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Background. Sub-Saharan Africa experiences an epidemic surge in hypertension. Studies in African Americans led to the recommendation to initiate antihypertensive treatment in Blacks with a diuretic or a low-dose fixed combination including a diuretic. We mounted the Newer versus Older Antihypertensive Agents in African Hypertensive Patients (NOAAH) trial to compare in native African patients a fixed combination of newer drugs, not involving a diuretic, with a combination of older drugs including a diuretic. Methods. Patients aged 30-69 years with uncomplicated hypertension (140-179/90-109 mmHg) and two or fewer associated risk factors are eligible. After a 4-week run-in period off treatment, 180 patients will be randomized to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg or amlodipine/valsartan 5/160 mg. To attain and maintain blood pressure below 140/90 mmHg during 6 months of follow-up, the doses of bisoprolol and amlodipine in the combination tablets will be increased to 10 mg/day with the possible addition of α-methyldopa or hydralazine. NOAAH is powered to demonstrate a 5-mmHg between-group difference in sitting systolic pressure with a two-sided p-value of 0.01 and 90% power. NOAAH is investigator-led and complies with the Helsinki declaration. Results. Six centers in four sub-Saharan countries started patient recruitment on September 1, 2010. On December 1, 195 patients were screened, 171 were enrolled, and 51 were randomized and followed up. The trial will be completed in the third quarter of 2011. Conclusions. NOAAH (NCT01030458) is the first randomized multicenter trial of antihypertensive medications in hypertensive patients born and living in sub-Saharan Africa. ispartof: Blood Pressure vol:20 issue:5 pages:256-266 ispartof: location:England status: published

INTRODUCTION: : In a previous meta-analysis, we derived pooled estimates for the association of left ventricular mass (LVM) and hypertrophy (LVH), as diagnosed by electrocardiography or echocardiography, with the ACE D/I polymorphism. We updated this meta-analysis until May 2009 only considering echocardiographic phenotypes. METHODS: : We computed pooled estimates from a random-effects model. RESULTS: : Across 38 studies, both DD homozygotes (n = 2440) and DI heterozygotes ( n = 4310) had higher (p ≤ 0.002) LVM or LVM index than II homozygotes (n = 2229). Across 21 studies with available data, this was due to increased mean wall thickness (MWT) with no difference in left ventricular internal diameter (LVID). Standardised differences (DD versus II) were 0.39 (p < 0.001) for LVM, 0.34 (p = 0.009) for MWT, and 0.066 (p = 0.26) for LVID. Across 16 studies (4894 participants), the pooled odds ratios of LVH (versus II homozygotes) were 1.11 (p = 0.29) and 1.02 (p = 0.88) for the DD and DI genotypes, respectively. Sensitivity analyses were confirmatory. CONCLUSIONS: : Our meta-analysis supports the hypothesis that the enhanced ACE activity associated with the D allele is associated with higher LV mass. Smaller sample size might explain the lack of significant association with LVH. ispartof: Journal of the Renin-Angiotensin-Aldosterone System vol:12 issue:3 pages:243-253 ispartof: location:England status: published

Baseline blood pressure (BP) is the strongest known determinant of progression to hypertension, but for an individualized prediction of the incidence of hypertension, the identification of additional biomarkers is crucial. In animal models of hypertension, renal nitric oxide (NO) handling modifies the systemic BP responses prior to the development of hypertension. This study aimed to evaluate whether urinary NO metabolites (NOx) predict the progression of hypertension in normotensive subjects. Among 62 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes, we assessed progression to hypertension over 4.6 years. In a case-control design, 49 normotensive subjects including 10 subjects with high-normal blood pressure were enrolled of whom 25 remained normotensive (controls), whereas 24 'progressed' to hypertension (progressors). Thirteen hypertensive patients served as negative controls. Urinary NOx concentration, renal function and the urinary excretion of electrolytes were assessed at baseline and follow-up. At baseline, progressors showed higher BP values than controls and urinary NOx concentration was significantly lower in progressors as compared to the normotensive controls (p < 0.01). In all initially normotensive subjects baseline urinary NOx concentration was associated with follow-up BP (r=-0.55, p < 0.001) and the relative increase of BP over time (r=-0.47, p < 0.001). In progressors baseline urinary NOx was associated with follow-up BP (r=-0.52, p < 0.009) and the relative increase of BP over time (r=-0.44, p=0.033). Baseline urinary NOx and BP were independent predictors for the relative BP increase. A urinary NOx threshold of < 130.5 mg/L predicted 75% of all progressors. In context with high-normal baseline BP, 87.5% of all progressors were identified. These findings indicate that urinary NO metabolites are associated with BP development in normotensive subjects. Moreover, urinary NOx predicts the progression to hypertension independent of baseline BP suggesting urinary NOx as a biomarker for individual new-onset hypertension. ispartof: European Journal of Cardiovascular Prevention and Rehabilitation vol:18 issue:4 pages:656-663 ispartof: location:England status: published

It remains unknown whether diabetes and high blood pressure (BP) are simply additive risk factors for cardiovascular outcome or whether they act synergistically and potentiate one another. We performed 24-h ambulatory BP monitoring in 8494 subjects (mean age, 54.6 years; 47.0% women; 6.9% diabetic patients) enrolled in prospective population studies in 10 countries. In multivariable-adjusted Cox regression, we assessed the additive as opposed to the synergistic effects of BP and diabetes in relation to a composite cardiovascular endpoint by testing the significance of appropriate interaction terms. During 10.6 years (median follow-up), 1066 participants had a cardiovascular complication. Diabetes mellitus as well as the 24-h ambulatory BP were independent and powerful predictors of the composite cardiovascular endpoint. However, there was no synergistic interaction between diabetes and 24-h, daytime, or nighttime, systolic or diastolic ambulatory BP (P for interaction, 0.07P0.97). The only exception was a borderline synergistic effect between diabetes and daytime diastolic BP in relation to the composite cardiovascular endpoint (P=0.04). In diabetic patients, with normotension as the reference group, the adjusted hazard ratios for the cardiovascular endpoint were 1.35 (95% confidence interval (CI), 0.87-2.11) for white-coat hypertension, 1.78 (95% CI, 1.22-2.60) for masked hypertension and 2.44 (95% CI, 1.92-3.11) for sustained hypertension. The hazard ratios for non-diabetic subjects were not different from those of diabetic patients (P-values for interaction, 0.09P0.72). In conclusion, in a large international population-based database, both diabetes mellitus and BP contributed equally to the risk of cardiovascular complications without evidence for a synergistic effect.Hypertension Research advance online publication, 10 February 2011; doi:10.1038/hr.2011.6. ispartof: Hypertension research : official journal of the Japanese Society of Hypertension vol:34 issue:6 pages:714-721 ispartof: location:England status: published

Aims 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 ( h 2= 0.36 and 0.53, respectively), whereas the mitral inflow A peak had weak heritability ( h 2 = 0.25) and the E peak was not heritable ( h 2 = 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. Conclusion 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.

To analyze sex-specific relative and absolute risks associated with blood pressure (BP), we performed conventional and 24-hour ambulatory BP measurements in 9357 subjects (mean age, 52.8 years; 47% women) recruited from 11 populations. We computed standardized multivariable-adjusted hazard ratios for associations between outcome and systolic BP. During a course of 11.2 years (median), 1245 participants died, 472 of cardiovascular causes. The number of fatal combined with nonfatal events was 1080, 525, and 458 for cardiovascular and cardiac events and for stroke, respectively. In women and men alike, systolic BP predicted outcome, irrespective of the type of BP measurement. Women compared with men were at lower risk (hazard ratios for death and all cardiovascular events=0.66 and 0.62, respectively; P P =0.020) and the relations of total mortality ( P =0.023) and all cardiovascular ( P =0.0013), cerebrovascular ( P =0.045), and cardiac ( P =0.034) events with nighttime BP were steeper in women than in men. Consequently, per a 1-SD decrease, the proportion of potentially preventable events was higher in women than in men for all cardiovascular events (35.9% vs 24.2%) in relation to 24-hour systolic BP (1-SD, 13.4 mm Hg) and for all-cause mortality (23.1% vs 12.3%) and cardiovascular (35.1% vs 19.4%), cerebrovascular (38.3% vs 25.9%), and cardiac (31.0% vs 16.0%) events in relation to systolic nighttime BP (1-SD, 14.1 mm Hg). In conclusion, although absolute risks associated with systolic BP were lower in women than men, our results reveal a vast and largely unused potential for cardiovascular prevention by BP-lowering treatment in women.

Numerous studies addressed the predictive value of the nighttime blood pressure (BP) as captured by ambulatory monitoring. However, arbitrary cutoff limits in dichotomized analyses of continuous variables, data dredging across selected subgroups, extrapolation of cross-sectional studies to prospective outcomes, and lack of comprehensive adjustments for confounders make interpretation of the literature difficult. We reviewed prospective studies with total mortality or a composite cardiovascular end point as an outcome in relation to the level and the circadian profile of systolic BP. We analyzed studies in hypertensive patients (n=23 856) separately from those in individuals randomly recruited from populations (n=9641). We pooled summary statistics and individual subject data, respectively. In both patients and populations, in analyses in which nighttime BP was additionally adjusted for daytime BP and vice versa, nighttime BP was a stronger predictor than daytime BP. With adjustment for the 24-hour BP, both the night-to-day BP ratio and dipping status remained significant predictors of outcome but added little prognostic value over and beyond the 24-hour BP level. In the absence of conclusive evidence proving that nondipping is a reversible risk factor, the option whether or not to restore the diurnal blood pressure profile to a normal pattern should be left to the clinical judgment of doctors and should be individualized for each patient. Current guidelines on the interpretation of ambulatory BP recording need to be updated. ispartof: Hypertension vol:57 issue:1 pages:3-10 ispartof: location:United States status: published

BackgroundParathyroid hormone (PTH) and vitamin D interactively regulate calcium fluxes across membranes, and thereby modulate insulin sensitivity, blood pressure, and arterial calcification. We hypothesized that lower calcium intake as reflected by circulating PTH and 25-OH-D(3) might be associated with the metabolic syndrome (MS) and arterial calcification.MethodsIn a random population sample (n = 542; 50.5% women; mean age, 49.8 +/- 13.1 years), we measured MS prevalence (International Diabetes Federation (IDF) and American Heart Association (AHA) criteria), PTH and 25-OH-D(3), serum and 24-h urinary calcium, MS components, carotid intima-media thickness (CIMT), and calcium intake from dairy products. We assessed associations in multivariable-adjusted analyses, using linear and logistic regressions.ResultsThe prevalence of MS was 21.0% (IDF criteria) and 23.6% (AHA criteria). MS prevalence, blood pressure, waist circumference, body mass index, fasting blood glucose, insulin and triglycerides, and CIMT increased (P

We focus on the recent evidence that elucidates our understanding about the effects of cadmium (Cd) on human health and their prevention. Recently, there has been substantial progress in the exploration of the shape of the Cd concentration-response function on osteoporosis and mortality. Environmental exposure to Cd increases total mortality in a continuous fashion without evidence of a threshold, independently of kidney function and other classical factors associated with mortality including age, gender, smoking and social economic status. Pooled hazard rates of two recent environmental population based cohort studies revealed that for each doubling of urinary Cd concentration, the relative risk for mortality increases with 17% (95% CI 4.2-33.1%; P < 0.0001). Tubular kidney damage starts at urinary Cd concentrations ranging between 0.5 and 2 mug urinary Cd/g creatinine, and recent studies focusing on bone effects show increased risk of osteoporosis even at urinary Cd below 1 mug Cd/g creatinine. The non-smoking adult population has urinary Cd concentrations close to or higher than 0.5 mug Cd/g creatinine. To diminish the transfer of Cd from soil to plants for human consumption, the bioavailability of soil Cd for the plants should be reduced (external bioavailability) by maintaining agricultural and garden soils pH close to neutral (pH-H(2)O of 7.5; pH-KCL of 6.5). Reducing the systemic bioavailability of intestinal Cd can be best achieved by preserving a balanced iron status. The latter might especially be relevant in groups with a lower intake of iron, such as vegetarians, and women in reproductive phase of life. In exposed populations, house dust loaded with Cd is an additional relevant exposure route. In view of the insidious etiology of health effects associated with low dose exposure to Cd and the current European Cd intake which is close to the tolerable weekly intake, one should not underestimate the importance of the recent epidemiological evidence on Cd toxicity as to its medical and public health implications. The Environmental Health research at Hasselt University is supported by grants from the Flemish Fund for Scientific Research (FWO, krediet aan navorsers to T.N.) and internal Hasselt University grants (Bijzonder Onderzoekdsfonds, BOF).

BACKGROUND: We and other investigators previously reported that isolated nocturnal hypertension on ambulatory measurement (INH) clustered with cardiovascular risk factors and was associated with intermediate target organ damage. We investigated whether INH might also predict hard cardiovascular endpoints. METHODS AND RESULTS: We monitored blood pressure (BP) throughout the day and followed health outcomes in 8711 individuals randomly recruited from 10 populations (mean age 54.8 years, 47.0% women). Of these, 577 untreated individuals had INH (daytime BP /=120/70 mmHg) and 994 untreated individuals had isolated daytime hypertension on ambulatory measurement (IDH; daytime BP >/=135/85 mmHg and night-time BP

Ambulatory blood pressure (BP) monitoring provides information not only on the BP level but also on the diurnal changes in BP. In the present review, we summarized the main findings of the International Database on Ambulatory BP in relation to Cardiovascular Outcome (IDACO) with regard to risk stratification based on BP variability. The predictive accuracy of daytime and nighttime BP and the night-to-day BP ratio depended on the disease outcome under study and treatment status, and differed for fatal outcomes compared with the composite of fatal and nonfatal diseases. An exaggerated morning surge, exceeding the 90th percentile of the population, is an independent risk factor for mortality and cardiovascular and cardiac events. Conversely, a sleep-trough or preawakening morning surge in systolic BP below 20 mm Hg is probably not associated with an increased risk of death or cardiovascular events. BP variability as captured by the average of the daytime and nighttime s.d. weighted for the duration of the daytime and nighttime interval (s.d.(dn)) and the average real variability (ARV(24)) predicted the outcome, but improved the prediction of the composite of all cardiovascular events by only 0.1%. In conclusion, the IDACO observations support the concept that BP variability adds to risk stratification, but above all highlight that 24-h ambulatory BP level remains the main predictor to be considered in clinical practice. ispartof: Hypertension Research vol:33 issue:8 pages:757-766 ispartof: location:England status: published

In previous studies, of which several were underpowered, the relation between cardiovascular outcome and blood pressure (BP) variability was inconsistent. We followed health outcomes in 8938 subjects (mean age: 53.0 years; 46.8% women) randomly recruited from 11 populations. At baseline, we assessed BP variability from the SD and average real variability in 24-hour ambulatory BP recordings. We computed standardized hazard ratios (HRs) while stratifying by cohort and adjusting for 24-hour BP and other risk factors. Over 11.3 years (median), 1242 deaths (487 cardiovascular) occurred, and 1049, 577, 421, and 457 participants experienced a fatal or nonfatal cardiovascular, cardiac, or coronary event or a stroke. Higher diastolic average real variability in 24-hour ambulatory BP recordings predicted ( P ≤0.03) total (HR: 1.14) and cardiovascular (HR: 1.21) mortality and all types of fatal combined with nonfatal end points (HR: ≥1.07) with the exception of cardiac and coronary events (HR: ≤1.02; P ≥0.58). Higher systolic average real variability in 24-hour ambulatory BP recordings predicted ( P P ≥0.54). SD predicted only total and cardiovascular mortality. While accounting for the 24-hour BP level, average real variability in 24-hour ambulatory BP recordings added

We reviewed 6 recent outcome trials of blood pressure (BP)-lowering drugs in 74 524 randomized hypertensive or high-risk patients. Over interpretation of nonsignificant or marginal probability values in large trials with overlapping end points, exclusion of patients not tolerating or not adhering to experimental treatments, labeling nonsignificant treatment effects as modest, and insufficient information on the quality of the BP measurements or on the BP changes early after randomization raise concern. From a clinical viewpoint, results should not be extrapolated to patients with characteristics dissimilar from those randomized. The benefit beyond BP lowering in cardiovascular prevention is tiny. Dual inhibition of the renin system should only be used in patients at high risk, in whom all drug combinations have been tried and who cannot be controlled by a single renin system inhibitor. Current evidence does not support BP lowering in normotensive patients or the use of renin system inhibitors for prevention of stroke recurrence. Because angiotensin-receptor blockers might offer less protection against myocardial infarction than angiotensin-converting enzyme inhibitors, the latter should remain the preferred renin system inhibitor for cardiovascular prevention in angiotensin-converting enzyme inhibitor-tolerant patients. In 2 trials, in which new-onset diabetes was a predefined end point, 1000 patients had to be treated for 1 year with an angiotensin-receptor blocker instead of placebo to prevent just 2 cases. From a design viewpoint, the time has come to revise the concept of large simple trials and to pursue research questions that serve patient interests more than showing noninferiority or highlight the ancillary qualities of marketable antihypertensive drugs. (Hypertension. 2010;55:819-831.)

Thomas G. Pickering spent most of his scientific career in carrying out research on clinical hypertension and blood pressure (BP) measurement. In our review of Pickering's seminal work, we first focused on white-coat hypertension and masked hypertension, two terms that he had introduced. Next, we highlighted the early publications of Pickering on diurnal BP variability and on the clinical application of self-measured BP. Pickering's work inspired many investigators worldwide and constituted a solid basis for further research. Pickering's original ideas led to algorithms for risk stratification involving white-coat hypertension and masked hypertension, diurnal BP variability, and self-measured BP. Recent studies validated Pickering's observations in terms of cardiovascular outcome and bridged the path from concept to application in clinical practice. ispartof: Blood Pressure Monitoring vol:15 issue:2 pages:72-81 ispartof: location:England status: published

AIM: To evaluate the association between fetuin-A level (AHSG), its encoding gene (Thr256Ser) and arterial function in subjects with normal kidney function. INTRODUCTION: The aortic pulse wave velocity (aPWV) is a predictor for cardiovascular mortality. Fetuin-A is a calcification inhibitor and correlates negatively with increased vascular stiffness in dialysis patients. The fetuin-A polymorphism (Thr256Ser) is associated with reduced fetuin levels and accelerated vascular calcification in dialysis patients. Little is known about the role of fetuin-A as an independent predictor for the development of arterial stiffness in healthy subjects. MATERIALS AND METHODS: We studied 116 subjects with normal kidney function (age 47+/-12 years, 50 females and 66 males) of the FLEMENGHO study. Calcium measurements, plasma fetuin-A, its encoding gene (Thr256Ser) and indexes of arterial stiffness, such as aPWV and arterial distensibility, were determined. RESULTS: Fetuin-A levels were negatively correlated with aPWV (r=-0.21, p=0.029). After an adjustment for multiple covariables, fetuin-A levels were independently associated with aPWV (r=-0.30, p=0.022) in males but not in females. Male fetuin-A SerSer carrier had lower fetuin-A levels and higher aPWV (fetuin-A: 61.9+/-29.0 microg/ml; aPWV: 14.3+/-0.9 m/s) as compared to ThrThr (fetuin-A: 109.9+/-54.9 microg/ml; aPWV: 6.4+/-1.3 m/s) and ThrSer carrier (fetuin-A: 100.8+/-52.5 microg/ml; aPWV: 6.6+/-1.3 m/s). Other calcium variables were not significantly associated with arterial stiffness. CONCLUSION: With respect to common calcium variables, only fetuin-A level showed an inverse relation with aPWV in men with normal renal function. Male fetuin-A SerSer carriers demonstrate particularly high aortic stiffness, possibly implying a status of increased cardiovascular risk. ispartof: Regulatory Peptides vol:154 issue:1 pages:39-43 ispartof: location:Netherlands status: published

Previous studies reported on the association of left ventricular mass index (LVMI) with urinary sodium or with circulating or urinary aldosterone. We investigated the independent associations of LVMI with the urinary excretion of both sodium and aldosterone. We randomly recruited 317 untreated subjects from a white population (45.1% women; mean age 48.2 years). Measurements included echocardiographic left ventricular (LV) properties, the 24-hour urinary excretion of sodium and aldosterone, plasma renin activity (PRA), and proximal (RNa prox ) and distal (RNa dist ) renal sodium reabsorption, assessed from the endogenous lithium clearance. In multivariable-adjusted models, we expressed changes in LVMI per 1-SD increase in the explanatory variables, while accounting for sex, age, systolic blood pressure, and the waist-to-hip ratio. LVMI increased independently with the urinary excretion of both sodium (+2.48 g/m 2 ; P =0.005) and aldosterone (+2.63 g/m 2 ; P =0.004). Higher sodium excretion was associated with increased mean wall thickness (MWT: +0.126 mm, P =0.054), but with no change in LV end-diastolic diameter (LVID: +0.12 mm, P =0.64). In contrast, higher aldosterone excretion was associated with higher LVID (+0.54 mm; P =0.017), but with no change in MWT (+0.070 mm; P =0.28). Higher RNa dist was associated with lower relative wall thickness (−0.81×10 −2 , P =0.017), because of opposite trends in LVID (+0.33 mm; P =0.13) and MWT (−0.130 mm; P =0.040). LVMI was not associated with PRA or RNa prox. In conclusion, LVMI independently increased with both urinary sodium and aldosterone excretion. Increased MWT explained the association of LVMI with urinary sodium and increased LVID the association of LVMI with urinary aldosterone.

BACKGROUND: Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants. METHODS: 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 (h) of RNaprox and RNadist. RESULTS: 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). h of RNaprox and RNadist was high and significant (P < 0.001) in both countries. h 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. CONCLUSION: 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.

OBJECTIVE: No population study investigated whether 24-h ambulatory blood pressure (ABP) predicts distensibility of the elastic common carotid (DCar) and the muscular femoral (DFem) arteries over and beyond conventionally measured blood pressure (CBP). METHODS: At baseline, we measured CBP and 24-h ABP in 1063 randomly recruited participants (mean age, 44.3 years). CBP was the average of five consecutive readings obtained by trained observers at the participants' homes. We measured arterial distensibility by a wall-tracking ultrasound system, 21 months after CBP and ABP (5-95th percentile interval range, 13-33 months). RESULTS: Compared with men, women (49.2%) had higher (P

OBJECTIVE: The goal of this review study is to summarize 30 years of research on cut-off limits for the self-measured blood pressure. METHODS: We reviewed two meta-analyses, several prospective outcome studies in populations and hypertensive patients, studies in pregnant women, three clinical trials and the thresholds proposed in earlier and current hypertension guidelines. RESULTS: In line with existing guidelines, prospective studies support that levels of the self-measured blood pressure at home of greater than or equal to 135 mmHg systolic or greater than or equal to 85 mmHg diastolic indicate hypertension. Circumstantial data suggest that levels of the self-measured blood pressure below 120/80 and 130/85 mmHg are optimal and normal, respectively. Therapeutic targets of the self-measured blood pressure to be attained on antihypertensive drug treatment are currently unknown, but should logically be lower (

OBJECTIVES: Few studies have addressed the effect of cadmium toxicity on arterial properties. METHODS: We investigated the possible association of 24 h urinary cadmium excretion (an index of lifetime exposure) with measures of arterial function in a randomly selected population sample (n = 557) from two rural areas with low and high environmental exposure to cadmium. RESULTS: 24 h urinary cadmium excretion was significantly higher in the high compared with the low exposure group (p

Activation of type-1 dopamine receptors ( DRD1 ) reduces renal sodium reabsorption. In a family-based random sample of 611 untreated whites (women, 45.0%; mean age, 38.6 years), we measured blood pressure (BP). We used the endogenous lithium clearance to assess fractional sodium excretion (FE Na ) and proximal (RNa prox ) and distal (RNa dist ) tubular sodium reabsorption. We investigated multivariate-adjusted associations with the DRD1 promoter ( A − 48G , G − 94A , and C − 800T ) and GRK4 (Ala142Val ). The frequent DRD1 haplotypes were AGC (48.2%), GGT (34.4%), and AAC (14.3%). While standardizing to mean sodium excretion (8.7 mmol/h) and adjusting for covariates and relatedness, RNa dist was lower in DRD1 − 94GG homozygotes than − 94A allele carriers (effect size, −0.94%; P =0.005) with opposite findings for FE Na (+0.084%; P =0.014). AGC carriers (−0.88%; P =0.012) and AAC carriers (+1.00%; P =0.004) had different RNa dist compared to corresponding noncarriers. Furthermore, FE Na was lower in AAC carriers than in noncarriers (−0.082%; P =0.019). The family-based analyses identified a significant between-family component in the variance of the renal phenotypes associated with the DRD1 polymorphisms. Transmission of the DRD1 AGC haplotype was also associated with lower systolic (−3.54 mm Hg; P =0.016) and diastolic (−2.80 mm Hg; P =0.0064) BPs without significant between-family variance component. Plasma renin activity and urinary aldosterone excretion were not associated with DRD1 variation. The GRK4 Ala142Val polymorphism did not contribute to the phenotypes under study. In conclusion, renal sodium handling and BP were associated with genetic variation in the DRD1 promoter. The between-family variance component excluded population stratification for BP, but not for the renal phenotypes.

BACKGROUND: The 24-h ambulatory blood pressure (ABP) is a stronger predictor of cardiovascular disease than conventional blood pressure (CBP), but it remains unclear how it compares with "usual" blood pressure (UBP), estimated after CBP has been corrected for regression dilution bias (RDB). METHODS: We compared the associations of cardiovascular mortality (n = 50), cardiovascular events (n = 101), and cardiac events (n = 71) with systolic CBP, UBP, and ABP over 13 years of follow-up (median) in 1,167 randomly selected Belgians. We estimated the correction factor to compute UBP from CBP at the midpoint of follow-up (6.5 years) in 723 untreated individuals without cardiovascular disease. RESULTS: Cardiovascular disease increased across quartiles of systolic CBP, UBP, and ABP (P for trend < or =0.02). For each 10 mm Hg increment in systolic ABP, the multivariate-adjusted hazard ratios for cardiovascular mortality and for cardiovascular and cardiac events were 1.38, 1.27, and 1.33, respectively (P < 0.001 for all). For CBP, the corresponding hazard ratios were 1.10 (P = 0.21), 1.09 (P = 0.12), and 1.14 (P = 0.06); and for UBP, they were 1.18 (P = 0.21), 1.16 (P = 0.12), and 1.23 (P = 0.06), respectively. The risk function for cardiovascular disease in relation to ABP was significantly steeper than that for CBP, but not UBP. In Cox models, including CBP or UBP in the presence of ABP, only ABP predicted cardiovascular outcomes. CONCLUSIONS: Correcting CBP for RDB resulted in a steeper slope of events on blood pressure than observed for CBP. The association with UBP was not statistically significant and did not enhance the prediction of outcome to the level of ABP. ispartof: American Journal of Hypertension vol:21 issue:9 pages:994-1000 ispartof: location:United States status: published

The ambulatory arterial stiffness index (AASI) is derived from 24-hour ambulatory blood pressure recordings. We investigated whether the goodness-of-fit of the AASI regression line in individual subjects ( r 2 ) impacts on the association of AASI with established determinants of the relation between diastolic and systolic blood pressures. We constructed the International Database on the Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes (7604 participants from 6 countries). AASI was unity minus the regression slope of diastolic on systolic blood pressure in individual 24-hour ambulatory recordings. AASI correlated positively with age and 24-hour mean arterial pressure and negatively with body height and 24-hour heart rate. The single correlation coefficients and the mutually adjusted partial regression coefficients of AASI with age, height, 24-hour mean pressure, and 24-hour heart rate increased from the lowest to the highest quartile of r 2 . These findings were consistent in dippers and nondippers (night:day ratio of systolic pressure ≥0.90), women and men, and in Europeans, Asians, and South Americans. The cumulative z score for the association of AASI with these determinants of the relation between diastolic and systolic blood pressures increased curvilinearly with r 2 , with most of the improvement in the association occurring above the 20th percentile of r 2 (0.36). In conclusion, a better fit of the AASI regression line enhances the statistical power of analyses involving AASI as marker of arterial stiffness. An r 2 value of 0.36 might be a threshold in sensitivity analyses to improve the stratification of cardiovascular risk.

Low dietary intake of calcium stimulates the activation of vitamin D3 precursors to calcitriol in the kidney. This circulating hormone raises blood and urinary calcium by increasing both gastrointestinal absorption of calcium and bone resorption. Renal activation of vitamin D3 is under tight feedback control. Macrophages also activate vitamin D3, but, unlike renal tubular cells, they lack feedback suppression of the activating 1alpha-hydroxylase. In large-scale epidemiologic studies, blood pressure correlated positively with serum and urinary calcium but inversely with the dietary intake of calcium. Several population-based reports, including the Framingham Study, noticed an association of carotid plaques, arterial calcification, and increased arterial stiffness with lower bone-mineral content. Randomized clinical trials of calcium supplementation did not demonstrate a consistent effect on blood pressure. Macrophages in atherosclerotic lesions can locally activate vitamin D3 to calcitriol, which might contribute to arterial stiffening and hypertension. Calcitriol acts as a vasoactive and pro-oxidative substance on vascular smooth muscle cells. In animal models, active vitamin D3 promotes arterial stiffening and the pathogenesis of systolic hypertension and perpetuates a self-sustaining cycle leading to arterial damage and calcification. On the other hand, active vitamin D3 inhibits renin activity, thereby decreasing blood pressure in short-term, randomized trials. This article assesses the potential role of active vitamin D3 in causing cardiovascular complications via its effects on the structure of the arterial wall and the pathogenesis of hypertension. To set the stage and open up new perspectives, our article also summarizes the pathways leading to the renal and extrarenal activation and metabolism of vitamin D3 and will propose some directions for further research in this complex field. ispartof: American journal of hypertension vol:20 issue:9 pages:1007-1015 ispartof: location:United States status: published

PURPOSE OF REVIEW We examined the role of blood pressure-lowering compared with class-specific properties of antihypertensive drugs in cardiovascular prevention. RECENT FINDINGS We reviewed recently published trials and meta-regression analyses. SUMMARY From 150,000 to 180,000 randomized patients followed up from 3 to 5 years were required to demonstrate a 10-15% benefit 'beyond blood pressure lowering' of newer antihypertensive drugs, such as calcium channel blockers or angiotensin-converting enzyme inhibitors in the prevention of cause-specific cardiovascular complications. Assuming an absolute risk of new-onset diabetes mellitus on older drugs of approximately 10% over 5 years and a relative benefit on the newer drugs of approximately 30%, about 100 patients would have to be treated for 5 years with the newer agents to avert approximately three iatrogenic cases of diabetes. Whether or not new-onset diabetes is associated with increased risk is uncertain. In most patients, optimization of treatment at acceptable tolerance requires rotation through and combination of several drug classes. Combination of different classes of antihypertensive drugs not only enhances the blood pressure-lowering efficacy, but likely decreases the risk of metabolic adverse effects as well. True benefit beyond blood pressure lowering in hypertensive patients comes from multiple risk factor intervention.

Traditional teaching subdivides the dementia syndrome into neurodegenerative Alzheimer’s disease (AD), vascular dementia (VaD), and mixed variants. In spite of the vast and continuing literature on the dichotomy between AD and VaD, new emerging concepts highlight the role of cardiovascular risk factors in the pathogenesis of AD, especially in older patients.1,2 Hypertension is the major player in the pathogenesis of stroke, poststroke dementia, and VaD. AD is the most common cause of dementia, contributing from 45% to >75% of the cases in Asians and whites, respectively.3 This review will focus on the role of hypertension as a reversible risk factor in the development of dementia, in particular AD. To set the stage, we will first summarize current insights in the epidemiology of AD, the pathogenesis of VaD and AD, and the association between neurodegeneration and atherosclerosis. Across 36 cross-sectional studies, the prevalence of dementia increased exponentially from 0.3% to 1.0% in subjects aged 60 to 64 years to 10% to 20% in octogenarians and to >40% in the ninth decade of life.3 In 15 longitudinal studies, the incidence of dementia showed a similar age-related dependency with rates expressed in new cases per 1000 person-years ranging from 0.4 to 4 at 60 to 64 years to 20 to >40 at 80 to 85 years.3 Currently, 24.3 million people have dementia with an annual worldwide incidence of 4.6 million new cases.4 Because of the aging of populations, the number of demented patients will increase 2-fold every 20 years to 81.1 million by 2040, with >60% living in developing countries.4 The 2003 World Health Report5 estimated that adults aged ≥60 years lost ≈8.6 million disability-adjusted life years because of AD or other dementias. In this age group, only ischemic heart disease (31.5), cerebrovascular disease (29.6), and …

Sporting activities that involve repetitive stress to muscle compartments can elicit chronic exertional compartment syndrome. Its occurrence in the lower leg muscle compartments is most common, but other locations are less well known and the pathophysiology is not completely understood. In motocross racers, chronic exertional compartment syndrome can occur in the muscles of the lower arm. Currently, the only accepted treatment of correctly diagnosed chronic exertional compartment syndrome is surgical release of the fascia, which successfully relieves pain and allows patients to return to full activity. Open decompression is considered as the gold standard of treatment. This clinical paper describes our new endoscopic technique and investigates the functional outcome after surgery. We report on a series of 154 chronic exertional compartment syndromes afflicted motocross racers treated with an endoscopic release of the lower arm muscles. An MRI scan before and after strenuous exercise of the hand flexors (repetitive grip until exhaustion for 15 min) was performed to confirm the clinical diagnosis of chronic exertional compartment syndrome. Symptom severity before and after surgery was assessed using a visual analogue scale. Preoperative symptom severity scores were 1.1 ± 0.3 before exercise and 7.4 ± 1.5 after exercise. Post-operatively, these were 1.0 ± 0.2 and 1.7 ± 0.9. The pre- versus post-operative symptom scores after exercise were significantly different (p

ispartof: The Lancet Neurology vol:10 issue:1 pages:22-24 ispartof: location:England status: published

We investigated the effects of different antihypertensive drugs on the ambulatory arterial stiffness index (AASI), pulse pressure (PP), the arterio-ventricular coupling index (AVCI) and aortic pulse wave velocity (aPWV). After a 4-week placebo period, 94 and 107 patients with uncomplicated hypertension were randomly assigned to treatment with atenolol (AT) at dosage of 50 mg per day or perindopril/indapamide (PER/IND) at dosage of 2/0.6 mg per day for 1 year. From each patient's 24-h ambulatory blood pressure (BP) recording, we determined the 24-h systolic and diastolic BPs. We computed PP as the difference between 24-h systolic and diastolic BP, AASI as unity minus the regression slope of diastolic on systolic BP, and AVCI as (T/τ)/(1+2T/3τ), where T is the heart period in seconds and τ is the decay time of aortic BP during diastole. On AT compared with PER/IND, with adjustments applied for covariables, 24-h systolic BP (-9.5 vs. -13.7 mm Hg; P=0.009) and 24-h PP (-1.02 vs. -6.53 mm Hg; P

To the Editor: Hypertension at middle age is a risk factor for vascular and neurodegenerative dementia later in life.1 Because populations are aging, the number of demented patients will grow 2-fold every 20 years, from 24.3 million people in 2000 to 81.1 million by 2040, with >60% living in developing countries.2 The question of whether hypertension is a modifiable risk factor for dementia is therefore of great clinical importance. Our 2007 meta-analysis1 included 4 placebo-controlled trials of blood pressure–lowering therapies for prevention of dementia (18 196 patients and 642 dementia cases).3,–,6 The common odds ratio was 0.89 (CI, 0.75 to 1.04) and did not reach statistical significance ( P =0.15). However, sensitivity analyses revealed a difference ( P =0.04) that depended on whether active treatment started with or included a diuretic or dihydropyridine calcium channel blocker compared with an inhibitor of the renin system. The pooled …

OBJECTIVE: To our knowledge, few studies compared the association of brachial-ankle pulse wave velocity (baPWV) with cardiovascular risk factors among Chinese with type-2 diabetes mellitus and non-diabetic controls. This study addresses this issue. METHODS: We measured baPWV (OMRON VP1000) in 413 diabetic patients from Shanghai city (mean age: 58.7 years; 57% women) and 354 controls randomly recruited from the population of JingNing county, Zhejiang Province. We used stepwise multiple regression to identify covariables of baPWV and introduced interaction terms in the models to compare slopes. We expressed association sizes for continuous variables for a 1-SD increase in the dependent variable. RESULTS: Adjusted baPWV was higher in diabetic patients than controls (1678 vs 1583 cm/sec; P= 0.018). In diabetic patients, baPWV was independently correlated with female sex (-61 cm/sec; P = 0.061), age (+107 cm/sec; P < 0.0001), height (-51 cm/sec; P = 0.012), systolic pressure (+99 cm/sec; P < 0.0001), and the HDL-to-total cholesterol ratio (-38 cm/sec; P = 0.0004). In controls, the explanatory variables were female sex (-74 cm/sec; P = 0.045), age (+138 cm/sec; P < 0.0001), height (-262 cm/sec; P < 0.0001), systolic pressure (+202 cm/sec; P < 0.0001), but not the HDL-to-total cholesterol ratio (P = 0.48). Explained variance of baPWV was 34% and 61% in diabetic patients and controls, respectively. The associations of baPWV with age, height and systolic pressure were steeper (P < 0.04) in controls than diabetic patients. CONCLUSION: Sex, age, height and systolic pressure were the main determinants of baPWV in Chinese, irrespective of whether they had diabetes or not, but these associations were tighter in population-based controls without diabetes. ispartof: Acta Cardiologica vol:66 issue:5 pages:619-626 ispartof: location:England status: published

Long-term follow-up of clinical trials of blood pressure–lowering medications has suggested a continuation of event reduction after study completion. We evaluated the persistence of mortality benefit of these agents after the end of clinical trials, when all of the patients were advised to take the same open-label therapy. We performed a meta-analysis of randomized clinical trials using blood pressure–lowering medications, used in patients with hypertension, myocardial infarction, or left ventricular systolic dysfunction, (n=18; 132 854 patients; 11 988 deaths) when a second report describing results after the end of the trial was available. During the randomized (first) phase, 80% (interquartile range: 75% to 83%) of the patients randomized to receive active therapy actually received it compared with 16% (interquartile range: 7% to 22%) of those randomized to control. In this phase, mortality was lower in the intervention group (odds ratio: 0.84 [95% CI: 0.79 to 0.90]; P P

Experimental studies have implicated telomere dynamics in cardiomyocyte size and replication potential; shorter telomeres mark attenuated proliferation and increased apoptosis. The authors examined whether this translates into an impact of telomere length (TL) on left ventricular (LV) mass in the general population. In 334 randomly selected Flemish participants (mean age = 46.5 years; 52.5% women), they measured TL in circulating leukocytes using quantitative polymerase chain reaction, expressing it as telomere/genomic DNA ratio (T/S). After a median 7.4 years of follow-up (interquartile range, 6.2-8.5) during 1996-2007, they measured LV mass by echocardiography. In multivariable-adjusted analyses accounting for sex, age, body weight and height, systolic blood pressure, and antihypertensive drug use, LV mass and LV mass index significantly increased with mean leukocyte TL in the entire population and in the 198 normotensive subjects. For a 1-standard-deviation increment in T/S ratio, LV mass (mean = 170 g) and LV mass index (mean = 92 g/m(2)) increased by 5.20 g (P = 0.003) and 2.70 g/m(2) (P = 0.004), respectively, in all subjects and by 8.03 g (P = 0.0001) and 3.74 g/m(2) (P = 0.0007) in normotensive subjects. There were corresponding associations with LV wall thicknesses (P < 0.007) but not LV internal diameter (P = 0.26) in normotensive subjects. Longer mean leukocyte TL is associated with increased LV mass, particularly in normotensive subjects. This association could have a biologic basis related to the role of TL in determining cardiomyocyte size and replication potential. ispartof: American Journal of Epidemiology vol:172 issue:4 pages:440-450 ispartof: location:United States status: published

Pregnancy is a cardiovascular and metabolic challenge to the human female body. This review summarizes current knowledge on the regulation of blood pressure and plasma volume in normal and hypertensive pregnant women. During pregnancy, systemic vascular resistance and blood pressure decrease, whereas cardiac output and blood volume increase to safeguard an adequate circulation in the utero-placental arterial bed. Hypertension affects 10% of all pregnancies and is accompanied by an increase in foetal and maternal morbidity and mortality. Hypertension in pregnancy includes a wide spectrum of conditions, including pre-eclampsia and eclampsia, pre-eclampsia superimposed on chronic hypertension, chronic hypertension, and gestational hypertension. Endothelial dysfunction, oxidative stress and an exaggerated inflammatory response are features related to hypertensive disorders. Microangiopathic disorders can easily mimic hypertensive disorders during pregnancy. Although they have some symptoms in common, they require another type of management. To reduce the risk of maternal and foetal complications due to haemodynamic maladaptations, the current management includes rest at home or in the hospital, close monitoring of maternal and foetal signs and symptoms, early start of antihypertensive therapy, and timely delivery regarding maternal and foetal survival chances. Thresholds to initiate blood pressure lowering treatment during pregnancy are 160 mmHg systole or 110 mmHg diastole. Below these thresholds, treatment must be individualized because current evidence does not support aggressive medical interventions. Alpha-methyldopa and dihydropyridinic calcium channel blockers are among the recommended antihypertensives. ispartof: Acta Clinica Belgica vol:65 issue:4 pages:229-236 ispartof: location:England status: published

BACKGROUND: Endogenous ouabain, an endogenous digitalis-like steroid, is synthesized in the adrenal glands and possibly in the hypothalamus. In vitro and in vivo, endogenous ouabain triggers growth and proliferation of cardiomyocytes. OBJECTIVE: We therefore investigated the association between left ventricular structure and function and plasma endogenous ouabain in a general population. METHODS: We randomly recruited 536 individuals from a general population (50.7% women, mean age 53.1 years). Measurements included echocardiographic left ventricular structure and function, blood pressure, plasma endogenous ouabain, and the 24-h urinary excretion of sodium. RESULTS: The geometric mean plasma endogenous ouabain was 95.5 pmol/l (interquartile range 79.4-120.2 pmol/l). We expressed effect sizes for a 1-SD increase in plasma endogenous ouabain (0.21 on the logarithmic scale), while accounting for important covariables. For a 1-SD increment in plasma endogenous ouabain, SBP, left ventricular posterior wall, the interventricular septum, and relative wall thickness increased by 1.59 mmHg (P = 0.009), 0.138 mm (P = 0.003), 0.152 mm (P = 0.013), and 0.71 x 10 (P = 0.008), respectively. In a sensitivity analysis, involving 431 individuals aged 29-71 years (10-90th percentile interval), a 1-SD increase in plasma endogenous ouabain was associated with opposite trends in ejection fraction (+0.90%, P = 0.005) and left ventricular systolic longitudinal strain (-0.48%, P = 0.011). Moreover, in individuals whose sodium excretion was above median (160 mmol/24 h), the aforementioned associations reached a higher level of statistical significance. CONCLUSION: Our population-based study suggested that endogenous ouabain might have a trophic effect on the myocardium, independent of blood pressure and other covariables. The clinical implication of these findings remains to be elucidated. ispartof: Journal of Hypertension vol:27 issue:9 pages:1884-91 ispartof: location:Netherlands status: published

validity. The HIJ-CREATE investigators recruited among selected hospitalized patients undergoing coronary angiography. Patients without stenotic coronary lesions were eligible for randomization in the presence of a history of coronary revascularization or coronary spasm. Of those screened, only 40.9% were enrolled. The trial was powered to detect a 20% reduction in the primary endpoint at a rate in the control group of 100 events per 1000 patientyears. The observed rate was only 67 events per 1000 patientyears and explains why the trial was underpowered. The primary endpoint included weak events, such as a clinically defined diagnosis of heart failure or growing aortic aneurysm without dissection. The daily dose of candesartan used in the HIJ-CREATE trial (range 4‐12 mg) was lower than in most other countries (8‐16 mg in hypertensive patients, and up to 32 mg in patients with heart failure). By the end of the trial, 23.0% of patients of the non-ARB group had crossed over to treatment with ARBs. Furthermore, the HIJ-CREATE trial had a prospective randomized open blinded endpoint (PROBE) design. 2 An independent and blinded endpoint committee adjudicated the endpoints. However, such a PROBE design does not protect against observer bias in the assessment and reporting of endpoints or side effects. Only reported endpoints and symptoms qualify for blinded validation. HIJ-CREATE was not a trial of differential cardiovascular outcomes on ARB vs. non-ARB treatment, but a comparison of candesartan with a number of unspecified ACEIs. 1 In the non-ARB group, the use of ACEIs increased from 38.0% at randomization to 70.5%. About half of the patients in both treatment groups were on treatment with calcium channel blockers or b-blockers. Only 10% of patients were on treatment with diuretics. The investigators reported that the incidence of side effects leading to discontinuation of medications was 5.7% on candesartan and 12.2% on non-ARB treatment. Not unexpectedly, cough

High counts of wear particles and activated macrophages are strong predictors of prosthetic loosening in total joint arthroplasty patients. The tissue response, dominated by macrophages, with production of inflammatory mediators and matrix-degrading enzymes, triggers a self-accelerating cycle of osteolysis, ultimately resulting in failure of the arthroplasty, high treatment cost and poor patient outcome. Vitamin D is frequently used as a treatment for osteoporosis, but might also contribute to osteolysis in inflammatory joints. Here, we review the effects of extrarenal vitamin D3 activation by macrophages in the joint space. The summarized pathways contribute to increased bone resorption in the setting of the inflammatory micro-environment at the bone-prosthesis interface. If further evidence confirms a role of oral vitamin D3 as a risk factor for aseptic loosening, this might influence the current treatment strategies for patients at risk for this condition.

Earlier studies have demonstrated the interaction between ADD1 and ACE in relation to arterial properties. We investigated whether arterial characteristics might also be related to interactions of ADD1 with other renin-angiotensin system genes. Using a family-based sampling frame, we randomly recruited 1064 Flemish subjects (mean age, 43.6 years; 50.4% women). By means of a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries. In multivariate-adjusted analyses, we assessed the multiple gene effects of ADD1 (Gly460Trp), AGT (C-532T and G-6A) and AT1R (A1166C). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes (P-value for interaction < or =0.014), femoral cross-sectional compliance was significantly higher (0.74 vs 0.65 mm(2) kPa(-1); P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (11.3 vs 10.2 x 10(-3) kPa(-1); P=0.055). These associations were independent of potential confounding factors, including age. Family-based analyses confirmed these results. Brachial diameter (4.35 vs 4.18 mm) and plasma renin activity (PRA) (0.23 vs 0.14 ng ml(-1) h(-1)) were increased (P< or =0.005) in AGT CG haplotype homozygotes compared with non-carriers, whereas the opposite was true for brachial distensibility (12.4 vs 14.4 x 10(-3) kPa(-1); P=0.011). There was no interaction between AGT and any other gene in relation to the measured phenotypes. ADD1 and AT1R interactively determine the elastic properties of the femoral artery. There is a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA. ispartof: Journal of Human Hypertension vol:23 issue:1 pages:55-64 ispartof: location:England status: published

BACKGROUND: Nepsilon-carboxymethyllysine (CML) is the major non-cross linking advanced glycation end product (AGE). CML is elevated in diabetic patients and apparent in atherosclerotic lesions. AGEs are associated with hypertension and arterial stiffness potentially by qualitative changes of elastic fibers. We investigated whether CML affects carotid and aortic properties in normoglycemic subjects. METHODS: Hundred-two subjects (age 48.2+/-11.3 years) of the FLEMENGHO study were stratified according to the median of the plasma CML level (200.8 ng/ml; 25th percentile: 181.6 ng/ml, 75th percentile: 226.1 ng/ml) into "high CML" versus "low CML" as determined by ELISA. Local carotid artery properties, carotid intima media thickness (IMT), aortic pulse wave velocity (PWV), blood pressure and fetuin-A were analyzed. In 26 patients after carotidectomy, CML was visualized using immunohistochemistry. RESULTS: According to the CML median, groups were similar for anthropometric and biochemical data. Carotid diameter was enlarged in the "high" CML group (485.7+/-122.2 versus 421.2+/-133.2 microm; P

BACKGROUND: Adducin is a membrane skeleton protein, which consists of either alpha- and beta- or alpha- and gamma-subunits. We investigated whether arterial characteristics might be related to the genes encoding ADD1 (Gly460Trp-rs4961), ADD2 (C1797T-rs4984), and ADD3 (IVS11+386A>G-rs3731566). METHODS: We randomly recruited 1,126 Flemish subjects (mean age, 43.8 years; 50.3% women). Using a wall-tracking ultrasound system, we measured the properties of the carotid, femoral, and brachial arteries. We studied multivariate-adjusted phenotype-genotype associations, using a population- and family-based approach. RESULTS: In single-gene analyses, brachial diameter was 0.15 mm (P = 0.0022) larger, and brachial distensibility and cross-sectional compliance were 1.55 x 10(-3)/kPa (P = 0.013) and 0.017 mm(2)/kPa (P = 0.0029) lower in ADD3 AA than ADD3 GG homozygotes with an additive effect of the G allele. In multiple-gene analyses, the association of brachial diameter and distensibility with the ADD3 G allele occurred only in ADD1 GlyGly homozygotes. Otherwise, the associations between the arterial phenotypes in the three vascular beds and the ADD1 or ADD2 polymorphisms were not significant. In family-based analyses, the multivariate-adjusted heritability was 0.52, 0.38, and 0.30 for brachial diameter, distensibility, and cross-sectional compliance, respectively (P < 0.001). There was no evidence for population stratification (0.07 < or = P < or = 0.96). Transmission of the mutated ADD3 G allele was associated with smaller brachial diameter in 342 informative offspring (-0.12 +/- 0.04 mm; P = 0.0085) and in 209 offspring, who were ADD1 GlyGly homozygotes (-0.14 +/- 0.06 mm; P = 0.018). CONCLUSIONS: In ADD1 GlyGly homozygotes, the properties of the brachial artery are related to the ADD3 (A386G) polymorphism, but the underlying mechanism needs further clarification. ispartof: American Journal of Hypertension vol:22 issue:1 pages:21-26 ispartof: location:United States status: published

Background— Because the process of myocardial remodelling starts before the onset of symptoms, recent heart failure (HF) guidelines place special emphasis on the detection of subclinical left ventricular (LV) systolic and diastolic dysfunction and the timely identification of risk factors for HF. Our goal was to describe the prevalence and determinants (risk factors) of LV diastolic dysfunction in a general population and to compare the amino terminal probrain natriuretic peptide level across groups with and without diastolic dysfunction. Methods and Results— In a randomly recruited population sample (n=539; 50.5% women; mean age, 52.5 years), we measured early and late diastolic peak velocities of mitral inflow (E and A), pulmonary vein flow by pulsed-wave Doppler, and the mitral annular velocities (Ea and Aa) at 4 sites by tissue Doppler imaging. A healthy subsample of 239 subjects (mean age, 43.7 years) provided age-specific cutoff limits for normal E/A and E/Ea ratios and the differences in duration between the mitral A and the reverse pulmonary vein flows during atrial systole (ΔAd−ARd). The number of subjects in diastolic dysfunction groups 1 (impaired relaxation), 2 (elevated LV end-diastolic filling pressure), and 3 (elevated E/Ea and abnormally low E/A) were 53 (9.8%), 76 (14.1%), and 18 (3.4%), respectively. We used Δ(AdP =0.015) and group 2 (209 versus 275 pmol/L; P =0.0003) but not group 3 (209 versus 224 pmol/L; P =0.65) had a significantly higher adjusted NT-probrain natriuretic peptide. Higher age, body mass index, heart rate, systolic blood pressure, serum insulin, and creatinine were significantly associated with a higher risk of LV diastolic dysfunction. Conclusions— The overall prevalence of LV diastolic dysfunction in a random sample of a general population, as estimated from echocardiographic measurements, was as high as 27.3%.

OBJECTIVE: Studies directly comparing the associations of intima-media thickness with blood pressure (BP) on manual sphygmomanometric blood pressure measurement (SBPM) and 24-h ambulatory blood pressure measurement (ABPM) are scarce and have a cross-sectional design. METHODS: At baseline, we measured systolic and diastolic blood pressures, pulse pressure, and mean arterial pressure in 532 randomly recruited patients (women, 48.3%; mean age, 38.9 years) by SBPM and ABPM. SBPM was the average of five consecutive readings obtained by trained observers at the patients' homes. We measured carotid intima-media thickness (CIMT) and femoral intima-media thickness (FIMT) by a wall-tracking ultrasound system, 26 months (median) after BP measurement (interquartile range, 21-29 months). We adjusted all analyses for observer, sex, age, BMI, smoking, and total/high-density lipoprotein-cholesterol ratio. RESULTS: The multivariable-adjusted associations of CIMT and FIMT with all BP components on SBPM were not significant (P >or= 0.12). In multivariable-adjusted models, CIMT increased with 24-h systolic blood pressure (effect size per SD increase, +0.131 mm; P = 0.003) and 24-h pulse pressure (+0.139 mm; P = 0.001), whereas FIMT increased with 24-h diastolic blood pressure (+0.091 mm; P = 0.03) and 24-h mean arterial pressure (+0.090 mm; P = 0.04). Models including the ambulatory blood pressure components additionally adjusted for SBPM and more covariables than those listed above were confirmatory. CONCLUSION: In a general population, BP on ABPM predicts CIMT and FIMT over and beyond highly standardized SBPM. At the elastic carotid artery, CIMT increased predominantly with the pulsatile component of BP, whereas at the muscular femoral artery, FIMT increased with the steady component of BP. ispartof: Journal of Hypertension vol:27 issue:4 pages:813-821 ispartof: location:Netherlands status: published

Blood pressure and metabolic phenotypes in relation to the ADRB1 Arg389Gly and ADRA2B I/D polymorphisms in a White population

BACKGROUND: We studied the repeatability of the ambulatory arterial stiffness index (AASI), which can be computed from 24-h blood pressure (BP) recordings as unity minus the regression slope of diastolic on systolic BP. METHODS: One hundred and fifty-two hypertensive outpatients recruited in Nijmegen (mean age = 46.2 years; 76.3% with systolic and diastolic hypertension) and 145 patients enrolled in the Systolic Hypertension in Europe (Syst-Eur) trial (71.0 years) underwent 24-h BP monitoring at a median interval of 8 and 31 days, respectively. We used the repeatability coefficient, which is twice the SD of the within-participant differences between repeat recordings, and expressed it as a percentage of four times the SD of the mean of the paired measurements. RESULTS: Mean AASI (crude or derived by time-weighted or robust regression) and 24-h pulse pressure (PP) were similar on repeat recordings in both cohorts. In Nijmegen patients, repeatability coefficients of AASI and PP were approximately 50%. In Syst-Eur trial patients, repeatability coefficient was approximately 60% for AASI and approximately 40% for PP. For comparison, repeatability coefficients for 24-h systolic and diastolic BP were approximately 30%. Differences in AASI between paired recordings were correlated with differences in the goodness of fit (r2) of the AASI regression line as well as with differences in the night-to-day BP ratio. However, in sensitivity analyses stratified for type of hypertension, r2, or dipping status, repeatability coefficients for AASI did not widely depart from 50 to 60% range. CONCLUSION: Estimates of mean AASI were not different between repeat recordings, and repeatability coefficients were within the 50-60% range. ispartof: Journal of Hypertension vol:26 issue:10 pages:1993-2000 ispartof: location:Netherlands status: published

The American Society of Anesthesiologists Physical Status Classification System (ASA) ranks patients for risk of adverse events during a surgical procedure. The ASA classification is used as a surrogate for the patient's underlying severity of illness and has been recommended for use in Surgical Site Infection (SSI) and risk stratification. We assessed the predictive power of the ASA score for total knee replacement surgery infection, and compared it to a comorbidity score. All patients who had TKA (total knee arthroplasty) surgery performed during the period of 1993 to 1999 at one institution were identified. One hundred and thirteen infected cases were matched with 236 controls and nominal variables were statistically processed. A total co-morbidity score (TCOMORBID) was created to help the analysis. All possible predictors of infection were tested against infection in bivariate analysis. The association of the ASA score with infection was examined in detail. An ASA score beyond 2 showed an increased risk of infection. The average ASA score for the infected TKA group was 2.3 +/- 0.6, and the non-infected TKA average score was 2.6 +/- 0.7 (cohort effect). The relationship between the ASA score and TCOMORBID score was poor; Spearman rank correlation rho = 0.2, (p0.0001). In fact, the ASA score predicted only 6% of the occurrences of infection, but since it predicts 98% of the cases where there is no infection correctly, it is 70% accurate over all. Infection in TKA surgery was associated with an increased ASA score, but only when the high ASA score was due to a combination of specific co-morbidities. We propose that the ASA score should be cross-checked with the current co-morbidities, like rheumatoid arthritis or active infections in order to assess TKA infection risk.

The evidence relating mortality and morbidity to heart rate remains inconsistent. We performed 24-hour ambulatory blood pressure monitoring in 6928 subjects (not on beta-blockers; mean age: 56.2 years; 46.5% women) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We computed standardized hazard ratios for heart rate, while stratifying for cohort, and adjusting for blood pressure and other cardiovascular risk factors. Over 9.6 years (median), 850, 325, and 493 deaths accrued for total, cardiovascular, and noncardiovascular mortality, respectively. The incidence of fatal combined with nonfatal end points was 805, 363, 439, and 324 for cardiovascular, stroke, cardiac, and coronary events, respectively. Twenty-four-hour heart rate predicted total (hazard ratio: 1.15) and noncardiovascular (hazard ratio: 1.18) mortality but not cardiovascular mortality (hazard ratio: 1.11) or any of the fatal combined with nonfatal events (hazard ratio: < or =1.02). Daytime heart rate did not predict mortality (hazard ratio: < or =1.11) or any fatal combined with nonfatal event (hazard ratio: < or =0.96). Nighttime heart rate predicted all of the mortality outcomes (hazard ratio: > or =1.15) but none of the fatal combined with nonfatal events (hazard ratio: < or =1.11). The night:day heart rate ratio predicted total (hazard ratio: 1.14) and noncardiovascular mortality (hazard ratio: 1.12) and all of the fatal combined with nonfatal events (hazard ratio: > or =1.15) with the exception of stroke (hazard ratio: 1.06). Sensitivity analyses, in which we stratified by risk factors or from which we excluded 1 cohort at a time or the events occurring within 2 years of enrollment, showed consistent results. In the general population, heart rate predicts total and noncardiovascular mortality. With the exception of the night:day heart rate ratio, heart rate did not add to the risk stratification for fatal combined with nonfatal cardiovascular events. Thus, heart rate adds little to the prediction of cardiovascular risk. ispartof: Hypertension vol:52 issue:2 pages:229-235 ispartof: location:United States status: published

Aims Strain and strain rate (SR) are measures of deformation that reflect left ventricular (LV) function. To our knowledge, no previous study described these indexes in a general population. We therefore described peak-systolic strain and SR of the LV in the general population and derived diagnostic thresholds for these measurements in a healthy subgroup. Methods and results In 480 subjects enrolled in a family-based population study (50.5% women; mean age, 50.5 years; 37.2% hypertensive), we measured: (i) end-systolic longitudinal strain and peak-systolic SR from the basal portion of the LV inferior and inferolateral free walls; (ii) radial deformation of the LV inferolateral wall. Longitudinal (mean, 22.9%) and radial (59.2%) strain and longitudinal (1.31 s−1) and radial (3.40 s−1) SR decreased with age ( P ≤ 0.007). Longitudinal and radial strain independently decreased ( P ≤ 0.006) with relative wall thickness (RWT), longitudinal strain with the waist-to-hip ratio, and radial strain with body weight. In contrast, LV ejection fraction increased ( P ≤ 0.0001) with age and RWT. Longitudinal and radial stain rate increased with heart rate ( P ≤ 0.05). In healthy subgroup ( n = 236), the fifth percentiles were 18.4 and 44.3%, and 0.99 and 2.43 s−1, for longitudinal and radial strain and SR, respectively. Conclusion We explored the early signs of LV systolic dysfunction in a general population, using tissue Doppler imaging technique. LV strain and SR decrease with age, body weight, central obesity, and RWT. Our current study resulted in the proposal for diagnostic thresholds for strain and SR, based on a healthy subgroup recruited via random sampling of the population.

BACKGROUND: We investigated the possible association between left ventricular diastolic function and the ADD1 Gly460Trp and ADD3 IVS11 +386A>G polymorphisms alone and in combination. METHODS: In a family-based population study (473 subjects; 50.5% women; mean age 50.5 years), we measured early (Ea) and late (Aa) diastolic peak velocities of the mitral annulus by tissue Doppler imaging. In multivariate-adjusted analyses, we investigated phenotype-genotype associations, while accounting for confounders and family structure. RESULTS: Lateral Ea/Aa ratio was higher in ADD1 Trp allele carriers than in GlyGly homozygotes (1.51 vs. 1.40; P = 0.005) and was lower in ADD3 A allele carriers than in GG homozygotes (1.42 vs. 1.55; P = 0.005). The effects of ADD1 on the lateral Ea and Ea/Aa weakened with older age (P < 0.05). The best fitting model for lateral Ea and Ea/Aa included ADD1, ADD3, and the three-way interaction term of both genes with age. Below the age of 50 years, the lateral Ea/Aa ratio was higher in ADD1 Trp allele carriers than in GlyGly homozygotes (1.91 vs. 1.73; P = 0.006), particularly in the presence of ADD3 GG homozygosity (2.46 vs. 1.80; P = 0.0008). In older subjects, these phenotype-genotype associations were not significant (P > 0.20). Transmission of the ADD1 Trp allele to offspring was associated with higher lateral Ea (+0.91; P = 0.026) and Ea/Aa ratio (+0.23; P = 0.0008). CONCLUSION: Our population-based study demonstrated that left ventricular diastolic relaxation is modulated by genetic variation in ADD1 and ADD3. This association was more prominent in younger subjects in whom longstanding environmental factors and ageing are less likely to mask genetic effects. ispartof: Journal of Hypertension vol:26 issue:6 pages:1229-1236 ispartof: location:Netherlands status: published

BACKGROUND: Few population studies have reported on the long-term changes in the internal cadmium dose and simultaneously occurring mortality. OBJECTIVE: We monitored blood cadmium (BCd), 24-hr urinary cadmium (UCd), and mortality in an environmentally exposed population. METHODS: 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. RESULTS: 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 < or = 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. CONCLUSIONS: 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. ispartof: Environmental health perspectives vol:116 issue:12 pages:1620-1628 ispartof: location:United States status: published

BACKGROUND: Environmental exposure to cadmium decreases bone density indirectly through hypercalciuria resulting from renal tubular dysfunction. OBJECTIVE: We sought evidence for a direct osteotoxic effect of cadmium in women. METHODS: 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. RESULTS: 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/cm(2) (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/cm(2) (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 microg/day). CONCLUSIONS: 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. ispartof: Environmental Health Perspectives vol:116 issue:6 pages:777-783 ispartof: location:United States status: published