Serum/glucocorticoid-regulated kinase 1 inhibition as a novel therapeutic approach in long QT syndrome
Congenital long QT syndrome (LQTS) is a rare heart disease that is characterized by a prolonged QT interval on the electrocardiogram and the occurrence of rhythm disturbances (arrhythmias). LQTS can be caused by mutations in different genes encoding cardiac ion channels. The most common LQTS subtypes are LQT1, LQT2 (both caused by mutations in potassium channels) and LQT3 (caused by mutations in sodium channels).
Patients with LQTS have an increased risk to develop cardiac arrhythmias, which can cause syncope or sudden cardiac death. Current therapeutic strategies (such as avoidance of certain drugs, lifestyle changes, beta blockade, left cardiac sympathetic denervation or the implantation of cardioverter defibrillators) are symptom-directed strategies able to prevent or terminate arrhythmias. However, current strategies still fail to avoid sudden cardiac death in several LQTS patients. Hence, the development of novel therapies is needed.
To address this unmet need, we sought to examine a novel therapy, targeting one of the mechanisms responsible for the arrhythmias, i.e. disturbed sodium-calcium homeostasis (balance of sodium and calcium ion influx and efflux) in cardiac cells, caused (in)directly by the underlying genetic defects. In particular, we studied a novel inhibitor of the so-called serum/glucocorticoid-regulated kinase-1 (SGK1). This enzyme is involved in sodium-calcium handling in cardiac cells and its overactivation has been shown to mimic diseases with prolonged QT.
In our study, we investigated the potential beneficial effects of inhibiting SGK1 in LQT1 and LQT2 rabbit models and human induced pluripotent derived cardiomyocytes obtained from LQT1 and LQT2 patients. We demonstrated that the inhibition of SGK1 was effective in shortening the prolonged cardiac repolarization in all LQT2 models (with different mutations) but had variable effects in the different LQT1 models, thus suggesting gene-specific difference in its therapeutic effect.
Given these promising first data, we consider SGK1 inhibition a potential future treatment option for LQT2. We are currently investigating the underlying mechanisms of its beneficial effects in more detail.
Giannetti F, Barbieri M, Shiti A, Casini S, Sager PT, Das S, Pradhananga S, Srinivasan D, Nimani S, Alerni N, Louradour J, Mura M, Gnecchi M, Brink P, Zehender M, Koren G, Zaza A, Crotti L, Wilde AAM, Schwartz PJ, Remme CA, Gepstein L, Sala L, Odening KE. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2. Europace. 2023 May 19;25(5):euad094. doi: 10.1093/europace/euad094. PMID: 37099628; PMCID: PMC10228615.
Prepared by Miriam Barbieri