A study published in the Journal of the American College of Cardiology (JACC) provides the first direct evidence that KCNQ1 antibodies are able to suppress arrhythmias in a cellular model of long QT syndrome type 2 (LQTS2), its authors claim, presenting a novel promising therapeutic approach for patients with the condition. Authored by Ange Maguy and prinicpal author Jin Li (University of Bern, Bern, Switzerland), the study suggests that KCNQ1 antibodies activate IKs channels to shorten action potential duration and to suppress arrhythmias in cellular LQTS2.
In the paper, Maguy and colleagues note that LQTS is responsible for a significant proportion of cardiac deaths, writing that patients with the condition are predisposed to life threatening arrhythmias. A delay in cardiac repolarization is characteristic of the disease, they add. The study notes that pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation are the current treatment options, but no target therapy for LQTS exists to date.
Previous studies have indicated that induced autoimmunity against voltage-gated KCNQ1 K+ accelerates cardiac repolarization, however a causative relationship between KCNQ1 antibodies and the observed electrophysiological effect has never been demonstrated. The aim of the present study was to validate this link.
Maguy and colleagues purified KCNQ1 antibodies and performed whole-cell patch clamp experiments as well as single channel recordings on Chinese hamster ovary cells overexpressing IKs, and then studied the effect of purified KCNQ1 antibodies on human cardiomyocytes derived from induced pluripotent stem cells.
Discussing the findings, the study team write that they found a concentration-dependent response, whereby doubling of the KCNQ1 antibody concentration increased the IKs current density by two fold in CHO KCNQ1/KCNE1 cells. Patch clamp recordings disclosed a dual effect of KCNQ1 antibodies, which included a negative shift in voltage sensitivity and a marked slowing of IKs channel deactivation.
To better understand the mechanisms underlying the IKs increase, the study team performed single-channel recordings. At +40 mV, IKs activation is near maximal in both conditions (control versus KCNQ1 antibodies), they note. Therefore, they opted to study single-channel behaviour at this particular potential, reducing the impact of the shift in activation. In the presence of KCNQ1 antibodies, the study team found that the observed gain of function of KCNQ1 channels resulted mainly from an increased mean open dwell time as well as open probability, in addition to the shift in activation.
A mathematical model was used to predict the effect of KCNQ1 antibodies on human ventricular action potentials, simulating three different genotypes (wild-type, heterozygous, and homozygous LQTS2). As LQTS1 is due to a mutation in the KCNQ1 gene, the study team writes, “it seems unlikely that antibodies targeting these defective channels would increase IKs“. Their investigation therefore, focus on LQTS2 that are, they note, more likely to benefit from KCNQ1 antibodies by compensating for the loss of the IKr repolarizing current through IKs up-regulation.
The study team then studied the therapeutic potential of KCNQ1 antibodies in a cellular model of LQTS2 using human induced-pluripotent stem cell-derived cardiomyocytes from a patient with LQTS2. KCNQ1 antibodies not only normalized the action potential duration, they completely suppressed arrhythmias.
The study concludes: “Taken together, this is the first proof-of-concept study providing evidence that KCNQ1 antibodies are potent IKs activators. We elucidated the mechanisms of action of KCNQ1 antibodies on the single-channel level. Moreover, we demonstrated the therapeutic potential of KCNQ1 antibodies by enhancing repolarization reserve and restoring electrical stability in LQTS2.”
In contrast to previous studies on antibodies with almost exclusively inhibitory effects on channels, the study team writes, the KCNQ1 antibody is unique in its kind, “because it induces a gain-of-function of the KCNQ1 channel.” KCNQ1 antibody therapy thus holds promise as an innovative, unprecedented treatment approach for patients with LQTS, the study team notes.