title: Irregular rhythm adversely influences calcium handling in ventricular myocardium: implications for the interaction between heart failure and atrial fibrillation.
abstract: BACKGROUND
  Despite adequate rate control, the combination of atrial fibrillation with heart failure (HF) has been shown, in a number of studies, to hasten HF progression. In this context, we aimed to test the hypothesis that an irregular ventricular rhythm causes an alteration in ventricular cardiomyocyte excitation-contraction coupling which contributes to the progression of HF.
  
  
  RESULTS
  We investigated the effects of electrical field stimulation (average frequency 2 Hz) in an irregular versus regular drive train pattern on the expression of calcium-handling genes and proteins in rat ventricular myocytes. The effect of rhythm on intracellular calcium transients was examined using Fura-2AM fluorescence spectroscopy. In conjunction, calcium-handling protein expression was examined in left ventricular samples obtained from end-stage HF patients, in patients with either persistent atrial fibrillation or sinus rhythm. Compared with regularly paced ventricular cardiomyocytes, in cells paced irregularly for 24 hours, there was a significant reduction in the expression of sarcoplasmic reticulum calcium (Ca(2+)) ATPase together with reduced serine-16 phosphorylation of phospholamban. These findings were accompanied by a 59% reduction (P<0.01) in the peak Ca2+ transient in irregulary paced myocytes compared with those with regular pacing. Consistent with these observations, we observed a 54% (P<0.05) decrease in sarcoplasmic reticulum Ca(2+)ATPase protein expression and an 85% (P<0.01) reduction in the extent of phosphorylation of phospholamban in the left ventricular myocardium of HF patients in atrial fibrillation compared with those in sinus rhythm.
  
  
  CONCLUSIONS
  Together, these data demonstrate that ventricular rhythmicity contributes significantly to excitation-contraction coupling by altering the expression and activity of key calcium-handling proteins. These data suggest that control of rhythm may be of benefit in patients with HF.
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Liang-han
authors.initials: LH
authors.lastname: Ling
authors.forename: Ouda
authors.initials: O
authors.lastname: Khammy
authors.forename: Melissa
authors.initials: M
authors.lastname: Byrne
authors.forename: Fatemah
authors.initials: F
authors.lastname: Amirahmadi
authors.forename: Anna
authors.initials: A
authors.lastname: Foster
authors.forename: Gefeng
authors.initials: G
authors.lastname: Li
authors.forename: Linda
authors.initials: L
authors.lastname: Zhang
authors.forename: Cris
authors.initials: C
authors.lastname: dos Remedios
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D001281:Atrial Fibrillation / Q000150:complications / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004558:Electric Stimulation; D056966:Excitation Contraction Coupling / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban