Prevention of myofilament dysfunction by beta-blocker therapy in postinfarct remodeling

Circ Heart Fail. 2009 May;2(3):233-42. doi: 10.1161/CIRCHEARTFAILURE.108.806125. Epub 2009 Mar 25.


Background: Myofilament contractility of individual cardiomyocytes is depressed in remote noninfarcted myocardium and contributes to global left ventricular pump dysfunction after myocardial infarction (MI). Here, we investigated whether beta-blocker therapy could restore myofilament contractility.

Methods and results: In pigs with a MI induced by ligation of the left circumflex coronary artery, beta-blocker therapy (bisoprolol, MI+beta) was initiated on the first day after MI. Remote left ventricular subendocardial biopsies were taken 3 weeks after sham or MI surgery. Isometric force was measured in single permeabilized cardiomyocytes. Maximal force (F(max)) was lower, whereas Ca(2+) sensitivity was higher in untreated MI compared with sham (both P<0.05). The difference in Ca(2+) sensitivity was abolished by treatment of cells with the beta-adrenergic kinase, protein kinase A. beta-blocker therapy partially reversed F(max) and Ca(2+) sensitivity to sham values and significantly reduced passive force. Despite the lower myofilament Ca(2+) sensitivity in MI+beta compared with untreated myocardium, the protein kinase A induced reduction in Ca(2+) sensitivity was largest in cardiomyocytes from myocardium treated with beta-blockers. Phosphorylation of beta-adrenergic target proteins (myosin binding protein C and troponin I) did not differ among groups, whereas myosin light chain 2 phosphorylation was reduced in MI, which coincided with increased expression of protein phosphatase 1. beta-blockade fully restored the latter alterations and significantly reduced expression of protein phosphatase 2a.

Conclusions: beta-blockade reversed myofilament dysfunction and enhanced myofilament responsiveness to protein kinase A in remote myocardium after MI. These effects likely contribute to the beneficial effects of beta-blockade on global left ventricular function after MI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects*
  • Actin Cytoskeleton / metabolism
  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Bisoprolol / pharmacology*
  • Calcium Signaling / drug effects
  • Cardiac Myosins / metabolism
  • Carrier Proteins / metabolism
  • Connectin
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Female
  • Male
  • Muscle Proteins / metabolism
  • Myocardial Contraction / drug effects*
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / physiopathology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Myosin Light Chains / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein Phosphatase 1 / metabolism
  • Protein Phosphatase 2 / metabolism
  • Recovery of Function
  • Swine
  • Time Factors
  • Troponin I / metabolism
  • Ventricular Dysfunction, Left / drug therapy*
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Remodeling / drug effects*


  • Adrenergic beta-Antagonists
  • Carrier Proteins
  • Connectin
  • Muscle Proteins
  • Myosin Light Chains
  • Troponin I
  • myosin light chain 2
  • myosin-binding protein C
  • Protein Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Phosphatase 1
  • Protein Phosphatase 2
  • Cardiac Myosins
  • Bisoprolol