title: Distinct myocardial effects of beta-blocker therapy in heart failure with normal and reduced left ventricular ejection fraction.
abstract: OBJECTIVE
  Left ventricular (LV) myocardial structure and function differ in heart failure (HF) with normal (N) and reduced (R) LV ejection fraction (EF). This difference could underlie an unequal outcome of trials with beta-blockers in heart failure with normal LVEF (HFNEF) and heart failure with reduced LVEF (HFREF) with mixed results observed in HFNEF and positive results in HFREF. To investigate whether beta-blockers have distinct myocardial effects in HFNEF and HFREF, myocardial structure, cardiomyocyte function, and myocardial protein composition were compared in HFNEF and HFREF patients without or with beta-blockers.
  
  
  RESULTS
  Patients, free of coronary artery disease, were divided into beta-(HFNEF) (n = 16), beta+(HFNEF) (n = 16), beta-(HFREF) (n = 17), and beta+(HFREF) (n = 22) groups. Using LV endomyocardial biopsies, we assessed collagen volume fraction (CVF) and cardiomyocyte diameter (MyD) by histomorphometry, phosphorylation of myofilamentary proteins by ProQ-Diamond phosphostained 1D-gels, and expression of beta-adrenergic signalling and calcium handling proteins by western immunoblotting. Cardiomyocytes were also isolated from the biopsies to measure active force (F(active)), resting force (F(passive)), and calcium sensitivity (pCa(50)). Myocardial effects of beta-blocker therapy were either shared by HFNEF and HFREF, unique to HFNEF or unique to HFREF. Higher F(active), higher pCa(50), lower phosphorylation of troponin I and myosin-binding protein C, and lower beta(2) adrenergic receptor expression were shared. Higher F(passive), lower CVF, lower MyD, and lower expression of stimulatory G protein were unique to HFNEF and lower expression of inhibitory G protein was unique to HFREF.
  
  
  CONCLUSIONS
  Myocardial effects unique to either HFNEF or HFREF could contribute to the dissimilar outcome of beta-blocker therapy in both HF phenotypes.
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.forename: Loek
authors.initials: L
authors.lastname: van Heerebeek
authors.forename: Attila
authors.initials: A
authors.lastname: Borbély
authors.forename: Nicky M
authors.initials: NM
authors.lastname: Boontje
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Zuidwijk
authors.forename: Jean G F
authors.initials: JG
authors.lastname: Bronzwaer
authors.forename: Warner S
authors.initials: WS
authors.lastname: Simonides
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D003430:Cross-Sectional Studies; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000473:pathology; D010766:Phosphorylation; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology
chemical_list: D000319:Adrenergic beta-Antagonists; D008840:Microfilament Proteins