A 47-year-old man with severe radiation-induced aortic stenosis was rejected for cardiac surgery ... more A 47-year-old man with severe radiation-induced aortic stenosis was rejected for cardiac surgery because of porcelain aorta. We successfully implanted an Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA), but the patient was readmitted 3 weeks later for heart failure with a continuous murmur on auscultation. Echocardiography showed a small defect between the aorta and the infundibulum of the right ventricle, which was also confirmed with aortography and computed tomography. Medical therapy was optimized; however, he died unexpectedly a few weeks later. We concluded that irradiated tissues are particularly fragile and require specific attention during transcatheter aortic valve implantation. Furthermore, this case suggests that a more aggressive closure should have been applied.
Background: Coronary artery by-pass graft surgery is the treatment of choice for patient with mut... more Background: Coronary artery by-pass graft surgery is the treatment of choice for patient with mutivessel disease. This is a palliative therapy in which risk factors must be controlled to prevent ischemic heart disease resurgence and ischemic heart failure. The goal of our study was to evaluate prematurely the outcome of cardiovascular risk factors after CABG, and to adjust an aggressive
The incidence of peripheral arterial disease is rising and despite advances in clinical managemen... more The incidence of peripheral arterial disease is rising and despite advances in clinical management, many problems remain unsolved. Better knowledge of the mechanisms and consequences associated with chronic muscle ischemia has opened the way for development of new treatment strategies, including therapeutic angiogenesis. Therapeutic angiogenesis is a promising technique based on experimental studies showing that growth factors or genes able to increase capillary density can be used to reduce the impact of muscle ischemia and increase blood flow to ischemic tissue. Enthusiasm for this technique has prompted numerous clinical trials with encouraging results, but data are still inconclusive. Optimal indications for gene therapy must be defined and further experimental progress is needed to respond to ethical issues. Therapeutic angiogenesis should be viewed as an adjunct to rather than as a competitor of current surgical revascularization techniques.
Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled ... more Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI). Methods and Results—We demonstrated an upregulation of sFRP-1 and distinct
Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled ... more Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI). Methods and Results—We demonstrated an upregulation of sFRP-1 and distinct
Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percu... more Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percutaneous coronary intervention. We now report on the immunologic origin of thrombocytopenia developing between 7 and 12 days after the onset of abciximab infusion. Antibodies directed against abciximabcoated platelets were located in 5 patients with delayed thrombocytopenia, just as they were present in a patient whose platelet count fell within a few hours after receiving the drug. Abciximab-dependent IgG antibody was revealed in serum using control platelets in the monoclonal antibody immobilization of platelet antigens assay (MAIPA) performed with SZ22, a MoAb to GPIIb. The presence of IgG antibodies specific for platelets sensitized with abciximab was confirmed by flow cytometry. They were not located in 13 patients receiving abciximab but whose platelet counts remained stable. For three patients, antibodies were transient and their presence related to the extent of the thrombocytopenia. Surprisingly, antibodycontaining plasma from three patients induced abciximabdependent activation and aggregation of normal platelets, a finding confirmed by electron microscopy. Immunogold labeling revealed that abciximab was associated with platelets in the aggregate, suggesting that its inhibitory effect was overcome by the platelet stimulation. In summary, these results show that abciximab-dependent thrombocytopenia can be delayed and potentially prothrombotic.
Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percu... more Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percutaneous coronary intervention. We now report on the immunologic origin of thrombocytopenia developing between 7 and 12 days after the onset of abciximab infusion. Antibodies directed against abciximabcoated platelets were located in 5 patients with delayed thrombocytopenia, just as they were present in a patient whose platelet count fell within a few hours after receiving the drug. Abciximab-dependent IgG antibody was revealed in serum using control platelets in the monoclonal antibody immobilization of platelet antigens assay (MAIPA) performed with SZ22, a MoAb to GPIIb. The presence of IgG antibodies specific for platelets sensitized with abciximab was confirmed by flow cytometry. They were not located in 13 patients receiving abciximab but whose platelet counts remained stable. For three patients, antibodies were transient and their presence related to the extent of the thrombocytopenia. Surprisingly, antibodycontaining plasma from three patients induced abciximabdependent activation and aggregation of normal platelets, a finding confirmed by electron microscopy. Immunogold labeling revealed that abciximab was associated with platelets in the aggregate, suggesting that its inhibitory effect was overcome by the platelet stimulation. In summary, these results show that abciximab-dependent thrombocytopenia can be delayed and potentially prothrombotic.
Mesenchymal stem cell (MSC) transplantation offers a great angiogenic opportunity in vascular reg... more Mesenchymal stem cell (MSC) transplantation offers a great angiogenic opportunity in vascular regenerative medicine. The canonical Wnt/beta-catenin signaling pathway has been demonstrated to play an essential role in stem cell fate. Recently, genetic studies have implicated the Wnt/Frizzled (Fz) molecular pathway, namely Wnt7B and Fz4, in blood growth regulation. Here, we investigated whether MSC could be required in shaping a functional vasculature and whether secreted Frizzled-related protein-1 (sFRP1), a modulator of the Wnt/Fz pathway, could modify MSC capacities, endowing MSC to increase vessel maturation. In the engraftment model, we show that murine bone marrow-derived MSC induced a beneficial vascular effect through a direct cellular contribution to vascular cells. MSC quickly organized into primitive immature vessel tubes connected to host circulation; this organization preceded host endothelial cell (EC) and smooth muscle cell (SMC) recruitment to later form mature neovessel. MSC sustained neovessel organization and maturation. We report here that sFRP1 forced expression enhanced MSC surrounding neovessel, which was correlated with an increase in vessel maturation and functionality. In vitro, sFRP1 strongly increased platelet-derived growth factor-BB (PDGF-BB) expression in MSC and enhanced beta-catenin-dependent cell-cell contacts between MSC themselves and EC or SMC. In vivo, sFRP1 increased their functional integration around neovessels and vessel maturation through a glycogen synthase kinase 3 beta (GSK3beta)-dependent pathway. sFRP1-overexpressing MSC compared with control MSC were well elongated and in a closer contact with the vascular wall, conditions required to achieve an organized mature vessel wall. We propose that genetically modifying MSC to overexpress sFRP1 may be potentially effective in promoting therapeutic angiogenesis/arteriogenesis processes. Disclosure of potential conflicts of interest is found at the end of this article.
A 47-year-old man with severe radiation-induced aortic stenosis was rejected for cardiac surgery ... more A 47-year-old man with severe radiation-induced aortic stenosis was rejected for cardiac surgery because of porcelain aorta. We successfully implanted an Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA), but the patient was readmitted 3 weeks later for heart failure with a continuous murmur on auscultation. Echocardiography showed a small defect between the aorta and the infundibulum of the right ventricle, which was also confirmed with aortography and computed tomography. Medical therapy was optimized; however, he died unexpectedly a few weeks later. We concluded that irradiated tissues are particularly fragile and require specific attention during transcatheter aortic valve implantation. Furthermore, this case suggests that a more aggressive closure should have been applied.
Background: Coronary artery by-pass graft surgery is the treatment of choice for patient with mut... more Background: Coronary artery by-pass graft surgery is the treatment of choice for patient with mutivessel disease. This is a palliative therapy in which risk factors must be controlled to prevent ischemic heart disease resurgence and ischemic heart failure. The goal of our study was to evaluate prematurely the outcome of cardiovascular risk factors after CABG, and to adjust an aggressive
The incidence of peripheral arterial disease is rising and despite advances in clinical managemen... more The incidence of peripheral arterial disease is rising and despite advances in clinical management, many problems remain unsolved. Better knowledge of the mechanisms and consequences associated with chronic muscle ischemia has opened the way for development of new treatment strategies, including therapeutic angiogenesis. Therapeutic angiogenesis is a promising technique based on experimental studies showing that growth factors or genes able to increase capillary density can be used to reduce the impact of muscle ischemia and increase blood flow to ischemic tissue. Enthusiasm for this technique has prompted numerous clinical trials with encouraging results, but data are still inconclusive. Optimal indications for gene therapy must be defined and further experimental progress is needed to respond to ethical issues. Therapeutic angiogenesis should be viewed as an adjunct to rather than as a competitor of current surgical revascularization techniques.
Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled ... more Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI). Methods and Results—We demonstrated an upregulation of sFRP-1 and distinct
Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled ... more Background—FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI). Methods and Results—We demonstrated an upregulation of sFRP-1 and distinct
Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percu... more Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percutaneous coronary intervention. We now report on the immunologic origin of thrombocytopenia developing between 7 and 12 days after the onset of abciximab infusion. Antibodies directed against abciximabcoated platelets were located in 5 patients with delayed thrombocytopenia, just as they were present in a patient whose platelet count fell within a few hours after receiving the drug. Abciximab-dependent IgG antibody was revealed in serum using control platelets in the monoclonal antibody immobilization of platelet antigens assay (MAIPA) performed with SZ22, a MoAb to GPIIb. The presence of IgG antibodies specific for platelets sensitized with abciximab was confirmed by flow cytometry. They were not located in 13 patients receiving abciximab but whose platelet counts remained stable. For three patients, antibodies were transient and their presence related to the extent of the thrombocytopenia. Surprisingly, antibodycontaining plasma from three patients induced abciximabdependent activation and aggregation of normal platelets, a finding confirmed by electron microscopy. Immunogold labeling revealed that abciximab was associated with platelets in the aggregate, suggesting that its inhibitory effect was overcome by the platelet stimulation. In summary, these results show that abciximab-dependent thrombocytopenia can be delayed and potentially prothrombotic.
Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percu... more Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percutaneous coronary intervention. We now report on the immunologic origin of thrombocytopenia developing between 7 and 12 days after the onset of abciximab infusion. Antibodies directed against abciximabcoated platelets were located in 5 patients with delayed thrombocytopenia, just as they were present in a patient whose platelet count fell within a few hours after receiving the drug. Abciximab-dependent IgG antibody was revealed in serum using control platelets in the monoclonal antibody immobilization of platelet antigens assay (MAIPA) performed with SZ22, a MoAb to GPIIb. The presence of IgG antibodies specific for platelets sensitized with abciximab was confirmed by flow cytometry. They were not located in 13 patients receiving abciximab but whose platelet counts remained stable. For three patients, antibodies were transient and their presence related to the extent of the thrombocytopenia. Surprisingly, antibodycontaining plasma from three patients induced abciximabdependent activation and aggregation of normal platelets, a finding confirmed by electron microscopy. Immunogold labeling revealed that abciximab was associated with platelets in the aggregate, suggesting that its inhibitory effect was overcome by the platelet stimulation. In summary, these results show that abciximab-dependent thrombocytopenia can be delayed and potentially prothrombotic.
Mesenchymal stem cell (MSC) transplantation offers a great angiogenic opportunity in vascular reg... more Mesenchymal stem cell (MSC) transplantation offers a great angiogenic opportunity in vascular regenerative medicine. The canonical Wnt/beta-catenin signaling pathway has been demonstrated to play an essential role in stem cell fate. Recently, genetic studies have implicated the Wnt/Frizzled (Fz) molecular pathway, namely Wnt7B and Fz4, in blood growth regulation. Here, we investigated whether MSC could be required in shaping a functional vasculature and whether secreted Frizzled-related protein-1 (sFRP1), a modulator of the Wnt/Fz pathway, could modify MSC capacities, endowing MSC to increase vessel maturation. In the engraftment model, we show that murine bone marrow-derived MSC induced a beneficial vascular effect through a direct cellular contribution to vascular cells. MSC quickly organized into primitive immature vessel tubes connected to host circulation; this organization preceded host endothelial cell (EC) and smooth muscle cell (SMC) recruitment to later form mature neovessel. MSC sustained neovessel organization and maturation. We report here that sFRP1 forced expression enhanced MSC surrounding neovessel, which was correlated with an increase in vessel maturation and functionality. In vitro, sFRP1 strongly increased platelet-derived growth factor-BB (PDGF-BB) expression in MSC and enhanced beta-catenin-dependent cell-cell contacts between MSC themselves and EC or SMC. In vivo, sFRP1 increased their functional integration around neovessels and vessel maturation through a glycogen synthase kinase 3 beta (GSK3beta)-dependent pathway. sFRP1-overexpressing MSC compared with control MSC were well elongated and in a closer contact with the vascular wall, conditions required to achieve an organized mature vessel wall. We propose that genetically modifying MSC to overexpress sFRP1 may be potentially effective in promoting therapeutic angiogenesis/arteriogenesis processes. Disclosure of potential conflicts of interest is found at the end of this article.
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Papers by Lionel Leroux