Mutations in Conserved Amino Acids in the KCNQ1 Channel and Risk of Cardiac Events in Type‐1 Long‐QT Syndrome

Danish National Research Foundation Center of Arrhythmias, University of Copenhagen, Denmark
Journal of Cardiovascular Electrophysiology (Impact Factor: 2.96). 07/2009; 20(8):859 - 865. DOI: 10.1111/j.1540-8167.2009.01455.x


Background: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events.
Methods and Results: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0–0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470–0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy.
Conclusions: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy.

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    ABSTRACT: Electrical cardiomyopathies contain the long QT syndrome (LQTS), the short QT syndrome (SQTS), the Brugada syndrome, and the catecholaminergic polymorphic ventricular tachycardia (CPVT). Patients diagnosed with an electrical cardiomyopathy have an increased risk of syncope and sudden cardiac death (SCD). Usually, we are dealing with young patients or even children. The prevalence of these diseases is low. No large prospective randomized studies exist with respect to outcome based on different clinical and genetic parameters. Thus, risk stratification in these patients is based on retrospective data from single- or multicenter registries. The implantable cardioverter defibrillator is the only reliable therapy in patients with Brugada syndrome and SQTS, as no pharmacological therapy has been proven to prevent SCD. In LQTS and CPVT, the primary therapy relies on β-blockers. In high-risk patients, the ICD is indicated. In all electrical diseases, risk stratification is based on the clinical phenotype, including the electrocardiogram, the history of unexplained or disease-related syncope, and sudden cardiac arrest. In LQTS and CPVT, demographic data like age and gender are important factors for risk stratification. The genotype contributes to risk stratification only in LQTS and CPVT. Patients with electrical cardiomyopathies have to be risk-stratified individually based on the data and the current guidelines available.
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    ABSTRACT: Family members of patients with established long-QT syndrome (LQTS) often lack definitive clinical findings, yet may have inherited an LQTS mutation and be at risk of sudden death. Genetic testing can identify mutations in 75% of patients with LQTS, but genetic testing of family members remains controversial. We used a Markov model to assess the cost-effectiveness of 3 strategies for treating an asymptomatic 10-year-old, first-degree relative of a patient with clinically evident LQTS. In the genetic testing strategy, relatives undergo genetic testing only for the mutation identified in the index patient, and relatives who test positive for the mutation are treated with β-blockers. This strategy was compared with (1) empirical treatment of relatives with β-blockers and (2) watchful waiting, with treatment only after development of symptoms. The genetic testing strategy resulted in better survival and quality-adjusted life years at higher cost, with a cost-effectiveness ratio of $67 400 per quality-adjusted life year gained compared with watchful waiting. The cost-effectiveness of the genetic testing strategy improved to less than $50 000 per quality-adjusted life year gained when applied selectively either to (1) relatives with higher clinical suspicion of LQTS (pretest probability 65% to 81%), or to (2) families with a higher than average risk of sudden death, or to (3) larger families (2 or more first-degree relatives tested). Genetic testing of young first-degree relatives of patients with definite LQTS is moderately expensive, but can reach acceptable thresholds of cost-effectiveness when applied to selected patients.
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