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首页> 外文学位 >Electrocardiographic Intervals in African-Americans: Clinical Correlates, Heritability, Effects of the SCN5A Variant S1103Y, and Interaction with Diuretic-Associated Hypokalemia (The Jackson Heart Study).
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Electrocardiographic Intervals in African-Americans: Clinical Correlates, Heritability, Effects of the SCN5A Variant S1103Y, and Interaction with Diuretic-Associated Hypokalemia (The Jackson Heart Study).

机译：非裔美国人的心电图间隔：临床相关性，遗传性，SCN5A变异S1103Y的作用以及与利尿药相关性低钾血症的相互作用（杰克逊心脏研究）。

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摘要

Every year, sudden cardiac arrest (SCA) claims hundreds of thousands of lives in the United States and millions worldwide and prevention of the SCA deaths presents a major challenge. Though it commonly occurs in cardiac patients, it can also happen in previously asymptomatic individuals, many of whom are young. The rates of SCA are higher in African Americans than in European Americans, but causes of the difference are not fully understood.;Known risk factors for SCA include coronary artery disease, hypertension, smoking, electrocardiographic QT interval prolongation, and family history. Several genetic mutations have been associated with potentially fatal arrhythmias. Moreover, sudden death due to cardiac arrest caused by an arrhythmia in the absence of structural abnormalities is now believed to be a predominantly inherited condition.;Hypokalemia is another serious condition associated with increased risk of QT interval prolongation, arrhythmia, and SCA. Hypokalemia is mostly caused by excessive potassium loss and is a common consequence of diuretic use. Diuretics have been recommended as the initial therapy for uncomplicated hypertension and are widely used in antihypertensive treatment. With a high prevalence of hypertension in the US (and even higher among African-Americans compared to the general population), maintaining plasma potassium levels in hypertensive and other patients at risk for SCA is extremely important.;The S1103Y missense allele of the human SCN5A cardiac sodium channel gene is a common variant of African ancestry that has been associated with increased risk of QT interval prolongation, ventricular arrhythmias, and sudden cardiac death. Recent studies have also implicated the S1103Y variant in sudden infant death syndrome. Based on its biophysical properties, it has been predicted to increase the risk of QT prolongation and arrhythmia in response to hypokalemia and/or medications that inhibit cardiac repolarization. However, the effects of this allele on cardiac conduction and repolarization in the general population have not been sufficiently studied.;The objectives of this research were to determine the clinical correlates of the electrocardiographic (EKG) measures of cardiac conduction (PR and QRS intervals) and repolarization (QT interval) and estimate heritability of these parameters in the Jackson Heart Study (JHS) as well as to investigate the association between the SCN5a S1103Y allele and the three EKG intervals and explore the potential interaction between the allele and diuretic-induced hypokalemia in prolonging the QTc interval in this large African-American cohort.;A total of 5301 participants attended the JHS baseline examination from 2000–2004. Participant demographic, anthropometric, and clinical data, including 12-lead ECG and serum chemistries, as well as DNA samples were collected. EKG records were read centrally using the Minnesota Code Modular ECG Analysis System. A total of 4477 participants were genotyped for the S1103Y allele.;Individuals without EKG or genetic data or with bundle branch block or paced rhythm were excluded from all analyses. In addition, patients with atrial fibrillation/flutter were excluded from PR and QT interval analyses while those with intraventricular conduction delay or QRS >120 msec were excluded from analyses of QT interval. Also, those treated with medications altering any of the three EKG interval, were excluded from the analyses of that measure. The final analysis sample consisted of 4348 participants eligible for analysis of at least one EKG interval.;Associations between PR, QRS and QT intervals and the S1103Y allele were tested using multivariable linear mixed effects models. Heritability of the EKG measures was estimated in a subset of 1,481 participants in 264 families. Interaction between S1103Y and diuretic-associated hypokalemia was examined by comparing allele carriers to non-carriers for each diuretic-hypokalemia group.;The S1103Y carrier and allele frequencies in the study sample were 15.4% and 8%, respectively. The heritability estimates were 50% for PR, 47% for QT, and 33% for QRS interval. The S1103Y allele was significantly associated with decrease in PR (−5.3 msec) and QRS interval (−1.5 msec) intervals and increase in QTc interval (2.1 msec) in multivariable-adjusted additive genetic models, consistent with expectations based on biophysical properties of the S1103Y amino acid substitution. The effect of QTc prolongation by diuretic-associated hypokalemia was significantly potentiated by the presence of the S1103Y allele. These findings warrant further investigation as they could have important clinical implications for treatment guidelines, recommending use of diuretics in carriers of this genetic variant with hypertension or heart failure.
机译：每年，心脏骤停（SCA）导致美国成千上万人的生命死亡以及全世界数百万人的生命，而预防SCA死亡是一项重大挑战。尽管它通常发生在心脏病患者中，但也可能发生在以前无症状的个体中，其中许多是年轻的。非裔美国人的SCA发病率高于欧洲裔美国人，但差异的原因尚不完全清楚。SCA的已知危险因素包括冠心病，高血压，吸烟，心电图QT间隔延长和家族史。几种遗传突变与潜在的致命性心律失常有关。而且，现在认为在没有结构异常的情况下由心律失常引起的心脏骤停导致的猝死是主要的遗传病。低钾血症是与QT间隔延长，心律不齐和SCA风险增加相关的另一种严重疾病。低钾血症主要由钾过多流失引起，是利尿剂使用的常见后果。利尿剂已被推荐作为单纯性高血压的初始疗法，并广泛用于降压治疗。在美国，高血压患病率很高（在非裔美国人中甚至比普通人群更高），维持高血压和其他患有SCA风险的患者的血浆钾水平非常重要。;人SCN5A的S1103Y错义等位基因心脏钠通道基因是非洲血统的常见变体，与QT间隔延长，室性心律不齐和猝死有关。最近的研究还表明S1103Y变异可能与婴儿猝死综合征有关。基于其生物物理特性，已预测由于低钾血症和/或抑制心脏复极的药物会增加QT延长和心律不齐的风险。然而，该等位基因对普通人群心脏传导和复极化的影响尚未得到充分研究。这项研究的目的是确定心电图（EKG）对心脏传导的测量的临床相关性（PR和QRS间隔）和重新极化（QT间隔），并在杰克逊心脏研究（JHS）中估计这些参数的遗传力，并研究SCN5a S1103Y等位基因与三个EKG间隔之间的关联，并探索等位基因与利尿剂引起的低钾血症之间的潜在相互作用在这个庞大的非裔美国人队列中延长QTc间隔。；从2000年至2004年，共有5301名参与者参加了JHS基线检查。收集了参与者的人口统计学，人体测量学和临床数据，包括12导联心电图和血清化学成分以及DNA样本。使用明尼苏达州代码模块化ECG分析系统集中读取EKG记录。对S1103Y等位基因进行基因分型的共有4477名参与者;所有分析均不包括无EKG或遗传数据，无束支传导阻滞或节奏性节奏的个体。此外，房颤/颤动的患者被排除在PR和QT间隔分析之外，而脑室内传导延迟或QRS> 120毫秒的患者被排除在QT间隔分析之外。同样，那些用改变了三个EKG间隔的药物治疗的患者也被排除在该措施的分析之外。最终的分析样本由4348名参与者组成，这些参与者符合至少一个EKG区间的分析要求；使用多变量线性混合效应模型测试了PR，QRS和QT区间与S1103Y等位基因之间的关联。在264个家庭的1,481名参与者中，估计了心电图测量的遗传力。通过比较每个利尿低钾血症组的等位基因携带者与非携带者之间的关系，检查了S1103Y与利尿相关的低钾血症之间的相互作用。研究样本中的S1103Y携带者和等位基因频率分别为15.4％和8％。 PR的遗传力估计值分别为50％，QT的47％和QRS间隔的33％。在多变量调整的加成遗传模型中，S1103Y等位基因与PR（-5.3毫秒）和QRS间隔（-1.5毫秒）间隔的减少和QTc间隔（2.1毫秒）的增加显着相关，这与基于动物的生物物理特性的预期一致S1103Y氨基酸取代。 S1103Y等位基因的存在显着增强了利尿相关的低钾血症对QTc延长的影响。这些发现值得进一步研究，因为它们可能对治疗指南具有重要的临床意义，建议在这种遗传变异伴有高血压或心力衰竭的患者中使用利尿剂。

著录项

  • 作者

    Akylbekova, Ermeg Lina.;

  • 作者单位

    The University of Mississippi Medical Center.;

  • 授予单位 The University of Mississippi Medical Center.;
  • 学科 Biology Genetics.;Health Sciences Epidemiology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 89 p.
  • 总页数 89
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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