Journal of cardiovascular pharmacology and therapeutics, 2006
Molecular biologic techniques have a variety of applications in the study of ischemic heart disea... more Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.
Molecular biologic techniques have a variety of applications in the study of ischemic heart disea... more Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness
Journal of cardiovascular pharmacology and therapeutics, 2004
Recently there has been considerable interest in the role of cyclooxygenase-2 (COX-2) in thrombos... more Recently there has been considerable interest in the role of cyclooxygenase-2 (COX-2) in thrombosis and myocardial infarction. A large number of clinical and basic studies have focused on whether COX-2 inhibitors can induce a prothrombotic disorder and increase the risk of cardiovascular thrombosis. This article reviews (1) the roles of COX-2 in the metabolism of prostaglandins; (2) the influence of COX-2 inhibition in the platelet aggregation and the antithrombotic function of vascular endothelium; (3) the roles of COX-2 inhibition in atherothrombosis; and (4) clinical trials that examine COX-2 inhibition in relationship to the risk of myocardial infarction. Based on the published data, this review suggests that COX-2 plays varying and sometimes conflicting roles in thrombogenesis, in prostaglandins' metabolism of endothelium in healthy or dysfunctional conditions, and in atherothrombosis. Future investigations under different pathologic conditions are needed to fully understan...
Stem cell transplantation provides a potential regenerative therapy for the heart damaged by myoc... more Stem cell transplantation provides a potential regenerative therapy for the heart damaged by myocardial infarction. Numerous scientific studies have been undertaken in animals and humans to analyze the safety and efficacy of this new approach. However, at the present time, the results have been mixed and inconclusive, and the mechanism of stem cell transplantation therapy remains unclear. This review discusses the controversies and problems that need to be addressed in future investigations.
AimsIdeally, mesenchymal stem cells (MSC) home to and/or remain at the site of damaged myocardium... more AimsIdeally, mesenchymal stem cells (MSC) home to and/or remain at the site of damaged myocardium when administered after myocardial infarction. However, MSC may not remain in the heart, but instead relocate to other areas. We investigated quantitatively the distribution of labeled rat MSC, given by two routes after coronary artery occlusion/reperfusion in rats.
Journal of cardiovascular pharmacology and therapeutics, 2003
Acetaminophen is widely prescribed as an analgesic agent in hospitals and clinics. However, aceta... more Acetaminophen is widely prescribed as an analgesic agent in hospitals and clinics. However, acetaminophen theoretically could influence myocardial infarct size by reducing prostaglandin synthesis in vivo. To date, the effect of acetaminophen on myocardial infarct size is unknown. The present study investigated (1) whether acetaminophen has any effect on myocardial infarct size when given in an analgesic dose and (2) whether acetaminophen can affect the cardioprotective effect of the early phase of ischemic preconditioning in rats. Female Sprague-Dawley rats were randomly assigned to four groups (n=12 each). Group 1 (no preconditioning): Vehicle (intravenous ethanol, 0.9 mL/kg) was given 39 minutes prior to ischemia. Group 2 (acetaminophen plus no preconditioning): intravenous acetaminophen (125 mg/kg) was given 39 minutes prior to ischemia. Group 3 (preconditioning): The heart was preconditioned before ischemia, and the vehicle (intravenous ethanol, 0.9 mL/kg) was given 39 minutes p...
Journal of cardiovascular pharmacology and therapeutics, 2014
Although preconditioning remains one of the most powerful maneuvers to reduce myocardial infarct ... more Although preconditioning remains one of the most powerful maneuvers to reduce myocardial infarct size, it is not feasible in the clinical setting to pretreat patients prior to acute myocardial infarction (MI). The purpose of this study was to investigate the effect of more clinically relevant therapies of remote perconditioning, postconditioning, and the combined effect of remote perconditioning and postconditioning on myocardial infarct size in an anesthetized rat model. Anesthetized rats were subjected to 45 minutes of proximal left coronary artery occlusion followed by 2 hours of reperfusion. Remote perconditioning was performed 5 minutes after left coronary occlusion with 4 cycles of 5 minutes of occlusion and reperfusion of both the femoral arteries. Postconditioning was applied immediately prior to 2 hours of full reperfusion with 6 cycles of 10 seconds occlusion-reperfusion of the coronary artery. The combined effect was produced by preceding the postconditioning regimen with...
To determine whether neonatal cardiomyocytes grafted into the aortic wall contract, develop press... more To determine whether neonatal cardiomyocytes grafted into the aortic wall contract, develop pressure, and can be paced. Medium only (n = 9) or neonatal cardiomyocytes (n = 12, 5 x 10(6) cells each) were injected into the outer aortic wall in adult female Fischer rats. At 6 weeks after implantation, 11 out of 12 cardiomyocyte-treated aortas showed spontaneous rhythmic beating at the grafted site following excision of the heart. The spontaneous beating rate changed with pacing frequency. Five out of the 11 beating aortas had intra-aortic pressure generated by the spontaneously contracting cardiomyocytes. The pulse pressure generated by the grafted cardiomyocytes was 0.36 +/- 0.05 mmHg without pacing; during pacing it was 0.78 +/- 0.21 mmHg with systolic pressure up to 3.8 mmHg. Hematoxylin and eosin staining showed viable grafts in the outer wall of the cardiomyocyte-treated aortas in 12 out of 12 aortas. Neonatal cardiomyocytes in the graft matured with cross striations. Immunohistoc...
Methods in molecular biology (Clifton, N.J.), 2010
As a novel potential therapeutic strategy for cardiac disease, cell transplantation therapy has b... more As a novel potential therapeutic strategy for cardiac disease, cell transplantation therapy has been extensively investigated in experimental studies and clinical trials. Although encouraging results have been demonstrated, a number of critical questions still remain to be answered. For example, what kind of stem cell and how many cells should be used; what is the best time for cell transplantation after acute myocardial infarction; which delivery approach is better, intravenous injection or direct intramyocardial injection? Transplantation of cells derived from human tissues into experimental animals may elicit an immune rejection. Immunodeficient nude rats provide a useful myocardial infarction model for cell transplantation therapy studies. We introduce our detailed methods of direct intramyocardial injection of immature heart cells and stem cells into the myocardial infarction region of rats and nude rats. Careful maintenance under aseptic conditions and proper surgical techniqu...
Recent experimental studies and clinical trials have demonstrated that cell transplantation thera... more Recent experimental studies and clinical trials have demonstrated that cell transplantation therapy has the potential to improve cardiac function after myocardial infarction. However, the mechanisms responsible for the observed therapeutic effects remain unknown. Different mechanisms have been proposed to explain the beneficial effects, including regeneration of contractile myocardial tissue, therapeutic neovascularization, prevention of left ventricular remodeling, release of paracrine growth
Morphological and functional development of implanted neonatal cardiac cells in the wall of the a... more Morphological and functional development of implanted neonatal cardiac cells in the wall of the abdominal aorta in rats was investigated. Cardiomyocytes from neonatal Fischer rats (both sexes) or medium were injected into the wall of the abdominal aorta in female Fischer rats (n=22 in each group). Two or 6 weeks later, the grafted site was exposed and fixed for histological and immunohistological examination. Polymerase chain reaction analysis of the SRY gene to identify male cells was performed in the treated aortas. Seven of 10 cell-treated aortas but none of 10 medium-treated aortas showed spontaneous rhythmic beating at the grafted site after excision of the heart at 2 weeks. Polymerase chain reaction of the SRY gene was positive in 3 cell-treated aortas and none of 3 medium-treated aortas at 6 weeks. Hematoxylin-and-eosin staining showed viable grafts in 9 of 10 aortas at 2 weeks and 9 of 9 aortas at 6 weeks in the cell-treated group but in none of the aortas receiving medium. ...
Cellular cardiomyoplasty is a promising approach for rebuilding scar tissue after acute myocardia... more Cellular cardiomyoplasty is a promising approach for rebuilding scar tissue after acute myocardial infarction. However, the angiogenic potential of transplanted immature cardiomyocytes and their effect on regional myocardial blood flow (RMBF) after coronary artery occlusion remain to be evaluated. Intramyocardial injection of cultured neonatal cardiomyocytes (4 x 10(6) cells/50-70 microliter) into the scar 1 week after permanent coronary occlusion in rats resulted in improved RMBF in the infarct 4 weeks after transplantation (radioactive microspheres, 0.97 +/- 0.18 ml/min/g) in comparison to medium-injected hearts (0.61 +/- 0.11 ml/min/g, P < 0.047). The macroscopic perfusion defect after in vivo staining with the blue dye 50% Uniperse blue was significantly smaller in the cell transplantation group (1.5 +/- 0.3% of the heart) compared to the medium group (3.0 +/- 0.6%, P < 0.017). Clusters of engrafted cells within the scar demonstrated a high capillary density (1217 +/- 114 perfused (blue) capillaries/mm(2)); however, in the scar tissue itself capillary density in the cell group (156 +/- 62/mm(2)) did not significantly differ from the medium group (125 +/- 10/mm(2)), suggesting that neo-angiogenesis was confined to regions of successful engraftment (non-infarcted tissue: 1924 +/- 114 perfused capillaries/mm(2)). The transplantation group was characterized by smaller diastolic and systolic left ventricular volumes, as assessed by intravenous ventriculography, along with thickened infarcts (0.93 +/- 0.07 vs. 0.75 +/- 0.04 mm, P < 0.020) and lower infarct expansion indices (0.64 +/- 0.07 vs. 0.83 +/- 0.06, P < 0.023), as determined by post-mortem morphometry of histologic slides. Transplantation of neonatal cardiomyocytes induced neo-angiogenesis in zones of successful cell engraftment within the scar, which effectively enhanced tissue perfusion.
Journal of cardiovascular pharmacology and therapeutics, 2006
Molecular biologic techniques have a variety of applications in the study of ischemic heart disea... more Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.
Molecular biologic techniques have a variety of applications in the study of ischemic heart disea... more Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness
Journal of cardiovascular pharmacology and therapeutics, 2004
Recently there has been considerable interest in the role of cyclooxygenase-2 (COX-2) in thrombos... more Recently there has been considerable interest in the role of cyclooxygenase-2 (COX-2) in thrombosis and myocardial infarction. A large number of clinical and basic studies have focused on whether COX-2 inhibitors can induce a prothrombotic disorder and increase the risk of cardiovascular thrombosis. This article reviews (1) the roles of COX-2 in the metabolism of prostaglandins; (2) the influence of COX-2 inhibition in the platelet aggregation and the antithrombotic function of vascular endothelium; (3) the roles of COX-2 inhibition in atherothrombosis; and (4) clinical trials that examine COX-2 inhibition in relationship to the risk of myocardial infarction. Based on the published data, this review suggests that COX-2 plays varying and sometimes conflicting roles in thrombogenesis, in prostaglandins' metabolism of endothelium in healthy or dysfunctional conditions, and in atherothrombosis. Future investigations under different pathologic conditions are needed to fully understan...
Stem cell transplantation provides a potential regenerative therapy for the heart damaged by myoc... more Stem cell transplantation provides a potential regenerative therapy for the heart damaged by myocardial infarction. Numerous scientific studies have been undertaken in animals and humans to analyze the safety and efficacy of this new approach. However, at the present time, the results have been mixed and inconclusive, and the mechanism of stem cell transplantation therapy remains unclear. This review discusses the controversies and problems that need to be addressed in future investigations.
AimsIdeally, mesenchymal stem cells (MSC) home to and/or remain at the site of damaged myocardium... more AimsIdeally, mesenchymal stem cells (MSC) home to and/or remain at the site of damaged myocardium when administered after myocardial infarction. However, MSC may not remain in the heart, but instead relocate to other areas. We investigated quantitatively the distribution of labeled rat MSC, given by two routes after coronary artery occlusion/reperfusion in rats.
Journal of cardiovascular pharmacology and therapeutics, 2003
Acetaminophen is widely prescribed as an analgesic agent in hospitals and clinics. However, aceta... more Acetaminophen is widely prescribed as an analgesic agent in hospitals and clinics. However, acetaminophen theoretically could influence myocardial infarct size by reducing prostaglandin synthesis in vivo. To date, the effect of acetaminophen on myocardial infarct size is unknown. The present study investigated (1) whether acetaminophen has any effect on myocardial infarct size when given in an analgesic dose and (2) whether acetaminophen can affect the cardioprotective effect of the early phase of ischemic preconditioning in rats. Female Sprague-Dawley rats were randomly assigned to four groups (n=12 each). Group 1 (no preconditioning): Vehicle (intravenous ethanol, 0.9 mL/kg) was given 39 minutes prior to ischemia. Group 2 (acetaminophen plus no preconditioning): intravenous acetaminophen (125 mg/kg) was given 39 minutes prior to ischemia. Group 3 (preconditioning): The heart was preconditioned before ischemia, and the vehicle (intravenous ethanol, 0.9 mL/kg) was given 39 minutes p...
Journal of cardiovascular pharmacology and therapeutics, 2014
Although preconditioning remains one of the most powerful maneuvers to reduce myocardial infarct ... more Although preconditioning remains one of the most powerful maneuvers to reduce myocardial infarct size, it is not feasible in the clinical setting to pretreat patients prior to acute myocardial infarction (MI). The purpose of this study was to investigate the effect of more clinically relevant therapies of remote perconditioning, postconditioning, and the combined effect of remote perconditioning and postconditioning on myocardial infarct size in an anesthetized rat model. Anesthetized rats were subjected to 45 minutes of proximal left coronary artery occlusion followed by 2 hours of reperfusion. Remote perconditioning was performed 5 minutes after left coronary occlusion with 4 cycles of 5 minutes of occlusion and reperfusion of both the femoral arteries. Postconditioning was applied immediately prior to 2 hours of full reperfusion with 6 cycles of 10 seconds occlusion-reperfusion of the coronary artery. The combined effect was produced by preceding the postconditioning regimen with...
To determine whether neonatal cardiomyocytes grafted into the aortic wall contract, develop press... more To determine whether neonatal cardiomyocytes grafted into the aortic wall contract, develop pressure, and can be paced. Medium only (n = 9) or neonatal cardiomyocytes (n = 12, 5 x 10(6) cells each) were injected into the outer aortic wall in adult female Fischer rats. At 6 weeks after implantation, 11 out of 12 cardiomyocyte-treated aortas showed spontaneous rhythmic beating at the grafted site following excision of the heart. The spontaneous beating rate changed with pacing frequency. Five out of the 11 beating aortas had intra-aortic pressure generated by the spontaneously contracting cardiomyocytes. The pulse pressure generated by the grafted cardiomyocytes was 0.36 +/- 0.05 mmHg without pacing; during pacing it was 0.78 +/- 0.21 mmHg with systolic pressure up to 3.8 mmHg. Hematoxylin and eosin staining showed viable grafts in the outer wall of the cardiomyocyte-treated aortas in 12 out of 12 aortas. Neonatal cardiomyocytes in the graft matured with cross striations. Immunohistoc...
Methods in molecular biology (Clifton, N.J.), 2010
As a novel potential therapeutic strategy for cardiac disease, cell transplantation therapy has b... more As a novel potential therapeutic strategy for cardiac disease, cell transplantation therapy has been extensively investigated in experimental studies and clinical trials. Although encouraging results have been demonstrated, a number of critical questions still remain to be answered. For example, what kind of stem cell and how many cells should be used; what is the best time for cell transplantation after acute myocardial infarction; which delivery approach is better, intravenous injection or direct intramyocardial injection? Transplantation of cells derived from human tissues into experimental animals may elicit an immune rejection. Immunodeficient nude rats provide a useful myocardial infarction model for cell transplantation therapy studies. We introduce our detailed methods of direct intramyocardial injection of immature heart cells and stem cells into the myocardial infarction region of rats and nude rats. Careful maintenance under aseptic conditions and proper surgical techniqu...
Recent experimental studies and clinical trials have demonstrated that cell transplantation thera... more Recent experimental studies and clinical trials have demonstrated that cell transplantation therapy has the potential to improve cardiac function after myocardial infarction. However, the mechanisms responsible for the observed therapeutic effects remain unknown. Different mechanisms have been proposed to explain the beneficial effects, including regeneration of contractile myocardial tissue, therapeutic neovascularization, prevention of left ventricular remodeling, release of paracrine growth
Morphological and functional development of implanted neonatal cardiac cells in the wall of the a... more Morphological and functional development of implanted neonatal cardiac cells in the wall of the abdominal aorta in rats was investigated. Cardiomyocytes from neonatal Fischer rats (both sexes) or medium were injected into the wall of the abdominal aorta in female Fischer rats (n=22 in each group). Two or 6 weeks later, the grafted site was exposed and fixed for histological and immunohistological examination. Polymerase chain reaction analysis of the SRY gene to identify male cells was performed in the treated aortas. Seven of 10 cell-treated aortas but none of 10 medium-treated aortas showed spontaneous rhythmic beating at the grafted site after excision of the heart at 2 weeks. Polymerase chain reaction of the SRY gene was positive in 3 cell-treated aortas and none of 3 medium-treated aortas at 6 weeks. Hematoxylin-and-eosin staining showed viable grafts in 9 of 10 aortas at 2 weeks and 9 of 9 aortas at 6 weeks in the cell-treated group but in none of the aortas receiving medium. ...
Cellular cardiomyoplasty is a promising approach for rebuilding scar tissue after acute myocardia... more Cellular cardiomyoplasty is a promising approach for rebuilding scar tissue after acute myocardial infarction. However, the angiogenic potential of transplanted immature cardiomyocytes and their effect on regional myocardial blood flow (RMBF) after coronary artery occlusion remain to be evaluated. Intramyocardial injection of cultured neonatal cardiomyocytes (4 x 10(6) cells/50-70 microliter) into the scar 1 week after permanent coronary occlusion in rats resulted in improved RMBF in the infarct 4 weeks after transplantation (radioactive microspheres, 0.97 +/- 0.18 ml/min/g) in comparison to medium-injected hearts (0.61 +/- 0.11 ml/min/g, P < 0.047). The macroscopic perfusion defect after in vivo staining with the blue dye 50% Uniperse blue was significantly smaller in the cell transplantation group (1.5 +/- 0.3% of the heart) compared to the medium group (3.0 +/- 0.6%, P < 0.017). Clusters of engrafted cells within the scar demonstrated a high capillary density (1217 +/- 114 perfused (blue) capillaries/mm(2)); however, in the scar tissue itself capillary density in the cell group (156 +/- 62/mm(2)) did not significantly differ from the medium group (125 +/- 10/mm(2)), suggesting that neo-angiogenesis was confined to regions of successful engraftment (non-infarcted tissue: 1924 +/- 114 perfused capillaries/mm(2)). The transplantation group was characterized by smaller diastolic and systolic left ventricular volumes, as assessed by intravenous ventriculography, along with thickened infarcts (0.93 +/- 0.07 vs. 0.75 +/- 0.04 mm, P < 0.020) and lower infarct expansion indices (0.64 +/- 0.07 vs. 0.83 +/- 0.06, P < 0.023), as determined by post-mortem morphometry of histologic slides. Transplantation of neonatal cardiomyocytes induced neo-angiogenesis in zones of successful cell engraftment within the scar, which effectively enhanced tissue perfusion.
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Papers by Robert Kloner