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Treatment with granulocyte colony stimulating factor in a mouse model of chronic chagasic cardiomyopathy
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Abstracts / Cardiovascular Revascularization Medicine 8 (2007) 116 – 154
Evaluation of therapeutic potential of umbilical cord blood mononuclear cells on an experimental model of acute myocardial infarction ACV Maia, V Pinho-Ribeiro, JPS Werneck de Castro, PF Oliveira, RH Costa e Souza, JS Nascimento, DB Mello, RCS Goldenberg, AC Campos de Carvalho Laborato´rio de Cardiologia Celular e Molecular, Instituto de Biofı´sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil
Introduction: Human umbilical cord mononuclear cells (HUCBC) contain progenitor cells that can potentially differentiate into capillaries and cardiomyocytes in vitro. Objective: To evaluate the efficacy of HUCBC intramyocardial transplantation (im) on an experimental model of acute infarction (AMI) by permanent left anterior descending coronary artery ligation. Methods: Wistar rats were submitted to AMI. Infarction was confirmed by echo- and electrocardiogram exams. After 3 h, cells were labeled and injected into contracting wall bordering the infarction. Three weeks later, ECG, echocardiographic, and hemodynamic parameters [left ventricular developed pressure (LVDP), dP/dT max, and dP/dT min] and oxygen consumption (VO2) were determined in each group. The animals were divided into three groups: (1) infarcted+im-HUCBC (n=7), (2) infarcted+im-saline (n=6), and (3) sham group (n=7). Results: At the third week, both infarcted groups (1 and 2) exhibited impaired cardiac function compared to the sham group: LVEDD 8.9F0.6 and 8.8F0.4 vs. 6.6F0.6 mm, SF% 20.1F5.6 and 21.2F2.3 vs. 57.7F15%. The HUCBC group had an electrocardiographic pattern similar to the saline group (QRS N908). An index of myocardial contractility, (dP/ dT max), was not statistically different between cell and saline-treated groups, but both were significantly different from the sham-operated group (5484F875 vs. 5739F666 vs. 8119F864 mm Hg/min, respectively). The same result was observed with dP/dT min (index of myocardial relaxation) and LVDP: 3921F637 vs. 4202F455 vs. 6200F645 mm Hg/min and 91.6F18.4 vs. 90.7F12 vs. 129F16 mm Hg, respectively. Moreover, no measured cardiac functional parameters were statistically different between the two infarcted groups under resting conditions as well as after treadmill exercise stress test (VO2 24.8F5.0 for Group 1 and 22.9F5.0 for Group 2 vs. 40.5F6.4 ml/kg per minute for Group 3). Conclusion: Our findings show that local transplantation of HUCBC 3 h after infarction does not improve heart function in a rat model of AMI. doi:10.1016/j.carrev.2007.03.117
Treatment with granulocyte colony stimulating factor in a mouse model of chronic chagasic cardiomyopathyB R Dos Santosa,b, SG Macambiraa, RS Limaa, JF Senraa, C Costaa, P Guimaraesa, M Soaresa,b a Centro de Pesquisas Gonc¸alo Moniz, Fundac¸a˜o Oswaldo Cruz, Salvador, Ba, Brazil b Hospital Sa˜o Rafael, Salvador, BA, Brazil
Introduction: Chagas’ disease, caused by Trypanosoma cruzi infection, is one of the main causes of death due to heart failure in Latin American countries. About one fourth of infected individuals develop chronic cardiomyopathy, the most severe form of the disease. The unique treatment available for patients with severe heart failure is heart transplantation. Stem cell-based therapy is currently being investigated as a treatment for heart failure, including for Chagas’ disease. An alternative to stem cell transplantation is the use of growth factors to mobilize bone marrow cells to the periphery. In this work, we investigated the effects of G-CSF administration in our experimental model of chronic chagasic cardiomyopathy. Methods: We used a well-established model of chronic chagasic cardiomyopathy in C57Bl/6 mice inoculated with 1000 trypomastigotes of the Colombian strain of T. cruzi. Three different experimental groups were analyzed. The first one without treatment, the second treated with
human recombinant G-CSF administered in a dose of 200 Ag/kg per day during 5 consecutive days (one cycle of treatment) and the third one treated with three cycles of G-CSF administration. We started functional and histopathological analysis 2 months after the end of treatment. We performed functional analysis by ECG recording in all experimental groups with animals under anesthesia (xilasine and ketamine). Data were stored for analysis using Chart 5 software for evaluation of physiological parameters. Histopathological evaluation was done by morphometry studies in order to quantify the number of inflammatory cells by light microscopy in sections stained with standard hematoxylin and eosin. The fibrotic area was evaluated after Sirius red staining. Morphometric analyses were carried out using the Image Pro Program to integrate the areas of fibrotic and nonfibrotic tissue in each field. Results: In the group treated with three cycles of G-CSF, the reduction in fibrotic area was 73% and the number of inflammatory cells was diminished in 38% compared to control mice. In the group treated with one cycle of GCSF administration, a discrete reduction in fibrosis (13%) was found, but no alteration in the degree of inflammation was observed. All chronic chagasic mice had cardiac electrical disturbances that included atrioventricular blockage, intraventricular conduction disturbances and abnormal cardiac rhythm before treatment. The functional analysis by ECG did not reveal any improvement in cardiac electrogenesis 2 months after treatment. Conclusion: Treatment with G-CSF decreases inflammation and fibrosis in chronic chagasic mice. This effect, however, did not reflect a reversion of cardiac electrical disturbances characteristic of chronic chagasic cardiomyopathy. doi:10.1016/j.carrev.2007.03.118 B
Financial support: FIOCRUZ, CNPq/MCT, NIH grant HL073732-01.
Can dipyridamole replace aspirin and clopidogrel for DES patients undergoing noncardiac surgery? A Magd, H Ragy, M Elkhadem Ahar University and NHI, Cairo, Egypt
Background: The number of patients undergoing PCI using a drug-eluting stent has mushroomed dramatically with the estimated number of patients worldwide in the millions. Most of these patients will receive prolonged dual antiplatelet therapy in the form of aspirin and clopidogrel for 1–2 years due to the fear of potential late stent thrombosis. Unfortunately, a significant percentage of these patients end up needing some form of noncardiac surgery requiring discontinuation of all antiplatelet drugs preoperatively, with the heightened potential for sudden stent thrombosis. Dipyridamole is a weak antiplatelet agent but may be more effective on nonbiologic surfaces. Thus, it may be useful in these circumstances. Methods: Twenty-two consecutive patients with a history of a drug-eluting stent implanted within 10 months, who required a noncardiac surgical procedure requiring discontinuation of their ASA and clopidogrel, were treated with dipyridamole 150 mg TID for at least 5 days preprocedure, while the ASA and clopidogrel were stopped for at least 5 days. Both antiplatelet agents were restarted postprocedure (mean=2 days). Platelet aggregation was measured in 14 patients just before stopping ASA and clopidogrel and then again on the day of the procedure with only dipyridamole on board (mean=5 days). This was done with an optical aggregometer using ADP 5 and 10 mM, and collagen as inductors. Also, the level of soluble P-selectin was measured. Results: During the hospital stay, all patients had an uneventful surgical procedure with no cases of stent thrombosis at a mean of 4 months’ follow-up postprocedure. There were no cases of excess surgical bleeding noted. The level of maximal thrombocyte aggregation values returned to near normal levels by the fifth day as did the P selectin with no apparent effect of the dipyridamole. Conclusion: Dipyridamole at a dose of 150 mg TID may be a potentially safe and effective substitute for DES patients requiring discontinuation of both ASA and clopidogrel for a noncardiac surgical procedure. The exact
Abstracts / Cardiovascular Revascularization Medicine 8 (2007) 116 – 154
Evaluation of therapeutic potential of umbilical cord blood mononuclear cells on an experimental model of acute myocardial infarction ACV Maia, V Pinho-Ribeiro, JPS Werneck de Castro, PF Oliveira, RH Costa e Souza, JS Nascimento, DB Mello, RCS Goldenberg, AC Campos de Carvalho Laborato´rio de Cardiologia Celular e Molecular, Instituto de Biofı´sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil
Introduction: Human umbilical cord mononuclear cells (HUCBC) contain progenitor cells that can potentially differentiate into capillaries and cardiomyocytes in vitro. Objective: To evaluate the efficacy of HUCBC intramyocardial transplantation (im) on an experimental model of acute infarction (AMI) by permanent left anterior descending coronary artery ligation. Methods: Wistar rats were submitted to AMI. Infarction was confirmed by echo- and electrocardiogram exams. After 3 h, cells were labeled and injected into contracting wall bordering the infarction. Three weeks later, ECG, echocardiographic, and hemodynamic parameters [left ventricular developed pressure (LVDP), dP/dT max, and dP/dT min] and oxygen consumption (VO2) were determined in each group. The animals were divided into three groups: (1) infarcted+im-HUCBC (n=7), (2) infarcted+im-saline (n=6), and (3) sham group (n=7). Results: At the third week, both infarcted groups (1 and 2) exhibited impaired cardiac function compared to the sham group: LVEDD 8.9F0.6 and 8.8F0.4 vs. 6.6F0.6 mm, SF% 20.1F5.6 and 21.2F2.3 vs. 57.7F15%. The HUCBC group had an electrocardiographic pattern similar to the saline group (QRS N908). An index of myocardial contractility, (dP/ dT max), was not statistically different between cell and saline-treated groups, but both were significantly different from the sham-operated group (5484F875 vs. 5739F666 vs. 8119F864 mm Hg/min, respectively). The same result was observed with dP/dT min (index of myocardial relaxation) and LVDP: 3921F637 vs. 4202F455 vs. 6200F645 mm Hg/min and 91.6F18.4 vs. 90.7F12 vs. 129F16 mm Hg, respectively. Moreover, no measured cardiac functional parameters were statistically different between the two infarcted groups under resting conditions as well as after treadmill exercise stress test (VO2 24.8F5.0 for Group 1 and 22.9F5.0 for Group 2 vs. 40.5F6.4 ml/kg per minute for Group 3). Conclusion: Our findings show that local transplantation of HUCBC 3 h after infarction does not improve heart function in a rat model of AMI. doi:10.1016/j.carrev.2007.03.117
Treatment with granulocyte colony stimulating factor in a mouse model of chronic chagasic cardiomyopathyB R Dos Santosa,b, SG Macambiraa, RS Limaa, JF Senraa, C Costaa, P Guimaraesa, M Soaresa,b a Centro de Pesquisas Gonc¸alo Moniz, Fundac¸a˜o Oswaldo Cruz, Salvador, Ba, Brazil b Hospital Sa˜o Rafael, Salvador, BA, Brazil
Introduction: Chagas’ disease, caused by Trypanosoma cruzi infection, is one of the main causes of death due to heart failure in Latin American countries. About one fourth of infected individuals develop chronic cardiomyopathy, the most severe form of the disease. The unique treatment available for patients with severe heart failure is heart transplantation. Stem cell-based therapy is currently being investigated as a treatment for heart failure, including for Chagas’ disease. An alternative to stem cell transplantation is the use of growth factors to mobilize bone marrow cells to the periphery. In this work, we investigated the effects of G-CSF administration in our experimental model of chronic chagasic cardiomyopathy. Methods: We used a well-established model of chronic chagasic cardiomyopathy in C57Bl/6 mice inoculated with 1000 trypomastigotes of the Colombian strain of T. cruzi. Three different experimental groups were analyzed. The first one without treatment, the second treated with
human recombinant G-CSF administered in a dose of 200 Ag/kg per day during 5 consecutive days (one cycle of treatment) and the third one treated with three cycles of G-CSF administration. We started functional and histopathological analysis 2 months after the end of treatment. We performed functional analysis by ECG recording in all experimental groups with animals under anesthesia (xilasine and ketamine). Data were stored for analysis using Chart 5 software for evaluation of physiological parameters. Histopathological evaluation was done by morphometry studies in order to quantify the number of inflammatory cells by light microscopy in sections stained with standard hematoxylin and eosin. The fibrotic area was evaluated after Sirius red staining. Morphometric analyses were carried out using the Image Pro Program to integrate the areas of fibrotic and nonfibrotic tissue in each field. Results: In the group treated with three cycles of G-CSF, the reduction in fibrotic area was 73% and the number of inflammatory cells was diminished in 38% compared to control mice. In the group treated with one cycle of GCSF administration, a discrete reduction in fibrosis (13%) was found, but no alteration in the degree of inflammation was observed. All chronic chagasic mice had cardiac electrical disturbances that included atrioventricular blockage, intraventricular conduction disturbances and abnormal cardiac rhythm before treatment. The functional analysis by ECG did not reveal any improvement in cardiac electrogenesis 2 months after treatment. Conclusion: Treatment with G-CSF decreases inflammation and fibrosis in chronic chagasic mice. This effect, however, did not reflect a reversion of cardiac electrical disturbances characteristic of chronic chagasic cardiomyopathy. doi:10.1016/j.carrev.2007.03.118 B
Financial support: FIOCRUZ, CNPq/MCT, NIH grant HL073732-01.
Can dipyridamole replace aspirin and clopidogrel for DES patients undergoing noncardiac surgery? A Magd, H Ragy, M Elkhadem Ahar University and NHI, Cairo, Egypt
Background: The number of patients undergoing PCI using a drug-eluting stent has mushroomed dramatically with the estimated number of patients worldwide in the millions. Most of these patients will receive prolonged dual antiplatelet therapy in the form of aspirin and clopidogrel for 1–2 years due to the fear of potential late stent thrombosis. Unfortunately, a significant percentage of these patients end up needing some form of noncardiac surgery requiring discontinuation of all antiplatelet drugs preoperatively, with the heightened potential for sudden stent thrombosis. Dipyridamole is a weak antiplatelet agent but may be more effective on nonbiologic surfaces. Thus, it may be useful in these circumstances. Methods: Twenty-two consecutive patients with a history of a drug-eluting stent implanted within 10 months, who required a noncardiac surgical procedure requiring discontinuation of their ASA and clopidogrel, were treated with dipyridamole 150 mg TID for at least 5 days preprocedure, while the ASA and clopidogrel were stopped for at least 5 days. Both antiplatelet agents were restarted postprocedure (mean=2 days). Platelet aggregation was measured in 14 patients just before stopping ASA and clopidogrel and then again on the day of the procedure with only dipyridamole on board (mean=5 days). This was done with an optical aggregometer using ADP 5 and 10 mM, and collagen as inductors. Also, the level of soluble P-selectin was measured. Results: During the hospital stay, all patients had an uneventful surgical procedure with no cases of stent thrombosis at a mean of 4 months’ follow-up postprocedure. There were no cases of excess surgical bleeding noted. The level of maximal thrombocyte aggregation values returned to near normal levels by the fifth day as did the P selectin with no apparent effect of the dipyridamole. Conclusion: Dipyridamole at a dose of 150 mg TID may be a potentially safe and effective substitute for DES patients requiring discontinuation of both ASA and clopidogrel for a noncardiac surgical procedure. The exact