Autoimmune channelopathies: questions remain

We read with interest the Review by Lazzerini et al. (Autoimmune channelopathies as a novel mechanism in cardiac arrhythmias. Nat.Rev.Cardiol.http://dx.doi.org/10.1038/nrcardio.2017.61;2017)¹. In their manuscript, Lazzerini et al. provide a comprehensive overview of the current understanding of autoimmune-mediated cardiac arrhythmias. However, several aspects need to be clarified. Special focus is given to antibodies targeting cardiac ion channels, and the authors adopt the term “autoimmune cardiac channelopathies” (Ref. 1), a designation first introduced by Li et al. in 2013 to define this disease entity².

In Figures 1 and 3 and their respective legends, Lazzerini et al. illustrate and state that autoantibodies against K⁺ voltage-gated channel subfamily KQT member 1 (KCNQ1) “enhance the slow component of the delayed rectifier K⁺ current (I_Ks)” (Ref. 1). Furthermore, they claim that the anti-KCNQ1 autoantibodies “exerted an agonist-like electrophysiological effect on the KCNQ1 K⁺ channel”. Our concern is that anti-KCNQ1 autoantibodies per se have not been proven to be the mediators of the increase in I_Ks. Previous data have shown that patient serum that contains anti-KCNQ1 autoantibodies increases I_Ks current density in human embryonic kidney (HEK) 293 cells expressing KCNQ1 and K⁺ voltage-gated channel subfamily E member 1 (KCNE1)², and that cardiac action potentials are shortened as a result of an increase in I_Ks in cardiomyocytes isolated from KCNQ1-immunized rabbits³. However, to date, no studies have been performed to establish a direct link between anti-KCNQ1 autoantibodies and an increase in I_Ks.

Finally, Lazzerini et al. state that “anti-Na_v1.5 autoantibodies inhibiting I_Na were detected” (Ref. 1). This claim constitutes an overstatement of the current literature, most probably arising from a misconception. Although a causative relationship between circulating anti-Na_v1.5 autoantibodies and the observed electrophysiological effects is likely, such a relationship has not been demonstrated⁴. From this perspective, we believe that Figures 1 and 2 and their respective legends illustrating anti-Na_v1.5 antibody-mediated I_Na inhibition are misleading and overemphasize the current state of knowledge in this field.