Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

Barry London; Linda C Baker; Polina Petkova-Kirova; Jeanne M Nerbonne; Bum-Rak Choi; Guy Salama

doi:10.1113/jphysiol.2006.122622

$Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT$

Journal article

Open access

Peer reviewed

Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

Barry London, Linda C Baker, Polina Petkova-Kirova, Jeanne M Nerbonne, Bum-Rak Choi and Guy Salama

The Journal of physiology, Vol.578(Pt 1), pp.115-129

01/01/2007

DOI: 10.1113/jphysiol.2006.122622

PMCID: PMC2075135

PMID: 17110412

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Abstract

Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, I(to,f), have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4-/-) that lack the slow component of I(to) (I(to,s)), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DN x Kv1.4-/-) mice that lack both I(to,f) and I(to,s), have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 +/- 2.5 ms, P < 0.01, n = 6), Kv1.4-/- (28.4 +/- 0.4 ms, P < 0.01, n = 5) and Kv4.2DN x Kv1.4-/- (34.3 +/- 2.6 ms, P < 0.01, n = 6) mice than controls (20.3 +/- 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 +/- 0.5 ms, n = 6, P < 0.05) but enhanced in Kv1.4-/- (14.2 +/- 2.0 ms, n = 5, P < 0.05) and Kv4.2DN x Kv1.4(-/-) (15.0 +/- 3 ms, n = 5, P < 0.5) mice compared with controls (10 +/- 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4-/- (n = 4/5) and Kv4.2DN x Kv1.4-/- hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that I(to,f) was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability.

Refractory Period, Electrophysiological - physiology

Mice, Inbred C57BL

Potassium Channels - physiology

Mice, Transgenic

Arrhythmias, Cardiac - physiopathology

Long QT Syndrome - physiopathology

Potassium Channels - genetics

Action Potentials - physiology

Refractory Period, Electrophysiological - genetics

Patch-Clamp Techniques

Phenotype

Animals

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - physiology

Heart Conduction System - physiology

Long QT Syndrome - genetics

Female

Mice

Kinetics

Arrhythmias, Cardiac - genetics

Details

Title: Subtitle: Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT
Creators: Barry London - University of Pittsburgh, Cardiovascular Institute, Pittsburgh, PA 15213, USA
Linda C Baker
Polina Petkova-Kirova
Jeanne M Nerbonne
Bum-Rak Choi
Guy Salama
Resource Type: Journal article
Publication Details: The Journal of physiology, Vol.578(Pt 1), pp.115-129
Publisher: England
DOI: 10.1113/jphysiol.2006.122622
PMID: 17110412
PMCID: PMC2075135
ISSN: 0022-3751
eISSN: 1469-7793
Grant note: R01 HL 59614 / NHLBI NIH HHS R01 HL 70722 / NHLBI NIH HHS R01 HL057929 / NHLBI NIH HHS R01 HL066388 / NHLBI NIH HHS R01 HL034161 / NHLBI NIH HHS R01 HL070722 / NHLBI NIH HHS R01 HL 34161 / NHLBI NIH HHS R01 HL 59629 / NHLBI NIH HHS R01-66096 / PHS HHS R01 HL 066388 / NHLBI NIH HHS R01 HL066096 / NHLBI NIH HHS
Language: English
Date published: 01/01/2007
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984025580402771

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