April 24, 2014

Circulation Research Features UM Team’s Cellular Therapy Findings

Two Miller School of Medicine studies led by a team from the Interdisciplinary Stem Cell Institute use highly advanced cardiac imaging techniques to establish for the first time how stem cell injections are able to improve the structure of the heart — an important finding for the evolving field of regenerative medicine. The “Poseidon” and “Prometheus” studies were published in a recent issue of Circulation Research, which featured the Poseidon work on the cover and included an independent editorial on the significance of the results.

“We designed a protocol that enabled us to measure precisely what was happening in the heart following the stem cell injections,” said Joshua M. Hare, M.D., the Louis Lemberg Professor of Medicine and Director of the Miller School’s Interdisciplinary Stem Cell Institute (ISCI). “Our findings have important therapeutic implications for cardiac patients.”

The studies, conducted in collaboration with Johns Hopkins University, involved the injection of mesenchymal stem cells (MSCs) into patients with chronic heart failure.

“Using advanced imaging techniques, we were able to see clearly that the greatest benefit to the heart structure occurred at the site of the injections,” said Hare, who is also Chief Science Officer and Senior Associate Dean for Experimental and Regenerative Therapies, and co-chair of curriculum for the Research Education component of the Clinical and Translational Science Institute.

The cover of the April 11 issue of Circulation Research featured the Miller School Poseidon study, led by Alan W. Heldman, M.D., professor of medicine, “Does Transendocardial Injection of Mesenchymal Stem Cells Improve Myocardial Function Locally or Globally?: An Analysis From the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) Randomized Trial.”

The clinical results of the Poseidon trial, published in the Journal of the American Medical Association in November 2012, showed improvement in heart function and quality of life after stem cells were injected into the hearts of patients with muscle damage from a prior heart attack. Heldman, who performed the injection procedures, says the current Circulation Research study shows that “a detailed analysis of the imaging data from that trial teaches us that the sites where we inject the stem cells are a crucial determinant of the results. After using a variety of stem cell delivery catheters in several trials over the years, I am glad to see that the quality of the work we do in the cardiac catheterization lab really matters.”

The Poseidon study found that transendocardial stem cell injection (TESI) with MSCs improved heart remodeling in chronic ischemic cardiomyopathy, a dangerous weakening of the heart’s left ventricle in patients with coronary artery disease. Due to a lack of blood supply, scar tissue forms on the ventricle, reducing its pumping ability.

In this study, 510 scar segments of the left ventricle were analyzed in 30 patients before and 13 months after the stem cell injections. “Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites,” said the Miller School researchers. “Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.”

The Miller School co-authors were Viky Y. Suncion, M.D., post-doctoral associate; Eduard Ghersin, M.D., associate professor of radiology; Joel E. Fishman, M.D., Ph.D., professor of radiology; Vasileios Karantalis, M.D., post-doctoral fellow; third-year student Nicole Mandel; Darcy L. DiFede, RN, Director of Research; Ivonne H. Schulman, M.D., associate professor of medicine; fourth-year student Sabrina N. Taldone; Adam R. Williams, M.D., post-doctoral associate; Cristina Sanina, M.D., post-doctoral associate; Jose Da Silva, Ph.D., associate scientist and cGMP laboratory manager; and Muzammil Mushtaq, M.D., assistant professor of medicine.

Ghersin, who provided the imaging sequences, said, “The novel use of ECG gated multidetector CT technology for assessment of cell-based therapies for chronic heart disease is groundbreaking.”

The Prometheus study published in Circulation Research focused on six cardiac patients who were injected withMSCs in the left ventricle in conjunction with bypass coronary artery surgery. Magnetic resonance imaging (MRI) was used to measure scar, perfusion, wall thickness, and heart contractility prior to the injections and at 3, 6, and 18 months afterwards.

The stem cell injections improved both the structure and functioning of the left ventricle, according to the study, “Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) Trial.”

In addition to Karantalis, DiFede, Mushtaq, Suncion, Heldman, and Fishman, Miller School co-authors were James Symes, M.D., professor of surgery; Pradip Pattany, Ph.D., research associate professor of radiology; John Byrnes, M.D., professor of medicine; and Maureen Lowery, M.D., professor of medicine.

In an independent Circulation Research editorial, “PROMETHEUS and POSEIDON: Harnessing the Power of Advanced Cardiac Imaging,” authors Atul R. Chugh, M.D., of the University of Louisville, and Joao A.C. Lima, M.D., of Johns Hopkins University, noted that the two studies provide a better understanding of the potential therapeutic effects of cellular therapies in cardiovascular medicine. “Overall, the two studies break new grounds in the field of stem cell research imaging,” said the authors.

Citing the Prometheus study, the two authors said the results suggest that the MSCs were able to influence the heart beyond the site of the injections and onto adjacent revascularized segments of the artery. “For the first time, imaging-based evidence [shows] that synergistic mechanisms may be at play when using cell treatment in conjunction with revascularization,” they said. “Such information is critical to the future development of cell therapy, particularly when considering cell delivery strategies and combination therapies.”

“It is especially gratifying,” said Heldman, “that our colleagues from other leading institutions recognized in their comments the work being done by our group at the Miller School’s Interdisciplinary Stem Cell Institute, where we believe that we are taking a measured and scientific approach to learn how to administer cell therapy, so that it achieves the most benefit for patients with heart failure.”

Hare adds that “Together these papers provide solid support for the merits of cell-based therapy for chronic heart disease. We plan to continue our development program with additional larger studies of this approach to meet important unmet needs of a large population of patients with advanced heart disease.”


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