Abstract 401: Nuclear Remodeling After Mechanical Circulatory Support
Rationale: Cardiomyocytes increase DNA content in normal growth and in response to stress in humans by both increases in nuclear number and ploidy. This observation complicates analysis of human cardiomyocyte proliferation as DNA content can increase in the absence of cytokinesis. Proliferation has been reported in cardiomyocytes following LVAD unloading which may represent a reversal of this process. However, cardiac recovery from LVAD is rare. Thus, we sought to analyze changes in cardiomyocyte nuclear characteristics for clues to this paradox. Objective: We used a novel technique to determine changes in nuclear content to test the hypothesis that adult cardiomyocytes can complete cell cycle progression by mitosis after long-term hemodynamic unloading of the failing heart. Methods and Results: The makeup of myocyte nuclear number, ploidy (per cell and per nucleus) and the frequency of cell cycling markers were evaluated by imaging flow cytometry. Hypertrophic hearts from 15 subjects with left ventricular assist device (LVAD) were compared with 8 non-LVAD unloaded hearts. After hemodynamic unloading for 13.7 ± 9.1 months, myocyte nuclear makeup, specifically the average sizes of both cell and individual nuclei, did not significantly change. DNA content per nucleus was significantly decreased (P < 0.01). The frequency of cell cycle markers, i.e. Ki67 and phospho-histon3 (H3P) were not increased after hemodynamic unloading. Conclusions: Our data demonstrate that unloading of failing hearts with mechanical ventricular assist devices does not alter nucleation state of cardiomyocytes. However, unloading 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.