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Genotype-phenotype aspects of type 2 long QT syndrome.

ABSTRACT: The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS).Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology.Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contributions of clinical and genetic factors to the first cardiac events.For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (hazard ratio [HR]: 2.87 and 1.86, respectively), but the transmembrane nonpore (S1-S4) region was not (HR: 1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane nonpore regions (HR: 1.54 and 2.42, respectively). However, for nonmissense mutations, these other regions were no longer riskier than the C-terminus (HR: 1.13, 0.77, and 0.46, respectively). Likewise, subjects with nonmissense mutations were at significantly higher risk than were subjects with missense mutations in the C-terminus region (HR: 2.00), but that was not the case in other regions. This mutation location-type interaction was significant (p = 0.008). A significantly higher risk was found in subjects with mutations located in alpha-helical domains than in subjects with mutations in beta-sheet domains or other locations (HR: 1.74 and 1.33, respectively). Time-dependent beta-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p < 0.001).The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.

SUBMITTER: Shimizu W

PROVIDER: S-EPMC2808400 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Genotype-phenotype aspects of type 2 long QT syndrome.

Shimizu Wataru W Moss Arthur J AJ Wilde Arthur A M AA Towbin Jeffrey A JA Ackerman Michael J MJ January Craig T CT Tester David J DJ Zareba Wojciech W Robinson Jennifer L JL Qi Ming M Vincent G Michael GM Kaufman Elizabeth S ES Hofman Nynke N Noda Takashi T Kamakura Shiro S Miyamoto Yoshihiro Y Shah Samit S Amin Vinit V Goldenberg Ilan I Andrews Mark L ML McNitt Scott S

Journal of the American College of Cardiology 20091101 22

<h4>Objectives</h4>The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS).<h4>Background</h4>Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology.<h4>Methods</h4>Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-ha ...[more]

PMID: 19926013

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Project description:Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in Langendorff-perfused guinea pig hearts (n = 34). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel β1-subunit adhesion domain antagonist (βadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and βadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by means of managing sodium levels and preventing cardiac edema in patients.NEW & NOTEWORTHY This is the first study to demonstrate that the long-QT syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating extracellular sodium concentrations and/or the intercalated disc separation. The animal experiments and computational modeling in the current study reveal a critically important clinical implication: sodium dysregulation in the presence of edema within the intercalated disc can markedly increase the risk of arrhythmia in LQT3. These findings strongly suggest that maintaining extracellular sodium within normal physiological limits may be an effective and inexpensive therapeutic option for patients with congenital or acquired sodium channel gain-of-function diseases.

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Genotype-phenotype aspects of type 2 long QT syndrome.

Publications

Genotype-phenotype aspects of type 2 long QT syndrome.

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