Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

This corrects the article DOI: 10.1038/ncomms15805.

Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74

Sitting behaviour is not associated with incident diabetes over 13 years: the Whitehall II cohort study.

BACKGROUND: Although certain types of sedentary behaviour have been linked to metabolic risk, prospective studies describing the links between sitting with incident diabetes are scarce and often do not account for baseline adiposity. We investigate the associations between context-specific sitting and incident diabetes in a cohort of mid-aged to older British civil servants. METHODS: Using data from the Whitehall II study (n=4811), Cox proportional hazards models (adjusted for age, sex, ethnicity, employment grade, smoking, alcohol intake, fruit and vegetable consumption, self-rated health, physical functioning, walking and moderate-to-vigorous physical activity, and body mass index (BMI)) were fitted to examine associations between total sitting and context-specific sitting time (work, television (TV), non-TV leisure time sitting at home) at phase 5 (1997-1999) and fasting glucose-defined incident diabetes up to 2011. RESULTS: Total sitting (HR of the top compared with the bottom group: 1.26; 95% CI 1.00 to 1.62; p=0.01) and TV sitting (1.33; 95% CI 1.03 to 1.88; p=0.05) showed associations with incident diabetes; once BMI was included in the model these associations were attenuated for both total sitting (1.19; 95% CI 0.92 to 1.55; p=0.22) and TV sitting (1.31; 95% CI 0.96 to 1.76; p=0.14). CONCLUSION: We found limited evidence linking sitting and incident diabetes over 13 years in this occupational cohort of civil servants.

Alcohol Consumption and Common Carotid Intima-Media Thickness: The USE-IMT Study.

AIMS: Epidemiological evidence indicates a protective effect of light to moderate alcohol consumption compared to non-drinking and heavy drinking. Although several mechanisms have been suggested, the effect of alcohol on atherosclerotic changes in vessel walls is unclear. Therefore, we explored the relationship between alcohol consumption and common carotid intima media thickness, a marker of early atherosclerosis in the general population. METHODS: Individual participant data from eight cohorts, involving 37,494 individuals from the USE-IMT collaboration were used. Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) with alcohol consumption. RESULTS: The mean age was 57.9 years (SD 8.6) and the mean CIMT was 0.75 mm (SD 0.177). About, 40.5% reported no alcohol consumed, and among those who drank, mean consumption was 13.3 g per day (SD 16.4). Those consuming no alcohol or a very small amount (<5 g per day) had significantly lower common CIMT values than those consuming >10 g per day, after adjusting for a range of confounding factors. CONCLUSION: In this large CIMT consortium, we did not find evidence to support a protective effect of alcohol on CIMT.

Clustering of cardiovascular risk factors and carotid intima-media thickness: The USE-IMT study.

BACKGROUND: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. METHODS: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. RESULTS: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. CONCLUSION: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.

Associations of sitting behaviours with all-cause mortality over a 16-year follow-up: the Whitehall II study.

BACKGROUND: Sitting behaviours have been linked with increased risk of all-cause mortality independent of moderate to vigorous physical activity (MVPA). Previous studies have tended to examine single indicators of sitting or all sitting behaviours combined. This study aims to enhance the evidence base by examining the type-specific prospective associations of four different sitting behaviours as well as total sitting with the risk of all-cause mortality. METHODS: Participants (3720 men and 1412 women) from the Whitehall II cohort study who were free from cardiovascular disease provided information on weekly sitting time (at work, during leisure time, while watching TV, during leisure time excluding TV, and at work and during leisure time combined) and covariates in 1997-99. Cox proportional hazards models were used to investigate prospective associations between sitting time (h/week) and mortality risk. Follow-up was from date of measurement until (the earliest of) death, date of censor or July 31 2014. RESULTS: Over 81 373 person-years of follow-up (mean follow-up time 15.7 ± 2.2 years) a total of 450 deaths were recorded. No associations were observed between any of the five sitting indicators and mortality risk, either in unadjusted models or models adjusted for covariates including MVPA. CONCLUSIONS: Sitting time was not associated with all-cause mortality risk. The results of this study suggest that policy makers and clinicians should be cautious about placing emphasis on sitting behaviour as a risk factor for mortality that is distinct from the effect of physical activity.

Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.

BACKGROUND: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events. METHODS: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity. RESULTS: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites. CONCLUSION: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.

Common carotid intima-media thickness relates to cardiovascular events in adults aged <45 years.

Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavorable risk factor burden.

Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration.

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

Depressive disorder, coronary heart disease, and stroke: dose-response and reverse causation effects in the Whitehall II cohort study.

BACKGROUND: Systematic reviews examining associations of depressive disorder with coronary heart disease and stroke produce mixed results. Failure to consider reverse causation and dose-response patterns may have caused inconsistencies in evidence. DESIGN: This prospective cohort study on depressive disorder, coronary heart disease, and stroke analysed reverse causation and dose-response effects using four 5-year and three 10-year observation cycles (total follow up 24 years) based on multiple repeat measures of exposure. METHODS: Participants in the Whitehall II study (n = 10,036, 31,395 person-observations, age at start 44.4 years) provided up to six repeat measures of depressive symptoms via the 30-item General Health Questionnaire (GHQ-30) and one measure via Center for Epidemiologic Studies Depression Scale (CES-D). The cohort was followed up for major coronary events (coronary death/nonfatal myocardial infarction) and stroke (stroke death/morbidity) through the national mortality register Hospital Episode Statistics, ECG-screening, medical records, and self-report questionnaires. RESULTS: GHQ-30 caseness predicted stroke over 0-5 years (age-, sex- and ethnicity-adjusted HR 1.60, 95% CI 1.1-2.3) but not over 5-10 years (HR 0.94, 95% CI 0.6-1.4). Using the last 5-year observation cycle, cumulative GHQ-30 caseness was associated with incident coronary heart disease in a dose-response manner (1-2 times a case: HR 1.12, 95% CI 0.7-1.7; 3-4 times: HR 2.06, 95% CI 1.2-3.7), and CES-D caseness predicted coronary heart disease (HR 1.81, 95% CI 1.1-3.1). CONCLUSIONS: There was evidence of a dose-response effect of depressive symptoms on risk of coronary heart disease. In contrast, prospective associations of depressive symptoms with stroke appeared to arise wholly or partly through reverse causation.

Sitting behavior and obesity: evidence from the Whitehall II study.

BACKGROUND: Prospective studies report associations between indicators of time spent sitting and obesity risk. Most studies use a single indicator of sedentary behavior and are unable to clearly identify whether sedentary behavior is a cause or a consequence of obesity. PURPOSE: To investigate cross-sectional and prospective associations between multiple sitting time indicators and obesity and examine the possibility of reverse causality. METHODS: Using data from the Whitehall II cohort, multiple logistic models were fitted to examine associations between prevalent obesity (BMI ≥30) at Phase 5 (1997-1999), and incident obesity between Phases 5 and 7 (2003-2004) across four levels of five sitting exposures (work sitting, TV viewing, non-TV leisure-time sitting, leisure-time sitting, and total sitting). Using obesity data from three prior phases (1985-1988, 1991-1993; and recalled weight at age 25 years), linear regression models were fitted to examine the association between prior obesity and sitting time at Phase 5. Analyses were conducted in 2012. RESULTS: None of the sitting exposures were associated with obesity either cross-sectionally or prospectively. Obesity at one previous measurement phase was associated with a 2.43-hour/week (95% CI=0.07, 4.78) increase in TV viewing; obesity at three previous phases was associated with a 7.42-hour/week (95% CI=2.7, 12.46) increase in TV-viewing hours/week at Phase 5. CONCLUSIONS: Sitting time was not associated with obesity cross-sectionally or prospectively. Prior obesity was prospectively associated with time spent watching TV per week but not other types of sitting.

Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis.

CONTEXT: The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. OBJECTIVE: To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. DATA SOURCES: Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. STUDY SELECTION: Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. DATA EXTRACTION: Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. RESULTS: We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. CONCLUSION: The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Rising adiposity curbing decline in the incidence of myocardial infarction: 20-year follow-up of British men and women in the Whitehall II cohort.

Aims To estimate the contribution of risk factor trends to 20-year declines in myocardial infarction (MI) incidence in British men and women. Methods and results From 1985 to 2004, 6379 men and 3074 women in the Whitehall II cohort were followed for incident MI and risk factor trends. Over 20 years, the age-sex-adjusted hazard of MI fell by 74% (95% confidence interval 48-87%), corresponding to an average annual decline of 6.5% (3.2-9.7%). Thirty-four per cent (20-76%) of the decline in MI hazard could be statistically explained by declining non-HDL cholesterol levels, followed by increased HDL cholesterol (17%, 10-32%), reduced systolic blood pressure (13%, 7-24%), and reduced cigarette smoking prevalence (6%, 2-14%). Increased fruit and vegetable consumption made a non-significant contribution of 7% (-1-20%). In combination, these five risk factors explained 56% (34-112%). Rising body mass index (BMI) was counterproductive, reducing the scale of the decline by 11% (5-23%) in isolation. The MI decline and the impact of the risk factors appeared similar for men and women. Conclusion In men and women, over half of the decline in MI risk could be accounted for by favourable risk factor time trends. The adverse role of BMI emphasizes the importance of addressing the rising population BMI.

Arterial stiffness, physical function, and functional limitation: the Whitehall II Study.

Arterial stiffness has been proposed as an indicator of vascular aging. We aimed to examine this concept by analyzing associations of arterial stiffness with age, subjective and objective measures of physical functioning, and self-reported functional limitation. We measured aortic pulse wave velocity by applanation tonometry among 5392 men and women aged 55 to 78 years. Arterial stiffness was strongly associated with age (mean difference [SE] per decade: men, 1.37 m/s [0.06 m/s]; women: 1.39 m/s [0.10 m/s]). This association was robust to individual and combined adjustment for pulse pressure, mean arterial pressure, antihypertensive treatment, and chronic disease. Participants took an 8.00-ft (2.44-m) walking speed test, a spirometry lung function test, and completed health functioning and (instrumental) activities of daily living questionnaires. Associations of stiffness and blood pressure with physical function scores scaled to SD of 10 were compared. One-SD higher stiffness was associated with lower walking speed (coefficient [95% CI]: -0.96 [-1.29 to -0.64] m/s) and physical component summary score (-0.91 [-1.21 to -0.60]) and poorer lung function (-1.23 [-1.53 to -0.92] L) adjusted for age, sex, and ethnic group. Pulse pressure and mean arterial pressure were linked inversely only with lung function. Associations of stiffness with functional limitation were robust to multiple adjustment, including pulse pressure and chronic disease. In conclusion, the concept of vascular aging is reinforced by the observation that arterial stiffness is a robust correlate of physical functioning and functional limitation in early old age. The nature of the link between arterial stiffness and quality of life in older people merits attention.

History of coronary heart disease and cognitive performance in midlife: the Whitehall II study.

AIMS: Some studies show coronary heart disease (CHD) to be a risk factor for cognitive function while others report no association between the two. We examined the effect of CHD history and duration on cognition in a middle-aged population. METHODS AND RESULTS: Data come from the Whitehall II study of 10,308 participants (33% women), aged 35-55 years at baseline (Phase 1; 1985-88). CHD events were assessed up to Phase 7 (2002-04) when 5837 participants (28.4% women) undertook six cognitive tests: reasoning, vocabulary, phonemic and semantic fluency, memory and the mini-mental-state-examination (MMSE); standardized to T-scores (mean = 50, standard deviation = 10). Analysis of covariance was used first to model the association between CHD history and cognition and then to examine the effect of time since first CHD event (in the last 5 years, 5-10 years ago, >10 years ago). Among men, in analyses adjusted for age, education, marital status and medication for cardiovascular disease, CHD history was associated with lower T-scores on reasoning [-1.16; 95% confidence interval (CI) = -2.07, -0.25], vocabulary (-2.11; 95% CI = -3.01, -1.21), and the MMSE (-1.45; 95% CI = -2.42, -0.49). In women, these effects were also evident for phonemic and semantic fluency. Among men, the trend within CHD cases suggested progressively lower scores on reasoning, vocabulary and semantic fluency among those with longer duration of CHD. CONCLUSION: Our findings go some way towards suggesting an association between CHD history and cognitive performance in middle-aged adults.

Vascular disease and cognitive function: evidence from the Whitehall II Study.

OBJECTIVES: : To test the hypothesis of an inverse association between indicators of vascular disease and cognitive function in the general, stroke-free population. DESIGN: : A longitudinal, British civil service-based cohort study. Measures of vascular disease examined were prevalent at baseline or traced over a median of 11 years, between Phases 1 (1985-1988) and 5 (1997-1999) of data collection. Cognitive function was assessed at Phase 5 of data collection. SETTING: : Twenty London-based Civil Service departments. PARTICIPANTS: : Four thousand one hundred forty-one men and 1,681 women, aged 46 to 68 when tested for cognitive function. MEASUREMENTS: : A battery of cognitive tests consisting of: memory test, Alice Heim 4, Mill-Hill, phonemic, and semantic fluency. RESULTS: : The occurrence of angina pectoris (P<.001), myocardial infarction (P=.02), all coronary heart disease (P<.001), and intermittent claudication (P=.004) was associated with poor cognitive function. These effects were independent of age and socioeconomic status. The association between indicators of vascular disease and cognitive function applied to the entire range of cognitive function measures examined in the study. CONCLUSION: : The findings support the view that vascular disease is predictive of poor cognitive function in the general population. The fact that presence of vascular disease was associated with diminished cognitive function even in a relatively young cohort has implications for the management of vascular disease.