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Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure
Steven Reiken1, Xander H T Wehrens, John A Vest
1Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Insights
Beta-adrenergic receptor blockade improves heart failure outcomes by restoring normal function of the cardiac calcium release channel (RyR2). This involves normalizing protein interactions and reducing channel leakage, enhancing cardiac contractility.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Chronic beta-adrenergic receptor (beta-AR) blockade benefits heart failure patients, but mechanisms are unclear.
- Sympathetic activation in heart failure causes leaky cardiac ryanodine receptors (RyR2) due to PKA hyperphosphorylation and FKBP12.6 depletion.
- This study investigates if beta-AR blockade restores RyR2 function in heart failure.
Purpose of the Study:
- To test if beta-AR blockade improves cardiac muscle function by restoring normal RyR2 channel function in heart failure patients.
- To elucidate the molecular mechanisms linking beta-AR blockade to improved cardiac contractility.
Main Methods:
- Assessed effects of beta-AR blockade on left ventricular volume and beta-agonist response in human heart samples.
- Analyzed RyR2 phosphorylation, FKBP12.6 association, and channel function using biochemical and biophysical techniques.
- Studied hearts from heart failure patients treated/untreated with beta-AR blockers and normal controls.
Main Results:
- Beta-AR blockers reduced left ventricular volume (reverse remodeling) and restored beta-agonist response in heart failure muscle.
- Treatment normalized FKBP12.6 levels in the RyR2 complex and improved RyR2 channel function.
- These molecular improvements correlated with enhanced cardiac muscle function.
Conclusions:
- Improved cardiac muscle function in heart failure during beta-AR blockade is linked to normalized cardiac Ca2+ release channel (RyR2) function.
- Restoration of RyR2 channel integrity and FKBP12.6 association is a key mechanism for beta-AR blockade benefits.
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.
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