Abstract 11681: Increased Nitrosative/Oxidative Stress Lowers Myocardial Protein Kinase G Activity in Heart Failure with Preserved Ejection Fraction
Elevated cardiomyocyte passive force (Fpassive) contributes to raised diastolic left ventricular (LV) stiffness in patients (pts) with heart failure and preserved ejection fraction (HFPEF). Fpassive, in HFPEF is higher than in HF with reduced ejection fraction (HFREF) or in aortic stenosis (AS). High Fpassive of HFPEF cardiomyocytes is also acutely lowered in-vitro following administration of protein kinase G (PKG). The present study therefore assessed myocardial PKG activity, cardiomyocyte Fpassive and myocardial nitrosative/oxidative stress, which can lower PKG activity, in LV biopsies of pts with HFPEF (n=36), HFREF (n=43) and severe AS (n=67). All pts were free of coronary artery disease and biopsies demonstrated no evidence for infiltrative or inflammatory myocardial disease. HFPEF pts had LVEF>50%, LV end diastolic volume index <97 mL/m2 and LV end diastolic pressure >16 mmHg. HFREF pts had a LVEF <45%. LV myocardium was procured by transvascular biopsy in HFPEF and HFREF and by peroperative biopsy in AS. Myocardial PKG activity was immunohistochemically measured by ratio of vasodilatory stimulated phosphoprotein (VASP) phosphorylated at Ser239 (PVASP) to total VASP (PVASP/VASP) ratio. Myocardial nitrosative/oxidative stress was indirectly measured via detection of myocardial nitrotyrosine content. Fpassive was measured in single, mechanically isolated cardiomyocytes with sarcomere lengths fixed at 2.2 μm. Myocardial PKG activity was lower in HFPEF (0.70±0.03) than in HFREF (0.85±0.03;p<0.001) and in AS (0.84±0.02;p<0.001). Myocardial nitrotyrosine content was higher in HFPEF (3.94±0.24%) than in HFREF (2.64±0.24%;p<0.001) and in AS (3.26±0.13%;p=0.008). Cardiomyocyte Fpassive was also higher in HFPEF (7.6±0.4 kN/m2) than in HFREF (5.1±0.2 kN/m2;p<0.001) and in AS (3.2±0.2 kN/m2;p<0.001). More HFPEF pts were obese (p<0.05) or had diabetes mellitus (p<0.05).
Conclusion: Myocardial PKG activity is reduced in HFPEF because of high nitrosative/oxidative stress, possibly related to HFPEF pts having metabolic disorders. This low PKG activity raises cardiomyocyte stiffness and could become a valuable target for a specific HFPEF treatment strategy.
- © 2011 by American Heart Association, Inc.