https://orcid.org/0000-0002-9241-1733
This editorial refers to ‘The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of Short QT Syndrome type 3’, by A.I. Moreno-Manuel et al., https://doi.org/10.1093/cvr/cvae019.
When atrial fibrillation (AF) is diagnosed as the cause of palpitations or fainting in a young person, it is so unusual that we may find an inherited cardiac condition if we look for it, and even a rare one. While long QT syndrome is well known in the cardiovascular community, short QT syndrome (SQTS) was only described at the beginning of the millennium and is rare. This heritable cardiac condition can lead to AF at an early age and can be complicated by ventricular arrhythmias and sudden death. It is currently defined by a short QT interval in the electrocardiogram of <320 ms alone or <360 ms in combination with a family history of SQTS, aborted cardiac arrest in the absence of heart disease, or another pathogenic variant.1 SQTS was primarily associated with gain-of-function pathological variants in the repolarizing potassium channel genes (KCNH2, KCNQ1, KCNJ21,2) and more recently with loss of function in the chloride-bicarbonate exchanger gene (SLC4A3). Recommendations for treatment are still limited and based on expert consensus rather than evidence. Therefore, there is an unmet need to unveil disease mechanisms and pharmacological targets. Mechanisms and therapeutic options can be challenging to study in patients with SQTS. Only a few families with the syndrome are known, patients are often still juvenile at diagnosis, and complications can occur suddenly.
Fortunately, the list of models to study mechanisms and therapeutic strategies of SQTS3–7 just got longer: Moreno-Manuel et al.8 created an original in-vivo mouse model expressing a human mutated KCNJ2, clinically known as the molecular basis of SQTS type 3 (SQTS3). While the cardiac sodium channel Nav1.5 is conserved between mice and men, working with K+ channels in mice is challenging because K+ channels differ more between mice and human, and wildtype mice do not express IKr, the main repolarizing ion current and target of many drugs. However, authors sought to avoid this problem by introducing humanoid mutated channels via AAV9 cardiac expression (see beautiful graphical abstract of Ref. 8 and Figure 1). With a wealth of experimental methods, from electrophysiology to immunochemistry, the SQT3 murine model was phenotyped and in silico modelling was applied. Diverse methods, ranging from molecular to whole-organ level, deciphered ion channel function, and cardiac electrophysiological function. The results indeed demonstrate a very short QT interval, a short PR interval as well as short refractory periods and action potential durations in the SQTS model compared to wildtype.8 Isoproterenol normalized repolarization in this SQTS3 mouse model in line with suggested clinical benefit of isoproterenol infusion in SQT patients with electrical storm. The main molecular mechanism underlying SQTS3 involves K+ ions passing more efficiently through the mutated channel structure. Polyamines were unable to penetrate and block the mutant IK1 current.8
Illustration of exemplary models of short QT syndrome (SQTS) and first findings. GoF, gain-of-function; LoF, loss of function; ECG, electrocardiogram; AP, action potential; MAP, monophasic action potential; APD, action potential duration; ICD, implantable cardioverter-defibrillator. Non-exhaustive list.
Interestingly, the mutated IK1 had different effects on atrial vs. ventricular transfected cardiomyocytes, which could be specific for this variant of SQT3. Differences in a number of ion channel subunits may explain this.8 An exciting observation suggests that the Kir2.1 variant increases excitability of the ventricles by modifying Nav1.5 function,8 meaning that the gain-of-function variant in a K+ channel gene might modify interactions between K+ channel and the cardiac Na+ channel. Similarly, a genetic SQT1 rabbit model with gain-of-function in IKr showed decreased calcium currents.6
These observations in models highlight that cardiac ion channels might not act as single players as previously suggested, but more like an interactive team of players in the membrane. This could also have implications for treatment, as many drugs are multi-channel blockers. Targeting channel trafficking or overarching structures could be explored as a treatment strategy.
The experimental study helps to find subtype-specific therapies, vital for young individuals with a high risk of arrhythmias. Expanding clinical registry datasets through close international collaboration will be necessary to confirm whether experimental observations in SQT and its subtypes are translatable to humans and identify the most effective therapies.
Currently, quinidine is the empirical pharmacological treatment for SQTS patients for chronic use.1 Preclinical investigations have found the main effects of quinidine via IKr (in open and inactivated state) and INa inhibition, reducing excitability, and conduction velocity, but also prolonging effective refractory periods and reducing dispersion of repolarization and ventricular ectopic activity6,7 (Figure 1). However, quinidine is associated with adverse effects, mostly gastrointestinal, which reduces adherence. Availability of quinidine is restricted in some countries while QT prolonging antiarrhythmic drugs like sotalol or amiodarone seemed less effective,9 possibly due to reduced sensitivity when IKr inactivation is attenuated.10 Until new evidence is found, standard care, such as treatment of AF or the implantable defibrillator for ventricular arrhythmias remains an option for symptomatic SQTS patients, although the risk of inadequate defibrillator shocks is increased in these young otherwise healthy and active patients with peaked T waves and atrial arrhythmias.
In summary, novel findings beyond the rare form of SQTS type 3 contribute to enhancing the understanding of the complex relationship between a single variant of gene encoding an ionic channel and cardiac arrhythmias. The SQTS is a fascinating model to investigate cardiovascular pathophysiology far beyond the question of what is too long, too short, or just right.
Acknowledgements
We thank Dr V.A. Murukutla for their expert graphical design.
Funding
L.F. acknowledges support by EU Horizon 2020 (grant agreement number 965286 MAESTRIA), NIHR, BHF, and DZHK.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
Conflict of interest: L.F. has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (U.K.), DFG, German Centre for Heart Research DZHK and several biomedical companies. L.F. is also a member of the AFNET steering committee and is listed as an inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016021783). M.L. has recieved institutional research grants from the Research Promotion Fund of the Faculty of Medicine (Hamburg, Germany) and a research grant from FARAPULSE 2021.
