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

摘要

HMG-CoA reductase inhibitors have been reported to increase circulating bone marrow progenitor cells (BMPCs) and variably improve global function in heart failure. The potential role of improved perfusion vs. direct effects of statins on cardiac myocytes has not been established. We chronically instrumented swine with an 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 five-weeks with pravastatin (n=12) vs. untreated controls (n=10). Regional LAD wall thickening was depressed under baseline conditions (LAD 3.7±0.3 vs. 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+ BMPCs and increased myocardial tissue levels (LAD CD133+ cells from 140±33 to 884±167 cells/10⁶myocyte nuclei and cKit+ cells from 223±49 to 953±123 cells/10⁶myocyte nuclei). Pravastatin increased myocytes in mitosis (phospho-histone-H3; 9±5 to 43±7 nuclei/10⁶myocyte nuclei, p<0.05) and the growth phase of the cell cycle (Ki67; 410±82 to 1261±235 nuclei/10⁶myocyte 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+ BMPCs which stimulate myocyte proliferation resulting in quantitative increases in myocyte nuclear density.