Sonja Schrepfer, MD, PhD, Selected as Vivien Thomas Young Investigators Award Finalist

Sponsored by the Council on Cardiovascular Surgery and Anesthesia (one of the 16 scientific councils of the American Heart Association), the Vivien Thomas Young Investigator Award acknowledges the accomplishments of young investigators focused on fundamental and applied surgical research.

Sonja Schrepfer, MD, PhD, Clinical Instructor in the Cardiothoracic Transplantation Laboratory in the Department of Cardiothoracic Surgery, has been selected as a finalist for the award based on her research, entitled, "Cytokine enhancement with HGF or VEGF in the infarct border zone is key to attenuating the negative remodelling after myocardial infarction."

Schrepfer's work was presented at the American Heart Association's annual meeting in New Orleans on November 9th, 2008.

Abstract

Title: Cytokine enhancement with HGF or VEGF in the infarct border zone is key to attenuating the negative remodelling after myocardial infarction

Authors: Sonja Schrepfer (1), Tobias Deuse (1), Christoph Peter (2), William Stein IV (1), Tim Doyle (3), Hermann Reichenspurner (4), Wolfram H. Zimmermann (5), Thomas Eschenhagen (5), Marc P. Pelletier (1), Joseph Wu (6), Robert C. Robbins (1)

(1) Department of Cardiothoracic Surgery, (2) Department of Cardiovascular Medicine, (3) Department of Pediatrics (Neonatology), Stanford University School of Medicine, Stanford, CA 94305-5407, USA; (4) University Heart Center Hamburg, (5) Department of Pharmacology, University Hospital Hamburg, Martinistr. 52, 20246 Hamburg, Germany, (6) Department of Medicine, Cardiology and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305-5407, USA.

Introduction: Adult mesenchymal stem cell (MSC)-based treatment strategies have been proposed to alleviate the consequences of myocardial infarction (MI).

Methods and Results: The cytokine release of ischemic myocardium was investigated in vivo after LAD ligations in mice and in vitro in cultured cardiomyocytes. Of all cytokines that were at least 5-fold upregulated during ischemia, only HGF and VEGF proved to promote MSC proliferation, and chemotaxis in vitro. Homing of intranenously (IV) injected MSCs (0.5×10 6 per animal) into the infarct border zone after LAD ligation was inefficient (1±0.5 cells/HPF). Cytokine enhancement (CE) of HGF or VEGF by intramyocardial injection at the time of MI significantly facilitated MSC homing (11±4 cells/HPF and 7±4 cells/HPF, respectively; p=0.001). To our knowledge, this is the first study monitoring cardiac geometry and function over a long-term period of 6 months. using ECG-triggered contrast Micro-CT. It revealed that the progressive decrease in EF over time (to 19±1%) could be attenuated by CE with HGF (29±6%; p=0.003) or VEGF (28±4%; p=0.004) and subsequent IV MSC injection. However, LVEFs of animals treated with CE with HGF or VEGF only, but received no MSC injection, were similar to those groups that also received IV MSCs (p=0.127 and p=0.54, respectively). Best results were finally achieved by prolonged presence of HGF or VEGF, achieved by intramyocardial injection of MSCs stably transfected to produce HGF or VEGF and firefly luciferase into the infarct border zone. Duration of cytokine release was estimated by monitoring MSC survival using in vivo bioluminescence imaging (BLI). BLI signals were detectable for 10 days in contrast to the rapid fate of the cytokines after single dose administration in the CE group, resulting in preserved LVEFs at 6 months to 33.2±2% and 34.4±7%, respectively. Differentation of MSCs into cardiomyocyte-like cells was not observed.

Conclusion: This study highlights the beneficial effect of HGF and VEGF to attenuate the negative LV remodelling after MI and diminishes the role of the MSCs to a pure delivery system for paracrine effects.