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Original Articles |
From the Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal (Y.H.Y., R.W., X.Q., D.C., P.C., S.N.), Montreal, Canada; the Department of Pharmacology and Toxicology (R.W., U.R., D.D.), Dresden University of Technology, Dresden, Germany; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.), Tao-Yuan, Taiwan; the Department of Pharmacology and Toxicology (P.B.), University of Münster, Münster, Germany; and Ludwig-Maximilians University, Department of Medicine I, Klinikum Grosshadern (R.W., S.K.), Munich, Germany.
Correspondence: Correspondence to Stanley Nattel, MD, 5000 Belanger St E, Montreal, Quebec, Canada, H1T 1C8. E-mail stanley.nattel{at}icm-mhi.org
Received November 22, 2007; accepted February 29, 2008.
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 (Ca2+) handling contributes to the CHF-related atrial arrhythmogenic substrate.
Methods and Results— CHF was induced in dogs by ventricular tachypacing (240 bpm x2 weeks). Cellular Ca2+-handling properties and expression/phosphorylation status of key Ca2+ handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left atrial diastolic intracellular Ca2+ concentration ([Ca2+]i), [Ca2+]i transient amplitude, and sarcoplasmic reticulum (SR) Ca2+ load (caffeine-induced [Ca2+]i release). SR Ca2+ overload was associated with spontaneous Ca2+ transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca2+ release (ryanodine) or Na+/Ca2+ exchange. Mechanisms underlying abnormal SR Ca2+ handling were then studied. CHF increased atrial action potential duration and action potential voltage clamp showed that CHF-like action potentials enhance Ca2+i loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, potentially enhancing SR Ca2+ uptake by reducing phospholamban inhibition of SR Ca2+ ATPase, but it did not affect phosphorylation of SR Ca2+-release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca2+-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 Ca2+ transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase II
expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits.
Conclusions— CHF causes profound changes in Ca2+-handling and -regulatory proteins that produce atrial fibrillation–promoting atrial cardiomyocyte Ca2+-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction.
Key Words: atrial fibrillation congestive heart failure delayed afterdepolarization calcium sarcoplasmic reticulum
*Drs Yeh and Wakili contributed equally to this work.
Drs Nattel and Dobrev share senior authorship.
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