Sex Hormones Prolong the QT Interval and Downregulate Potassium Channel Expression in the Rabbit Heart

Drici, Milou Daniel; Burklow, Thomas R.; Haridasse, Vedanandam; Glazer, Robert I.; Woosley, Raymond L.

doi:10.1161/01.cir.94.6.1471

Cited by 349 publications

(276 citation statements)

References 23 publications

Supporting

Mentioning

255

Contrasting

Unclassified

Order By: Relevance

“…Sex and hormonal differences in ion channel distribution have been described in the heart and could cause alterations in disease penetrance. 23 It is also not known if other clinical conditions that cause STE or J-point elevation (ischemia, hypothermia, acidosis) cause arrhythmias by mechanisms similar to the Brugada syndrome. The identification of novel genes that cause the Brugada syndrome and the correlation of phenotype to genotype may lead to improvements in diagnosis, assessment of prognosis, and choice of therapeutic alternatives for patients with this rare inherited propensity to arrhythmias.…”

Section: Molecular Basis Of the Brugada Syndromementioning

confidence: 99%

Clinical and molecular heterogeneity in the brugada syndrome. A novel gene locus on chromosome 3

Weiss¹,

Barmada²,

Nguyen³

2002

ACC Current Journal Review

View full text Add to dashboard Cite

Background-Brugada syndrome is a form of idiopathic ventricular fibrillation characterized by a right bundle-branch block pattern and ST elevation (STE) in the right precordial leads of the ECG. Sodium channel blockers increase STE. Mutations of the cardiac sodium channel SCN5A cause the disorder, and an implantable cardioverter-defibrillator is often recommended for affected individuals. Mutations in other genes have not been identified, and it is not known if the efficacy of drug testing or the malignancy of arrhythmias correlates to the gene defect. Methods and Results-We performed histories, physical examinations, ECGs, and drug testing on a large multigenerational family with Brugada syndrome. DNA isolated from blood samples, polymorphic genomic markers, and polymorphisms within candidate sodium channels were used for a genome-wide screen, fine mapping, and linkage analysis. We identified 12 affected individuals (right bundle-branch block, Ն1-mm STE) with an autosomal dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age and sex. Four affected individuals had syncope and 2 had documented ventricular arrhythmias, but there was minimal family history of sudden death. Procainamide infusions did not identify additional affected individuals. Linkage was present to an Ϸ15-cM region on chromosome 3p22-25 (maximum LOD scoreϭ4.00). The sodium channel genes SCN5A, SCN10A, and SCN12A on chromosome 3 were excluded as candidates (LOD scores ՅϪ2). Conclusions-A Brugada syndrome locus distinct from SCN5A is associated with progressive conduction disease, a low sensitivity to procainamide testing, and a relatively good prognosis in a single large pedigree.

show abstract

Section: Molecular Basis Of the Brugada Syndromementioning

confidence: 99%

Clinical and molecular heterogeneity in the brugada syndrome. A novel gene locus on chromosome 3

Weiss¹,

Barmada²,

Nguyen³

2002

ACC Current Journal Review

View full text Add to dashboard Cite

show abstract

“…However, Drici et al 21 demonstrated that testosterone and estrogen treatment in castrated female rabbits downregulates message levels of certain potassium channels. mRNA levels of HK2 (also known as hKv1.5, a human clone of the ultrarapidly activating delayed rectifier, I Kur ) 22 were reduced compared with placebo-treated rabbits.…”

Section: Mechanism Of Dht Actionmentioning

confidence: 99%

“…However, their mRNA data did not correspond with the changes in QT intervals that they noted. 21 Liu et al 8 evaluated sex-related differences in 3 major repolarizing K ϩ currents (I to , I K1 , and I Kr ) in the heart. They found no difference in I to density between male and female rabbits and reported a significant difference in I K1 at a single voltage, Ϫ50 mV (1.46Ϯ0.06 pA/pF in females and 1.67Ϯ0.08 pA/pF in males), but no difference at any other voltages.…”

Section: Mechanism Of Dht Actionmentioning

confidence: 99%

Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits

et al. 2002

View full text Add to dashboard Cite

Background-Recent clinical and experimental data suggest that testosterone may protect males against the deleterious effects of repolarization-prolonging drugs. This study tests the hypothesis that 5␣-dihydrotestosterone (DHT) protects normal females against drug-induced excessive prolongation of repolarization. Methods and Results-We used microelectrode techniques to study isolated preparations of rabbit ventricular endocardium from age-matched normal control female rabbits and female rabbits treated with DHT for 4 weeks. Serum 17␤-estradiol levels were identical in the control and DHT-treated animals, whereas DHT levels were high (equaling those in normal males) only in the DHT-treated animals. Basal action potential duration to 90% repolarization (APD 90 ) was significantly shorter in DHT-treated (155Ϯ7.4 ms, nϭ32) than control females (178Ϯ6.7 ms, nϭ29; PϽ0.05) at cycle lengthϭ1000 ms. The increase in APD 90 induced by 10 Ϫ8 mol/L dofetilide at cycle lengthϭ1000 ms was significantly less in DHT-treated females than normal females (⌬APD 90 ϭ8Ϯ7 and 29Ϯ5 ms, respectively, PϽ0.05). At 10 Ϫ6 mol/L dofetilide, the incidence of early afterdepolarizations was 28% in DHT-treated and 55% in normal female rabbits (PϽ0.05). Conclusions-Elevating DHT levels diminishes the effects of dofetilide to increase APD and induce early afterdepolarizations in females. Moreover, treatment of females with DHT results in prolongation of APD and an incidence of early afterdepolarization equal to values previously reported by us for dofetilide-treated normal males. That serum levels of 17␤-estradiol were the same in DHT-treated and untreated females suggests that estradiol is not involved in the response to dofetilide. Thus, these data suggest that DHT and perhaps other androgenic hormones may protect normal females against the risk of dofetilide-induced arrhythmia. Key Words: arrhythmia Ⅲ sex Ⅲ dofetilide Ⅲ hormones D rugs that prolong the QT interval induce a greater incidence of arrhythmias (ie, torsades de pointes [TdP]) in women than in men. [1][2][3] The greater propensity to druginduced TdP in females is generally associated with a sex-related difference in ventricular repolarization in the heart such that the rate-corrected QT interval is longer in females than males. 4 -6 Recent clinical and experimental studies propose that gonadal steroids may modulate the sex-related differences in QT interval and propensity toward drug-induced TdP. [7][8][9][10] Bidoggia et al 7 showed that women with virilization exhibit a shorter and faster repolarization time than normal women and castrated men, suggesting that testosterone is an important modulator of ventricular repolarization. In addition, Rodriguez et al 9 demonstrated that women are at greater risk of drug-induced QT prolongation during menstruation and the ovulatory phase of the menstrual cycle, with decreased risk during the luteal phase.Given that progesterone levels are higher during the luteal than the ovulatory and menstruation phases, Rodriguez et al suggest that androgen ...

show abstract

“…It is suggested that stressful situations during ovulatory periods and menstruation may cause increased 17-hydroxy corticosterone levels with resulting eosinopenia 2 . Platelet function is periodically altered during the ovarian cycle due to the influence of progesterone and estrogen on Von Willebrand factor concentrations 3 . Ovarian hormones influence almost all the systems of the body.…”

Section: Introductionmentioning

confidence: 99%

Hematological Modulation in Different Phases of Menstrual Cycle

Malipatil¹,

Patil²

2013

Int Jour of Biomed Res

View full text Add to dashboard Cite

Sex Hormones Prolong the QT Interval and Downregulate Potassium Channel Expression in the Rabbit Heart

Cited by 349 publications

References 23 publications

Clinical and molecular heterogeneity in the brugada syndrome. A novel gene locus on chromosome 3

Clinical and molecular heterogeneity in the brugada syndrome. A novel gene locus on chromosome 3

Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits

Hematological Modulation in Different Phases of Menstrual Cycle

Contact Info

Product

Resources

About