa, M Carpen, MA Kotowycz, K Ho, A Krimly, CB Overgaard, PH Seidelin, V Dz˘avík Toronto, Ontario
There is currently a lack of data and absence of clear guideline recommendations regarding optimal treatment of lesions located at the anastomosis of the the internal thoracic artery (ITA). The objective of the present study was to assess the long-term outcomes of percutaneous coronary intervention (PCI) at the ITA anastomosis and to compare outcomes according to delivered treatment: deployment of a drug-eluting stent (DES), bare metal stent (BMS) or balloon angioplasty only (POBA). METHODS AND RESULTS: We used a prospective PCI registry at a large Canadian teaching hospital to identify all patients who underwent PCI at the ITA-CA anastomosis between June 2000 and June 2010. Our primary end point was repeat target lesion revascularization (TLR) at follow-up. Fifty three patients were included in the study (mean age 67.1 ⫾ 10.7; 84.9% males). Of these, PCI was successfully completed in 45 (84.9%). Twenty-three patients (51.1%) received DES, 18 (40%) BMS and 4 (8.9%) POBA. After a median follow-up of 29.2 months (range 11.1 to 77.7 months), TLR was 47.8% with DES, 7.1% with BMS, and 50% with POBA (P ⫽ 0.032). Patients who underwent repeat revascularization were more likely to have a longer stent length than those who did not (18.2 mm vs. 14.2 mm, P ⫽ 0.043). CONCLUSIONS: Deployment of a DES for the treatment of anastomotic lesions of the ITA appears to be associated with a higher rate of repeat revascularization compared to BMS. Further studies will be necessary to evaluate if the present results are an sporadic observation or might be a result of the different BACKGROUND:
Canadian Journal of Cardiology Volume 27 2011
lative rate of MI was 6.1% with rates at 1, 2 and 3 years were 4.0%, 1.4% and 0.6%, respectively. All cause mortality was 2.8%, 2.4% and 0.6%, whereas cardiac mortality was 1.6%, 1.8 % and 0.6% at 1, 2 and 3 year followup, respectively. CONCLUSIONS: The rates of the clinical outcomes of TVR and TLR in this study were relatively low and were similar to those reported in earlier randomized studies, despite use of the Endeavor stent in an unrestricted population. Our results do not suggest an increased rate of late stent thrombosis.
RHS allows complete revascularization equivalent to conventional bypass. The significant lower MBB-level on the arterial side of ECC may lead to a potential reduction of neurocognitive impairment after CABG.
CONCLUSIONS:
194 THREE YEAR CLINICAL OUTCOMES ASSOCIATED WITH THE USE OF THE ZOTAROLIMUS-ELUTING STENT IN AN UNRESTRICTED CONTEMPORARY PRACTICE L Drzymala, K Giles, M Armstrong, A Ha, D So, C Glover Ottawa, Ontario BACKGROUND: Drug eluting stents (DES) have improved clinical outcomes by reducing the need for target vessel revascularization. However, the randomized trials from which this data originated included only patients with single, non-complex lesions and excluded patients with acute coronary syndromes. There has been a suggestion in the literature that DES may be associated with late (⬎1 year) stent thrombosis. The objective of this study was to evaluate clinical outcomes associated with the use of the Endeavor stent in a single center unrestricted clinical practice over a three-year period. METHODS: Percutaneous coronary intervention was performed at the discretion of the Interventional Cardiologist. Telephone follow-up and review of hospital and clinic records were conducted 2 years post procedure. At three years, hospital and clinic records were re-reviewed and patients living outside the immediate Ottawa area were re-contacted by telephone. The primary outcome was clinically driven target vessel revascularization (TVR), target lesion revascularization (TLR) and stent thrombosis (ST) at one, two and three years. Secondary endpoints included acute myocardial infarction (MI), cardiac death and non-cardiac death. RESULTS: Four hundred ninety four consecutive patients treated with Endeavor stents from June 2005 to Feb 2007 were followed. 717 stents were used to treat 625 lesions. Clinicallydriven TLR rates were 6.2%, 1.1% and 0.3% at 1, 2 and 3 years respectively. TVR rates were 8.1%, 2.4% and 0.5% for the same time periods. The cumulative rates of TLR and TVR for the three-year period were 7.7% and 11.0%, respectively. There were 4 cases of ARC definite stent thrombosis involving 3 patients and 1 case of ARC probable stent thrombosis, all occurring within 12 months, with a rate of 0.7%. The cumu-
195 UTERINE STEM CELLS ARE RECRUITED TO THE INFARCTED MYOCARDIUM FOR CARDIAC REGENERATION K Hatta, M Xaymardan, Z Sun, M Tsukashita, F Konecny, RD Weisel, R Li Toronto, Ontario BACKGROUND: Pre-menopausal women have fewer cardiovascular complications than age-matched men. The mechanisms responsible for this protection have not been conclusively identified. We evaluated the hypothesis that uterine stem cells may home to the injured myocardium and improve outcomes. METHODS/RESULTS: (1) Hysterectomy (Hx) was performed in young female rats (leaving the ovaries intact), and 7 days later the left coronary artery was occluded to produce a myocardial infarction (MI). Young female and male rats also underwent coronary occlusion as controls. Cardiac function in all groups at 28 days after MI was measured using echocardiography. Fractional shortening was best in non-Hx females and lower in both Hx females and males (n ⫽ 10/group, P ⬍ 0.05). (2) To investigate the homing of uterine stem cells to infarcted myocardium, uteri were removed from GFP rats and heterotopically transplanted into the abdomen of non-GFP recipients (n ⫽ 12). Seven days later, the uterine transplant recipients underwent coronary occlusion. GFP⫹ uterine cells were found in the recipient hearts 7 days after MI (n ⫽ 6) and persisted for 6 months (n ⫽ 6). Confocal analysis showed that most homed uterine stem cells were located around blood vessels, suggesting their involvement in neovascularization by paracrine mechanisms. (3) Since the uterine stem cells can home to infarcted
S131
Abstracts
myocardium, we evaluated uterine cell transplantation for cardiac regeneration. GFP⫹ uterine cells were injected intravenously immediately after inducing an MI in female mice 7 days post-Hx. At 28 days after cell transplantation, GFP⫹ cells were found to home to the injured myocardium, stimulate angiogenesis, and improve function and survival (n ⫽ 6/group, P ⬍ 0.01) in comparison to Hx mice without cell implantation. CONCLUSION: Uterine stem cells can home to the injured myocardium, enhance tissue repair, and prevent cardiac dysfunction. Uterine stem cells may play a role in the prevention of cardiovascular complications in young females. Canadian Institutes of Health Research (CIHR) 196 INJECTABLE MATRIX ACTIVATES MYOGENIC DIFFERENTIATION IN EMBRYONIC STEM CELLS AND REGENERATES MUSCLE IN ISCHEMIC TISSUE D Kuraitis, D Ebadi, P Zhang, B Vulesevic, A Al-Madhoun, T Sofrenovic, TG Mesana, I Skerjanc, M Ruel, EJ Suuronen Ottawa, Ontario BACKGROUND: Previously, we demonstrated that an injectable collagen-based matrix containing sialyl LewisX (sLeX) applied to ischemic tissue amplified the endogenous progenitor cell response and increased vascular regeneration and perfusion, with evidence of enhanced myogenesis. In this study, we further explored the myogenic effects of this material. METHODS/RESULTS: The ability of collagen and sLeX-collagen matrices to promote the myogenic process was evaluated in vitro using mouse embryonic stem (mES) cell-matrix cultures. Q-PCR analysis showed higher expression of the skeletal muscle precursor markers Pax3 and Pax7 in cells differentiating on matrix compared to control tissue culture plates (P ⬍ 0.05), indicative of enhanced myogenic progenitor formation. Furthermore, expression of myogenic regulatory factors, Myf5 and myogenin, and of the final differentiation marker MHC3 was greater on matrices (P ⬍ 0.05), suggesting enhanced myoblast/ myotube formation. For evaluation in vivo, C57BL/6J mice were irradiated and received marrow transplantation from GFP⫹ donor mice. After marrow reconstitution (6-wk), injury was induced by femoral artery ligation followed by an intramuscular injection of: 1) PBS; 2) collagen matrix; or 3) sLeXcollagen matrix. By day 14, the sLeX-matrix group demonstrated increased arteriole density (P ⬍ 0.03), the greatest arteriole diameter (3-fold greater than PBS; P ⬍ 0.0002), and the greatest improvement in perfusion (P ⬍ 0.04). Immunohistochemical analysis revealed increases in GFP⫹ marrow-derived cells (by 5.5-fold) and CXCR4⫹ cells (by 3.8-fold) in sLeXtreated hindlimbs (P ⬍ 0.03) and a 70% decrease in apoptotic cells, compared to PBS (P ⫽ 0.02). GFP⫹ cells were not observed to differentiate into, or integrate into vasculature or myocytes. The frequency of regenerating myocytes, indicated by centralized nuclei, increased 6.7-fold with sLeX-matrix treatment (P ⫽ 0.02). Using a non-marrow transplant model, there were no differences in myogenic transcripts or regenerating myocytes at day 3 post-treatment. At 10 days, there were
4.2-fold more new myocytes with sLeX-matrix treatment (P ⫽ 0.01), combined with increases in local transcripts of Six1, M-Cadherin, Myf5, myogenin (P ⬍ 0.05), Pax7 and MyoD (P ⬍ 0.1), as measured by Q-PCR. CONCLUSION: In vitro, the matrix was able to enhance myogenesis in mES cells, suggesting its suitability for generating therapeutic muscle precursors for transplantation. In vivo, the sLeX-collagen matrix restores perfusion to ischemic tissue, associated with the formation of more arterioles of greater size, in addition to reducing local levels of apoptosis and improving muscle regeneration. Together, these results suggest that the application of sLeX-collagen matrix is a promising novel therapeutic option for the treatment of ischemic muscle, enhancing both the vasculogenic and myogenic repair processes without stem cell transplantation.
197 LONG-TERM OUTCOMES AFTER PERCUTANEOUS INTERVENTION OF THE INTERNAL THORACIC ARTERY ANASTOMOSIS: THE USE OF DRUG-ELUTING STENTS IS ASSOCIATED WITH A HIGHER REPEAT REVASCULARIZATION RATE X Freixa, M Carpen, MA Kotowycz, K Ho, A Krimly, CB Overgaard, PH Seidelin, V Dz˘avík Toronto, Ontario
There is currently a lack of data and absence of clear guideline recommendations regarding optimal treatment of lesions located at the anastomosis of the the internal thoracic artery (ITA). The objective of the present study was to assess the long-term outcomes of percutaneous coronary intervention (PCI) at the ITA anastomosis and to compare outcomes according to delivered treatment: deployment of a drug-eluting stent (DES), bare metal stent (BMS) or balloon angioplasty only (POBA). METHODS AND RESULTS: We used a prospective PCI registry at a large Canadian teaching hospital to identify all patients who underwent PCI at the ITA-CA anastomosis between June 2000 and June 2010. Our primary end point was repeat target lesion revascularization (TLR) at follow-up. Fifty three patients were included in the study (mean age 67.1 ⫾ 10.7; 84.9% males). Of these, PCI was successfully completed in 45 (84.9%). Twenty-three patients (51.1%) received DES, 18 (40%) BMS and 4 (8.9%) POBA. After a median follow-up of 29.2 months (range 11.1 to 77.7 months), TLR was 47.8% with DES, 7.1% with BMS, and 50% with POBA (P ⫽ 0.032). Patients who underwent repeat revascularization were more likely to have a longer stent length than those who did not (18.2 mm vs. 14.2 mm, P ⫽ 0.043). CONCLUSIONS: Deployment of a DES for the treatment of anastomotic lesions of the ITA appears to be associated with a higher rate of repeat revascularization compared to BMS. Further studies will be necessary to evaluate if the present results are an sporadic observation or might be a result of the different BACKGROUND: