Author(s): Suzuki G, Iyer V, Cimato T, Canty JM Jr
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Abstract 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/10(6) myocyte nuclei and cKit(+) cells from 223+/-49 to 953+/-123 cells/10(6) myocyte nuclei). Pravastatin increased myocytes in mitosis (phospho-histone-H3; 9+/-5 to 43+/-7 nuclei/10(6) myocyte nuclei, P<0.05) and the growth phase of the cell cycle (Ki67; 410+/-82 to 1261+/-235 nuclei/10(6) 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/mm(2) (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.
This article was published in Circ Res
and referenced in Journal of Autacoids and Hormones