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Novel insights into the cellular basis of atrial fibrillation.

ABSTRACT: Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atria. While pulmonary vein myocytes most likely contribute to atrial ectopic beats initiating atrial fibrillation, emerging evidence suggests the existence of other cell populations that may also contribute to atrial arrhythmias. In addition to sinus node-like and intestinal Cajal-like cells, we recently characterized a novel, melanocyte-like cell population in murine and human hearts that may contribute to atrial arrhythmogenic triggers in mice. Murine cardiac melanocyte-like cells are electrically excitable, and express adrenergic and muscarinic receptors. Adult mice lacking the gene encoding dopachrome tautomerase (Dct) are susceptible to atrial arrhythmias, and Dct is expressed by both murine and human cardiac melanocytes. While Dct-expressing cells are present in human hearts in regions from which atrial arrhythmias often arise, the contribution of these cells to clinical atrial arrhythmias remains to be determined.

SUBMITTER: Patel VV

PROVIDER: S-EPMC2924633 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Novel insights into the cellular basis of atrial fibrillation.

Patel Vickas V VV

Expert review of cardiovascular therapy 20100701 7

Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atria. While pulmonary vein myocytes most likely contribute to atrial ectopic beats initiating atrial fibrillation, emerging evidence suggests the existence of other cell populations that may also contribute to atrial arrhythmias. In addition to sinus node-like and intestinal Cajal-like cells, we recently characterized a novel, melanocyte-like cell popul ...[more]

PMID: 20602552

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Project description:Obscurins are giant, modular, cytoskeletal proteins that regulate striated muscle structure and function. Immunoglobulin domains 58/59 (Ig58/59) of obscurin interact with diverse proteins including titin variants and phospholamban. Mutations within Ig58/59 that alter these binding interactions have been linked to the development of myopathy in humans, underscoring the pathophysiological significance of this module. We previously generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59 and comprehensively characterized the effects of this deletion on cardiac morphology and function through aging. Our findings demonstrated that Obscn-ΔIg58/59 male animals develop severe arrhythmia characterized by spontaneous atrial fibrillation/junctional escape by 6-months of age, with atrial enlargement and ventricular remodeling manifesting by 12-months. Herein, we aim to mechanistically evaluate the impact of the Ig58/59 deletion in atria at the cellular level and determine the molecular basis for atrial enlargement and arrhythmia due to the physiological process of aging. Ultrastructural evaluation of sedentary aging male Obscn-ΔIg58/59 atria revealed prominent Z-disk streaming and misalignment. More importantly, Obscn-ΔIg58/59 atrial cardiomyocytes exhibited increased Ca2+ spark frequency and age-specific alterations in Ca2+ cycling kinetics and sarcoplasmic reticulum Ca2+ content that preceded those observed in Obscn-ΔIg58/59 ventricular cardiomyocytes. Proteomic and phospho-proteomic analyses revealed extensive and novel alterations in the expression and phosphorylation profile of major cytoskeletal proteins, Ca2+ regulators, and Z-disk associated protein complexes in Obscn-ΔIg58/59 atria through aging that likely underlie the observed atrial pathologies. These studies are the first to evaluate the role of obscurin in atria and to reveal chamber-specific molecular alterations due to Ig58/59 deletion. Moreover, our findings provide new molecular insights into a genetic model of spontaneous atrial fibrillation and remodeling where atrial dysfunction precedes ventricular maladaptation.

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Novel insights into the cellular basis of atrial fibrillation.

Publications

Novel insights into the cellular basis of atrial fibrillation.

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