Distinct myocardial effects of beta-blocker therapy in heart failure with normal and reduced left ventricular ejection fraction.
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.
Hamdani
Nazha
N
Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.
Paulus
Walter J
WJ
van Heerebeek
Loek
L
Borbély
Attila
A
Boontje
Nicky M
NM
Zuidwijk
Marian J
MJ
Bronzwaer
Jean G F
JG
Simonides
Warner S
WS
Niessen
Hans W M
HW
Stienen
Ger J M
GJ
van der Velden
Jolanda
J
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
D000319:Adrenergic beta-Antagonists; D008840:Microfilament Proteins