Long QT syndrome: long story short

The first report of long QT syndrome (LQTS) dates back to 1856 when Friedrich Ludwig Meissner, a German obstetrician and pediatrician, described a child with deafness, who died while being publicly reprimanded by the schoolteacher.¹ It took nearly a century to document the very first electrocardiogram (ECG) of a prolonged QT interval coinciding with deafness and syncope.² The association between sudden deaths in children with congenital deafness and QT prolongation was brought up by two concurrent publications authored by Anton Jervell with Fred Lange-Nielsen and Samuel A. Levine with Clyde R. Woodworth.³ Following closely, Cesarino Romano et al. and Owen C. Ward described analogous cases in the absence of the auditory component.³ Although Levine and Woodworth’s contribution was never acknowledged, two eponyms, Jervell-Lange-Nielsen and Romano-Ward syndromes, were coined with reference to the congenital form of LQTS with or without deafness, respectively.³ Because syncope and cardiac arrest mainly occurred in stressful situation, sympathetic imbalance was long believed to underlie LQTS.³ It would take 40 years to find the fault in the genes. With the biological Rosetta stone deciphered, research has become ever more crucial to translate gene expression into clinical care for LQTS. While the spectrum of mutations initially encompassed 17 genes reported to be linked to LQTS, 7 are now classified as having disputed evidence.⁴ Mutations in three genes (KCNQ1, KCNH2, and SCN5A) encoding for cardiac voltage-gated K⁺ (K_v7.1 or KCNQ1, K_v11.1 or hERG) and Na⁺ channels (Na_v1.5) causing a delay in cardiac repolarization account for the majority of LQTS forms (types 1, 2, and 3, respectively).⁴ LQTS types 1 and 2 are based on a loss-of-function in K_v7.1 and K_v11.1 channels, respectively, reducing repolarizing outward K⁺ currents (I_Ks and I_Kr). In contrast, LQTS type 3 relates to an increased late Na⁺ inward current (I_{Na, late}) resulting from gain-of-function in Na_v1.5 channels.⁴ While LQTS type 1 typically manifests during childhood, LQTS types 2 and 3 patients become symptomatic after the onset of puberty. Because of the decreased K_v11.1 channel density compared to male as well as the direct inhibitory effect of estrogen, female LQTS type 2 patients are at particular risk for arrhythmias.⁴ Such cardiac events predominantly occur at rest in LQTS type 3. In contrast, exercise and acoustic/emotional stimuli may trigger malignant arrhythmias in patients with LQTS type 1 and type 2, respectively. Mechanistically, the LQTS heart fails to adapt (impaired repolarization reserve) in response to the excess Ca²⁺ inflow resulting from sustained adrenergic tone (exercise) or an adrenergic surge (sudden arousal).⁴ Given the crucial role of sympathetic activity, it is no surprise that beta-blockers are advocated for LQTS patients. Late Na⁺ channel blockers present a viable adjunct in the pharmacological treatment of LQTS type 3. Left cardiac sympathetic denervation is a surgical antiadrenergic intervention mainly reserved to patients refractory to standard of care. An implantable cardioverter-defibrillator is considered in high-risk and resuscitated patients for the prevention of sudden cardiac death.⁴ Collectively, none of these treatment modalities addresses the cause of LQTS. In addition, some LQTS patients continue to experience breakthrough cardiac events despite maximal therapy, sparking research efforts in developing new treatment strategies.

Moving towards a paradigm shift in LQTS treatment, the observation that patients with autoantibodies directed against K_v7.1 channel present a shorter QT length on ECG inspired new avenues of research.⁵ Immunization of New Zealand White rabbits with the target K_v7.1 peptide was able to recapitulate clinical findings: rabbits with K_v7.1 autoantibodies demonstrated QT interval shortening.⁶ Correspondingly, myocardial IgG deposition was evident on immunohistological staining.⁶ In the endeavor to understand the underlying mechanism, K_v7.1 antibodies were purified from immunized rabbits and tested in vitro across several cell models.⁷ K_v7.1 antibody-induced increase in K⁺ outflow across the human I_Ks channel stably expressed on Chinese Hamster Ovary cells formed the basis of shortened cardiac repolarization phase. The agonistic effect was accompanied by a shift in voltage dependence of activation and slowed deactivation of I_Ks. Single channel patch clamp studies revealed that K_v7.1 antibodies increased both the open time and open probability of the channel.⁷ Even though we recognize that the IgG specifically targets the third extracellular loop near the pore domain, it remains to be elucidated how it mediates a conformational change of the channel to upregulate I_Ks current. That being said, K_v7.1 antibodies shortened the action potential duration of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMCs).⁷ These findings prompted the idea to use K_v7.1 antibody to treat LQTS, a condition defined by abnormally long repolarization. A drug-induced (selective K_v11.1-inhibiting E-4031) and patient-derived cellular model of LQTS type 2 provided the proof-of-concept: K_v7.1 antibodies not only reversed pathologically prolonged action potential duration, but they also suppressed arrhythmias in forms of early afterdepolarizations (EADs), arrhythmic beating and beating arrest in hiPSC-CMCs.⁷ Going back to the in vivo setting, when challenged with a selective K_v11.1 channel blocker (dofetilide) to pharmacologically induce LQTS type 2, rabbits with K_v7.1 autoantibodies were protected from excessive QT prolongation.⁶

Although in its infancy, anti-arrhythmic antibody therapy is conceptually new (Figure 1). In the same way, new hope emerges from gene therapy using suppression-replacement strategies for LQTS as well as serum and glucocorticoid kinase-1 inhibition to restore repolarization in LQTS type 3.^8,9 Moreover, a clinical trial is under way evaluating the efficacy of a K_v11.1 channel trafficking chaperone, lumacaftor-ivacaftor, for LQTS type 2.¹⁰ Taken together, the landscape of LQTS treatment is changing rapidly. Research will continue to stimulate new hypotheses and explore promising approaches to expand the treatment options for our LQTS patients.

Funding

This work was supported by the Swiss National Science Foundation (Eccellenza PCEFP3_203333 to J.L.).

Data availability

No new data were generated or analysed in support of this research.

References

Author notes