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Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure
- Source :
- Circulation: Arrhythmia and Electrophysiology. 1:93-102
- Publication Year :
- 2008
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2008.
-
Abstract
- 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. Methods and Results— CHF was induced in dogs by ventricular tachypacing (240 bpm �2 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 IIδ 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.
- Subjects :
- medicine.medical_specialty
Patch-Clamp Techniques
Atrial action potential
Diastole
Action Potentials
Calsequestrin
Ryanodine receptor 2
Dogs
Oscillometry
Tachycardia
Physiology (medical)
Internal medicine
Atrial Fibrillation
Reaction Time
medicine
Animals
Myocytes, Cardiac
Heart Atria
Protein kinase A
Heart Failure
business.industry
Ryanodine receptor
Myocardium
Hemodynamics
Proteins
Heart
medicine.disease
Myocardial Contraction
Phospholamban
Electrophysiology
Actin Cytoskeleton
Sarcoplasmic Reticulum
Endocrinology
Heart failure
cardiovascular system
Calcium
Cardiology and Cardiovascular Medicine
business
Subjects
Details
- ISSN :
- 19413084 and 19413149
- Volume :
- 1
- Database :
- OpenAIRE
- Journal :
- Circulation: Arrhythmia and Electrophysiology
- Accession number :
- edsair.doi.dedup.....4043b3bc5f5a6f5e56d368401f8be57c