Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes

Mank-Seymour, Amy R.; Richmond, Jodi; Wood, Linda; Reynolds, Jennifer M.; Fan, Yu-Ti; Warnes, Gregory R.; Milos, Patrice M.; Thompson, John F.

doi:10.1016/j.ahj.2006.08.020

Cited by 51 publications

(40 citation statements)

References 32 publications

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“…Additionally, subtle mutations have been discovered in LQTrelated genes like KCNQ1 (29), KCNH2 (29), SCN5A (45), and KCNE2/MirP1 (1,43) in various healthy humans with drug-induced LQTS (22,51). Thus anesthesia-associated QT prolongation and arrhythmia might be of clinical significance even in apparently healthy patients, especially in the presence of other drugs and compounding factors like hypokalemia and bradycardia.…”

Section: Discussionmentioning

confidence: 99%

“…The risk for anesthesiainduced malignant pVT is particularly pronounced in individuals with congenital long QT (LQT) syndromes (LQTS) (2,14,17,18,31,35,40) (12) are responsible for the LQT1 and LQT2 phenotypes, respectively. Furthermore, subtle mutations in LQT-related genes can predispose healthy individuals to drug-induced QT prolongation and ventricular arrhythmia (20,22,29,51). Therefore, anesthetic agents might have more serious implications for apparently healthy individuals in the general population.…”

mentioning

confidence: 99%

“…Loss-of-function mutations in K ϩ voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1; KvLQT1, ␣-subunit of slow delayed rectifier K ϩ current (I Ks )] (49) and K ϩ voltage-gated channel, subfamily H, member 2 [KCNH2; human ether-a-go-go related gene (HERG), ␣-subunit of rapidly activating K ϩ current (I Kr )] (12) are responsible for the LQT1 and LQT2 phenotypes, respectively. Furthermore, subtle mutations in LQT-related genes can predispose healthy individuals to drug-induced QT prolongation and ventricular arrhythmia (20,22,29,51). Therefore, anesthetic agents might have more serious implications for apparently healthy individuals in the general population.…”

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confidence: 99%

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Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

Odening

Hyder

Chaves

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization. Am J Physiol Heart Circ Physiol 295: H2264 -H2272, 2008. First published October 3, 2008 doi:10.1152/ajpheart.00680.2008.-Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K ϩ currents (IKs) or rapidly activating K ϩ currents (IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K ϩ current (IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced I Kr . repolarization reserve; long QT syndrome types 1 and 2; sudden cardiac death; ventricular fibrillation COMMONLY USED ANESTHETIC AGENTS influence cardiac repolarization, with effects on surface ECG such as changes in QT interval duration and T-wave morphology (23,26,37,41). Drug-induced QT prolongation is known to precede potentially lethal arrhythmias such as polymorphic ventricular tachycardia (pVT) (reviewed in Refs. 3 and 15). The risk for anesthesiainduced malignant pVT is particularly pronounced in individuals with congenital long QT (LQT) syndromes (LQTS) (2,14,17,18,31,35,40) (12) are responsible for the LQT1 and LQT2 phenotypes, respectively. Furthermore, subtle mutations in LQT-related genes can predispose healthy individuals to drug-induced QT prolongation and ventricular arrhythmia (20,22,29,51). Therefore, anesthetic agents might have more serious implications for apparently healthy individuals in the general population.In vitro patch-clamp experiments have revealed that several anesthetic drugs block cardiac repolarizing ion currents; isoflurane (47) and pro...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

Odening

Hyder

Chaves

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Candidate single nucleotide polymorphisms (SNPs) were selected among those previously described as modulating ECG intervals [11][12][13][14][15][16][17] or predisposition to arrhythmic events. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] In particular, most variants were located in genes encoding cardiac voltage-dependent channels (KCNQ1, KCNH2, SCN5A, KCNJ11, KCNE1, KCNE2, KCNJ2), structural proteins (ANK2, GJA5, PALLD), sympathetic system modulators (ADRB1, ADRB2, ADRB3), blood pressure regulators (NOS1AP, PAI-1), modulators of ionic flows (PLN, CERKL, SLCO3A1), transcription factors (BRUNOL4, LITAF), regulators of cell morphology (NRG3) and other genes known to be associated to ECG intervals modulation (MDR1, CASQ2, NDRG4, NUBPL, RNF207; Supplementary Table S2).…”

Section: Genetic Analysismentioning

confidence: 99%

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

Sommariva¹,

Pappone

Boneschi³

et al. 2013

Eur J Hum Genet

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Brugada syndrome is an inherited arrhythmogenic disorder leading to sudden death predominantly in the 3-4 decade. To date the only reliable treatment is the implantation of a cardioverter defibrillator; however, better criteria for risk stratification are needed, especially for asymptomatic subjects. Brugada syndrome genetic bases have been only partially understood, accounting for o30% of patients, and have been poorly correlated with prognosis, preventing inclusion of genetic data in current guidelines. We designed an observational study to identify genetic markers for risk stratification of Brugada patients by exploratory statistical analysis. The presence of genetic variants, identified by SCN5A gene analysis and genotyping of 73 candidate polymorphisms, was correlated with the occurrence of major arrhythmic events in a cohort of 92 Brugada patients by allelic association and survival analysis. In all, 18 mutations were identified in the SCN5A gene, including 5 novel, and statistical analysis indicated that mutation carriers had a significantly increased risk of major arrhythmic events (P ¼ 0.024). In addition, we established association of five polymorphisms with major arrhythmic events occurrence and consequently elaborated a pilot risk stratification algorithm by calculating a weighted genetic risk score, including the associated polymorphisms and the presence of SCN5A mutation as function of their odds ratio. This study correlates for the first time the presence of genetic variants with increased arrhythmic risk in Brugada patients, representing a first step towards the design of a new risk stratification model.

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“…Mutations of KCNH2, KCNQ1, KCNE2 and ANKB genes have been identified in some patients with drug induced torsades de pointes of which KCNQ1 mutation is the most common one whose expression results into variability of IKs channel functioning. [12][13][14] Furthermore IKs amplitude variability majorly contributes to variability in response to IKr block. More is the IKs amplitude; more is its efficiency to counteract the IKr blocking drugs i.e, QT prolonging drugs.…”

Section: Mechanism Of Tdpmentioning

confidence: 99%

Pharmacological and therapeutical basis of torsades de pointes

Thota

Pakanati

Siddamshetty

et al. 2016

Int J Basic Clin Pharmacol

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Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes

Cited by 51 publications

References 32 publications

Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

Pharmacological and therapeutical basis of torsades de pointes

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