Abstract 11716: Statins Favourably Affect Cardiomyocyte Hypertrophy and Myocardial Protein Kinase G Activity in Heart Failure with Preserved Ejection Fraction
Despite modern heart failure (HF) therapy, prognosis of HF with preserved ejection fraction (HFPEF) did not improve over the last decades. In experimental HF models, statin treatment reduces cardiomyocyte hypertrophy and lowers myocardial oxidative stress thereby enhancing nitric oxide bioavailability and protein kinase G (PKG)-dependent signaling. In addition, statin treatment was reported to be associated with improved survival in HFPEF patients (pts). The present study compared cardiomyocyte hypertrophy, myocardial nitrosative/oxidative stress and myocardial PKG activity in LV endomyocardial biopsy tissue from HFPEF pts treated with (HFPEFstat+)(n=15) or without statins (HFPEFstat-)(n=21). Moreover, as HFPEF cardiomyocytes have high diastolic stiffness evident from raised passive force (Fpassive), the present study also compared cardiomyocyte Fpassive in both groups. All pts were free of coronary artery disease and biopsies demonstrated no evidence for infiltrative or inflammatory myocardial disease. All pts had LVEF>50%, LV end diastolic volume index <97 mL/m2 and LV end diastolic pressure >16 mmHg. Cardiomyoycte diameter (MyD,μm) was determined by histomorphometric analysis and Fpassive was measured in single, mechanically isolated cardiomyocytes with sarcomere lengths fixed at 2.2 μm. Myocardial nitrosative/oxidative stress was indirectly measured via detection of myocardial nitrotyrosine content. Myocardial PKG activity was immunohistochemically measured by ratio of vasodilatory stimulated phosphoprotein (VASP) phosphorylated at Ser239 (PVASP) to total VASP (PVASP/VASP) ratio. Myocardial PKG activity was higher in HFPEFstat+ than in HFPEFstat- (0.80±0.03 vs 0.62±0.04;p=0.002) pts. MyD (26.3±0.2 μm vs 29.3±0.3 μm;p<0.001), cardiomyocyte Fpassive (5.2±0.2 kN/m2 vs 7.9±0.3 kN/m2;p<0.001) and myocardial nitrotyrosine content (2.84±0.17% vs 4.49±0.24%;p<0.001), were lower in HFPEFstat+ than in HFPEFstat- pts.
Conclusion: In HFPEF, statin treatment lowered both cardiomyocyte hypertrophy and stiffness, probably because of raised myocardial PKG activity in the presence of reduced myocardial nitrosative/oxidative stress. These findings suggest statin treatment to be of therapeutic value in HFPEF.
- © 2011 by American Heart Association, Inc.