Nicotine Induces a Long QT Phenotype in Kcnq1-Deficient Mouse Hearts

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][1]). In the present study, we explore the hypothesis that autonomic neuroeffector transmission represents the “extra cardiac” 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 nicotine-induced 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 μM 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. [1]: #ref-7