Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure.
BACKGROUND
Congestive heart failure (CHF) is a common cause of atrial fibrillation. Focal sources of unknown mechanism have been described in CHF-related atrial fibrillation. The authors hypothesized that abnormal calcium (Ca(2+)) handling contributes to the CHF-related atrial arrhythmogenic substrate.


RESULTS
CHF was induced in dogs by ventricular tachypacing (240 bpm x2 weeks). Cellular Ca(2+)-handling properties and expression/phosphorylation status of key Ca(2+) handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left atrial diastolic intracellular Ca(2+) concentration ([Ca(2+)](i)), [Ca(2+)](i) transient amplitude, and sarcoplasmic reticulum (SR) Ca(2+) load (caffeine-induced [Ca(2+)](i) release). SR Ca(2+) overload was associated with spontaneous Ca(2+) transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca(2+) release (ryanodine) or Na(+)/Ca(2+) exchange. Mechanisms underlying abnormal SR Ca(2+) handling were then studied. CHF increased atrial action potential duration and action potential voltage clamp showed that CHF-like action potentials enhance Ca(2+)(i) loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, potentially enhancing SR Ca(2+) uptake by reducing phospholamban inhibition of SR Ca(2+) ATPase, but it did not affect phosphorylation of SR Ca(2+)-release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca(2+)-binding protein) expression were significantly reduced, by 65% and 15%, potentially contributing to SR dysfunction. CHF decreased expression of total and protein kinase A-phosphorylated myosin-binding protein C (a key contractile filament regulator) by 27% and 74%, potentially accounting for decreased contractility despite increased Ca(2+) transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase IIdelta expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits.


CONCLUSIONS
CHF causes profound changes in Ca(2+)-handling and -regulatory proteins that produce atrial fibrillation-promoting atrial cardiomyocyte Ca(2+)-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction.
Yeh
Yung-Hsin
YH
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Canada.
Wakili
Reza
R
Qi
Xiao-Yan
XY
Chartier
Denis
D
Boknik
Peter
P
Kääb
Stefan
S
Ravens
Ursula
U
Coutu
Pierre
P
Dobrev
Dobromir
D
Nattel
Stanley
S
D008841:Actin Cytoskeleton / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D003971:Diastole; D004285:Dogs; D004594:Electrophysiology; D006321:Heart / Q000503:physiopathology; D006325:Heart Atria; D006333:Heart Failure / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009991:Oscillometry; D018408:Patch-Clamp Techniques; D011506:Proteins / Q000378:metabolism; D011930:Reaction Time; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013610:Tachycardia / Q000209:etiology
D011506:Proteins; D002118:Calcium