This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 116/10/1137    most recent CIRCULATIONAHA.107.707877v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ruan, Y. Articles by Priori, S. G. Search for Related Content PubMed PubMed Citation Articles by Ruan, Y. Articles by Priori, S. G. Related Collections Cardiovascular Pharmacology Arrythmias-basic studies

(Circulation. 2007;116:1137-1144.)
© 2007 American Heart Association, Inc.

Genetics

Gating Properties of SCN5A Mutations and the Response to Mexiletine in Long-QT Syndrome Type 3 Patients

Yanfei Ruan, MD; Nian Liu, MD; Raffaella Bloise, MD; Carlo Napolitano, MD, PhD; Silvia G. Priori, MD, PhD

From the Molecular Cardiology, Fondazione Salvatore Maugeri (Y.R., N.L., R.B., C.N., S.G.P.), and Department of Cardiology, University of Pavia (S.G.P.), Pavia, Italy.

Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology, Fondazione Salvatore Maugeri, Via Maugeri 10/10A, 27100 Pavia, Italy. E-mail spriori{at}fsm.it

Received April 6, 2007; accepted July 3, 2007.

Background— Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations.

Methods and Results— We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg · kg^–1 · d^–1). We classified the mutations as sensitive to Mex (P1332L, R1626P; 10% of QTc shortening and QTc <500 ms or no arrhythmias) or insensitive to Mex (S941N, M1652R; negligible or no QTc shortening and sudden death). We measured Na⁺ current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na⁺ current, but the mutations identified in patient responders to Mex (P1332L, R1626P) showed a hyperpolarizing shift of V_1/2 of steady-state inactivation. Furthermore, Mex produced use-dependent block with the order R1626P=P1332L>S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block.

Conclusions— We propose that voltage dependence of channel availability and shifts of V_1/2 of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3.

---

 

CLINICAL PERSPECTIVE