Long QT syndrome: long story short.

Abstract

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+ (Kv7.1 or KCNQ1, Kv11.1 or hERG) and Na+ channels (Nav1.5) 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 Kv7.1 and Kv11.1 channels, respectively, reducing repolarizing outward K+ currents (IKs and IKr). In contrast, LQTS type 3 relates to an increased late Na+ inward current (INa, late) resulting from gain-of-function in Nav1.5 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 Kv11.1 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.