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(Circulation Research. 1999;85:872-874.)
© 1999 American Heart Association, Inc.

Editorials

Sodium "Channelopathies" and Sudden Death

Must You Be So Sensitive?

Jeffrey R. Balser

From the Departments of Anesthesiology and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Jeffrey R. Balser, MD, PhD, Room 560, MRB II, Vanderbilt University School of Medicine, Nashville, TN 37232. E-mail jeff.balser@mcmail.vanderbilt.edu

Key Words: Na⁺ channel • inactivation • Brugada syndrome • antiarrhythmic drug

	Introduction

 
Recognizing the diverse cascade of ionic currents that compose the cardiac action potential, and the wisdom of nature to provide redundant systems that protect us from environmental insults, one wonders whether the heart could really notice the aberrant behavior of a single group of excitable proteins. Nonetheless, the first linkage of Na⁺ channel mutations to an inherited form of the long-QT syndrome (LQT3)¹ made it amply clear that badly behaved Na⁺ channels are not well tolerated. Even more surprising were the functional studies of channels carrying the LQT3-linked mutations. Although Na⁺ channels normally open only briefly (and then inactivate) as the action potential commences, channels carrying these autosomal dominant mutations occasionally "forget" to inactivate, causing a small inward current that persists during the action potential plateau.² It appears that this excess current, essentially a gain of Na⁺ channel function, delays cellular repolarization, prolongs the QT interval, and predisposes patients to torsades de pointes.

Surprisingly, the size of this "pathologic" current is minuscule compared with the overall size of the Na⁺ current (I_Na) in its full glory (so-called "peak I_Na"). For the 1505-1507 KPQ III-IV interdomain linker deletion mutant,³ and the recently identified C-terminus mutation E1784K,⁴ the sustained current accounts for only 2% of the peak I_Na. Even more striking, the R1644H long-QT mutation produces a sustained current that is 0.5% of the peak current.^{3 5} Nonetheless, a mechanistic linkage between this small defect, action potential prolongation, and proarrhythmic triggered activity ("EADs") was recently validated in an elegant . . . [Full Text of this Article]

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