Editors' ChoiceMolecular Cardiology

Ankyring the Heart Rhythm

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Science Translational Medicine  14 Sep 2011:
Vol. 3, Issue 100, pp. 100ec149
DOI: 10.1126/scitranslmed.3003168

In Edgar Allan Poe’s panic-inducing story The Tell Tale Heart, the old man’s ticker allegedly beats louder and louder; according to modern medicine, his heart likely beat faster and irregularly, too. Indeed, atrial fibrillation (AF) is the most common cardiac arrhythmia in elderly patients, and its incidence and prevalence are on the rise. However, despite advances in our knowledge of cardiac electrophysiology, the molecular pathogenesis of AF remains poorly understood. Now, Cunha et al. use insights from genetic studies to uncover one potential mechanism of AF.

More effective treatments are needed for AF patients, who experience disabling symptoms such as palpitations and shortness of breath as well as an increased risk of stroke. In an elegant translational study using mouse models of AF and clinical specimens, the authors evaluated the role, in AF, of ankyrin-B protein (encoded by the ANK2 gene), a multifunctional adaptor molecule implicated in membrane targeting of ion channels, transporters, and signaling molecules. This study was born out of the observation that AF incidence is increased in patients who harbor mutations in ANK2. The authors showed that ankyrin-B deficiency or insufficiency in mice resulted in atrial electrophysiological dysfunction and increased susceptibility to AF, manifested by a shortened action potential measured by a patch-clamp amplifier. Next, the researchers found that ankyrin-B likely exerted its functions through direct interaction with a subgroup of voltage-gated Ca2+ channels (Cav 1.3) in the mouse heart tissue. Most important, loss of ankyrin-B in atrial myocytes isolated from the transgenic mutant mice resulted in decreased Cav 1.3 expression, membrane localization, and function, relative to control monocytes, sufficient to produce shortened atrial action potentials and atrial arrhythmias (again measured using a patch-clamp amplifier), all hallmarks of AF. Last, ankyrin-B and Cav 1.3 expression was reduced in heart biopsies from 10 AF patients, as compared with 12 control patients without AF.

These findings shed light on a molecular pathway and network of signaling molecules that may be involved in the pathogenesis of AF. Moreover, the authors’ elegant mouse model system, although not the first, recapitulated many of the electrical aspects seen in AF patients, thus providing opportunities for future investigations into the roles of other network components using transgenic and crossbreeding technology. Furthermore, given the currently available genomic sequencing technology, it is possible to screen for ANK2 gene mutations, thus allowing clinicians and scientists to correlate clinical and pathological features of AF patients with such genetic variations. Last, researchers can explore the druggable aspects of the Cav 1.3 and ankyrin-B deficiencies in AF, such as restorative delivery of Cav 1.3 protein to atrial myocytes; selective up-regulation of Cav 1.3 protein expression via signaling pathways; or small-molecule drugs that selectively enhance the interaction and membrane targeting of both proteins. One day, we will fear AF no more.

S. R. Cunha et al., Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation 22 August 2011 (10.1161/ CIRCULATIONAHA.111.023986). [Abstract]

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