Low Myocardial Protein Kinase G Activity in Heart Failure With Preserved Ejection Fraction

• Type: Article in International Scientific Journal
• Date: 2012

Authors

van Heerebeek, L (Author) Other; Hamdani, N (Author) Other; Falcao Pires, I (Author) FMUP; Leite-Moreira AF (Author) FMUP; Begieneman, MPV (Author) Other; Bronzwaer, JGF (Author) Other; van der Velden, J (Author) Other; Stienen, GJM (Author) Other; Laarman, GJ (Author) Other; Somsen, A (Author) Other; Verheugt, FWA (Author) Other; Niessen, HWM (Author) Other; Paulus, WJ (Author) Other

Journal

Title: Circulation

Vol. 126

Pages: 830-+

ISSN: 0009-7322

Publisher: Wolters Kluwer Health

Indexing

ISI Web of Knowledge - 353 Citations

Scopus - 388 Citations

Other information

Authenticus ID: P-002-6YN

DOI: 10.1161/circulationaha.111.076075

Abstract (EN): Background-Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F-passive) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F-passive and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF). Methods and 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. F-passive 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. Lower PKG activity in HFPEF than in aortic stenosis (P<0.01) or HFREF (P<0.001) was associated with higher cardiomyocyte F-passive (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/oxidative stress (P<0.05). Higher F-passive in HFPEF was corrected by in vitro PKG administration. Conclusions-Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F-passive 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. (Circulation.2012;126:830-839.)

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13