Revealing the Concealed Nature of Long-QT Type 3 Syndrome

Abstract

Background Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction due to reduced sodium current driving force, termed “self-attenuation.” We tested the novel hypothesis that self-attenuation can “mask” the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs). Methods and Results Acute interstitial edema (AIE) was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, AIE exacerbated action potential duration prolongation and produced EADs, in particular at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, while for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs. Conclusions We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

“…They observed small APs with a reduced amplitude that propagates and impacts conduction failure. In patients with long QT syndrome type 3, the distribution changes in Na + channels with the gain-of-function mutation have significantly affected the propagation in APs with early afterdepolarizations [44][45][46] . Also Jaeger et al 47 have demonstrated a mechanism of conduction failure due to changes in Na + channel distribution.…”

Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation

“…Previously, we reported that perinexal separation in guinea pig ventricular myocardium is approximately 12 nm ( Veeraraghavan et al, 2015 ). We later found with different observers that perinexal separation can vary between 10 and 25 nm depending on the ex vivo perfusate used to sustain the heart through studies ( George et al, 2015 , 2016 , 2017 ; Entz et al, 2016 ; Greer-Short et al, 2017 ).…”

Year in Review in Cardiac Electrophysiology

“…Sugrue et al 27 looked at cases of genetically confirmed cases of long-QT syndrome types 1 and 2 and found that left slope of the surface T wave in lead V6 and the T-wave center of gravity x axis (last 25% of the wave) in lead 1 were predictors of future long-QT syndrome-associated cardiac events, especially in long-QT syndrome type 2. Greer-Short et al 28 were interested in revealing the concealed nature of long-QT syndrome type 3 syndrome and looked at gain of function mutations in the voltage-gated Na channel (Nav1.5), which is associated with the long-QT syndrome type 3 syndrome. The authors showed that by increasing intercellular cleft width at cell-cell connections, this resulted in action potential duration prolongation and produced early after depolarizations, possibly triggering arrhythmogenesis.…”