Distinct myocardial effects of beta-blocker therapy in heart failure with normal and reduced left ventricular ejection fraction

• Published in: European heart journal Vol. 30; no. 15; pp. 1863 - 1872
• Main Authors: Hamdani, Nazha, Paulus, Walter J., van Heerebeek, Loek, Borbély, Attila, Boontje, Nicky M., Zuidwijk, Marian J., Bronzwaer, Jean G.F., Simonides, Warner S., Niessen, Hans W. M., Stienen, Ger J. M., van der Velden, Jolanda
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-08-2009; Oxford Publishing Limited (England)
• Subjects: Adrenergic beta-Antagonists - therapeutic use; Aged; Cross-Sectional Studies; Diastole; Female; Heart failure; Heart Failure - drug therapy; Heart Failure - pathology; Heart Failure - physiopathology; Humans; Hypertrophy; Male; Microfilament Proteins - metabolism; Middle Aged; Myocardium; Myocardium - pathology; Myocardium - ultrastructure; Myocytes, Cardiac - pathology; Phosphorylation; Stroke Volume - drug effects; Stroke Volume - physiology; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - pathology; Ventricular Dysfunction, Left - physiopathology; β-blockers; Heart failure; Myocardium; β-blockers; Diastole; Hypertrophy
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehp189

Aims 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 β-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 β-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 β-blockers. Methods and results Patients, free of coronary artery disease, were divided into β−HFNEF (n = 16), β+HFNEF (n = 16), β−HFREF (n = 17), and β+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 β-adrenergic signalling and calcium handling proteins by western immunoblotting. Cardiomyocytes were also isolated from the biopsies to measure active force (Factive), resting force (Fpassive), and calcium sensitivity (pCa50). Myocardial effects of β-blocker therapy were either shared by HFNEF and HFREF, unique to HFNEF or unique to HFREF. Higher Factive, higher pCa50, lower phosphorylation of troponin I and myosin-binding protein C, and lower β2 adrenergic receptor expression were shared. Higher Fpassive, 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. Conclusion Myocardial effects unique to either HFNEF or HFREF could contribute to the dissimilar outcome of β-blocker therapy in both HF phenotypes.