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PRE-CLINICAL RESEARCH

Noninvasive Quantification and Optimization of Acute Cell Retention by In Vivo Positron Emission Tomography After Intramyocardial Cardiac-Derived Stem Cell Delivery

John Terrovitis, MD^_*, Riikka Lautamäki, MD, PhD, Michael Bonios, MD, James Fox, BS^||, James M. Engles, MS, MBA, Jianhua Yu, BS^||, Michelle K. Leppo, BS, Martin G. Pomper, MD, PhD^||, Richard L. Wahl, MD, Jurgen Seidel, PhD, Benjamin M. Tsui, PhD^||, Frank M. Bengel, MD, M. Roselle Abraham, MD and Eduardo Marbán, MD, PhD^_*,_*

^_* The Heart Institute, Cedars Sinai Medical Center, Los Angeles, California
Department of Cardiology, Johns Hopkins University, Baltimore, Maryland
Department of Diagnostic Imaging Physics, Johns Hopkins University, Baltimore, Maryland
Department of Nuclear Medicine, Johns Hopkins University, Baltimore, Maryland
^|| Department of Radiology, Johns Hopkins University, Baltimore, Maryland

Manuscript received January 2, 2009; revised manuscript received March 16, 2009, accepted April 13, 2009.

^_* Reprint requests and correspondence: Dr. Eduardo Marbán, Director, The Heart Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, 1090 Davis Building, Los Angeles, California 90048 (Email: Eduardo.Marban{at}csmc.edu).

Objectives: The aim of this study was to quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods with positron emission tomography (PET).

Background: Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery.

Methods: The CDCs were derived from syngeneic, male Wistar Kyoto (WK) rats labeled with [¹⁸F]-fluoro-deoxy-glucose (¹⁸FDG) and injected intramyocardially into the ischemic region of female WK rats after permanent left coronary artery ligation. The effects of fibrin glue (FG), bradycardia (adenosine), and cardiac arrest were examined. Imaging with ¹⁸FDG PET was performed for quantification of cell retention. Quantitative polymerase chain reaction (PCR) for the male-specific SRY gene was performed to validate the PET results.

Results: Myocardial retention of cells suspended in phosphate-buffered saline 1 h after delivery was 17.6 ± 11.5% by PCR and 17.8 ± 7.3% by PET. When CDCs were injected immediately after induction of cardiac arrest, retention was increased to 75.6 ± 18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4 ± 5.3%). A similar increase in CDC retention was observed after epicardial application of FG at the injection site (37.5 ± 8.2%). The PCR revealed a significant increase in 3-week cell engraftment in the FG animals (22.1 ± 18.6% and 5.3 ± 3.1%, for FG and phosphate-buffered saline, respectively).

Conclusions: In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with FG or lowering ventricular rate by adenosine might be clinically translatable methods for improving stem cell engraftment in a beating heart.

Key Words: adenosine • cardiac stem cells • fibrin glue • PET

Abbreviations and Acronyms   18FDG = [18F]-fluoro-deoxy-glucose   BDM = 2,3-butanedione-2-monoxime   CDC = cardiac-derived stem cells   CT = computed tomography   FAC = fractional area change   FG = fibrin glue   MI = myocardial infarction   PBS = phosphate-buffered saline   PCR = polymerase chain reaction   PET = positron emission tomography   qPCR = quantitative polymerase chain reaction   WKY = Wistar Kyoto

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