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Protracted QTc Prolongation following Treadmill Testing Identifies a Type 1 Long QT Mutation that is Resistant to PKA Activation

Heart Rhythm
DOI: 10.1016/j.hrthm.2012.09.109
  • Biology
  • Medicine


Background Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in KCNQ1, the gene that encodes the pore-forming α-subunit of the slowly activating delayed rectifier K+ current (IKs). During β-adrenergic stimulation, protein kinase A (PKA) activation increases IKs to prevent a dangerous prolongation of the ventricular action potential. LQT1 patients with mutations resistant to PKA activation are at greater risk for life-threatening arrhythmias. The purpose of this study is to identify LQT1 mutations resistant to PKA activation. Methods Retrospective analyses of the treadmill stress test results of LQT1 patients indicated that KCNQ1-I235N (p.Iso235Asn) exacerbated the delay in QTc latency recovery following treadmill stress testing. We used voltage-clamping techniques to study KCNQ1 current (IKCNQ1) in HEK293 cells expressing wild-type KCNQ1 (WT) or WT+I235N (to mimic the patients’ genotype), the IKs β-subunit KCNE1, and the IKs PKA regulatory protein AKAP9 (Yotiao). Results LQT1 patients typically show a peak in QTc prolongation at 3 minutes during their recovery from treadmill stress testing. The change in QTc between the first and fifth minutes of recovery (ΔQTc) is typically <12 ms. Patients with the LQT1 mutation I235N showed a pronounced delay in QTc recovery (ΔQTc = 40 ± 12 ms, n = 5), which was absent in I235N patients receiving β-blocker therapy (ΔQTc = 0 ± 9 ms, n = 5). This led us to hypothesize that I235N is insensitive to PKA activation. Cells expressing WT conducted IKCNQ1 similar to native-like IKs (n = 11). Compared with WT, cells coexpressing WT+I235N conducted maximal IKCNQ1 that was 32% smaller (P <.05) and positively shifted the midpoint potential of activation by 16 mV (n = 12, P <.05). PKA activation with forskolin and IBMX increased maximal IKCNQ1 in cells expressing WT by 64% (n = 4, P <.05), but maximal IKCNQ1 only increased 23% in cells expressing WT+I235N (n = 4 each, P >.05). Conclusions LQT1 patients with delayed recovery in QTc prolongation following treadmill testing might indicate mutations that are resistant to PKA activation. These patients could be at high risk for life-threatening events but may derive a pronounced benefit from β-blocker therapy.

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