Abstract
Results Patients with HFPEF (n=36), AS (n=67), and HFREF (n=43) were free of coronary artery disease. More HFPEF patients were obese (P<0.05) or had diabetes mellitus (P<0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. Fpassive was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Cardiomyocyte Fpassive was higher in HFPEF (7.6±0.4 kN/m 2 ) than in AS (3.4±0.2 kN/m 2 ; P<0.001) and in HFREF (5.1±0.2 kN/m 2 ; P<0.001). In-vitro administration of PKG acutely lowered cardiomyocyte stiffness in all groups with the largest decrement in Fpassive in DHF patients. PKG activity in myocardial tissue homogenates was significantly lower in HFPEF (5.11±0.62 pmol/min/ mg) than in both AS (9.18±0.64 pmol/min/mg; P<0.01) and HFREF (11.51±2.0 pmol/min/mg; P<0.001). Immunohistochemical determination of myocardial PKG activity by pVASP/VASP ratio provided confirmatory evidence as it was also significantly lower in HFPEF (0.70±0.03) than in both AS (0.84±0.02; P<0.001) and HFREF (0.85±0.03; P<0.001). Lower PKG activity in HFPEF than in aortic stenosis or HFREF was associated with higher cardiomyocyte Fpassive (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/ oxidative stress (P<0.05). Reduced PKG activity and lower myocardial cGMP concentration in HFPEF did not result from altered myocardial sGC or PDE5A expression, which was similar in all groups nor from unequal BNP expression, which was comparable in HFPEF and AS. The downregulated cGMP-PKG signaling in HFPEF was therefore related to low myocardial nitric oxide bioavailability because of high nitrosative/ oxidative stress. Conclusion Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte Fpassive and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment.
Highlights
Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (Fpassive) [1,2,3,4] and cardiomyocyte hypertrophy [2]
Myocardial homogenates were used for assessment of protein kinase G (PKG) activity, cyclic guanosine monophosphate (cGMP) concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress
Lower PKG activity in HFPEF than in aortic stenosis or HF with reduced EF (HFREF) was associated with higher cardiomyocyte Fpassive (P
Summary
Loek van Heerebeek1,2*, Nazha Hamdani, Inês Falcão-Pires, Adelino F Leite-Moreira, Mark PV Begieneman, Jean GF Bronzwaer, Jolanda van der Velden, Ger JM Stienen, Gerrit J Laarman, Aernout Somsen, Freek WA Verheugt, Hans WM Niessen, Walter J Paulus. From 6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications Erfurt, Germany. From 6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications Erfurt, Germany. 28-30 June 2013
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
