Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure.

Abstract

BACKGROUND:

Chronic beta-adrenergic receptor (beta-AR) blockade improves cardiac contractility and prolongs survival in patients with heart failure; however, the mechanisms underlying these favorable responses are poorly understood. Stress-induced activation of the sympathetic nervous system results in protein kinase A (PKA)-mediated phosphorylation of the calcium (Ca2+) release channel/cardiac ryanodine receptor (RyR2), required for cardiac excitation-contraction (EC) coupling, activating the RyR2 channel, and increasing cardiac contractility. The hyperadrenergic state of heart failure results in leaky RyR2 channels attributable to PKA hyperphosphorylation and depletion of the stabilizing FK506 binding protein, FKBP12.6. We tested the hypothesis that improved cardiac muscle function attributable to beta-AR blockade is associated with restoration of normal RyR2 channel function in patients with heart failure.

METHODS AND RESULTS:

We assessed the effects of beta-AR blockade on left ventricular volume using isolated perfused hearts and beta-agonist responsiveness using muscle strips from patients undergoing transplantation. Twenty-four human hearts were examined, 10 from patients with heart failure treated with beta-AR blockers (carvedilol, metoprolol, or atenolol), 9 from patients with heart failure without beta-AR blocker treatment, and 5 normal hearts. RyR2 PKA phosphorylation was determined by back-phosphorylation, FKBP12.6 in the RyR2 macromolecular complex was determined by coimmunoprecipitation, and channel function was assayed using planar lipid bilayers. beta-AR blockers reduced left ventricular volume (reverse remodeling) and restored beta-agonist response in cardiac muscle from patients with heart failure. Improved cardiac muscle function was associated with restoration of normal FKBP12.6 levels in the RyR2 macromolecular complex and RyR2 channel function.

CONCLUSIONS:

Improved cardiac muscle function during beta-AR blockade is associated with improved cardiac Ca2+ release channel function in patients with heart failure.

• Authors: Steven Reiken, Xander H T Wehrens, John A Vest, Alessandro Barbone, Stefan Klotz, Donna Mancini, Daniel Burkhoff, Andrew R Marks
• Journal: Circulation (Circulation) Vol. 107 Issue 19 Pg. 2459-66 (May 20 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12743001 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Antagonists
• Calcium Channels
• Macromolecular Substances
• Receptors, Adrenergic, beta
• Ryanodine Receptor Calcium Release Channel
• Cyclic AMP-Dependent Protein Kinases
• Tacrolimus Binding Proteins
• tacrolimus binding protein 1B

Topics

• Adrenergic beta-Antagonists (pharmacology)
• Blood Pressure (drug effects)
• Calcium Channels (drug effects, metabolism)
• Cardiac Volume (drug effects)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Diastole (drug effects)
• Female
• Heart (drug effects, physiopathology)
• Heart Failure (drug therapy, physiopathology, surgery)
• Heart Transplantation
• Humans
• In Vitro Techniques
• Macromolecular Substances
• Male
• Middle Aged
• Perfusion
• Phosphorylation (drug effects)
• Receptors, Adrenergic, beta (drug effects, metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Tacrolimus Binding Proteins (metabolism)