A Cardiac Sodium Channel Mutation Associated with
Epinephrine-Induced Marked QT-Prolongation
Mohamad N. El Moheb MD1, Marwan M. Refaat
MD2
1Division of Trauma Emergency Surgery and Surgical
Critical Care, Massachusetts General Hospital, Boston, Massachusetts -
USA
2Division of Cardiology, Department of Internal
Medicine, American University of Beirut Medical Center Beirut, Lebanon
Running Title: SCN5A mutation associated with epinephrine-induced LQTS
Words (excluding references): 746
Disclosures: None
Funding: None
Keywords: Long QT Syndrome, Genetics, Variants, Cardiac Arrhythmias,
Cardiovascular Diseases
Correspondence:
Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FRCP
Associate Professor of Medicine
Director, Cardiovascular Fellowship Program
Department of Internal Medicine, Cardiovascular Medicine/Cardiac
Electrophysiology
Department of Biochemistry and Molecular Genetics
American University of Beirut Faculty of Medicine and Medical Center
PO Box 11-0236, Riad El-Solh 1107 2020- Beirut, Lebanon
Fax: +961-1-370814
Clinic: +961-1-350000/+961-1-374374 Extension 5800
Office: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366
(Direct)
Email: mr48@aub.edu.lb
The hereditary long QT syndrome (LQTS) is an important cause of
polymorphous ventricular tachycardia (torsades de pointes) and sudden
cardiac death in otherwise young and healthy individuals. Clinically,
this condition is caused by delayed ventricular repolarization and
manifests as an abnormally prolonged QT interval on the
electrocardiogram (ECG). The most common subtypes of LQTS are LQT1,
LQT2, and LQT3 (1-10). The life-threatening arrhythmias occur most
frequently during exercise in LQT1, upon auditory stimulation or
emotional stress in LQT2, and at rest or during sleep in LQT3 (11).
Patients with LQT1 have a mutation in the KCNQ1 gene which codes for the
subunit of the slow outward potassium current channel
(IKs) while patients with LQT3 have a mutation in the
SCN5A gene, which codes for the cardiac voltage-dependent sodium channel
(INa) (12). LQT1-affected individuals are more
vulnerable to β-adrenergic modulation than LQT3-affected individuals.
Exercise and epinephrine-infusion ECG tests are therefore useful in
differentiating between the LQTS subtypes and optimizing therapeutic
strategies in order to prevent sudden cardiac death. While beta-blockers
have been established as the standard of care for the treatment of the
LQT1 and LQT2 subtypes, their use in LQT3 remains controversial (13,
14). A new missense mutation has been recently identified in the
SCN5A-encoding INA channels and was found to be
associated with sinus node dysfunction and epinephrine-induced QT
prolongation (1). This atypical phenotype of LQT3 has so far been
observed in only one patient. Whether other mutations exist that can
cause a similar manifestation has yet to determined.
In the current issue of the Journal of Cardiovascular Electrophysiology,
Nakajima et al. describe a family with LQT3 that exhibited
epinephrine-induced marked QT prolongation. The SCN5A V1667I mutation
was found to be responsible for this atypical phenotype which resulted
in prolongation of the QT interval in the proband as well as in family
members carrying the mutation. The SCN5A V1667I mutation is a gain of
function mutation located in domain IV-segment 5 (DIV-S5) of the sodium
channel encoding SCN5A gene. To elucidate the pathophysiology of
the disease, the authors transfected a human kidney cell line (tsA-201)
to induce expression of wild-type and mutated sodium channels and
measured the membrane sodium currents (INA). They showed
that SCN5A V1667I mutation was associated with larger
INA peak density, depolarizing shift in steady-state
inactivation (SSI) leading to increased window current, and accelerated
recovery from depolarization. Additionally, an increased
hump in the INA of V1667I mutant cells
(V1667I-INA) was observed during a ramp pulse protocol
consistent with increased window current. There was no difference in
fast inactivation rate and steady-state activation between the
V1667I-INA and wild-type INA(WT-INA). The authors further examined the effects of
protein kinase A (PKA) activation on V1667I-INA to mimic
the effect of epinephrine. PKA activation resulted in a less significant
hyperpolarizing shift in SSI in V1667I-INA compared to
WT-INA leading to increased window current.
Additionally, V1667I mutation was found to be associated with
accelerated recovery from depolarization, and increased hump during ramp
pulse protocol in the setting of PKA activation. Chen et al. have also
reported the case of an individual with a mutation in SCN5A who
exhibited marked QT-prolongation after epinephrine infusion (1).
However, contrary to the SCN5A V1667I mutation described by Nakajima et
al, the SCN5A V2016M defect was a loss of function mutation causing a
decrease in INA peak density. The clinical
manifestations of the SCN5A mutations described by Chen et al. and
Nakajima et al. are more comparable to individuals with the LQT1 subtype
than those with the LQT3 subtype. Therefore, it should be considered
whether certain patients with SCN5A would benefit from beta-blocker
therapy.
Overall, the authors should be commended on their efforts to describe
for the first time a family with the SCN5A V1667I mutation and show that
this mutation is associated with epinephrine-induced marked QT
prolongation. The authors have also provided important insight into the
electrophysiological properties of the mutant channels and the
structure-function relationship of SCN5A. Further studies are needed to
elucidate the precise molecular mechanisms of PKA activation on WT-INa
and V1667I-INa. The results of this study have important clinical
implications. The efficacy of beta-blockers for the treatment of LQTS
has so far only been proven for the LQT1 and LQT2 subtypes, with
conflicting results for the LQT3 subtype (13, 14). Given the marked QT
prolongation in response to epinephrine infusion in carriers of the
SCN5A V1667I mutation, certain LQT3 patients may benefit from
beta-blocker therapy. Future studies should clarify whether
beta-blockers are effective in these patients.