Year: 2024
Type: editorial
Abstract: This editorial refers to ‘The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block’, by Y. Wada et al., https://doi.org/10.1093/cvr/cvae042. Long QT syndrome (LQTS) types 1 and 2 are the two major forms of the inherited channelopathy LQTS. Loss-of-function mutations in KCNQ1 (LQT1) or KCNH2 (LQT2) cause a reduction in one of the main cardiac repolarizing currents, IKs (LQT1) or IKr (LQT2), respectively. This prolongs cardiac action potential duration (APD) and consecutively the QT interval in surface ECG, thus predisposing the heart to an increased risk for polymorphic ventricular tachycardia and sudden cardiac death. In LQTS, this ‘genetic’ reduction of one of these major repolarizing currents leads additionally to a reduction in the so called ‘repolarization reserve’—a concept defined as the ability of cardiomyocytes to maintain sufficient/normal repolarization despite K+ channel-blocking effects of drugs by compensation via the non-affected redundant ‘reserve’ outward K+ currents.1,2 While in physiological conditions, this repolarization reserve is sufficient to prevent a major APD prolongation if healthy hearts are exposed to IKr-, IKs-, or IK1-blocking drugs or compounds, this is not the case in LQT1 or LQT2 hearts, in which the aforementioned channel-blocking drugs will cause a major APD/QT prolongation with a high proarrhythmic risk due to the genetically caused reduction of one repolarization K+ current.3–6 To prevent this further increase in the arrhythmogenic risk of LQTS patients, they are recommended to restrain from these K+ channel-blocking drugs, and should all receive a comprehensive list of potential QT-prolonging, and thus contra-indicated drugs (www.crediblemeds.org) from their treating physicians. In their study in this issue entitled ‘The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block’, Dan Roden’s group provides additional evidence for this reduced repolarization reserve, which even goes beyond the drug-induced component.7 They demonstrated that in healthy human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), a drug-induced IKs-blockade does not prolong the APD, while the genetic reduction of IKs in hiPSC-CM from a LQT1 patient with compound heterozygous loss-of-function variants in KCNQ1 let already at baseline to a marked APD prolongation—going beyond what one would expect from a reduction of the rather small baseline IKs currents in healthy hiPSC-CM. Moreover, they demonstrated an over-proportionally increase in the susceptibility of the LQT1 hiPSC-CM to IKr-blocking drugs, necessitating a 10-fold lower concentration of the IKr-blocker moxifloxacin to reach similar APD prolongations as in WT hiPSC-CM. This observation strongly suggests that there may be some KCNQ1-variant induced concomitant KCHN2/IKr down-regulation (Figure 1), which may contribute to both, a longer APD at baseline and the strongly increased susceptibility to further APD prolongation upon IKr-blockade. Schematic representation of the subtle effects of a loss-of-function variant in KCNQ1/I on the prolongation of the cardiac action potential duration (APD) (left) and the more pronounced APD prolonging effects observed in LQT1 cardiomyocytes due an KCNQ1-KCNH2 interaction, which leads to a concomitant reduction in I currents (right). Indeed, previous studies have demonstrated a direct protein–protein interaction between KCNQ1 and KCNH2 α-subunits8 and that the functional down-regulation of IKs current by loss-of-function variants may cause a concomitant functional down-regulation of IKr and vice versa in stable cell lines (Figure 1).9 We could even observe this remodelling in our transgenic LQT1 and LQT2 rabbit models,10 in which the phenotypes were accentuated by the down-regulation of IKs in the IKr loss-of-function (KCNH2-G628S) carrying LQT2 rabbit and by the down-regulation of IKr in the IKs loss-of-function (KCNQ1-Y315S) carrying LQT1 rabbit. Thus far, we could only speculate whether a likewise remodelling would also occur in human patients with LQT1 and LQT2. Here, Wada et al.8 provide at least indirect evidence that this may indeed be the case. A thorough assessment of the KCNH2/HERG protein expression and of IKr current characteristics would be important to further elucidate the exact mechanisms of potential KCNQ1–KCNH2 interactions in the here studied hiPSC-CM. Moreover, it would also be important to assess systematically both IKs and IKr characteristics when characterizing LQT1 cell lines in the future. This would give us some indications (1) whether this represents a commonly observed KCNQ1–KCNH2 interaction-induced remodelling in LQT1 (and maybe likewise also in LQT2) further reducing repolarization reserve, and if so (2) whether this interaction preferably occurs in specific types of KCNQ1 variants. The findings of Wada et al.8 further imply that assessment of arrhythmic risk in individual patients and their individual susceptibility to potential QT-prolonging drugs requires a more thorough assessment that extends beyond the ‘classical’ one gene–one ion current paradigm to not miss any potential further—remodelling induced—reduction of repolarization reserve.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvae074
Author: Katja E Odening
Institutions: University of Bern, University Hospital of Bern
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4394869023