Cardiothoracic Surgery Research at the NHLBI

The Cardiothoracic Surgery Research Program is an intramural research program within the National Heart, Lung, and Blood Institute at the NIH in Bethesda Md. The Director of the laboratory is Dr. Keith A. Horvath,

Currently the program focuses on three major research areas, represented by sections: cell-based therapy, bioengineering, and transplantation. In their 2010 quadrennial report, the group detailed 4 years of significant translational research"representing the return of cardiothoracic research to the NHLBI after a hiatus since 1990," according to Dr. Horvath.

The Cellular Biology Section is focused on cell-based therapy for myocardial ischemia using adult bone-marrow-derived mesenchymal stem cells (BMSCs).

Their research aims are focused on a large animal model to test the effects of BMSCs on chronic myocardial ischemia, to study the fate and differentiation of BMSCs after administration, and to further investigate gene expression patterns of BMSCs under both normoxic and hypoxic conditions.

The group has already demonstrated the benefits of direct injection of autologous BMSCs in to chronically ischemic myocardium.

Direct injection of autologous BMSCs into the ischemic myocardium showed regional ventricular wall thickening demonstrating significant improvement after cell treatment, whereas saline treated animals showed no improvement compared to baseline as assessed by echocardiography.

Global function was also improved following BMSC injection and increased vascularity was found in the BMSC group compared to saline injected controls.

BMSCs isolated from transgenic pigs designed to express enhanced green fluorescent proteins as the donors showed that allogeneic injection of the green BMSCs is safe, with no observable side effects or signs of graft versus host disease were observed.

The green cells were found migrating from the injected area into deeper layers of myocardium over the course of 1 to 6 weeks. By immunofluorescent staining, the green cells were associated with smooth muscle actin or vWF positive cells, suggesting that the transplanted cells were contributing to the formation of new vessels.

They found no evidence that these cells were associated with the new generation of cardiac myocytes, which suggests that the benefits of this therapy may be due to angiogenesis not the regeneration of cardiac myocytes. Gene profiling of the cells before and after transplantation showed that genes such as VEGF, HIF1-a, PDGF, ANGPT2 and CXCL14 were significantly up-regulated.

A clinical trial will be conducted at the NIH Heart Center at Suburban Hospital, Bethesda, and will follow the direct injection of BSMCs into ischemic areas in patients after coronary artery bypass grafting (CABG) or transmyocardial revascularization.

The Transplantation Section at CSRP has focused on developing a clinically relevant large animal cardiac xenotransplantation model, using genetically engineered pig hearts place in baboons.

Efforts are being focused on appropriate immunosuppression through drugs, stem cell, and genetic-engineering of donor hearts. These research efforts involve a working collaboration with Mayo Clinic, University of Pittsburgh, University of Maryland, Beth Israel Hospital, NIH Swine Center in Missouri, and Revivicor.

The Bioengineering Section is focused on developing and applying engineering technologies with devices, imaging and robotics with the goal of achieving "state-of-the-art minimally invasive cardiac operations.

"By enhancing precision and consistency, these novel procedures will improve clinical outcomes and expand the cohort of patients that can be treated."

The current work focuses on beating heart aortic valve replacement under real-time MRI guidance. Feasibility studies have been completed and long term animal studies are underway.

Active and passive markers have been added to the prostheses and delivery device to aid visualization and allow placement of the valve with the precision achieved in an open surgical procedure in 1/100th the time. The current goal is to translate this work into a clinical trial.

This column will keep track of these and other research efforts conducted by the CSRP, especially as they move from preclinical to clinical applications of their advanced research.☐

The Cardiothoracic Surgery Research Program is an intramural research program within the National Heart, Lung, and Blood Institute at the NIH in Bethesda Md. The Director of the laboratory is Dr. Keith A. Horvath,

Currently the program focuses on three major research areas, represented by sections: cell-based therapy, bioengineering, and transplantation. In their 2010 quadrennial report, the group detailed 4 years of significant translational research"representing the return of cardiothoracic research to the NHLBI after a hiatus since 1990," according to Dr. Horvath.

The Cellular Biology Section is focused on cell-based therapy for myocardial ischemia using adult bone-marrow-derived mesenchymal stem cells (BMSCs).

Their research aims are focused on a large animal model to test the effects of BMSCs on chronic myocardial ischemia, to study the fate and differentiation of BMSCs after administration, and to further investigate gene expression patterns of BMSCs under both normoxic and hypoxic conditions.

The group has already demonstrated the benefits of direct injection of autologous BMSCs in to chronically ischemic myocardium.

Direct injection of autologous BMSCs into the ischemic myocardium showed regional ventricular wall thickening demonstrating significant improvement after cell treatment, whereas saline treated animals showed no improvement compared to baseline as assessed by echocardiography.

Global function was also improved following BMSC injection and increased vascularity was found in the BMSC group compared to saline injected controls.

BMSCs isolated from transgenic pigs designed to express enhanced green fluorescent proteins as the donors showed that allogeneic injection of the green BMSCs is safe, with no observable side effects or signs of graft versus host disease were observed.

The green cells were found migrating from the injected area into deeper layers of myocardium over the course of 1 to 6 weeks. By immunofluorescent staining, the green cells were associated with smooth muscle actin or vWF positive cells, suggesting that the transplanted cells were contributing to the formation of new vessels.

They found no evidence that these cells were associated with the new generation of cardiac myocytes, which suggests that the benefits of this therapy may be due to angiogenesis not the regeneration of cardiac myocytes. Gene profiling of the cells before and after transplantation showed that genes such as VEGF, HIF1-a, PDGF, ANGPT2 and CXCL14 were significantly up-regulated.

A clinical trial will be conducted at the NIH Heart Center at Suburban Hospital, Bethesda, and will follow the direct injection of BSMCs into ischemic areas in patients after coronary artery bypass grafting (CABG) or transmyocardial revascularization.

The Transplantation Section at CSRP has focused on developing a clinically relevant large animal cardiac xenotransplantation model, using genetically engineered pig hearts place in baboons.

Efforts are being focused on appropriate immunosuppression through drugs, stem cell, and genetic-engineering of donor hearts. These research efforts involve a working collaboration with Mayo Clinic, University of Pittsburgh, University of Maryland, Beth Israel Hospital, NIH Swine Center in Missouri, and Revivicor.

The Bioengineering Section is focused on developing and applying engineering technologies with devices, imaging and robotics with the goal of achieving "state-of-the-art minimally invasive cardiac operations.

"By enhancing precision and consistency, these novel procedures will improve clinical outcomes and expand the cohort of patients that can be treated."

The current work focuses on beating heart aortic valve replacement under real-time MRI guidance. Feasibility studies have been completed and long term animal studies are underway.

Active and passive markers have been added to the prostheses and delivery device to aid visualization and allow placement of the valve with the precision achieved in an open surgical procedure in 1/100th the time. The current goal is to translate this work into a clinical trial.

This column will keep track of these and other research efforts conducted by the CSRP, especially as they move from preclinical to clinical applications of their advanced research.☐

The Cardiothoracic Surgery Research Program is an intramural research program within the National Heart, Lung, and Blood Institute at the NIH in Bethesda Md. The Director of the laboratory is Dr. Keith A. Horvath,

Currently the program focuses on three major research areas, represented by sections: cell-based therapy, bioengineering, and transplantation. In their 2010 quadrennial report, the group detailed 4 years of significant translational research"representing the return of cardiothoracic research to the NHLBI after a hiatus since 1990," according to Dr. Horvath.

The Cellular Biology Section is focused on cell-based therapy for myocardial ischemia using adult bone-marrow-derived mesenchymal stem cells (BMSCs).

Their research aims are focused on a large animal model to test the effects of BMSCs on chronic myocardial ischemia, to study the fate and differentiation of BMSCs after administration, and to further investigate gene expression patterns of BMSCs under both normoxic and hypoxic conditions.

The group has already demonstrated the benefits of direct injection of autologous BMSCs in to chronically ischemic myocardium.

Direct injection of autologous BMSCs into the ischemic myocardium showed regional ventricular wall thickening demonstrating significant improvement after cell treatment, whereas saline treated animals showed no improvement compared to baseline as assessed by echocardiography.

Global function was also improved following BMSC injection and increased vascularity was found in the BMSC group compared to saline injected controls.

BMSCs isolated from transgenic pigs designed to express enhanced green fluorescent proteins as the donors showed that allogeneic injection of the green BMSCs is safe, with no observable side effects or signs of graft versus host disease were observed.

The green cells were found migrating from the injected area into deeper layers of myocardium over the course of 1 to 6 weeks. By immunofluorescent staining, the green cells were associated with smooth muscle actin or vWF positive cells, suggesting that the transplanted cells were contributing to the formation of new vessels.

They found no evidence that these cells were associated with the new generation of cardiac myocytes, which suggests that the benefits of this therapy may be due to angiogenesis not the regeneration of cardiac myocytes. Gene profiling of the cells before and after transplantation showed that genes such as VEGF, HIF1-a, PDGF, ANGPT2 and CXCL14 were significantly up-regulated.

A clinical trial will be conducted at the NIH Heart Center at Suburban Hospital, Bethesda, and will follow the direct injection of BSMCs into ischemic areas in patients after coronary artery bypass grafting (CABG) or transmyocardial revascularization.

The Transplantation Section at CSRP has focused on developing a clinically relevant large animal cardiac xenotransplantation model, using genetically engineered pig hearts place in baboons.

Efforts are being focused on appropriate immunosuppression through drugs, stem cell, and genetic-engineering of donor hearts. These research efforts involve a working collaboration with Mayo Clinic, University of Pittsburgh, University of Maryland, Beth Israel Hospital, NIH Swine Center in Missouri, and Revivicor.

The Bioengineering Section is focused on developing and applying engineering technologies with devices, imaging and robotics with the goal of achieving "state-of-the-art minimally invasive cardiac operations.

"By enhancing precision and consistency, these novel procedures will improve clinical outcomes and expand the cohort of patients that can be treated."

The current work focuses on beating heart aortic valve replacement under real-time MRI guidance. Feasibility studies have been completed and long term animal studies are underway.

Active and passive markers have been added to the prostheses and delivery device to aid visualization and allow placement of the valve with the precision achieved in an open surgical procedure in 1/100th the time. The current goal is to translate this work into a clinical trial.

This column will keep track of these and other research efforts conducted by the CSRP, especially as they move from preclinical to clinical applications of their advanced research.☐