Jan A Staessen

Response to Antihypertensive Therapy in Older Patients With Sustained and Nonsustained Systolic Hypertension

BackgroundThe goal of the present study was to assess the effect of antihypertensive therapy on clinic (CBP) and ambulatory (ABP) blood pressures, on ECG voltages, and on the incidence of stroke and cardiovascular events in older patients with sustained and nonsustained systolic hypertension. Methods and ResultsPatients who were ≥60 years old, with systolic CBP of 160 to 219 mm Hg and diastolic CBP of <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both. Patients enrolled in the Ambulatory Blood Pressure Monitoring Side Project were classified according to daytime systolic ABP into 1 of 3 subgroups: nonsustained hypertension (<140 mm Hg), mild sustained hypertension (140 to 159 mm Hg), and moderate sustained hypertension (≥160 mm Hg). At baseline, patients with nonsustained hypertension had smaller ECG voltages (P <0.001) and, during follow-up, a lower incidence of stroke (P <0.05) and of cardiovascular complications (P =0.01) than other groups. Active treatment reduced ABP and CBP in patients with sustained hypertension but only CBP in patients with nonsustained hypertension (P <0.001). The influence of active treatment on ECG voltages (P <0.05) and on the incidence of stroke (P <0.05) and cardiovascular events (P =0.06) was more favorable than that of placebo only in patients with moderate sustained hypertension. ConclusionsPatients with sustained hypertension had higher ECG voltages and rates of cardiovascular complications than did patients with nonsustained hypertension. The favorable effects of active treatment on these outcomes were only statistically significant in patients with moderate sustained hypertension.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

Prognostic significance of exercise versus resting blood pressure in hypertensive men.

The outcome of 143 male hypertensive patients, investigated in the period 1972-1982, was ascertained in 1989 to determine if brachial artery pressure measured during a progressive graded exercise test on the bicycle ergometer is a better predictor of mortality and cardiovascular events than pressure at rest During the total follow-up time of 1,573 patient years, 27 patients suffered at least one fatal or nonfatal cardiovascular event and 13 patients died. Using the Cox regression model, the age-adjusted relative hazard rates of systolic pressure at supine rest, at 50 W, at peak work load, and at 50% of peak exercise capacity were significant for total mortality (psO.Ol) and for cardiovascular events (p^0.03). Pressure during exercise, however, did not significantly (p=0.11-0.97) predict the outcome of the patients when age and pressure at rest were taken into account The results were similar for diastolic pressure. In conclusion, intra-arterial pressures at rest and during submaximal and peak exercise significantly predict mortality and the incidence of cardiovascular events in hypertensive men, independent of age. However, there is no additional prognostic precision of the exercise pressures when age and the rest pressure are taken into account

Effect of endurance training on blood pressure at rest, during exercise and during 24 hours in sedentary men

The effect of 4 months of physical training on resting, exercise and 24-hour blood pressure (BP) was studied using a randomized crossover design in 26 healthy, sedentary men, with an average age of 39 +/- 10 (standard deviation) years. Peak oxygen uptake increased by 14% (p less than 0.001) and the physical working capacity at a heart rate of 130 beats/min by 25% (p less than 0.001). The heart rate was reduced by 7 beats/min at night (p less than 0.01) and by 6 beats/min during the day (p less than 0.001). Training-induced changes of BP varied according to measuring conditions. A decrease in BP at rest while sitting in the morning in the laboratory was significant for diastolic (-5 mm Hg, p less than 0.01) but not for systolic BP. During exercise, systolic BP was significantly lower after training, when measured at the same submaximal workloads. However, when workload was expressed as a percentage of peak oxygen uptake, systolic BP was not different before and after training. When measured during 24 hours, the training-induced change in BP was not significant at night either for systolic or diastolic BP. During the day the decrease in diastolic BP was significant (-5 mm Hg, p less than 0.001), but the change in systolic BP was not.

Prognostic significance of ambulatory blood pressure in hypertensive patients with history of cardiovascular disease.

ObjectiveTo assess the prognostic significance of nighttime and daytime blood pressure (BP), their ratio and the nighttime dipping pattern for mortality and recurrent cardiovascular (CV) events in patients with CV disease at baseline. BackgroundThe prognostic value of ambulatory BP has not been reported in hypertensive patients with a history of CV disease. MethodsWe performed a meta-analysis on individual data of 302 patients with hypertension and CV disease from three prospective studies performed in Europe. ResultsAge of the patients averaged 69±9 years; 50% were men and 62% were under antihypertensive treatment at the time of ambulatory BP monitoring. Office, daytime and nighttime BP averaged 161±20/86±12, 144±16/83±11 and 132±18/72±12u2009mmHg. Total follow-up time amounted to 2049 patient – years. Multivariable Cox regression analysis revealed that nighttime BP, but not daytime BP significantly predicted CV mortality (P≤0.05) and major CV events (P≤0.01) after adjustment for office BP and other confounders. When both nighttime and daytime BP were entered into the models, the predictive power of nighttime BP remained significant (P≤0.05); daytime BP did not add prognostic precision to nighttime BP. The systolic nightday BP ratio predicted all outcomes, and outcome was significantly worse in reverse dippers and nondippers than in dippers, both before and after adjustment for 24-h BP (P≤0.05). ConclusionNighttime BP is the better predictor of death and recurrent CV events in hypertensive patients with a history of CV disease. The night–day BP ratio and the dipping pattern significantly predict outcome, even after adjustment for 24-h BP.

Short-term and long-term repeatability of the morning blood pressure in older patients with isolated systolic hypertension

Objective Using 24-h ambulatory blood pressure monitoring, we studied the repeatability of the morning blood pressure in older (≥60 years) patients with isolated systolic hypertension. Methods The sleep-through morning surge was the morning blood pressure minus the lowest nighttime blood pressure. The preawake morning surge was the morning blood pressure minus the preawake blood pressure. In addition, we determined the cusum plot height of blood pressure from 04:00 to 10:00 h from a plot of cumulative sums. Results In 173 patients with repeat recordings within 33 days (median), the short-term repeatability coefficients, expressed as percentages of maximal variation, ranged from 35 to 41% for the daytime and nighttime blood pressures and from 50 to 56% for the night-to-day blood pressure ratios. Short-term repeatability ranged from 52 to 75% for the sleep-through and the preawake morning surge, and from 51 to 62% for the cusum plot height. In 219 patients with repeat recordings within 10 months (median), the corresponding long-term estimates ranged from 45 to 64%, from 69 to 71%, from 76 to 83%, and from 50 to 78%, respectively. In categorical analyses of the short-term repeatability of the sleep-through morning surge and the preawake morning surge, using the 75th percentile as arbitrary cut-off, surging status changed in 28.0 and 26.8% of patients (κ-statistic ≤0.33). In the long-term interval, these proportions were 32.0 and 32.0%, respectively (κ-statistic ≤0.20). The κ-statistic threshold for moderate reproducibility is 0.4. Conclusion The morning surge of blood pressure is poorly reproducible, irrespective of whether it is analysed as continuous or categorical variable.

A urinary proteome-based classifier for the early detection of decline in glomerular filtration

Background. Chronic kidney disease (CKD) progression is currently assessed by a decline in estimated glomerular filtration rate (eGFR) and/or an increase in urinary albumin excretion (UAE). However, these markers are considered either to be late‐stage markers or to have low sensitivity or specificity. In this study, we investigated the performance of the urinary proteome‐based classifier CKD273, compared with UAE, in a number of different narrow ranges of CKD severity, with each range separated by an eGFR of 10 mL/min/1.73 m2. Methods. A total of 2672 patients with different CKD stages were included in the study. Of these, 394 individuals displayed a decline in eGFR of >5 mL/min/1.73 m2/year (progressors) and the remaining individuals were considered non‐progressors. For all samples, UAE values and CKD273 classification scores were obtained. To assess UAE values and CKD273 scores at different disease stages, the cohort was divided according to baseline eGFRs of ≥80, 70–79, 60–69, 50–59, 40–49, 30–39 and <29 mL/min/1.73 m2. In addition, areas under the curve for CKD273 and UAE were calculated. Results. In early stage CKD, the urinary proteome‐based classifier performed significantly better than UAE in detecting progressors. In contrast, UAE performed better in patients with late‐stage CKD. No significant difference in performance was found between CKD273 and UAE in patients with moderately reduced renal function. Conclusions. These results suggest that urinary peptides, as combined in the CKD273 classifier, allow the detection of progressive CKD at early stages, a point where therapeutic intervention is more likely to be effective. However, late‐stage disease, where irreversible damage of the kidney is already present, is better detected by UAE.

Arterial structure and function and environmental exposure to cadmium

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 (nu200au200a557) 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<0.001). Even though systolic (pu200au200a0.42), diastolic (pu200au200a0.14) and mean arterial pressure (pu200au200a0.68) did not differ between the high and low exposure groups, aortic pulse wave velocity (pu200au200a0.008), brachial pulse pressure (pu200au200a0.026) and femoral pulse pressure (pu200au200a0.008) were significantly lower in the high exposure group. Additionally, femoral distensibility (p<0.001) and compliance (pu200au200a0.001) were significantly higher with high exposure. Across quartiles of 24 h urinary cadmium excretion (adjusted for sex and age), brachial (p for trendu200au200a0.015) and femoral (p for trendu200au200a0.018) pulse pressure significantly decreased and femoral distensibility (p for trendu200au200a0.008) and compliance (p for trendu200au200a0.007) significantly increased with higher cadmium excretion. After full adjustment, the partial regression coefficients confirmed these associations. Pulse wave velocity (βu200au200a−0.79±0.27; pu200au200a0.004) and carotid (βu200au200a−4.20±1.51; pu200au200a0.006), brachial (βu200au200a−5.43±1.41; pu200au200a0.001) and femoral (βu200au200a−4.72±1.74; pu200au200a0.007) pulse pressures correlated negatively, whereas femoral compliance (βu200au200a0.11±0.05; pu200au200a0.016) and distensibility (βu200au200a1.70±0.70; pu200au200a0.014) correlated positively with cadmium excretion. Conclusion: Increased cadmium body burden is associated with lower aortic pulse wave velocity, lower pulse pressure throughout the arterial system, and higher femoral distensibility.

Association Between Arterial Properties and Renal Sodium Handling in a General Population

Mean arterial pressure drives pressure–natriuresis and determines arterial structure and function. In a population sample, we investigated the relation between arterial characteristics and renal sodium handling as assessed by the clearance of endogenous lithium. We ultrasonographically measured diameter, cross-sectional compliance (CC) and distensibility (DC) of the carotid, brachial, and femoral arteries in 1069 untreated subjects (mean age: 41.6 years; 50.1% women; 18.8% hypertensive subjects). While accounting for covariates and standardizing for the sodium excretion rate in both sexes, CC and DC of the femoral artery increased with higher fractional distal sodium reabsorption. Differences associated with a 1-SD change in fractional distal reabsorption of sodium were 51.7 mm2/kPa×10−3 (95% CI: 23.9 to 79.5; P=0.0002) and 0.56×10−3/kPa (95% CI: 0.17 to 0.94; P=0.004) for femoral CC and DC, respectively. In women as well as in men, a 1-SD increment in fractional proximal sodium reabsorption was associated with decreases in femoral and brachial diameter, amounting to 111.6 &mgr;m (95% CI: 38.2 to 185.1; P=0.003) and 52.5 &mgr;m (95% CI: 10.0 to 94.9; P=0.016), respectively. There was no consistent association between the properties of the elastic carotid artery and renal sodium handling. In conclusion, higher fractional sodium reabsorption in the distal nephron is associated with higher femoral CC and DC, and higher proximal sodium reabsorption is associated with decreased brachial and femoral diameters. These findings demonstrate that there might be an influence of renal sodium handling on arterial properties or vice versa or that common mechanisms might influence both arterial and renal function.

Neurobehavioural investigations in adolescents exposed to environmental pollutants

Environmental exposures to industrial pollutants have been associated with lowered intelligence and behavioural problems. The Flemish Environmental and Health Study focussed on biomonitoring of exposure and associated health effects. This part of the study investigated neurobehavioural performance in adolescents in relation to lead (blood Pb), cadmium (urine Cd), polychlorinated biphenyls (PCB concentration of congeners 138, 153 and 180) and compounds with dioxin-like activity (measured by the CALUX-assay). One-hundred and twenty girls and 80 boys (mean age 17.4 years) were enrolled. The NES battery was used to assess simple reaction time, switching attention, digit span forward, hand-eye coordination and symbol-digit substitution (SDS). Multiple regression analysis was performed to study dose-effect relationships between the neurobehavioural outcome variables and the exposure parameters in boys and girls. Slowing of SDS with increasing logPbB and logCdU was seen in boys only (PbB 39-1549nmol/L, CdU 0.02-0.40nmol/mmol creatinine). No dose-effect relations were found with serum PCB concentrations or CALUX-TEQs. Only one of several tests showed a performance decrease related to given environmental exposures to heavy metals. Further studies are needed to clarify whether the pattern of results reflects gender effects or the different exposure characteristics of boys and girls in our study.