Researchers Identify Possible Cellular Source of Atrial Fibrillation

University of Pennsylvania School of Medicine researchers have identified cells in the atria of the heart and pulmonary veins of humans and mice that may be a possible cause of atrial fibrillation.

According to a University of Pennsylvania School of Medicine press release, researchers there have “identified a population of cells in the atria of the heart and pulmonary veins of humans and mice that appear to be the seat of [atrial fibrillation], which “may lead to a more precise way to treat AF, with reduced side effects.”

Results from the study were published in the November 2 issue of The Journal of Clinical Investigation. In the article’s abstract, the authors note that “The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes,” and that, “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,” characterizing “a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal.”

According to the authors, the impetus for taking this particular approach was because “the implications of identifying a unique cell population that may contribute to atrial arrhythmias are significant, as they may unmask a previously unknown source or mechanism of arrhythmogenesis.” Further, they noted hat “in addition to descriptions of new cell types that may contribute to atrial arrhythmias, emerging evidence supports the contribution of atrial ectopy outside the thoracic veins to atrial arrhythmias. Since atrial myocytes do not possess the same cellular electrophysiological properties as those found in [pulmonary vein] PV myocytes, the theories proposed to explain the initiation of PV ectopy are unlikely to account for extrapulmonary vein foci. Therefore, the existence of a distinct cell population that may contribute to atrial triggers from the [PVs and extrapulmonary foci may help explain this apparent inconsistency.”

The authors found that “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.”

One of the authors, Jonathan Epstein, MD, William Wikoff Smith Professor, and chair of the Department of Cell and Developmental Biology at the University of Pennsylvania School of Medicine, said that “If these cells are truly the source of AF in some patients, and we can figure out a way to identify them, then our ablation can be far more precise and targeted, thus limiting potential side effects, making the procedure potentially more simple and rapid, and hence more cost effective.”

In the discussion section of the The Journal of Clinical Investigation article, the authors note that their conclusion that DCT—expressing cells in the PV and atrium contribute to atrial arrhythmias “is supported by the presence of induced and spontaneous arrhythmia in mice containing cardiac melanocytes that lack functional DCT, as well as by the absence of arrhythmia in mouse models that lack cardiac melanocytes (Kit mutants).” They also identify several characteristics of these cells that “further add support to their role in arrhythmogenesis: since they reside in locations that clinically originate abnormal electrical activity, they are excitable and electrically coupled to neighboring myocytes, and this activity can be regulated through changes in autonomic tone.”

The authors caution that although there is no other data that “directly correlate Dct-positive cells or Dct activity to clinical atrial arrhythmias,” the results of this study suggest that “further investigations into the role of Dct and cardiac melanocytes in clinical atrial arrhythmias are warranted.”