Extracardiac source of monogenic arrhythmogenesis

We previously generated a mouse line lacking the Kcne3 gene. KCNE3 regulates a number of voltage-gated potassium channels, including those formed from Kv2, Kv3 or Kv4 subfamily alpha subunits. KCNE3 also inhibits the hERG alpha subunit, which forms a current, IKr, crucial for human ventricular repolarization. Most notably, KCNE3 converts channels formed from the KCNQ1 alpha subunit into constitutively active channels that are weakly voltage-dependent (espeically when heterologously expressed in Xenopus oocytes). KCNE3 regulates KCNQ1 in the colon and Kv3.4 in skeletal muscle. KCNE3 gene variants are also associated with cardiac arrhythmias such as Long QT syndrome and Brugada syndrome. We wanted to determine what the cardiac phenotype of Kcne3 knockout (Kcne3-/-) mice would be, and what specifically KCNE3 does in cardiac myocytes.

One of the big surprises was that we could not detect KCNE3 expression adult mouse cardiac myocytes, in either the atria or ventricles. Yet, aging Kcne3-/- mice exhibited delayed ventricular repolarization and when we stressed Kcne3-/- mice with ischemia reperfusion injury they were much more prone to developing ventricular tachycardias than their wild-type (Kcne3+/+) littermates.

This combination of findings told us that we needed to adopt an holistic approach to understanding the mechanisms of Kcne3-linked arrhythmogenesis. Using this type of unbaised approach, we discovered that Kcne3 deletion causes hyperaldosteronism (in the absence of elevated angiotensin II). This was linked to an autoimmune response that targeted the adrenal glands of Kcne3-/- mice, an exciting and completely unexpected disovery. When we treated the mice with spironolactone, which blocks the receptor that responds to aldosterone, the arrythmia susceptibility of the Kcne3-/- mice was restored to match that of their Kcne3+/+ littermates, indicating that the increased arrhythmia susceptibility of Kcne3-/- mice arose from their hyperaldosteronism. This is, to our knowledge, the first example of a monogenic, extracardiac source of arrhythmogenesis. Future studies are required to now revisit the situation in people with KCNE3 mutations, to determine the possible role of hyperaldosteronism in human KCNE3-linked arrhythmias. This work was published in 2014 (Hu et al., FASEB J. 28, 935–945).