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

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.