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Cardiac Surgery

Research Summary

The incidence of congestive heart failure continues to increase. Surgical intervention with transplantation is limited by the availability of organ donors for transplantation. To circumvent this limitation, we have investigated the use of stem cells for cardiac restoration. Cardiac MRI was utilized to document improvement in regional and global cardiac function following the implantation of autologous multipotent adult progenitor stem cells derived from bone marrow in a canine model. Despite documented improvement in function, little is understood regarding mechanism of improved cardiac function. We believe stem cell implantation induces restoration of the normal myocardial microstructure, and that the improvement in heart function is directly correlated with the degree of structural restoration. We intend to verify this hypothesis utilizing the developed canine model as a means of comparing the impact of implantation of stem cells from different origins and to investigate the molecular biological signature of the post stem cell transplanted myocardium.

Specific Aims

1. Provide quantitative evidence of improved cardiac function following stem cell injection through the use of dynamic cardiac cine MRI imaging.

2. Provide quantitative evidence of the restoration of cardiac myocardial microstructure within the post stem cell transplantation zone through the use of dynamic cardiac MRI imaging. Histological validation of MRI observations will be performed at the completion of the study.

3. Evaluate the molecular biological signature with in the myocardium following stem cell therapy and compare this to the non-treated post MI state.

Background

Regeneration of injured myocardium can be accomplished by transplantation of donor primordial cells. Embryonic stem cells can differentiate into myocytes that allow for stable cardiac engraftment. However, ethical issues and the current governmental ban on the development of new lines limit the clinical utility. Consequently, stem cells derived from other sources are needed.

Technical Approach

This investigation will utilize the established canine chronic infarct model created by surgical ligation of the left anterior descending coronary artery. Once the injury is established, MRI imaging will localize and assess the degree of functional impairment. Stem cells derived from bone marrow, muscle and cloned cells will then be implanted in individual experimental animal groups. Cardiac MRI will be utilized to guide injection to the site of injury and then to follow subsequent long-term impact on cardiac function at 2 and 4 month intervals.

Significance

Morbidity and mortality associated with cardiovascular disease is substantial and is expected to increase as the incidence of congestive heart failure increases. Restoration of cardiac function is required for the treatment of the disease. Heart transplantation is a valid and successful method of treatment. However, donor organ availability will continue to limit its application. Further, the requirement for lifelong immunosuppression is costly and associated with known complications. Restoration of myocardium through the use of stem cells is a viable alternative to solid organ transplantation. MRI imaging will allow for localization and minimally invasive injection of stem cell. This study will identify optimal cell type and injection leading directly to translation clinical trials.

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Equipment & Techniques

State-of-the-art surgical suite, anesthetic equipment, and clinical grade MR scanners to perform large animal surgical procedures and imaging . In addition, at our disposal are various pieces of advanced equipment and techniques to perform molecular biologic investigation such as PCR, micro array evaluation, radioimmunoassays, mRNA and protein analysis, cell culture, immunofluorescence, digital imaging and confocal microscopy.

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