Nicotine Induces a Long QT Phenotype in Kcnq 1-Deficient Mouse

We have previously shown that targeted disruption of the mouse Kcnq1 gene produces a long QT phenotype in vivo that requires extracardiac factors for manifestation (Casimiro et al., 2001). In the present study, we explore the hypothesis that autonomic neuroeffector transmission represents the “extracardiac” stimulus that induces a long QT phenotype in mouse hearts lacking Kcnq1. Using the isolated perfused (Langendorff) mouse heart preparation, we challenged wild-type (Kcnq1 / ) and mutant (Kcnq1 / ) mouse hearts with nicotine, an autonomic stimulant. ECGs were recorded continuously, and QT intervals were compared at baseline and peak nicotineinduced heart rates. No significant differences in QT or any other ECG parameters were observed in Kcnq1 / versus Kcnq1 / hearts at baseline. In the presence of nicotine, however, the JT, QT, and rate-corrected QT (QTc) intervals were significantly prolonged in Kcnq1 / hearts relative to Kcnq1 / hearts (e.g., QTc 92 11 ms versus 66 2 ms, respectively, p 0.01). Similar findings were obtained when the hearts were challenged with either epinephrine or isoproterenol (0.1 M each), thereby suggesting that sympathetic stimulation drives the long QT phenotype in Kcnq1-deficient hearts. This idea is supported by in vivo ECG data obtained from unrestrained conscious mice using radiotelemetry recording techniques. Again, no significant ECG differences were observed in Kcnq1 / versus Kcnq1 / mice at baseline, but handling/ injection stress led to significant QTc increases in Kcnq1 / mice relative to wild-type controls (11 3 versus 1 1%, respectively, p 0.05). These data suggest that sympathetic stimulation induces a long QT phenotype in Kcnq1-deficient mouse hearts. Long QT syndrome (LQTS) is a disorder of impaired cardiac repolarization, manifesting long QT intervals on ECG recordings and resulting in increased risk of potentially lethal ventricular arrhythmias known as “Torsades de Pointes” (TdP) (Viskin, 1999; Camm et al., 2000;Chiang and Roden, 2000). LQTS can be acquired or inherited. Both forms ultimately appear to influence ion channel activity in the heart (Roden and Spooner, 1999). Patients with the most prevalent form of congenital LQTS, LQT1, have mutations or deletions in the KCNQ1 gene (previously known as KvLQT1), which encodes for a cardiac potassium channel thought to play an important role in cardiac repolarization (Wang et al., 1996; Yang et al., 1997). LQT1 patients are at high risk for developing TdP arrhythmias particularly during periods of acute stress when sympathetic tone and -adrenergic stimulation are high (Ackerman et al., 1999; Schwartz et al., 2001). We have recently described the initial characterization of a mouse model for Jervell and Lange-Nielsen syndrome, a relatively rare form of LQT1 that is also associated with severe bilateral deafness (Casimiro et al., 2001). This model was created through targeted disruption of the endogenous mouse Kcnq1 gene. We measured ECGs in sedated mice and demonstrated that Kcnq1-deficient (Kcnq1 / ) mice have impaired cardiac repolarization, as indicated by extended rate-corrected QT (QTc) intervals and altered T-wave morphologies compared with those found in wild-type littermates. In contrast, we found that these “baseline” ECG differences observed between diazepam-sedated Kcnq1 / and Kcnq1 / mice in vivo were not evident in ECG recordings from isolated perfused (Langendorff) mouse heart preparations. One specific hypothesis that could account for this apparent discrepancy is that autonomic regulation of Kcnq1 Financial support for this work was provided by grants from the National Institutes of Health (HL58743 and DK56920) and intramural funds from the National Institute of Child Health and Human Development/National Institutes of Health. Article, publication date, and citation information can be found at http://jpet.aspetjournals. org. DOI: 10.1124/jpet.103. 053017. ABBREVIATIONS. LQTS, long QT syndrome; TdP, Torsades de Pointes; QTc, rate-corrected QT interval; VPC, ventricular premature contraction; NSVT, nonsustained ventricular tachycardia. 0022-3565/03/3063-980–987$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 306, No. 3 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 53017/1083635 JPET 306:980–987, 2003 Printed in U.S.A.