BACKGROUND: Mechanical support in congestive heart failure (CHF) by a left ventricular assist device (LVAD) is associated with decreased cardiac hypertrophy and altered cardiomyocyte molecular pathways. Survivin initiates cell cycle progression by increased cyclinD1/cdk4 complexes by abrogation of the inhibitory effect of p16(INK4a) on cdk4. Accordingly, the role of survivin in CHF and after unloading was explored. METHODS: In 20 myocardial samples from patients with terminal CHF (before and after LVAD), the protein expression of survivin, cyclin D1, cdk4, p16(INK4a), and proliferating cell nuclear antigen (PCNA) was immunohistochemically investigated and morphometrically quantified by calculating the percentage of positive cardiomyocytes per visual field. These data were correlated with cardiomyocyte size and DNA content. RESULTS: The mean percentage of cardiomyocytes immunoreactive against survivin, cyclin D1, cdk4, p16(INK4a), and PCNA was significantly increased in CHF compared with controls and significantly decreased after unloading (57.6% to 26.6%, 42% to 18.3%, 45.4% to 15.3%, 73.0% to 60.5%, and 43.5% to 25.2%, respectively; p < 0.05). All investigated parameters, in particular survivin and cyclin D1, significantly correlated with cardiomyocyte diameters (r = 0.405; r = 0.563) and DNA content (r = 0.430; r = 0.480), both in CHF (cardiac remodelling) and after unloading (p < 0.05). CONCLUSIONS: These data indicate that survivin is reversibly regulated by ventricular unloading and might be involved in cell size/DNA content regulation and cardiomyocyte proliferation in cardiac remodelling during CHF. It is suggested that after ventricular unloading, decreased survivin protein expression might contribute to cardiac hypertrophy decrease by lowering the number of cyclin D1/cdk4 complexes.
BACKGROUND: Mechanical support in congestive heart failure (CHF) by a left ventricular assist device (LVAD) is associated with decreased cardiac hypertrophy and altered cardiomyocyte molecular pathways. Survivin initiates cell cycle progression by increased cyclinD1/cdk4 complexes by abrogation of the inhibitory effect of p16(INK4a) on cdk4. Accordingly, the role of survivin in CHF and after unloading was explored. METHODS: In 20 myocardial samples from patients with terminal CHF (before and after LVAD), the protein expression of survivin, cyclin D1, cdk4, p16(INK4a), and proliferating cell nuclear antigen (PCNA) was immunohistochemically investigated and morphometrically quantified by calculating the percentage of positive cardiomyocytes per visual field. These data were correlated with cardiomyocyte size and DNA content. RESULTS: The mean percentage of cardiomyocytes immunoreactive against survivin, cyclin D1, cdk4, p16(INK4a), and PCNA was significantly increased in CHF compared with controls and significantly decreased after unloading (57.6% to 26.6%, 42% to 18.3%, 45.4% to 15.3%, 73.0% to 60.5%, and 43.5% to 25.2%, respectively; p < 0.05). All investigated parameters, in particular survivin and cyclin D1, significantly correlated with cardiomyocyte diameters (r = 0.405; r = 0.563) and DNA content (r = 0.430; r = 0.480), both in CHF (cardiac remodelling) and after unloading (p < 0.05). CONCLUSIONS: These data indicate that survivin is reversibly regulated by ventricular unloading and might be involved in cell size/DNA content regulation and cardiomyocyte proliferation in cardiac remodelling during CHF. It is suggested that after ventricular unloading, decreased survivin protein expression might contribute to cardiac hypertrophy decrease by lowering the number of cyclin D1/cdk4 complexes.