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(Circulation Research. 2009;104:255.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133⁺ and cKit⁺ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle

Gen Suzuki, Vijay Iyer, Thomas Cimato, John M. Canty, Jr

From the Veterans Affairs Western New York Healthcare System, Departments of Medicine and Physiology and Biophysics, and Center for Research in Cardiovascular Medicine, University at Buffalo, The State University of New York.

Correspondence to John M. Canty, Jr, Division of Cardiology, University at Buffalo, Biomedical Research Building, Room 345, 3435 Main St, Buffalo, NY 14214. E-mail canty{at}buffalo.edu

3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors have been reported to increase circulating bone marrow progenitor cells and variably improve global function in heart failure. The potential role of improved perfusion versus direct effects of statins on cardiac myocytes has not been established. We chronically instrumented swine with a left anterior descending artery (LAD) stenosis to produce chronic hibernating myocardium with regional contractile dysfunction in the absence of heart failure. Hemodynamics, function, perfusion, and histopathology were assessed in pigs treated for 5 weeks with pravastatin (n=12) versus untreated controls (n=10). Regional LAD wall thickening was depressed under baseline conditions (LAD 3.7±0.3 versus 6.6±0.3 in remote regions, P<0.01). It remained unchanged in untreated animals but increased from 3.8±0.6 to 5.2±0.5 mm after pravastatin (P<0.01). There was no increase in myocardial perfusion at rest or during vasodilation. Pravastatin mobilized circulating CD133⁺/cKit⁺ bone marrow progenitor cells and increased myocardial tissue levels (LAD CD133⁺ cells from 140±33 to 884±167 cells/10⁶ myocyte nuclei and cKit⁺ cells from 223±49 to 953±123 cells/10⁶ myocyte nuclei). Pravastatin increased myocytes in mitosis (phospho–histone-H3; 9±5 to 43±7 nuclei/10⁶ myocyte nuclei, P<0.05) and the growth phase of the cell cycle (Ki67; 410±82 to 1261±235 nuclei/10⁶ myocyte nuclei, P<0.05) in diseased but not normal hearts. As a result, pravastatin increased LAD myocyte nuclear density from 830±41 to 1027±55 nuclei/mm² (P<0.05). These data indicate that, in the absence of impaired endothelial function and heart failure, dysfunctional hibernating myocardium improves after pravastatin. This effect is independent of myocardial perfusion and related to mobilization of CD133⁺/cKit⁺ bone marrow progenitor cells which stimulate myocyte proliferation resulting in quantitative increases in myocyte nuclear density.

Key Words: statins • hibernating myocardium • cardiac repair • bone marrow progenitor cells

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