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J Thorac Cardiovasc Surg 2008;135:292-299
© 2008 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Improvement in hemodynamic performance, exercise capacity, inflammatory profile, and left ventricular reverse remodeling after intracoronary delivery of mesenchymal stem cells in an experimental model of pressure overload hypertrophy

Ezequiel J. Molina, MDa, Jon Palma, MSa, Dipin Gupta, MDa, Denise Torres, MDa, John P. Gaughan, PhDb, Steven Houser, PhDb, Mahender Macha, MDc,*

a Division of Cardiac and Thoracic Surgery, Temple University School of Medicine, Philadelphia, Pa
b Department of Physiology, Temple University School of Medicine, Philadelphia, Pa
c Division of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, Mich

Received for publication May 22, 2006; revisions received September 26, 2007; accepted for publication October 2, 2007.

* Address for reprints: Mahender Macha, MD, 5144 Cardiovascular Center/5864, University of Michigan Medical Center, 1500 E. Medical Center Dr, Ann Arbor, MI 48109-5864. (Email: mmacha{at}med.umich.edu).

Objectives: In a rat model of pressure overload hypertrophy, we studied the effects of intracoronary delivery of mesenchymal stem cells on hemodynamic performance, exercise capacity, systemic inflammation, and left ventricular reverse remodeling.

Methods: Sprague–Dawley rats underwent aortic banding and were followed up by echocardiographic scanning. After a decrease in fractional shortening of 25% from baseline, animals were randomized to intracoronary injection of mesenchymal stem cells (MSC group; n = 28) or phosphate-buffered saline solution (control group; n = 20). Hemodynamic and echocardiographic assessment, swim testing to exhaustion, and measurement of inflammatory markers were performed before the rats were humanely killed on postoperative day 7, 14, 21, or 28.

Results: Injection of mesenchymal stem cells improved systolic function in the MSC group compared with the control group (mean ± standard deviation: maximum dP/dt 3048 ± 230 mm Hg/s vs 2169 ± 97 mm Hg/s at 21 days and 3573 ± 741 mm Hg/s vs 1363 ± 322 mm Hg/s at 28 days: P < .001). Time to exhaustion was similarly increased in the MSC group compared with controls (487 ± 35 seconds vs 306 ± 27 seconds at 28 days; P < .01). Serum levels of interleukins 1 and 6, tumor necrosis factor–alpha, and brain natriuretic peptide-32 were significantly decreased in animals treated with mesenchymal stem cells. Stem cell transplantation improved left ventricular fractional shortening at 21 and 28 days. Left ventricular end-systolic and end-diastolic diameters were also improved at 28 days.

Conclusions: In this model of pressure overload hypertrophy, intracoronary delivery of mesenchymal stem cells during heart failure was associated with an improvement in hemodynamic performance, maximal exercise tolerance, systemic inflammation, and left ventricular reverse remodeling. This study suggests a potential role of this treatment strategy for the management of hypertrophic heart failure resulting from pressure overload.

Abbreviations and Acronyms BNP-32 = brain natriuretic peptide; BrdU = bromodeoxyuridine; ELISA = enzyme-linked immunosorbent assay; GFP = green fluorescent protein; LV = left ventricular; LVEDD = left ventricular end-diastolic diameter; LVEDP = left ventricular end-diastolic pressure; LVESD = left ventricular end-systolic diameter; LVESP = left ventricular end-systolic pressure; MSC = mesenchymal stem cell; PBS = phosphate-buffered saline solution






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