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European Heart Journal Advance Access originally published online on May 31, 2009
European Heart Journal 2009 30(15):1863-1872; doi:10.1093/eurheartj/ehp189
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

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

Nazha Hamdani1, Walter J. Paulus1,*, Loek van Heerebeek1, Attila Borbély1, Nicky M. Boontje1, Marian J. Zuidwijk1, Jean G.F. Bronzwaer2, Warner S. Simonides1, Hans W. M. Niessen3, Ger J. M. Stienen1 and Jolanda van der Velden1

1 Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands
2 Department of Cardiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands
3 Department of Pathology and Cardiac Surgery, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands

Received 8 December 2008; revised 17 March 2009; accepted 21 April 2009; online publish-ahead-of-print 31 May 2009.

* Corresponding author. Tel: +31 20 4448133, Fax: +31 20 4448255, Email: wj.paulus{at}vumc.nl

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.

Key Words: β-blockers • Heart failure • Myocardium • Diastole • Hypertrophy


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