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In the recent years, short-term heart rate variability (HRV) describing complex variations of beat-to-beat interval series that are mainly controlled by the autonomic nervous system (ANS) has been increasingly analyzed to assess the ANS activity in different diseases and under various conditions. In contrast to long-term HRV analysis, short-term investigations (<30 min) provide a test result almost immediately. Thus, short-term HRV analysis is suitable for ambulatory care, patient monitoring and all those applications where the result is urgently needed. In a previous study, we could show significant variations of 5-min HRV indices according to age in almost all domains (linear and nonlinear) in 1906 healthy subjects from the KORA S4 cohort. Based on the same group of subjects, general gender-related influences on HRV indices are to be determined in this study. Short-term 5-min HRV indices from linear time and frequency domain and from nonlinear methods (compression entropy, detrended fluctuation analysis, traditional and segmented Poincaré plot analysis, irreversibility analysis, symbolic dynamics, correlation and mutual information analysis) were determined from 782 females and 1124 males. First, we examined the gender differences in two age clusters (25-49 years and 50-74 years). Secondly, we investigated the gender-specific development of HRV indices in five age decade categories, namely for ages 25-34, 35-44, 45-54, 55-64 and 65-74 years. In this study, significant modifications of the indices according to gender could be obtained, especially in the frequency domain and correlation analyses. Furthermore, there were significant modifications according to age in nearly all of the domains. The gender differences disappeared within the last two age decades and the age dependencies disappeared in the last decade. To summarize gender and age influences need to be considered when performing HRV studies even if these influences only partly differ.

Aims/hypothesis Cardiac autonomic nervous dysfunction (CAND) raises the risk of mortality, but the glycaemic threshold at which it develops is unclear. We aimed to determine the prevalence of, risk factors for and impact of CAND in glucose intolerance and diabetes. Methods Among 1,332 eligible participants aged 55–74 years in the population-based cross-sectional KORA S4 study, 130 had known diabetes mellitus (k-DM), and the remaining 1,202 underwent an OGTT. Heart rate variability (HRV) and QT variability were computed from supine 5 min ECGs. Results In all, 565 individuals had normal glucose tolerance (NGT), 336 had isolated impaired fasting glucose (i-IFG), 72 had isolated impaired glucose tolerance (i-IGT), 151 had combined IFG–IGT (IFG–IGT) and 78 had newly detected diabetes mellitus (n-DM). Adjusted normal HRV limits were defined in the NGT population (5th and 95th percentiles). Three HRV measures were more frequently abnormal in those with k-DM, n-DM, IFG–IGT and i-IFG than in those with NGT ( p <  0.05). The rates of CAND (≥2 of 4 HRV indices abnormal) were: NGT, 4.5%; i-IFG, 8.1%; i-IGT, 5.9%; IFG–IGT, 11.4%; n-DM, 11.7%; and k-DM, 17.5% ( p <  0.05 vs NGT, except for i-IGT). Reduced HRV was associated with cardiovascular risk factors used to construct a simple screening score for CAND. Mortality was higher in participants with reduced HRV ( p <  0.05 vs normal HRV). Conclusions/interpretation In the general population aged 55–74 years, the prevalence of CAND is increased not only in individuals with diabetes, but also in those with IFG–IGT and, to a lesser degree, in those with i-IFG. It is associated with mortality and modifiable cardiovascular risk factors which may be used to screen for diminished HRV in clinical practice.

Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent. Electrocardiograms of 1,945 participants aged 35-74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05-3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21-5.83, p = 0.015) for men between 35-54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58-6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90-9.61, p<0.001) for men between 35-54 y. HRs for all-cause mortality were weaker but reached significance. We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors' Summary.

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP ( CAPON ), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

This study has aimed to develop a novel pre-diagnostic tool for primary care screening of heart disease based on multivariate short-term heart rate variability (HRV) analyzed by linear (time and frequency domain) and nonlinear methods (compression entropy (CE), detrended fluctuation analysis (DFA), Poincaré plot analysis, symbolic dynamics) applied to 5-min ECG segments. Firstly, we applied HRV analysis to separate healthy subjects (REF) from heart disease patients (PAT). Then to optimize the results, we subdivided both groups according to gender: REF (♂ = 78, ♀ = 53) versus PAT (♂ = 378, ♀ = 115). Finally, we divided REF and PAT into two age subgroups (30-50 years vs. 51-70 years of age) to consider the influence of age on HRV. Heart disease patients were classified using a scoring system based on cut-off values calculated from all HRV indices obtained from the REF. After combining the optimum indices from all different analyzing methods, sensitivities of more than 72% and a specificity of 100% in all subgroups were revealed. Nonlinear indices proved to be better for discriminating heart disease patients from healthy subjects. Multivariate short-term HRV, analyzed by both linear and nonlinear methods appears to be a suitable pre-diagnostic tool for screening heart disease in primary care settings.

Left ventricular hypertrophy, a major independent risk factor for morbidity and mortality from cardiovascular disease, 1 – 4 is widely thought to be a consequence of left ventricular pressure overload 5 , 6 . However, the degree of such hypertrophy in patients with mildly elevated arterial pressure is not uniform and may range from normal ventricular mass to severe hypertrophy 6 , 7 . Furthermore, recent epidemiologic studies have shown that many subjects with left ventricular hypertrophy have normal blood pressure, suggesting that factors other than hemodynamic overload may contribute to the hypertrophy 4 . Neuroendocrine factors such as angiotensin II and bradykinin have been implicated in . . .

Arne Pfeufer and colleagues report a genome-wide association study of the electrocardiographic measurement of PR interval in seven population-based cohorts in the CHARGE consortium. They identify nine loci associated with PR interval and highlight candidate genes with a role in ion channels and cardiac development. The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA ( N = 28,517). We identified nine loci associated with PR interval at P < 5 × 10 −8 . At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A . Six of the loci were near cardiac developmental genes, including CAV1-CAV2 , NKX2-5 ( CSX1 ), SOX5 , WNT11 , MEIS1 , and TBX5-TBX3 , providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A , SCN10A , NKX2-5 , CAV1-CAV2 , and SOX5 , were also associated with atrial fibrillation ( N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Patrick Ellinor and colleagues report a genome-wide association study identifying variants in KCNN3 associated to lone atrial fibrillation. Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10 −12 ), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40–1.64; P = 1.83 × 10 −21 ). rs13376333 is intronic to KCNN3 , which encodes a potassium channel protein involved in atrial repolarization.

Prediction of Mortality Using Measures of Cardiac Autonomic Dysfunction in the Diabetic and Nondiabetic Population The MONICA/KORA Augsburg Cohort Study Dan Ziegler , MD, FRCPE 1 , Christian P. Zentai , MD 1 , Siegfried Perz , MSC 2 , Wolfgang Rathmann , MD, MSPH 3 , Burkhard Haastert , PHD 3 , Angela Döring , MD 4 , Christa Meisinger , MD 4 and for the KORA Study Group 1 Institute for Clinical Diabetes Research, German Diabetes Center, Leibniz Institute at the Heinrich Heine University, Düsseldorf, Germany 2 Institute of Medical Informatics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany 3 Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute at the Heinrich Heine University, Düsseldorf, Germany 4 Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany Address correspondence and reprint requests to Dr. Dan Ziegler, FRCPE, Institut für Klinische Diabetologie, Deutsches Diabetes-Zentrum, Leibniz-Zentrum an der Heinrich-Heine-Universität Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany. E-mail: dan.ziegler{at}ddz.uni-duesseldorf.de Abstract OBJECTIVES —To evaluate whether reduced heart rate variability (HRV), prolonged corrected QT (QTc) interval, or increased QT dispersion (QTD) are predictors of mortality in the general diabetic and nondiabetic population. RESEARCH DESIGN AND METHODS —Nondiabetic ( n = 1,560) and diabetic ( n = 160) subjects aged 55–74 years were assessed to determine whether reduced HRV, prolonged QTc interval, and increased QTD may predict all-cause mortality. Lowest quartiles for the maximum-minimum R-R interval difference (max-min, as measured at baseline from a 20-s standard 12-lead resting electrocardiogram without controlling for depth and rate of respiration), QTc >440 ms and QTD >60 ms, were used as cutpoints. RESULTS —During a 9-year follow-up, 10.5% of the nondiabetic and 30.6% of the diabetic population deceased. In the nondiabetic individuals, multivariate Cox proportional hazard models adjusted for cardiovascular risk factors and demographic variables showed that prolonged QTc interval (hazard ratio 2.02 [95% CI 1.29–3.17]; P = 0.002) but not low max-min (0.93 [0.65–1.34]; P = 0.700), and increased QTD (0.98 [0.60–1.60]; P = 0.939) were associated with increased mortality. In the diabetic subjects, prolonged QTc was also a predictor of mortality (3.00 [1.34–6.71]; P = 0.007), while a trend for an increased risk was noted in those with low max-min (1.74 [0.95–3.18]; P = 0.075), whereas increased QTD did not predict mortality (0.42 [0.06–3.16]; P = 0.402). CONCLUSIONS —Prolonged QTc interval, but not increased QTD, is an independent predictor of a twofold and threefold increased risk of mortality in the nondiabetic and diabetic elderly general population, respectively. Low HRV during spontaneous breathing tends to be associated with excess mortality in the diabetic but not nondiabetic population. ARIC, Atherosclerosis Risk in Communities CAN, cardiovascular autonomic neuropathy CVD, cardiovascular disease ECG, electrocardiogram HRV, heart rate variability KORA, Cooperative Health Research in the Region of Augsburg max-min, maximum-minimum R-R interval difference MONICA, Monitoring of Trends and Determinants in Cardiovascular Disease SDNN, SD of R-R intervals Footnotes Published ahead of print at http://care.diabetesjournals.org on 17 December 2007. DOI: 10.2337/dc07-1615. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Accepted December 11, 2007. Received August 15, 2007. DIABETES CARE

Arne Pfeufer, Aravinda Chakravarti and colleagues from the QTSCD consortium report genetic associations influencing the QT interval duration, a measure of cardiac repolarization which is a risk factor for sudden cardiac death, in five genome-wide association studies. The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10 −8 . Four loci map near the monogenic long-QT syndrome genes KCNQ1 , KCNH2 , SCN5A and KCNJ2 . Two other loci include A TP1B1 and PLN , genes with established electrophysiological function, whereas three map to RNF207 , near LITAF and within NDRG4-GINS3-SETD6-CNOT1 , respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.