Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers
Mark D. Levin, … , Jonathan A. Epstein, Vickas V. Patel
Mark D. Levin, … , Jonathan A. Epstein, Vickas V. Patel
Published October 12, 2009
Citation Information: J Clin Invest. 2009;119(11):3420-3436. https://doi.org/10.1172/JCI39109.
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Research Article Cardiology

Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers

Abstract

Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors and displayed transcriptional profiles distinct from dermal melanocytes. Adult mice lacking DCT displayed normal cardiac development but an increased susceptibility to atrial arrhythmias. Cultured primary cardiac melanocyte-like cells were excitable, and those lacking DCT displayed prolonged repolarization with early afterdepolarizations. Furthermore, mice with mutations in the tyrosine kinase receptor Kit lacked cardiac melanocyte-like cells and did not develop atrial arrhythmias in the absence of DCT. These data suggest that dysfunction of melanocyte-like cells in the atrium and pulmonary veins may contribute to atrial arrhythmias.

Authors

Mark D. Levin, Min Min Lu, Nataliya B. Petrenko, Brian J. Hawkins, Tara H. Gupta, Deborah Lang, Peter T. Buckley, Jeanine Jochems, Fang Liu, Christopher F. Spurney, Li J. Yuan, Jason T. Jacobson, Christopher B. Brown, Li Huang, Friedrich Beermann, Kenneth B. Margulies, Muniswamy Madesh, James H. Eberwine, Jonathan A. Epstein, Vickas V. Patel

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Figure 4

Hierarchical clustering and ANOVA of single-cell gene expression data.

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Hierarchical clustering and ANOVA of single-cell gene expression data. E...
Each column represents expression data from a single cell from 1 of 3 classes: cardiac Dct-expressing cell (pink), atrial myocyte (orange), or dermal Dct-expressing cell (green). Expression analysis was performed on those transcripts that had 2-fold expression above or below the mean in each cell class. The cluster analysis depicted at top was subsequently performed after ANOVA demonstrated significant expression differences between each of the 3 cell classes. Fold changes are represented graphically, with red tiles demonstrating greater than 2-fold expression above the median, yellow representing median expression, and blue demonstrating expression 2-fold below the median. See Supplemental Table 3 for the identity of the genes analyzed. Dendrograms show correlation of gene expression profiles between samples. The length of the dendrogram branches connecting pairs of nodes represents the level of correlation between samples. Note that each cell class segregates to a discrete node, with the cardiac Dct-expressing cells sharing greater correlation with atrial myocytes than dermal Dct-expressing cells, confirming that each cellular class has a distinct signature.