The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.

Abstract-The influence of left atrial size on cardiovascular events during antihypertensive treatment has not been reported previously from a long-term, prospective, randomized hypertension treatment trial. We recorded left atrial diameter by annual echocardiography and cardiovascular events in 881 hypertensive patients (41% women) with electrocardiographic left ventricular hypertrophy aged 55 to 80 (mean: 66) years during a mean of 4. S tudies in samples of the general population and in hypertensive patients have identified left atrial (LA) enlargement as a cardiovascular (CV) risk marker, in particular for atrial fibrillation and stroke. [1][2][3] We have shown previously that larger LA diameter in hypertensive patients is associated with other clinical and echocardiographic covariates of higher CV risk in hypertension, including higher body mass index, systolic blood pressure and age, left ventricular (LV) hypertrophy, eccentric LV geometry and mitral regurgitation by echocardiography, and atrial fibrillation. 4 However, less is known about the effect of antihypertensive treatment on LA diameter or on the relation between LA diameter and CV events during antihypertensive treatment. 5 Therefore, we evaluated the effect of losartan-or atenolol-based antihypertensive therapy on LA diameter and the relation between in-treatment LA diameter and CV events in the echocardiographic substudy of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Methods Patient PopulationThe LIFE echocardiography study was a prospectively planned substudy of the main LIFE study, which enrolled 960 of the 9193 participants in the parent trial for annual echocardiographic follow-up. 6,7 Patient characteristics and outcome results in the main LIFE study that randomly assigned patients aged 55 to 80 years with essential hypertension (baseline blood pressure: 160 to 200/95 to 115 mm Hg) and ECG LV hypertrophy (according to Cornell voltage duration or Sokolow-Lyon voltage criteria) to a mean of 4.8 years double-blind treatment with losartan compared with atenolol have been published, including the effects of treatment on CV events and regression of ECG LV hypertrophy. 6,8 Of the 960 patients enrolled in the LIFE echocardiographic substudy, 881 patients had LA diameter measured at enrollment and on Ն1 follow-up echocardiogram and, thus, were eligible for the present study (Table 1). Patients were classified as having isolated systolic hypertension if systolic blood pressure was Ն140 mm Hg and diastolic blood pressure Ͻ90 mm Hg, respectively, at baseline clinic visits. 9 Pulse pressure was calculated as the

Abstract-The ECG strain pattern of lateral ST depression and T-wave inversion is a marker for left ventricular hypertrophy (LVH) and adverse prognosis in population studies. However, whether ECG strain is an independent predictor of cardiovascular (CV) morbidity and mortality in the setting of aggressive antihypertensive therapy is unclear.ECGs were examined at study baseline in 8854 hypertensive patients with ECG LVH who were treated in a blinded manner with atenolol-or losartan-based regimens. Strain was defined by the presence of a downsloping convex ST segment with an inverted asymmetrical T wave opposite to the QRS axis in leads V 5 and/or V 6 and was present in 971 patients (11.0% Key Words: coronary disease Ⅲ electrocardiography Ⅲ hypertension T he classic strain pattern of ST depression and T-wave inversion on the ECG is a well recognized marker of the presence of anatomic left ventricular hypertrophy (LVH), 1-7 independent of the possible relationship of this repolarization abnormality to underlying coronary heart disease. 7 Indeed, the presence of even minimal degrees of ST depression in the lateral precordial leads is associated with increased LV mass and prevalence of anatomic LVH when repolarization is examined quantitatively on digital ECGs. 8 Incorporation of ECG strain into scores that include standard voltage criteria improves ECG detection of LVH. 2,6 ECG strain has also been associated with adverse prognosis in a variety of clinical populations, 9 -15 including patients with hypertension, 9,10 and implicated as the primary marker of untoward outcomes when ECG LVH criteria have been used for risk stratification. 9 -13 However, whether ECG strain is an independent predictor of cardiovascular (CV) morbidity and mortality after adjusting for the type and effectiveness of antihypertensive therapy is unclear.The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrated that therapy with losartan was more effective than atenolol in preventing CV morbidity and mortality in the setting of large and nearly identical reductions in systolic and diastolic pressure in both treatment arms. 16 In the prespecified echocardiographic substudy of the LIFE study, strain on the baseline ECG was associated with greater LV mass and a higher prevalence of LVH, 7 suggesting that ECG strain may also be associated with an increased risk of CV morbidity and mortality in LIFE. Therefore, the present study examined the relation of the strain pattern on the baseline ECG to major CV events in the LIFE study, independent of the effects of treatment type, baseline severity of hypertension and ECG LVH, and other potential risk factors. 16

Abstract-Left ventricular hypertrophy is a risk factor for cardiovascular mortality, including sudden cardiac death.Experimentally, left ventricular hypertrophy delays ventricular conduction and prolongs action potential duration. Electrocardiographic QRS duration and QT interval measures reflect these changes, but whether these measures can further stratify risk in patients with electrocardiographic left ventricular hypertrophy is unknown. We measured the QRS duration and QT intervals from the baseline 12-lead electrocardiograms in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, which included hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy randomized to either losartan-based or atenolol-based treatment to lower blood pressure. In the present study, we related study baseline electrocardiographic measures to cardiovascular and all-cause mortality. There were 5429 patients (male 45.8%; mean age 66Ϯ7 years) included in the present analyses. After a mean follow-up of 4.9Ϯ0.8 years, there were 417 deaths from all causes, including 214 cardiovascular deaths. In separate univariate Cox regression analyses, QRS duration and several QT measures were significant predictors of cardiovascular mortality and all-cause mortality. However, in multivariate Cox analyses including all electrocardiographic measures and adjusting for other risk factors as well as treatment strategy, only QRS duration and maximum rate-adjusted QT apex interval remained as significant independent predictors of cardiovascular (Pϭ0.022 and Pϭ0.037, respectively) and all-cause mortality (Pϭ0.038 and Pϭ0.002, respectively). In conclusion, in a hypertensive risk population identified by electrocardiographic left ventricular hypertrophy, increased QRS duration and maximum QT apex interval can further stratify mortality risk even in the setting of effective blood pressure-lowering treatment. Key Words: electrocardiography Ⅲ hypertension Ⅲ mortality Ⅲ hypertrophy L eft ventricular hypertrophy (LVH) is an important indicator of target organ damage in chronic arterial hypertension. Electrocardiographically and echocardiographically detected LVH independently predict increased morbidity and mortality, 1,2 including sudden cardiac death, 3,4 and the relative risk of these events increases with increasing LV mass. The impact of LVH on outcome may in part be mediated by adverse changes in LV mechanical function. However, LVH also induces potentially arrhythmogenic changes in LV electrophysiology. Experimental evidence shows that LVH alters ventricular conduction and repolarization. [5][6][7][8][9][10][11][12][13][14] In the 12-lead ECG, these changes may prolong the QRS and QT interval duration, respectively, and affect T-wave morphology. [15][16][17] In hypertensive patients with ECG LVH, increase in LV mass was associated with prolonged QRS and QT interval duration and measures of QT dispersion. 18 However, it is unknown if these ECG measures can further stratify risk in patients with LVH. T...

Ventricular repolarization abnormalities increase the risk of ventricular arrhythmias, and prolongation and shortening of the electrocardiographic QT interval increase the risk of SCD. 4,5 However, the association between QT duration and SCD in the general population has been relatively weak. Recently, an association between prolongation of the T-wave peak to T-wave end interval (TPE) and SCD was found in a general population sample.6 Furthermore, computerized measures of the 3-dimensional T-wave loop, the T-wave morphology parameters, have contained prognostic value for cardiovascular morbidity and mortality in several population studies, 7−12 but their relation specifically to SCD is less clear. The aim of the present study was to test the hypothesis that TPE and T-wave morphology parameters predict SCD in the general population.© 2013 American Heart Association, Inc. Original ArticleBackground-Previous population studies have found an association between electrocardiographic T-wave morphology parameters and cardiovascular mortality, but their relationship to sudden cardiac death (SCD) is not clear. To our knowledge, there are no follow-up studies assessing the association between electrocardiographic T-wave peak to T-wave end interval (TPE) and SCD. We assessed the predictive value of electrocardiographic T-wave morphology parameters and TPE for SCD in an adult general population sample. Methods and Results-A total of 4 T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, T-wave residuum) as well as TPE were measured from digital standard 12-lead ECGs in 5618 adults (46% men; mean age 50.9±12.5 years) participating in the Finnish population-based Health 2000 Study. After a mean follow-up time of 7.7±1.4 years, 72 SCDs had occurred. In univariable analyses, all T-wave morphology parameters were associated with an increased SCD risk. In multivariable Cox models, T-wave morphology dispersion and total cosine R-to-T remained as predictors of SCD, with T-wave morphology dispersion showing the highest SCD risk (hazard ratio of 1.4 [95% confidence interval 1.1−1.7, P=0.001] per 1 SD increase in the log e T-wave morphology dispersion). In contrast, TPE was not associated with SCD in univariable or multivariable analyses. Conclusions-Electrocardiographic T-wave morphology parameters describing the 3-dimensional shape of the T-wave stratify SCD risk in the general population, but we did not find an association between TPE and SCD.

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When clinical evidence of CHD is accounted for, ECG strain is likely to indicate the presence of anatomic LVH. Greater LV mass and higher prevalence of LVH in patients with strain offer insights into the known association of the strain pattern with adverse outcomes.

Abstract-LeftKey Words: left atrial size Ⅲ hypertrophy Ⅲ age Ⅲ body mass index L eft atrial (LA) enlargement diagnosed by electrocardiography or echocardiography is a common finding in hypertensive patients, indicating hypertensive heart disease. 1-4 Echocardiographic LA size in hypertension has been related to systolic blood pressure and left ventricular (LV) hypertrophy in older patients with isolated systolic hypertension. 1 Furthermore, echocardiographic studies in men with mild to moderate hypertension have suggested age, obesity, and race as other important covariates of LA size. 5,6 Recent studies have shown that LA enlargement is a risk factor for atrial fibrillation and stroke, especially in men. 7,8 LV hypertrophy has been suggested to mediate, at least partially, the relation between hypertension and LA enlargement. However, correlates of LA size in hypertensive patients with LV hypertrophy have so far not been assessed in a large-scale study. Thus, the aim of the present study was to describe factors associated with LA enlargement in hypertensive patients with electrocardiographic LV hypertrophy recruited into the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Methods PatientsThe present study was performed as an echocardiographic substudy to the LIFE study. From a total of 9194 hypertensive patients age 55 to 80 years who were recruited into the LIFE study at sites in Denmark, Finland, Iceland, Norway, Sweden, United Kingdom, and United States, 963 patients were enrolled in the echocardiographic substudy. All patients had casual blood pressure in the range 160 to 200/95 to 115 mm Hg, and electrocardiographic LV hypertrophy by either Sokolow-Lyon voltage criteria (SV1ϩRV5/RV6Ͼ38 mV) or Cornell voltage-duration criteria (Ն2440 mVϫms). Baseline characteristics of the total LIFE study population and study design for the LIFE echocardiographic substudy have been previously pub-