Cardiomyocyte nuclear remodeling after mechanical unloading

Cardiomyocytes increase DNA content in response to stress in humans. DNA content is reported to decrease in association with increased markers of proliferation in cardiomyocytes following left ventricular assist device (LVAD) unloading. However, cardiac recovery resulting in LVAD explant is rare. Thus, we sought to test the hypothesis that changes in DNA content with mechanical unloading occurs independent of cardiomyocyte proliferation by quantifying cardiomyocyte nuclear number, cell size, DNA content, and the frequency of cell-cycling markers using a novel imaging flow cytometry methodology comparing human subjects undergoing LVAD implantation or primary transplantation. We found that cardiomyocyte size was 15% smaller in unloaded versus loaded samples without differences in the percentage of mono-, bi-, or multinuclear cells. DNA content per nucleus was significantly decreased in unloaded hearts versus loaded controls. Cell-cycle markers, Ki67 and phospho-histon3 (H3P), were not increased in unloaded samples. In conclusion, unloading of failing hearts is associated with decreased DNA content of nuclei independent of nucleation state within the cell. As these changes were associated with a trend to decreased cell size but not increased cell-cycle markers, they may represent a regression of hypertrophic nuclear remodeling and not proliferation. Our data suggest that increases in DNA content that occur with cardiomyocyte hypertrophy in heart failure may reverse with mechanical unloading.