Bradley J. Martin

Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects

BACKGROUND A novel therapeutic option for the treatment of acute myocardial infarction involves the use of mesenchymal stem cells (MSCs). The purpose of this study was to investigate whether implantation of autologous MSCs results in sustained engraftment, myogenic differentiation, and improved cardiac function in a swine myocardial infarct model. METHODS MSCs were isolated and expanded from bone marrow aspirates of 14 domestic swine. A 60-minute left anterior descending artery occlusion was used to produce anterior wall infarction. Piezoelectric crystals were placed within the ischemic region for measurement of regional wall thickness and contractile function. Two weeks later animals autologous, Di-I-labeled MSCs (6 x 10(7)) were implanted into the infarct by direct injection. Hemodynamic and functional measurements were obtained weekly until the time of sacrifice. Immunohistochemistry was used to assess MSC engraftment and myogenic differentiation. RESULTS Microscopic analysis showed robust engraftment of MSCs in all treated animals. Expression of muscle-specific proteins was seen as early as 2 weeks and could be identified in all animals at sacrifice. The degree of contractile dysfunction was significantly attenuated at 4 weeks in animals implanted with MSCs (5.4% +/- 2.2% versus -3.37% +/- 2.7% in control). In addition, the extent of wall thinning after myocardial infarction was markedly reduced in treated animals. CONCLUSIONS Mesenchymal stem cells are capable of engraftment in host myocardium, demonstrate expression of muscle specific proteins, and may attenuate contractile dysfunction and pathologic thinning in this model of left ventricular wall infarction. MSC cardiomyoplasty may have significant clinical potential in attenuating the pathology associated with myocardial infarction.

Mesenchymal Stem Cells Differentiate into an Endothelial Phenotype, Enhance Vascular Density, and Improve Heart Function in a Canine Chronic Ischemia Model

Background—Bone marrow–derived stem cells are under investigation as a treatment for ischemic heart disease. Mesenchymal stem cells (MSCs) have been used preferentially in the acute ischemia model; data in the chronic ischemia model are lacking. Methods and Results—Twelve dogs underwent ameroid constrictor placement. Thirty days later, they received intramyocardial injections of either MSCs (100×106 MSCs/10 mL saline) (n=6) or saline only (10 mL) (controls) (n=6). All were euthanized at 60 days. Resting and stress 2D echocardiography was performed at 30 and 60 days after ameroid placement. White blood cell count (WBC), C-reactive protein (CRP), creatine kinase MB (CK-MB), and troponin I levels were measured. Histopathological and immunohistochemical analyses were performed. Mean left ventricular ejection fraction was similar in both groups at baseline but significantly higher in treated dogs at 60 days. WBC and CRP levels were similar over time in both groups. CK-MB and troponin I increased from baseline to 48 hours, eventually returning to baseline. There was a trend toward reduced fibrosis and greater vascular density in the treated group. MSCs colocalized with endothelial and smooth muscle cells but not with myocytes. Conclusions—In a canine chronic ischemia model, MSCs differentiated into smooth muscle cells and endothelial cells, resulting in increased vascularity and improved cardiac function.

In Vivo Magnetic Resonance Imaging of Mesenchymal Stem Cells in Myocardial Infarction

Background—We investigated the potential of magnetic resonance imaging (MRI) to track magnetically labeled mesenchymal stem cells (MR-MSCs) in a swine myocardial infarction (MI) model. Methods and Results—Adult farm pigs (n=5) were subjected to closed-chest experimental MI. MR-MSCs (2.8 to 16×107 cells) were injected intramyocardially under x-ray fluoroscopy. MRIs were obtained on a 1.5T MR scanner to demonstrate the location of the MR-MSCs and were correlated with histology. Contrast-enhanced MRI demonstrated successful injection in the infarct and serial MSC tracking was demonstrated in two animals. Conclusion—MRI tracking of MSCs is feasible and represents a preferred method for studying the engraftment of MSCs in MI.

Bone Marrow-Derived Stem Cell for Myocardial Regeneration: Preclinical Experience

Adult stem cells are found in many tissues and participate in adult growth as well as repair and regeneration of damaged tissue. Adult stem cells such as MSCs may be the cell of choice for tissue repair because the cellular and tissue environment in the adult is likely very different from the early embryo conditions that produce embryonic stem cells. Bone marrow provides an accessible and renewable source of adult mesenchymal stem cells that can be greatly expanded in culture and characterized. Culture-expanded and characterized MSCs have been tested for their ability to differentiate into several lineages in vitro and also tested in animal models for their ability to enhance tissue repair and undergo in vitro differentiation. One of their greatest attributes is their potential to supply growth factors and cytokines to repairing tissue. MSCs do not appear to be rejected by the immune system, allowing for large scale production, appropriate charaterization and testing, and the subsequent ready availability of allogeneic tissue repair enhancing cellular therapeutics. This provides for the further development of this new field and paves the way for the use of yet other stem cells. The potential to use MSCs to repair damaged cardiovascular tissue is very promising and moving forward quickly. The current results from many labs and early cardiac clinical studies suggest important therapeutic approaches will be forthcoming through the use of MSCs. Perhaps most importantly, the understanding of adult stem cells such as the MSCs will provide us with greater understanding of the role they play in human biology in the developing and aging man.

TCT-12 Real World Utilization of Computed Tomography Derived Fractional Flow Reserve: Single Center Initial Experience in the United States

BACKGROUND Pressure wire based fractional flow reserve (FFR) may be used for functional testing of stenosis-mediated ischemia. To further expand the use of physiological lesion assesment, quantitative flow ratio (QFR) based on computation of coronary angiography was recently developed. This is the first adequately powered, prospective study to evaluate the off-line feasibility and diagnostic performance of QFR.