Inhibition of cardiac K4.3 (I) channel isoforms by class I antiarrhythmic drugs lidocaine and mexiletine.

Transient outward K current, I, contributes to cardiac action potential generation and is primarily carried by K4.3 (KCND3) channels. Two K4.3 isoforms are expressed in human ventricle and show differential remodeling in heart failure (HF). Lidocaine and mexiletine may be applied in selected patients to suppress ventricular arrhythmias, without effects on sudden cardiac death or mortality. Isoform-dependent effects of antiarrhythmic drugs on K4.3 channels and potential implications for remodeling-based antiarrhythmic management have not been assessed to date. We sought to test the hypotheses that K4.3 channels are targeted by lidocaine and mexiletine, and that drug sensitivity is determined in isoform-specific manner. Expression of KCND3 isoforms was quantified using qRT-PCR in left ventricular samples of patients with HF due to either ischemic or dilated cardiomyopathies (ICM or DCM). Long (K4.3-L) and short (K4.3-S) isoforms were heterologously expressed in Xenopus laevis oocytes to study drug sensitivity and effects on biophysical characteristics activation, deactivation, inactivation, and recovery from inactivation. In the present HF patient cohort KCND3 isoform expression did not differ between ICM and DCM. In vitro, lidocaine (IC-K4.3-L: 0.8 mM; IC-K4.3-S: 1.2 mM) and mexiletine (IC-K4.3-L: 146 μM; IC-K4.3-S: 160 μM) inhibited K4.3 with different sensitivity. Biophysical analyses identified accelerated and enhanced inactivation combined with delayed recovery from inactivation as primary biophysical mechanisms underlying K4.3 current reduction. In conclusion, differential effects on K4.3 isoforms extend the electropharmacological profile of lidocaine and mexiletine. Patient-specific remodeling of K4.3 isoforms may determine individual drug responses and requires consideration during clinical application of compounds targeting K4.3.