The double product (DP), consisting of the systolic blood pressure (SBP) multiplied by the pulse rate (PR), is an index of myocardial oxygen consumption, but its prognostic value in the general population remains unknown.
We recorded health outcomes in 9,937 subjects (median age, 53.2 years; 47.3% women) randomly recruited from 11 populations and enrolled in the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) study. We obtained the SBP, PR, and DP for these subjects as determined through 24-hour ambulatory monitoring.
Over a median period of 11.0 years, 1,388 of the 9,937 study subjects died, of whom 536 and 794, respectively, died of cardiovascular (CV) and non-CV causes, and a further 1,161, 658, 494, and 465 subjects, respectively, experienced a CV, cardiac, coronary, or cerebrovascular event. In multivariate-adjusted Cox models, not including SBP and PR, DP predicted total, CV, and non-CV mortality (standardized hazard ratio [HR], ≥ 1.10; P ≤ 0.02), and all CV, cardiac, coronary, and stroke events (HR, ≥ 1.21; P < 0.0001). For CV mortality (HR, 1.34 vs. 1.30; P = 0.71) and coronary events (1.28 vs. 1.21; P = 0.26), SBP and the DP were equally predictive. As compared with DP, SBP was a stronger predictor of all CV events (1.39 vs. 1.27; P = 0.002) and stroke (1.61 vs. 1.36; P < 0.0001), and a slightly stronger predictor of cardiac events (1.32 vs. 1.22; P = 0.06). In fully adjusted models, including both SBP and PR, the predictive value of DP disappeared for fatal endpoints (P ≥ 0.07), coronary events (P = 0.06), and stroke (P = 0.12), or DP was even inversely associated with the risk of all CV and cardiac events (both P ≤ 0.01).
In the general population, we did not observe DP to add to risk stratification over and beyond SBP and PR.
blood pressure; double product; systolic blood pressure; cardiovascular risk; hypertension; general population
For many complex diseases, quantitative traits contain more information than dichotomous traits. One of the approaches used to analyse these traits in family-based association studies is the quantitative transmission disequilibrium test (QTDT). The QTDT is a regression-based approach that models simultaneously linkage and association. It splits up the association effect in a between- and a within-family genetic component to adjust and test for population stratification and includes a variance components method to model linkage. We extend this approach to detect gene–gene interactions between two unlinked QTLs by adjusting the definition of the between- and within-family component and the variance components included in the model. We simulate data to investigate the influence of the epistasis model, linkage disequilibrium patterns between the markers and the QTLs, and allele frequencies on the power and type I error rates of the approach. Results show that for some of the investigated settings, power gains are obtained in comparison with FAM-MDR. We conclude that our approach shows promising results for candidate-gene studies where too few markers are available to correct for population stratification using standard methods (for example EIGENSTRAT). The proposed method is applied to real-life data on hypertension from the FLEMENGHO study.
QTDT; epistasis; association; linkage
Background: The current risk assessment for environmental cadmium (Cd) largely relies on the assumption that urinary Cd (U-Cd) is a reliable biomarker of the Cd body burden. Recent studies have questioned the validity of this assumption.
Objectives: We studied the lifetime trend of U-Cd as a function of diuresis, gender, smoking status, and protein tubular reabsorption. We also analyzed the associations between U-Cd and urinary proteins.
Methods: Cd, retinol-binding protein, and albumin were measured in the urine of six cohorts of the general population of Belgium, with a mean age ranging from 5.7 to 88.1 years (n = 1,567). Variations of U-Cd with age were modeled using natural cubic splines.
Results: In both genders, U-Cd decreased to a minimum (~ 0.20 μg/L) at the end of adolescence, then increased until 60–70 years of age (~ 0.60 μg/L in never-smokers) before leveling off or decreasing. When U-Cd was expressed in micrograms per gram of creatinine, these variations were amplified (minimum, 0.15 µg/g creatinine; maximum, 0.70 µg/g creatinine) and much higher U-Cd values were observed in women. We observed no difference in U-Cd levels between never-smokers and former smokers, and the difference with current smokers did not increase over time. Lifetime curves of U-Cd were higher with increasing urinary retinol-binding protein or albumin, a consequence of the coexcretion of Cd with proteins.
Conclusions: At low Cd exposure levels, U-Cd and age are associated through nonlinear and nonmonotonic relationships that appear to be driven mainly by recent Cd intake and physiological variations in the excretion of creatinine and proteins.
Citation: Chaumont A, Voisin C, Deumer G, Haufroid V, Annesi-Maesano I, Roels H, Thijs L, Staessen J, Bernard A. 2013. Associations of urinary cadmium with age and urinary proteins: further evidence of physiological variations unrelated to metal accumulation and toxicity. Environ Health Perspect 121:1047–1053; http://dx.doi.org/10.1289/ehp.1306607
The association between cardiovascular health and salt intake remains controversial. The objective of our study was to assess the association between arterial stiffness and urinary sodium, both cross-sectionally and prospectively.
In 630 participants (mean age 40.6 years; 51% women), randomly recruited from a Flemish population, we measured sodium and creatinine in 24-hour urine samples at baseline and follow-up (median, 9.7 years) and the carotid and aortic augmentation indexes (AIs) standardized to heart rate at follow-up only.
From baseline to follow-up, the urinary sodium concentration decreased (117.1 vs. 105.2 mmol/L; P < 0.0001), whereas 24-hour urinary sodium did not change significantly (166.5 vs. 171.5 mmol/L; P = 0.12). In multivariable-adjusted longitudinal analyses, a 40 mmol/L (~1 SD) increase in the urinary sodium concentration was independently and inversely associated with the carotid AI (effect size, −1.38 ± 0.66%; P = 0.04) and aortic AI (−1.54 ± 0.72%; P = 0.02). In cross-sectional analyses of follow-up data, these estimates were −1.26 ± 0.70% (P = 0.07) and −1.52 ± 0.76% (P = 0.04), respectively. In the longitudinal and cross-sectional analyses, the carotid and aortic AIs were unrelated to the 24-hour urinary excretion of sodium.
Our study showed an inverse association between the central arterial AIs and the urinary sodium concentration. Further research is required to consolidate our findings, to unravel the underlying mechanism, and to establish the role of renal vasodilatation in the maintenance of sodium balance.
artery stiffness; blood pressure; cross-sectional; hypertension; prospective; urinary sodium; white population
We investigated the heritability and familial aggregation of various indexes of arterial stiffness and wave reflection and we partitioned the phenotypic correlation between these traits into shared genetic and environmental components.
Using a family-based population sample, we recruited 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years) from the population in Cracow, Poland (62 families), Hechtel-Eksel, Belgium (36), and Pilsen, the Czech Republic (50). We measured peripheral pulse pressure (PPp) sphygmomanometrically at the brachial artery; central pulse pressure (PPc), the peripheral augmentation indexes (PAIxs) and central augmentation indexes (CAIxs) by applanation tonometry at the radial artery; and aortic pulse wave velocity (PWV) by tonometry or ultrasound. In multivariate-adjusted analyses, we used the ASSOC and PROC GENMOD procedures as implemented in SAGE and SAS, respectively.
We found significant heritability for PAIx, CAIx, PPc and mean arterial pressure ranging from 0.37 to 0.41; P ≤ 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r > ≥ 0.12; P < ≤ 0.02) with the exception of PPc (r = −0.007; P = 0.90) in parent–offspring pairs. The sib–sib correlations were also significant for CAIx (r = 0.22; P = 0.001). The genetic correlation between PWV and the other arterial indexes were significant (ρG ≥ 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (ρE = 0.10, P = 0.03).
The observation of significant intrafamilial concordance and heritability of various indexes of arterial stiffness as well as the genetic correlations among arterial phenotypes strongly support the search for shared genetic determinants underlying these traits.
arterial stiffness; familial aggregation; heritability; pulse pressure; systolic augmentation
Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants.
We randomly recruited 95 nuclear families of black South African ancestry and 103 nuclear families of white Belgian ancestry. We measured the (FENa) and estimated the fractional renal sodium reabsorption in the proximal (RNaprox) and distal (RNadist) tubules from the clearances of endogenous lithium and creatinine. In multivariable analyses, we studied the relation of RNaprox and RNadist with FENa and estimated the heritability (h2) of RNaprox and RNadist.
Independent of urinary sodium excretion, South Africans (n =240) had higher RNaprox (unadjusted median, 93.9% vs. 81.0%; P < 0.001) than Belgians (n =737), but lower RNadist (91.2% vs. 95.1%; P < 0.001). The slope of RNaprox on FENa was steeper in Belgians than in South Africans (−5.40 ±0.58 vs. −0.78 ±0.58 units; P < 0.001), whereas the opposite was true for the slope of RNadist on FENa (−3.84 ± 0.19 vs. −13.71 ± 1.30 units; P < 0.001). h2 of RNaprox and RNadist was high and significant (P < 0.001) in both countries. h2 was higher in South Africans than in Belgians for RNaprox (0.82 vs. 0.56; P < 0.001), but was similar for RNadist (0.68 vs. 0.50; P = 0.17). Of the filtered sodium load, black participants reabsorb more than white participants in the proximal nephron and less postproximally.
Segmental sodium reabsorption along the nephron is highly heritable, but the capacity for regulation in the proximal and postproximal tubules differs between whites and blacks.
clinical genetics; epidemiology; kidney; lithium clearance; salt sensitivity; segmental tubular sodium transport
Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher (P<0.0001) among 229 diabetics (29.3%, n=67) than among 5486 nondiabetics (18.8%, n=1031). Over a median of 11.0 years of follow-up, the adjusted risk for a composite cardiovascular end point in untreated diabetic-masked hypertensives tended to be higher than in normotensives (hazard rate [HR], 1.96; 95% confidence interval [CI], 0.97–3.97; P=0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58–1.98; P=0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29–0.99; P=0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54–2.35; P=0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49–1.69; P=0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35–1.20; P=0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2±8.0/76.0±7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5±9.1/83.7±6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension.
ambulatory blood pressure; conventional blood pressure; diabetes mellitus; masked hypertension; population study
To understand better the mechanism of left ventricular (LV) remodeling related to hypertension, it is important to evaluate LV function in relation to the changes in loading conditions. The aim of this study was to investigate changes in conventional ventricular-arterial coupling indexes, LV strain, and a new index reflecting regional myocardial work assessed noninvasively at rest and during isometric exercise in a random sample including participants with normal blood pressure and those with hypertension.
A total of 148 participants (53.4% women; mean age, 52.0 years; 39.2% with hypertension) underwent simultaneous echocardiographic and arterial data acquisition at rest and during increased afterload (handgrip exercise). End-systolic pressure was determined from the carotid pulse wave. Arterial elastance (Ea) and LV elastance (Ees) were calculated as end-systolic pressure/stroke volume and end-systolic pressure/end-systolic volume. Doppler tissue imaging and two-dimensional speckle tracking were used to derive LV longitudinal strain. Regional myocardial work (ejection work density [EWD]) was the area of the pressure-strain loop during ejection.
At rest, with adjustments applied, Ees (3.06 vs 3.71 mmHg/mL,P = .0003), Ea/Ees (0.54 vs 0.47,P=.002) and EWD (670 vs 802 Pa/m2, P = .0001) differed significantly between participants with normal blood pressure and those with hypertension. During handgrip exercise, Ea and Ea/Ees significantly increased (P < .0001) in both groups. Doppler tissue imaging and two-dimensional LV strain decreased in participants with hypertension (P ≤ .008). Only in subjects with normal blood pressure EWD significantly increased (+14.7%, P = .0009).
Although patients with hypertension compared with those with normal blood pressure have increased LV systolic stiffness and regional myocardial work to match arterial load at rest, they might have diminished cardiac reserve to increase myocardial performance, as estimated by EWD during isometric exercise.
Echocardiography; Hypertension; Ventricular-arterial coupling; Strain
To assess the prognostic significance of blood pressure (BP) variability, we followed health outcomes in a family-based random population sample representative of the general population (n=2944; mean age: 44.9 years; 50.7% women). At baseline, BP was measured 5 times consecutively at each of 2 home visits 2 to 4 weeks apart. We assessed within-subject overall (10 readings), within- and between-visit systolic BP variability from variability independent of the mean, the difference between maximum and minimum BP, and average real variability. Over a median follow-up of 12 years, 401 deaths occurred and 311 participants experienced a fatal or nonfatal cardiovascular event. Overall systolic BP variability averaged (SD) 5.45 (2.82) units, 15.87 (8.36) mm Hg, and 4.08 (2.05) mm Hg for variability independent of the mean, difference between maximum and minimum BP, and average real variability, respectively. Female sex, older age, higher-mean systolic BP, lower body mass index, a history of peripheral arterial disease, and use of β-blockers were the main correlates of systolic BP variability. In multivariable-adjusted analyses, overall and within- and between-visit BP variability did not predict total or cardiovascular mortality or the composite of any fatal plus nonfatal cardiovascular end point. For instance, the hazard ratios for all cardiovascular events combined in relation to overall variability independent of the mean, difference between maximum and minimum BP, and average real variability were 1.05 (0.96–1.15), 1.06 (0.96–1.16), and 1.08 (0.98–1.19), respectively. By contrast, mean systolic BP was a significant predictor of all end points under study, independent of BP variability. In conclusion, in an unbiased population sample, BP variability did not contribute to risk stratification over and beyond mean systolic BP.
blood pressure variability; cardiovascular disease; population science; risk factors; epidemiology
The term “ultima ratio” has multiple, though related, meanings. The motto “ultima ratio regum,” cast on the cannons of the French army of King Louis XIV, meant that war is the last argument of kings, that is, the one to be used after all diplomatic arguments have failed. Along similar lines, we propose that, given the current evidence, renal denervation should be used as a last resort, after state-of-the-art drug treatment optimized at expert centers failed to control blood pressure.
Few population studies have described the heritability and intrafamilial concordance of the retinal microvessels, or the genetic or environmental correlations of the phenotypes of these vessels.
We randomly selected 413 participants from 70 families (mean age, 51.5 years; 50.1% women) from a Flemish population. We post-processed retinal images using IVAN software to generate the central retinal arteriole equivalent (CRAE), central retinal venule equivalent (CRVE), and arteriole-to-venule-ratio (AVR) from these images. We used SAGE version 6.2 and SAS version 9.2 to compute multivariate-adjusted estimates of heritability and intrafamilial correlations of the CRAE, CRVE, and AVR of the retinal microvessels in the images.
Sex, age, mean arterial pressure, and smoking explained up to 12.7% of the variance of the phenotypes of the retinal microvessels of the study participants. With adjustments applied for these covariates, the heritability estimates of CRAE, CRVE, and AVR were 0.213 (P = 0.044), 0.339 (P = 0.010), and 0.272 (P = 0.004), respectively. The parent–offspring correlations for CRAE, CRVE, and AVR were 0.118 (NS), 0.225 (P < 0.01), and 0.215 (P < 0.05), respectively. The corresponding values were 0.222 (P < 0.05), 0.213 (P < 0.05), and 0.390 (P < 0.001) for sib–sib correlations, respectively. The genetic and environmental correlations between CRAE and CRVE were 0.360 and 0.545 (P < 0.001 for both).
Our study showed moderate heritability for CRAE, CRVE, and AVR, and a significant genetic correlation of CRAE with CRVE in the Flemish population of our study. These findings suggest that genetic factors influence the diameter of the retinal microvessels, and that CRAE and CRVE share some genetic determinants.
blood pressure; heritability; hypertension; microcirculation; retina
The significance of white-coat hypertension in older persons with isolated systolic hypertension remains poorly understood. We analyzed subjects from the population-based 11-country International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes database who had daytime ambulatory blood pressure (BP; ABP) and conventional BP (CBP) measurements. After excluding persons with diastolic hypertension by CBP (≥90 mm Hg) or by daytime ABP (≥85 mm Hg), a history of cardiovascular disease, and persons <18 years of age, the present analysis totaled 7295 persons, of whom 1593 had isolated systolic hypertension. During a median follow-up of 10.6 years, there was a total of 655 fatal and nonfatal cardiovascular events. The analyses were stratified by treatment status. In untreated subjects, those with white-coat hypertension (CBP ≥140/<90 mm Hg and ABP <135/<85 mm Hg) and subjects with normal BP (CBP <140/<90 mm Hg and ABP <135/<85 mm Hg) were at similar risk (adjusted hazard rate: 1.17 [95% CI: 0.87–1.57]; P=0.29). Furthermore, in treated subjects with isolated systolic hypertension, the cardiovascular risk was similar in elevated conventional and normal daytime systolic BP as compared with those with normal conventional and normal daytime BPs (adjusted hazard rate: 1.10 [95% CI: 0.79–1.53]; P=0.57). However, both treated isolated systolic hypertension subjects with white-coat hypertension (adjusted hazard rate: 2.00; [95% CI: 1.43–2.79]; P<0.0001) and treated subjects with normal BP (adjusted hazard rate: 1.98 [95% CI: 1.49–2.62]; P<0.0001) were at higher risk as compared with untreated normotensive subjects. In conclusion, subjects with sustained hypertension who have their ABP normalized on antihypertensive therapy but with residual white-coat effect by CBP measurement have an entity that we have termed, “treated normalized hypertension.” Therefore, one should be cautious in applying the term “white-coat hypertension” to persons receiving antihypertensive treatment.
isolated systolic hypertension; ambulatory blood pressure; white-coat hypertension; white-coat effect; cardiovascular disease; epidemiology
The lack of outcome-driven operational thresholds limits the clinical application of home blood pressure (BP) measurement. Our objective was to determine an outcome-driven reference frame for home BP measurement. We measured home and clinic BP in 6470 participants (mean age, 59.3 years; 56.9% women; 22.4% on antihypertensive treatment) recruited in Ohasama, Japan (n=2520); Montevideo, Uruguay (n=399); Tsurugaya, Japan (n=811); Didima, Greece (n=665); and nationwide in Finland (n=2075). In multivariable-adjusted analyses of individual subject data, we determined home BP thresholds, which yielded 10-year cardiovascular risks similar to those associated with stages 1 (120/80 mm Hg) and 2 (130/85 mm Hg) prehypertension, and stages 1 (140/90 mm Hg) and 2 (160/100 mm Hg) hypertension on clinic measurement. During 8.3 years of follow-up (median), 716 cardiovascular end points, 294 cardiovascular deaths, 393 strokes, and 336 cardiac events occurred in the whole cohort; in untreated participants these numbers were 414, 158, 225, and 194, respectively. In the whole cohort, outcome-driven systolic/diastolic thresholds for the home BP corresponding with stages 1 and 2 prehypertension and stages 1 and 2 hypertension were 121.4/77.7, 127.4/79.9, 133.4/82.2, and 145.4/86.8 mm Hg; in 5018 untreated participants, these thresholds were 118.5/76.9, 125.2/79.7, 131.9/82.4, and 145.3/87.9 mm Hg, respectively. Rounded thresholds for stages 1 and 2 prehypertension and stages 1 and 2 hypertension amounted to 120/75, 125/80, 130/85, and 145/90 mm Hg, respectively. Population-based outcome-driven thresholds for home BP are slightly lower than those currently proposed in hypertension guidelines. Our current findings could inform guidelines and help clinicians in diagnosing and managing patients.
home blood pressure measurement; blood pressure; hypertension; epidemiology; thresholds
Blood pressure variability based on office measurement predicts outcome in selected patients. We explored whether novel indices of blood pressure variability derived from the self-measured home blood pressure predicted outcome in a general population. We monitored mortality and stroke in 2421 Ohasama residents (Iwate Prefecture, Japan). At enrollment (1988–1995), participants (mean age, 58.6 years; 60.9% women; 27.1% treated) measured their blood pressure at home, using an oscillometric device. In multivariable-adjusted Cox models, we assessed the independent predictive value of the within-subject mean systolic blood pressure (SBP) and corresponding variability as estimated by variability independent of the mean, difference between maximum and minimum blood pressure, and average real variability. Over 12.0 years (median), 412 participants died, 139 of cardiovascular causes, and 223 had a stroke. In models including morning SBP, variability independent of the mean and average real variability (median, 26 readings) predicted total and cardiovascular mortality in all of the participants (P≤0.044); variability independent of the mean predicted cardiovascular mortality in treated (P=0.014) but not in untreated (P=0.23) participants; and morning maximum and minimum blood pressure did not predict any end point (P≥0.085). In models already including evening SBP, only variability independent of the mean predicted cardiovascular mortality in all and in untreated participants (P≤0.046). The R2 statistics, a measure for the incremental risk explained by adding blood pressure variability to models already including SBP and covariables, ranged from <0.01% to 0.88%. In a general population, new indices of blood pressure variability derived from home blood pressure did not incrementally predict outcome over and beyond mean SBP.
blood pressure variability; variability independent of the mean index; average real variability; general population; home blood pressure; risk factors
No previous study addressed whether in the general population estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration formula]) adds to the prediction of cardiovascular outcome over and beyond ambulatory blood pressure. We recorded health outcomes in 5322 subjects (median age, 51.8 years; 43.1% women) randomly recruited from 11 populations, who had baseline measurements of 24-hour ambulatory blood pressure (ABP24) and eGFR. We computed hazard ratios using multivariable-adjusted Cox regression. Median follow-up was 9.3 years. In fully adjusted models, which included both ABP24 and eGFR, ABP24 predicted (P≤0.008) both total (513 deaths) and cardiovascular (206) mortality; eGFR only predicted cardiovascular mortality (P=0.012). Furthermore, ABP24 predicted (P≤0.0056) fatal combined with nonfatal events as a result of all cardiovascular causes (555 events), cardiac disease (335 events), or stroke (218 events), whereas eGFR only predicted the composite cardiovascular end point and stroke (P≤0.035). The interaction terms between ABP24 and eGFR were all nonsignificant (P≥0.082). For cardiovascular mortality, the composite cardiovascular end point, and stroke, ABP24 added 0.35%, 1.17%, and 1.00% to the risk already explained by cohort, sex, age, body mass index, smoking and drinking, previous cardiovascular disease, diabetes mellitus, and antihypertensive drug treatment. Adding eGFR explained an additional 0.13%, 0.09%, and 0.14%, respectively. Sensitivity analyses stratified for ethnicity, sex, and the presence of hypertension or chronic kidney disease (eGFR <60 mL/min per 1.73 m2) were confirmatory. In conclusion, in the general population, eGFR predicts fewer end points than ABP24. Relative to ABP24, eGFR is as an additive, not a multiplicative, risk factor and refines risk stratification 2- to 14-fold less.
ambulatory blood pressure; population science; renal function; cardiovascular risk factors; epidemiology
The objective of this study is to construct an International Database of HOme blood pressure in relation to Cardiovascular Outcome (IDHOCO). The main goal of this database is to determine outcome-based diagnostic thresholds for the self-measured home blood pressure (BP). Secondary objectives include investigating the predictive value of white-coat and masked hypertension, morning and evening BP, BP and heart rate variability, and the home arterial stiffness index. We also aim to determine an optimal schedule for home BP measurements that provides the most accurate risk stratification. Eligible studies are population-based, have fatal as well as nonfatal outcomes available for analysis, comply with ethical standards, and have been previously published in peer-reviewed journals. In a meta-analysis based on individual subject data, composite and cause-specific cardiovascular events will be related to various indexes derived by home BP measurement. The analyses will be stratified by a cohort and adjusted for the clinic BP and established cardiovascular risk factors. The database includes 6753 subjects from five cohorts recruited in Ohasama, Japan (n = 2777); Finland (n = 2075); Tsurugaya, Japan (n = 836); Didima, Greece (n = 665); and Montevideo, Uruguay (n = 400). In these five cohorts, during a total of 62 106 person-years of follow-up (mean 9.2 years), 852 subjects died and 740 participants experienced a fatal or nonfatal cardiovascular event. IDHOCO provides a unique opportunity to investigate several hypotheses that could not reliably be studied in individual studies. The results of these analyses should be of help to clinicians involved in the management of patients with suspected or established hypertension.
BP measurement; epidemiology; home; self-measurement
Essential hypertension is a multi-factorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a two-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions.
The discovery phase consisted of 1,865 cases and 1,750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1,385 cases and 1,246 controls that were genotyped with a custom array of 14,055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial nitric oxide synthase (eNOS) gene (odds ratio 1.54; 95% CI 1.37-1.73; combined p=2.58·10−13). A meta-analysis, using other in-silico/de novo genotyping data for a total of 21714 subjects, resulted in an overall odds ratio of 1.34 (95% CI 1.25-1.44, p=1.032·10−14). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI 0.16-3.66) for systolic and 1.40 (95% CI 0.25-2.55) for diastolic blood pressure. We identified in-silico a potential binding site for ETS transcription-factors directly next to rs3918226, suggesting a potential modulation of eNOS expression. Biological evidence links eNOS with hypertension, as it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
genetic epidemiology; risk factors; genetics-association studies; nitric oxide; Essential Hypertension
The epidemic surge in hypertension in sub-Saharan Africa is not matched by clinical trials of antihypertensive agents in Black patients recruited in this area of the world. We mounted the Newer versus Older Antihypertensive agents in African Hypertensive patients (NOAAH) trial to compare, in native African patients, a single-pill combination of newer drugs, not involving a diuretic, with a combination of older drugs including a diuretic.
Patients aged 30 to 69 years with uncomplicated hypertension (140 to 179/90 to 109 mmHg) and ≤2 associated risk factors are eligible. After a four week run-in period off treatment, 180 patients have to be randomized to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg (R) or amlodipine/valsartan 5/160 mg (E). To attain blood pressure <140/<90 mmHg during six months, the doses of bisoprolol and amlodipine should be increased to 10 mg/day with the possible addition of up to 2 g/day α-methyldopa.
At the time of writing of this progress report, of 206 patients enrolled in the run-in period, 140 had been randomized. At randomization, the R and E groups were similar (P ≥ 0.11) with respect to mean age (50.7 years), body mass index (28.2 kg/m2), blood pressure (153.9/91.5 mmHg) and the proportions of women (53.6%) and treatment naïve patients (72.7%). After randomization, in the R and E groups combined, blood pressure dropped by 18.2/10.1 mmHg, 19.4/11.2 mmHg, 22.4/12.2 mmHg and 25.8/15.2 mmHg at weeks two (n = 122), four (n = 109), eight (n = 57), and 12 (n = 49), respectively. The control rate was >65% already at two weeks. At 12 weeks, 12 patients (24.5%) had progressed to the higher dose of R or E and/or had α-methyldopa added. Cohort analyses of 49 patients up to 12 weeks were confirmatory. Only two patients dropped out of the study.
NOAAH (NCT01030458) demonstrated that blood pressure control can be achieved fast in Black patients born and living in Africa with a simple regimen consisting of a single-pill combination of two antihypertensive agents. NOAAH proves that randomized clinical trials of cardiovascular drugs in the indigenous populations of sub-Saharan Africa are feasible.
Antihypertensive therapy; Health policy and outcome research; Randomized clinical trial; Special populations
The aim of this study was to investigate the heritability as well as genetic and environmental correlations of left ventricular (LV) structural and functional traits in complex pedigrees of a Caucasian population.
Methods and results
We randomly recruited 459 white European subjects from 52 families (50% women; mean age 45 years). LV structure was measured by M-mode and 2D echocardiography and LV function was measured by conventional Doppler and tissue Doppler imaging (TDI). Other measurements included blood pressure, anthropometric, and biochemical measurements. We estimated the heritability of LV traits while adjusting for covariables, including sex, age, body height and weight, systolic and diastolic blood pressures, and heart rate. With full adjustment, heritability of LV mass was 0.23 (P= 0.025). The TDI-derived mitral annular velocities Ea and Aa showed moderate heritability (h2= 0.36 and 0.53, respectively), whereas the mitral inflow A peak had weak heritability (h2 = 0.25) and the E peak was not heritable (h2 = 0.11). We partitioned the total phenotypic correlation when it reached significance, into a genetic and an environmental component. The genetic correlations were 0.61 between the E and Ea peaks and 0.90 between the A and Aa peaks.
Our study demonstrated moderate heritability for LV mass as well as the mitral annular Ea and Aa peaks. We also found significant genetic correlations between the E and Ea peaks and between the A and Aa peaks. Our current findings support the ongoing research to map and detect genetic variants that contribute to the variation in LV mass and other LV structural and functional phenotypes.
Echocardiography; Heritability; Left ventricular phenotypes; Population science
Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence.
We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years).
In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively.
The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%.
Epidemiology; Echocardiography; Tissue Doppler Imaging; Diastole
The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase-2 dose-finding study of rostafuroxin, a digitoxygenin derivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans.
OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24-h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed).
Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P = 0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P = 0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P = 0.03) for systolic office BP; 0.70 mm Hg (P = 0.08) for diastolic office BP; 0.36 mm Hg (P = 0.49) for 24-h systolic BP; and 0.05 mm Hg (P = 0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤0.028), but carry-over effects were not significant (P ≥ 0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo.
In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose.
ClinicalTrials (NCT): NCT00415038
Few population studies have reported on the long-term changes in the internal cadmium dose and simultaneously occurring mortality.
We monitored blood cadmium (BCd), 24-hr urinary cadmium (UCd), and mortality in an environmentally exposed population.
Starting from 1985, we followed BCd (until 2003), UCd (until 1996), and mortality (until 2007) among 476 and 480 subjects, randomly recruited from low- exposure areas (LEA) and high-exposure areas (HEA). The last cadmium-producing plant in the HEA closed in 2002.
From 1985–1989 to 1991–1996, BCd decreased by 40.3% and 18.9% in the LEA and HEA, respectively (p < 0.0001 for between-area difference). From 1991–1996 until 2001–2003, BCd remained unchanged in the HEA (+ 1.8%) and increased by 19.7% in the LEA (p < 0.0001). Over the entire follow-up period, the annual decrease in BCd averaged 2.7% in the LEA (n = 258) and 1.8% in the HEA (n = 203). From 1985–1989 to 1991–1996, UCd fell by 12.9% in the LEA and by 16.6% in the HEA (p = 0.22), with mean annual decreases of 2.7% (n = 366) and 3.4% (n = 364). Over 20.3 years (median), 206 deaths (21.5%) occurred. At baseline, BCd (14.6 vs. 10.2 nmol/L) and UCd (14.1 vs. 8.6 nmol/24-hr) were higher in deaths than in survivors. The risks (p ≤ 0.04) associated with a doubling of baseline UCd were 20% and 44% for total and noncardiovascular mortality, and 25% and 33% for a doubling of BCd.
Even if zinc–cadmium smelters close, historical environmental contamination remains a persistent source of exposure. Environmental exposure to cadmium increases total and noncardiovascular mortality in a continuous fashion without threshold.
cadmium; environmental exposure; mortality
Environmental exposure to cadmium decreases bone density indirectly through hypercalciuria resulting from renal tubular dysfunction.
We sought evidence for a direct osteotoxic effect of cadmium in women.
We randomly recruited 294 women (mean age, 49.2 years) from a Flemish population with environmental cadmium exposure. We measured 24-hr urinary cadmium and blood cadmium as indexes of lifetime and recent exposure, respectively. We assessed the multivariate-adjusted association of exposure with specific markers of bone resorption, urinary hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), as well as with calcium excretion, various calciotropic hormones, and forearm bone density.
In all women, the effect sizes associated with a doubling of lifetime exposure were 8.4% (p = 0.009) for HP, 6.9% (p = 0.10) for LP, 0.77 mmol/day (p = 0.003) for urinary calcium, –0.009 g/cm2 (p = 0.055) for proximal forearm bone density, and –16.8% (p = 0.065) for serum parathyroid hormone. In 144 postmenopausal women, the corresponding effect sizes were –0.01223 g/cm2 (p = 0.008) for distal forearm bone density, 4.7% (p = 0.064) for serum calcitonin, and 10.2% for bone-specific alkaline phosphatase. In all women, the effect sizes associated with a doubling of recent exposure were 7.2% (p = 0.001) for urinary HP, 7.2% (p = 0.021) for urinary LP, –9.0% (p = 0.097) for serum parathyroid hormone, and 5.5% (p = 0.008) for serum calcitonin. Only one woman had renal tubular dysfunction (urinary retinol-binding protein > 338 μg/day).
In the absence of renal tubular dysfunction, environmental exposure to cadmium increases bone resorption in women, suggesting a direct osteotoxic effect with increased calciuria and reactive changes in calciotropic hormones.
bone; cadmium; pyridinium crosslinks
The Hypertension in the Very Elderly Trial (HYVET) is a placebo controlled double blind trial of treating hypertension with indapamide Slow Release (SR) ± perindopril in subjects over the age of 80 years. The primary endpoints are stroke (fatal and non fatal). In view of the fact that thiazide diuretics and indapamide reduce urinary calcium and may increase bone mineral density, a fracture sub study was designed to investigate whether or not the trial anti-hypertensive treatment will reduce the fracture rate in very elderly hypertensive subjects.
In the trial considerable care is taken to ascertain any fractures and to identify risk factors for fracture, such as falls, co-morbidity, drug treatment, smoking and drinking habits, levels of activity, biochemical abnormalities, cardiac irregularities, impaired cognitive function and symptoms of orthostatic hypotension.
The trial is expected to provide 10,500 patient years of follow-up. Given a fracture rate of 40/1000 patient years and a 20% difference in fracture rate, the power of the sub study is 58% to detect this difference at the 5% level of significance. The corresponding power for a reduction of 25% is 78%.
The trial is well under way, expected to complete in 2009, and on target to detect, if present, the above differences in fracture rate.
Polychlorinated aromatic hydrocarbons (PCAHs) have been described as endocrine disruptors in animals and in accidentally or occupationally exposed humans. In the present study we examined the effect of moderate exposure to PCAHs on sexual maturation. Two hundred adolescents (mean age, 17.4 years) who resided in two polluted suburbs and a rural control area in Flanders (Belgium) participated. We measured the serum concentration of polychlorinated biphenyl (PCB) congeners 138, 153, and 180 and dioxin-like compounds [chemically activated luciferase expression (CALUX) assay] as biomarkers of exposure. School physicians assessed the pubertal development of boys and girls and measured testicular volume. In one suburb near two waste incinerators, compared with the other suburb and the control area, fewer boys (p < 0.001) had reached the adult stages of genital development (62% vs. 92% and 100%, respectively) and pubic hair growth (48% vs. 77% and 100%). Also, in the same suburb, fewer girls (p = 0.04) had reached the adult stage of breast development (67% vs. 90% and 79%). In individual boys, a doubling of the serum concentration of PCB congener 138 increased the odds of not having matured into the adult stage of genital development by 3.5 (p = 0.04); similarly for PCB congener 153 in relation to male pubic hair growth, the odds ratio was 3.5 (p = 0.04). In girls, a doubling of the serum dioxin concentration increased the odds of not having reached the adult stage of breast development by 2.3 (p = 0.02). Left plus right testicular volume was lower in both polluted areas than in the control area (42.4 mL vs. 47.3 mL, p = 0.005) but was not related to the current exposure of the adolescents to PCAHs. Through endocrine disruption, environmental exposure to PCAHs may interfere with sexual maturation and in the long-run adversely affect human reproduction.