Biophysical defects of an SCN5A V1667I mutation associated with epinephrine‐induced marked QT prolongation

Abstract

BackgroundThe epinephrine infusion test (EIT) typically induces marked QT prolongation in LQT1, but not LQT3, while the efficacy of β‐blocker therapy is established in LQT1, but not LQT3. We encountered an LQT3 family, with an SCN5A V1667I mutation, that exhibited epinephrine‐induced marked QT prolongation.MethodsWild‐type (WT) or V1667I‐SCN5A was transiently expressed into tsA‐201 cells, and whole‐cell sodium currents (INa) were recorded using patch‐clamp techniques. To mimic the effects of epinephrine, INa was recorded after the application of protein kinase A (PKA) activator, 8‐CPT‐cAMP (200 μM), for 10 minutes.ResultsThe peak density of V1667I‐INa was significantly larger than WT‐INa (WT: 469 ± 48 pA/pF, n = 20; V1667I: 690 ± 62 pA/pF, n = 19, P < .01). The steady‐state activation (SSA) and fast inactivation rate of V1667I‐INa were comparable to WT‐INa. V1667I‐INa displayed a significant depolarizing shift in steady‐state inactivation (SSI) in comparison to WT‐INa (V1/2‐WT: −88.1 ± 0.8 mV, n = 17; V1667I: −82.5 ± 1.1 mV, n = 17, P < .01), which increases window currents. Tetrodotoxin (30 μM)‐sensitive persistent V1667I‐INa was comparable to WT‐INa. However, the ramp pulse protocol (RPP) displayed an increased hump in V1667I‐INa in comparison to WT‐INa. Although 8‐CPT‐cAMP shifted SSA to hyperpolarizing potentials in WT‐INa and V1667I‐INa to the same extent, it shifted SSI to hyperpolarizing potentials much less in V1667I‐INa than in WT‐INa (V1/2‐WT: −92.7 ± 1.3 mV, n = 6; V1667I: −85.3 ± 1.6 mV, n = 6, P < .01). Concordantly, the RPP displayed an increased hump in V1667I‐INa, but not in WT‐INa.ConclusionsWe demonstrated an increase of V1667I‐INa by PKA activation, which may provide a rationale for the efficacy of β‐blocker therapy in some cases of LQT3.

Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome

“…Genomic DNA was extracted from peripheral blood lymphocytes, and target panel sequencing of 72 genes, including inherited arrhythmia syndrome‐related genes, was performed as previously described (Nakajima et al., 2020). Average read depth in analyzable target region was 197 in male and 244 in female sample.…”

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

“…These findings explain why cardiac events in patients with LQT1 are associated with physical activity and why β-blocker therapy has been established in LQT1 but not in LQT3. However, our own group and Chen et al reported LQT3 patients (with a SCN5A V1667I or V2016M mutation) exhibiting epinephrine-induced marked QT prolongation [ 11 , 46 ]. Electrophysiological experiments revealed that both mutant channels caused a gain-of-function by β-adrenergic stimulation.…”

“…The predominance of outward currents over inward currents at the epicardium in RV outflow tract (RVOT) during the early phase of ventricular APs, due to a loss-of-function of inward currents (such as I Na and I Ca ) or a gain-of-function of outward currents (such as I to and ATP-sensitive inward rectifier potassium currents [I K-ATP ]), can augment the AP notch ( Figure 1 A), thereby inducing coved-type ST segment elevations in the right precordial ECG leads ( Figure 1 B), and result in the development of fatal arrhythmias through a so-called phase 2 re-entry [ 3 , 112 ]. During the slower heart rate or lower physical activity, I to is augmented due to a recovery from inactivation and I Ca is decreased due to a reduced β-adrenergic stimulation, while I Na is minimally affected ( Figure 2 ) [ 11 , 113 , 114 ]. The decreased heart rate- and reduced β-adrenergic stimulation-induced predominance of outward currents over inward currents during the early phase of RVOT APs can explain why cardiac events of BrS tend to occur during sleep or at rest [ 3 , 112 ].…”

“…In cases of electrical storm (ES), the use of isoproterenol, which increases I Ca and decreases I to due to an increase of heart rate, is recommended to suppress fatal arrhythmias [ 3 , 8 ]. Drugs that have an inhibitory effect on I to , such as quinidine and bepridil, and those that increase the heart rate and I Ca , such as cilostazol, have been shown to be somewhat effective as adjunctive therapy, although implantable cardioverter defibrillator is the only available therapy for preventing SCD [ 11 , 112 ].…”

“…The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [ 10 , 11 , 12 ]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [ 10 , 13 ].…”