Published Online
on April 30, 2008

A more recent version of this article appeared on June 1, 2008

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Original Article

Calcium Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs with Congestive Heart Failure

Yung-Hsin Yeh¹, Reza Wakili², Xiaoyan Qi, Denis Chartier, Peter Boknik³, Stefan Kääb⁴, Ursula Ravens⁵, Pierre Coutu, Dobromir Dobrev⁵ and Stanley Nattel^6,7

¹ Université de Montréal; Chang Gung Memorial Hospital Univ.;
² Université de Montréal; Ludwig-Maximilians Univ.; Klinikum Grobhadern;
³ University of Münster;
⁴ Ludwig-Maximilians University; Klinikum Grobhadern;
⁵ Dresden University of Technology;
⁶ Université de Montréal; McGill University

Correspondence: ⁷ E-mail: stanley.nattel{at}icm-mhi.org

Background—Congestive heart failure (CHF) is a common cause of atrial fibrillation (AF). Focal sources of unknown mechanism have been described in CHF-related AF. We hypothesized that abnormal Ca²⁺-handling contributes to the CHF-related atrial arrhythmogenic substrate.

Methods and Results—CHF was induced in dogs by ventricular tachypacing (240 bpmx2 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 [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 inhibition of SR Ca²⁺-release (ryanodine) or Na⁺/Ca²⁺-exchange. We then studied mechanisms underlying abnormal SR Ca²⁺-handling. CHF increased atrial action-potential duration (APD) and action-potential clamp showed that CHF-like action potentials enhance Ca²⁺_i-loading. CHF increased calmodulin-dependent protein kinase-II (CaMKII)-phosphorylation of phospholamban by 120%, potentially enhancing SR Ca²⁺-uptake by reducing phospholamban-inhibition of SR Ca²⁺-ATPase, but 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 PKA phosphorylated myosin binding protein-C (MyBP-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 CaMKII-expression/function and type-1 protein-phosphatase activity but downregulated regulatory protein-kinase A (PKA)-subunits.

Conclusions—CHF causes profound changes in Ca²⁺-handling and regulatory proteins that produce AF-promoting atrial-cardiomyocyte Ca²⁺-handling abnormalities, arrhythmogenic triggered activity and contractile dysfunction.

Key Words: calcium • sarcoplasmic reticulum • atrial fibrillation • congestive heart failure • delayed afterdepolarization

Author contributions: Y.H.Y. and R.W. share first-authorship. S.N. and D.D. share senior-authorship.

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