ABSTRACT
Long QT syndrome (LQTS) is an inherited disease involving mutations in the genes encoding a number of cardiac ion channels and a membrane adaptor protein. Among the genes that are responsible for LQTS, KCNE1 and KCNE2 are members of the KCNE family of genes, and function as ancillary subunits of Kv channels. The third KCNE gene, KCNE3, is expressed in cardiac myocytes and interacts with KCNQ1 to change the channel properties. However, KCNE3 has never been linked to LQTS. To investigate the association between KCNE3 and LQTS, we conducted a genetic screening of KCNE3 mutations and single nucleotide polymorphisms (SNPs) in 485 Japanese LQTS probands using DHPLC-WAVE system and direct sequencing. Consequently, we identified two KCNE3 missense mutations, located in the N- and C-terminal domains. The functional effects of these mutations were examined by heterologous expression systems using CHO cells stably expressing KCNQ1. One mutation, p.R99lambdaH was identified in a 76-year-old woman who suffered torsades de pointes (TdP) after administration of disopyramide. Another mutation, p.T4A was identified in a 16-year-old boy and 67-year-old woman. Although the boy carried another KCNH2 mutation, he was asymptomatic. On the other hand, the woman suffered from hypokalemia-induced TdP. In a series of electrophysiological analyses, the KCNQ1(Q1)+KCNE3(E3)-R99lambdaH channel significantly reduced outward current compared to Q1+E3-WT, though the current density of the Q1+E3-T4A channel displayed no statistical significance. This is the first report of KCNE3 mutations associated with LQTS. Screening for variants in the KCNE3 gene is of clinical importance for LQTS patients.
Subject(s)
Long QT Syndrome/genetics , Mutation, Missense , Potassium Channels, Voltage-Gated/genetics , Adolescent , Adult , Aged , Amino Acid Sequence , Animals , Base Sequence , CHO Cells , COS Cells , Chlorocebus aethiops , Cricetinae , Cricetulus , Female , Humans , KCNQ1 Potassium Channel/genetics , KCNQ1 Potassium Channel/metabolism , Long QT Syndrome/physiopathology , Male , Membrane Potentials , Patch-Clamp Techniques , Potassium Channels, Voltage-Gated/metabolism , Potassium Channels, Voltage-Gated/physiology , Protein Binding , TransfectionABSTRACT
OBJECTIVE: Sympathetic nervous and renin-angiotensin systems play important roles in essential hypertension. This study was aimed at assessing the effects of losartan or its combination with quinapril on the cardiac nervous system and neurohormonal status in essential hypertension. DESIGN AND METHODS: Randomized, comparative study of 105 patients with mild essential hypertension, carried out at Shizuoka General Hospital. In phase 1, 40 hypertensives were allocated randomly into the losartan (50 mg) group or the quinapril (10 mg) group. In phase 2, 65 hypertensives, after 3 months 10 mg quinapril monotherapy, were allocated randomly into groups with 50 mg losartan (n = 32) or 5 mg amlodipine (n = 33) added to quinapril, and were treated for a further 3 months. All patients underwent [(123)I]metaiodobenzylguanidine (MIBG) imaging and neurohormonal measurements before and 3 months after treatment. RESULTS: Both monotherapies significantly increased renin activity, while losartan monotherapy also increased angiotensin II (AII) concentration. In both the losartan and quinapril groups, the washout rate was significantly decreased (18.1 +/- 11.4 versus 13.9 +/- 11.0%, P < 0.0002 and 13.3 +/- 9.3 versus 12.3 +/- 9.1%, P < 00001, respectively) without changes in the heart to mediastinum ratio (H/M ratio). Both combined therapies lowered blood pressure to similar levels. A combination therapy with losartan and quinapril significantly increased the H/M ratio (1.93 +/- 0.29 and 2.02 +/- 0.29, P < 0.01) and decreased the washout rate (17.6 +/- 11.0 and 15.3 +/- 9.2%, P < 0.02) without affecting AII concentration, whereas a combination therapy with amlodipine and quinapril therapy did not affect the scintigraphic parameters with an increase in the AII concentration. CONCLUSIONS: With a usual antihypertensive dose, both losartan and quinapril had a little suppressive effect on the cardiac sympathetic activity in essential hypertension. In contrast, the combination therapy with losartan and quinapril, which results in a higher degree of inhibition of the renin-angiotensin system, could suppress the cardiac sympathetic activity effectively.
