Azimilide Hydrochloride

Implantable cardioverter-defibrillators (ICDs) have revolutionized the primary and secondary prevention of patients with ventricular arrhythmias. However, the adverse effects of appropriate or inappropriate shocks may require the adjunctive use of anti-arrhythmic drugs (AADs). Beta blockers are the cornerstone of pharmacological primary and secondary prevention of ventricular arrhythmias. In addition to their established efficacy at reducing the incidence of ventricular arrhythmias, beta-blockers are safe with few side effects. Amiodarone is superior to beta blockers and sotalol for the prevention of ventricular arrhythmia recurrence. However, long-term amiodarone use is associated with significant side effects that limit its utility. Sotalol and mexiletine are the main alternatives to amiodarone with a better side effect profile though they are less efficacious at preventing ventricular arrhythmia recurrence. Dofetilide, azimilide and ranolazine are emerging as therapeutic options for secondary prevention; more studies are needed to assess efficacy and safety in comparison to currently used agents. Beta blockers and amiodarone are the mainstay of therapy in patients experiencing electrical storm; their use reduces the frequency of ventricular arrhythmias and ICD intervention as well as affording time until catheter ablation can be considered.

The long QT syndrome (LQTS) is an arrhythmogenic disorder of QT interval prolongation that predisposes patients to life-threatening ventricular arrhythmias such as Torsades de pointes and sudden cardiac death. Clinical genetic testing has emerged as the standard of care to identify genetic variants in patients suspected of having LQTS. However, these results are often confounded by the discovery of variants of uncertain significance (VUS), for which there is insufficient evidence of pathogenicity.

The purpose of this study was to demonstrate that genome editing of patient-specific induced pluripotent stem cells (iPSCs) can be a valuable approach to delineate the pathogenicity of VUS in cardiac channelopathy.

Peripheral blood mononuclear cells were isolated from a carrier with a novel missense variant (T983I) in the KCNH2 (LQT2) gene and an unrelated healthy control subject. iPSCs were generated using an integration-free Sendai virus and differentiated to iPSC-derived cardiomyocytes (CMs).

Whole-cell patch clamp recordings revealed significant prolongation of the action potential duration (APD) and reduced rapidly activating delayed rectifier K⁺ current (I_Kr) density in VUS iPSC-CMs compared with healthy control iPSC-CMs. ICA-105574, a potent I_Kr activator, enhanced I_Kr magnitude and restored normal action potential duration in VUS iPSC-CMs. Notably, VUS iPSC-CMs exhibited greater propensity to proarrhythmia than healthy control cells in response to high-risk torsadogenic drugs (dofetilide, ibutilide, and azimilide), suggesting a compromised repolarization reserve. Finally, the selective correction of the causal variant in iPSC-CMs using CRISPR/Cas9 gene editing (isogenic control) normalized the aberrant cellular phenotype, whereas the introduction of the homozygous variant in healthy control cells recapitulated hallmark features of the LQTS disorder.

The results suggest that the KCNH2^T983I VUS may be classified as potentially pathogenic.