Sleep-time ambulatory blood pressure as a novel therapeutic target for cardiovascular risk reduction.

Diagnosis of hypertension and clinical decisions regarding its treatment are typically based upon daytime clinic blood pressure (BP) measurements, occasionally supplemented by wake-time patient self-assessment. Yet, correlation between BP level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is higher for ambulatory BP monitoring (ABPM) measurements. Numerous studies consistently reveal CVD events are better predicted by the asleep than awake or 24 h BP means. In addition, when the asleep BP mean is adjusted by the awake mean, only the former is a significant independent predictor of outcome. Endogenous circadian rhythms explain statistically and clinically significant ingestion time differences in efficacy, duration of action, safety and/or effects on the daily BP pattern of most hypertension medications and their combinations. Bedtime versus morning-time ingestion of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, independent of drug terminal half-life, both better reduces asleep BP and normalizes the daily BP profile into a more normal dipper pattern. The recently completed prospective outcome MAPEC Study verifies therapeutic restoration of the normal sleep-time BP decline, a novel therapeutic goal most effectively achieved by ingestion of the entire daily dose of ⩾ 1 conventional hypertension medications at bedtime, best decreases CVD morbidity and mortality. Our findings indicate around-the-clock ABPM is a clinical necessity to accurately detect abnormal sleep-time BP and assess CVD risk, and that hypertension ought to be managed by a bedtime therapeutic strategy, preferably one including medication that antagonizes the activities and actions of the renin-angiotensin-aldosterone system.

Uric acid and renal function in multiple sclerosis.

OBJECTIVE: The purpose of this study was to examine the circadian distribution of creatinine and uric acid clearances in subjects with Multiple Sclerosis. MATERIALS AND METHODS: Eleven subjects with MS, 6 women (48+/-7y) and 5 men (58+/-5y) volunteered for this circadian study. Thirteen healthy females (39+/-11y) served as controls. Data of seven healthy male controls (64+/-8 y) were extracted from a similar circadian study conducted previously. Each MS patient, and each male control had blood samples drawn around the clock, at 3h intervals (8/24h), and each collected urines over 3h periods (8/24h). Each female control contributed only one blood sample and one complete 24h urine collection. Blood and urine samples were analyzed for a number of relevant analytes: ELAM, IL-6, NO, insulin, ACTH, aldosterone, cortisol, electrolytes, lymphocytes, monocytes including creatinine and uric acid clearances. Those were standardized to an average body surface area of 1.73 m2. RESULTS: The relevant analytes demonstrated increased synthesis of insulin, IL-6, ELAM, monocytes, and reduced concentrations of serum NO. The creatinine clearances were significantly lower in MS females than in female controls, 63+/-22 vs.108+/-18 ml/min. They were also lower than those of MS males and male controls, 107.8+/-17, 97.5+/-8.2 ml/min. Uric acid clearances in MS females were also lower 6.9+/-2.4 vs. 10.5+/-4.4 ml/min. The uric acid clearance in MS males was higher than in male controls, 7.0+/-4.5 vs. 4.0+/-1.0 ml/min. CONCLUSIONS: The alterations in selected relevant analytes and the reduced creatinine and uric acid clearances in females but not in males, suggest a renal dysfunction in MS females. These observations may contribute to understanding better the mechanism of renal dysfunction in female patients and perhaps this may be an additional factor contributing to greater frequency of MS in females than in male subjects.

Circadian distribution of hematology variables in subjects with multiple sclerosis.

Hematology variables were measured in blood samples obtained every 3h (8/24h) from 10 multiple sclerosis (MS) patients and 34 healthy subjects and analyzed for circadian characteristics using the population multiple-components method. Red blood cell (RBC) and hemoglobin levels as well as hematocrits exhibited circadian rhythms with minimal amplitudes in healthy individuals and insignificant variability in the smaller group of MS patients. In contrast the total white blood cell (WBC) and platelet counts for MS patients and healthy individuals both showed significant circadian characteristics while the mean 24h WBC and platelet levels did not significantly differ between the two groups. When the different WBC subsets were examined independently, statistically significant circadian rhythms were seen for lymphocytes and eosinophils for both MS patients and healthy individuals and for neutrophils only in the latter. Moreover, the 24h mean levels of lymphocytes, basophils, and eosinophils were significantly higher for the healthy controls while those of monocytes were higher for the MS patients. However, of all the variables tested with significant circadian rhythms in both groups of individuals, only those of lymphocyte numbers exhibited different patterns with somewhat higher amplitude in healthy individuals and a peak level occurring over an hour after that of MS patients. These changes may be the reflection of a disturbance in the regulation of patterns of lymphocyte activity and migration in MS patients. In addition, the elevation in circulating monocytes in MS patients is consistent with the inflammatory nature of the disease.

Altered circadian relationship between serum nitric oxide, carbon dioxide, and uric acid in multiple sclerosis.

The free radical nitric oxide (NO*) is involved in a variety of diverse biological processes from acting as a vasodilator in the cardiovascular system to being the rate-limiting component in the production of peroxynitrite (ONOO-), a contributor to neurodegenerative disorders such as multiple sclerosis (MS). Uric acid (UA), the end product of purine metabolism in humans and a selective inhibitor of toxic reactions attributed to radicals formed by the interaction of ONOO- and CO2, is generally low in MS patients. We investigated the relationship between serum ONOO-, CO2, and UA in MS patients and normal controls by comparing the circadian characteristics of the NO* metabolites nitrite/ nitrate (NO), CO2, and UA. In this preliminary study, we found the functional relationship ascribed to the circadian timing of the peak and trough levels of NO, CO2, and UA in healthy subjects to be clearly altered in MS patients. These findings suggest that alterations in the temporal relationship between the 24h pattern in serum ONOO- formation and UA may either contribute to or reflect the disease processes in MS.

Day-night variations in blood levels of nitric oxide, T-TFPI, and E-selectin.

Circadian (8/24 hours) variations in serum nitric oxide (NO), total tissue factor pathway inhibitor (T-TFPI). and E-selectin levels were studied in healthy adults and in subjects with type II diabetes. We postulated a possibility a functional relationship between them because vascular endothelium is the primary site of their synthesis and functions. NO is released by the action of eNO synthase isoform and modulates physiologic responses (e.g., vascular dilation, relaxation, increasing blood flow, inhibition of platelet and white blood cell adhesion); T-TFPI, a coagulation inhibitor, is also released from endothelial cells, and is bound to plasma lipoproteins and to glycosaminoglycans; E-selectin is expressed on endothelial cells after activation by inflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha) and elevated levels have been reported in a variety of pathologic conditions, including diabetes. We found that obese diabetic subjects had greater mean concentrations of NO and E-selectin than healthy men, 39.25 versus 12.71 microM and 81.51 versus 26.03 ng/mL, respectively. The T-TFPI levels were essentially similar in both groups of men, 47.10 versus 48.76 ng/mL. We observed that the time of peak concentrations of T-TFPI and E-selectin was similar to the timing of NO trough levels, suggesting a possible functional relationship. It may be hypothesized, therefore, that the higher concentrations of NO, unbalanced by increases in T-TFPI and E-selectin, may result in increased vascular wall uptake of lipoproteins in diabetic subjects, who are at greater risk than healthy men for developing diffuse atherosclerosis.

Evaluation of the blood pressure load in the diagnosis of hypertension in pregnancy.

The use of a set of new end points obtained from ambulatory blood pressure monitoring, in addition to the blood pressure values themselves, has been advocated to improve sensitivity and specificity in the diagnosis of hypertension and the evaluation of a patient's response to treatment. Among these parameters is the use of blood pressure load, the percentage of values above a given constant reference limit or computed by reference to daytime and nighttime limits. We examined the effectiveness of this parameter as a potential screening test for the detection of hypertension in pregnancy. We analyzed 2014 blood pressure series systematically sampled by ambulatory monitoring for 48 consecutive hours every 4 weeks from the first obstetric visit (usually within the first trimester of pregnancy) until delivery of 205 normotensive pregnant women and 123 women who developed gestational hypertension or preeclampsia. The blood pressure load was obtained as the percentage of values >140/110/90 mm Hg (systolic/mean arterial/diastolic blood pressure) during active hours or 120/95/80 mm Hg during resting hours, as well as by comparison with limits obtained by progressively reducing the previous limits by 5 mm Hg, up to a final threshold of 125/95/75 mm Hg (day) and 105/80/65 mm Hg (night). Sensitivity for the blood pressure load computed by reference to the highest limits used here is <55% in all trimesters of pregnancy. The best results were obtained when 130/100/80 mm Hg (day) and 110/85/70 mm Hg (night) were used as references in the third trimester, and when the lowest tested limits of 125/95/75 and 105/80/65 mm Hg were used as references in the first and second trimesters (sensitivity always >73%). The optimum reference limits for calculating the blood pressure load, markedly < mm Hg, must be defined as a function of gestational age, in keeping with the predictable trends in blood pressure along pregnancy previously documented.

Predictable blood pressure variability in healthy and complicated pregnancies.

With the aim of describing the predictable pattern of blood pressure (BP) variability during gestation, we analyzed 2430 BP series systematically sampled by ambulatory monitoring for 48 consecutive hours every 4 weeks from the first obstetric visit (usually within the first trimester of pregnancy) until delivery in 235 normotensive women, 128 women who developed gestational hypertension, and 40 women who had a final diagnosis of preeclampsia. The pattern of variation along gestation of the 24-hour means of BP and heart rate was established for each group of women by polynomial regression analysis. For normotensive women, results indicate a steady decrease in BP up to 20 weeks of pregnancy, followed by an increase in BP up to the day of delivery, with an average 8% BP increase between the middle of gestation and delivery. In complicated pregnancies, BP is stable until the 22nd week of gestation and then increases linearly for the remainder of the pregnancy. Complicated pregnancies are characterized by a 9% and 13% increase in systolic and diastolic BPs, respectively, during the second half of gestation. Results also indicate that during the first half of pregnancy, systolic but not diastolic BP is slightly elevated in women who developed preeclampsia compared with those who developed gestational hypertension. During the second half of gestation, the linear trend of increasing BP for women who developed preeclampsia has a significantly higher slope than the trend for women with gestational hypertension. For both healthy and complicated pregnancies, heart rate increases until the end of the second trimester and slightly decreases thereafter. This study of women systematically sampled by 48-hour ambulatory BP monitoring throughout gestation confirms the predictable pregnancy-associated variability in BP and provides proper information for the establishment of reference limits for BP to be used in the early diagnosis of hypertensive complications in pregnancy. Those limits should be developed as a function of gestational age, taking into account the trends in BP throughout pregnancy demonstrated here.

Time-qualified reference values for ambulatory blood pressure monitoring in pregnancy.

To recognize the highly statistically significant circadian variability of blood pressure in pregnancy is to admit that the diagnosis of gestational hypertension or preeclampsia should be based not just on whether a casual blood pressure value is too high or too low, but rather on more pertinent questions: How long is blood pressure elevated above a given time-varying threshold? What is the excess blood pressure? When does most of the excess occur? Answers to these questions may be obtained by establishing (1) an adequate reference threshold for blood pressure and (2) a proper measurement of blood pressure elevation. Accordingly, we derived time-specified reference standards for blood pressure as a function of gestational age. We analyzed 1408 blood pressure series systematically sampled by ambulatory monitoring for 48 consecutive hours every 4 weeks from the first obstetric visit (usually within the first trimester of pregnancy) until delivery in 235 women with uncomplicated pregnancies. Data from each blood pressure series were synchronized according to the rest-activity cycle of each individual to avoid differences among women in actual times of daily activity. Data were then used to compute 90% circadian tolerance intervals for each trimester of pregnancy, in keeping with the trends in blood pressure along gestation previously documented. The method, derived on the basis of bootstrap techniques, does not need to assume normality or symmetry in the data, and therefore, it is highly appropriate to describe the circadian pattern of blood pressure variability. Results not only reflect expected changes in the tolerance limits as a function of gestational age, but also upper limits markedly below the thresholds currently used for diagnosing hypertension in pregnancy. The use of these time-qualified tolerance limits for the computation of a hyperbaric index as a measure of BP excess has already been show to provide high sensitivity and specificity in the early identification of gestational hypertension and preeclampsia.

Influence of parity and age on ambulatory monitored blood pressure during pregnancy.

Studies based on casual blood pressure measurements concluded that both age and parity have significant effects on blood pressure during pregnancy. We have tested these results on clinically healthy normotensive women who were systematically studied by ambulatory blood pressure monitoring during their pregnancies. We analyzed 1254 blood pressure series sampled for 48 consecutive hours every 4 weeks from the first obstetric visit (usually within the first trimester of pregnancy) until delivery in 205 normotensive pregnant women. Data were divided for comparative analysis by parity (nulliparous versus multiparous), age (/=36 years), and trimester of gestation. Circadian parameters established by population multiple-component analysis were compared between groups with a nonparametric test. Effects of age and parity on blood pressure were also tested by ANOVA. A highly statistically significant circadian pattern described by a model that includes components with periods of 24 and 12 hours is demonstrated for systolic and diastolic blood pressure for all groups of pregnant women in all trimesters (always P<0.001). There was no significant difference in 24-hour mean among groups divided by parity at any age or stage of pregnancy (always P>0.160). A trend of increasing blood pressure with age was found for diastolic but not systolic blood pressure. Although statistically significant, differences in the 24-hour mean of diastolic blood pressure among groups divided by age were always <1.5 mm Hg. Data obtained from systematic ambulatory monitoring in normotensive pregnant women indicate the lack of differences in blood pressure according to parity. The small, although significant, increase in diastolic blood pressure with age may have little influence in the proper identification of women with gestational hypertension. Reference thresholds for blood pressure to be used in the early identification of hypertensive complications in pregnancy could thus be developed as a function of rest-activity cycle and gestational age, independent of parity or maternal age.

Circadian rhythm of double (rate-pressure) product in healthy normotensive young subjects.

The double product (DP), systolic blood pressure multiplied by heart rate, is a surrogate measure of myocardial oxygen demand and cardiac workload used increasingly today in medicine. The double product is more strongly correlated with left ventricular mass than the daily blood pressure mean. The purpose of this study was to describe the normative circadian pattern of the double product in healthy normotensive young adults. We studied 125 men and 75 women, 23.0+/-3.3 (mean +/- SD) years of age, without medical history of hypertension and 24h ambulatory systolic/diastolic blood pressure mean consistently below 135/85 mm Hg. Subjects underwent ambulatory blood pressure monitoring at 30-minute intervals for 48 consecutive hours once each season of the year, yielding 930 protocol-correct blood pressure and heart rate time series. Subjects maintained their usual routine of diurnal activity and nocturnal sleep and avoided use of over-the-counter and other medication. Circadian rhythmicity in the double product was established by population multiple-component analysis. The double product rose rapidly from the lowest value, attained 3h before awaking from sleep at night, to a markedly elevated level at the commencement of morning activity. The double product was highest in the afternoon, roughly 7h after the commencement of diurnal activity. In both men and women, the shape of the high-amplitude circadian rhythm in the double product was best described by a complex model composed of three cosine curves having periods of 24h, 12h, and 6h. The 24h mean in the double product of 8092.51+/-42.76 (mean +/- SD) in men was significantly lower than that of 8353.17+/-37.48 in women (P < .001). The circadian double amplitude of the rhythm was statistically significantly greater (P < .001) in men (50% of the 24h mean) than women (44% of the 24h mean). The double product did not differ between seasons in women, but it did in men (P = .017) due to reduced heart rate in summer. The circadian pattern of large amplitude in the double product and its gender differences must be taken into account when using this variable to assess cardiac workload, risk of left ventricular hypertrophy, and efficiency of antihypertensive therapy.

Circadian variation of serum leptin in healthy and diabetic men.

Leptin, from the Greek leptos, meaning thin (in reference to its ability to reduce body fat stores), is a hormone secreted primarily by adipocytes. At one time, leptin was portrayed as a potential means of combating obesity. Recently, leptin has been identified as a potent inhibitor of bone formation, acting through the central nervous system. Since numerous studies clearly show that bone remodeling is circadian rhythmic with peak activity during sleep, it is of interest to explore circadian variability in serum leptin. Accordingly, circadian characteristics of serum leptin were examined in 7 clinically healthy men and 4 obese men with type II diabetes. Blood samples were collected for 24 h at 3 h intervals beginning at 19:00. The dark (sleep) phase of the light-dark cycle extended from 22:30 to 06:30, with brief awakening for sampling at 01:00 and 04:00. Subjects consumed general hospital meals (2400 calories) at 16:30, 07:30, and 13:30. Serum leptin levels were determined by a R&D Systems enzyme immunoassay technique. Data were analyzed by linear least-squares estimation using the population multiple components method. A statistically significant (P < .018) circadian rhythm modeled by a single 24 h cosine curve characterized the data of each group. The 24 h mean leptin level was statistically greater (P < .001) in the obese diabetic men than in the healthy men (9.47 +/- 0.66 ng/mL vs. 24.07 +/- 1.71 ng/mL, respectively). Higher leptin levels occurred between midnight and roughly 02:30, and lowest leptin levels occurred between noon and the early afternoon. The phasing of this rhythm is similar to the circadian rhythm in bone remodeling previously described. Our results suggest the findings from a single morning blood sampling for leptin may be misleading since it may underestimate the mean 24 h and peak concentrations of the hormone.

Blood pressure patterns in normal pregnancy, gestational hypertension, and preeclampsia.

With the aim to describe the daily pattern of blood pressure during the trimesters of pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia, we analyzed 1494 blood pressure series systematically sampled by ambulatory monitoring for 48 hours every 4 weeks after the first obstetric visit in 124 women with uncomplicated pregnancies, 55 with gestational hypertension, and 23 with a final diagnosis of preeclampsia. The circadian pattern of blood pressure variation for each group and trimester of gestation was established by population multiple-component analysis. A highly statistically significant circadian pattern represented by a linear model that includes components with periods of 24 and 12 hours is demonstrated for systolic and diastolic blood pressure for all groups of pregnant women in all trimesters (P:<0.001 in all cases). The differences in circadian rhythm-adjusted mean between complicated and uncomplicated pregnancies are highly statistically significant in all trimesters (always P:<0.001). There is also a statistically significant difference in circadian amplitude (extent of daily change) of blood pressure between healthy and complicated pregnancies in all trimesters (always P:<0.004). Results further indicate similar circadian characteristics between women who later developed gestational hypertension or preeclampsia in the first trimester of pregnancy. The difference between these 2 groups in circadian mean is statistically significant in the second trimester for systolic (P:=0.022) but not for diastolic blood pressure (P:=0.986). In the third trimester, the difference in circadian mean is highly statistically significant for both variables (P:<0.001). The differences in blood pressure between healthy and complicated pregnancies can be observed as early as in the first trimester of pregnancy. Those highly significant differences are found when both systolic and diastolic blood pressure for women with a later diagnosis of gestational hypertension or preeclampsia are well within the accepted normal physiological range of blood pressure variability. These differing changes in the circadian pattern of blood pressure with advancing gestational age between healthy and complicated pregnancies offer new end points that may lead to an early identification of hypertensive complications in pregnancy as well as to the establishment of prophylactic intervention.

Reproducibility of the hyperbaric index as a measure of blood pressure excess.

The approach of establishing a time-specified tolerance limit reflecting the circadian variability in blood pressure and then determining the hyperbaric index, the area of blood pressure excess above the upper limit of the tolerance interval, has been proposed for diagnosing hypertension as well as for evaluating the patient's response to treatment. The retrospective evaluation of this test provided high sensitivity and specificity in the diagnosis of hypertension, with a threshold value for the hyperbaric index of 15 mm Hg. h. To evaluate the stability and reproducibility of this tolerance-hyperbaric test, we studied 332 previously untreated subjects (218 men) who underwent sequential 48-hour ambulatory blood pressure monitoring for 2 years, providing a total of 1337 blood pressure profiles. Diagnosis of hypertension was established for each subject on the restricted basis of presenting at least 1 blood pressure profile with a hyperbaric index above the previously defined threshold. Sensitivity of this tolerance-hyperbaric test was 98.6%, with a negative predictive value of 99.7%. For the same subjects, the blood pressure load (percentage of values >140/110/90 mm Hg for systolic/mean arterial/diastolic blood pressure during activity or >120/95/80 mm Hg during resting hours) had a sensitivity of 49% and specificity of 25%. The 24-hour mean, still the most common approach for diagnosing hypertension on the basis of ambulatory monitoring, had sensitivities of 40% and 31% for systolic and diastolic blood pressure, respectively. Despite the limitations of ambulatory blood pressure monitoring, the tolerance-hyperbaric test represents a reproducible, noninvasive, and high-sensitivity test for the identification of subjects in need of prophylactic or therapeutic intervention.

Administration time-dependent effects of aspirin in women at differing risk for preeclampsia.

This study extends previous results on the effects of low-dose aspirin on blood pressure in pregnant women at differing risk of developing hypertension in pregnancy and who received aspirin at different times according to their rest-activity cycle. A double-blind, randomized, placebo-controlled trial was conducted in 240 pregnant women randomly assigned to 1 of 6 groups according to treatment (placebo or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Blood pressure and heart rate for each subject were automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery, as well as at puerperium (6 to 8 weeks after delivery). Subjects were further divided for comparative purposes according to the results of the tolerance-hyperbaric test for early identification of those with a higher risk for developing hypertensive complications in pregnancy. Results indicated that there was no effect of aspirin on blood pressure at time 1 (compared with placebo). A blood pressure reduction was, however, highly statistically significant at time 2 and, to a greater extent, at time 3 (mean reductions of 14.2 and 9.6 mm Hg in 24-hour means for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). Effects of aspirin on blood pressure were significantly larger for women with a positive test at the time of recruitment (P<0.001). Differences in blood pressure among pregnant women receiving aspirin at different times in the circadian cycle disappeared at puerperium (P>0.212). There was no effect of aspirin or placebo on heart rate. This study corroborates the statistically significant, time-dependent effect of low-dose aspirin on blood pressure in pregnant women with differing risk of developing hypertensive complications in pregnancy. Although the mechanism involved in the administration-time-dependent responsiveness of blood pressure to aspirin still remains uncertain, the use of doses of aspirin <80 mg/d that do not affect placental thromboxane, initiation of the use of aspirin after 16 weeks' gestation, and the lack of circadian timing for aspirin administration could all explain the lack of positive results in previous clinical trials.

Circadian variation of plasma cortisol in prepubertal children with normal stature, short stature and growth hormone deficiency.

OBJECTIVES: When studying the relationship between spontaneous secretion of growth hormone (GH) and cortisol in children, most studies show no correlation in mean levels of these two hormones, while others found positive or even strongly negative correlations. These contradictory results could be partly due to the inability to properly compare hormones that are characterized by circadian and ultradian variations in their secretory profiles. We aim here to study possible differences in rhythm characteristics of plasma cortisol with stature and to compare the circadian secretory patients of cortisol and GH. PATIENTS: We analysed data from 135 prepubertal children: (1) 14 GH-deficient children; (2) 36 children with short stature (2-3 SD below their peer group mean); (3) 57 children with very short stature (3-4 SD below their peer group mean); and (4) a reference group of 28 children with normal stature (+/- 2 SD). Subjects were living in a hospital setting on a diurnal waking (07.30-22.30 h), nocturnal resting routine during sampling, consuming the usual hospital diet at fixed times. MEASUREMENTS: Cortisol and GH concentrations were determined by radioimmunoassay in plasma obtained at about 2-3 h intervals during most of the day and at half-hour intervals between 22.00 and 02.00 h. Circadian rhythm characteristics obtained by least-squares estimation were compared between groups divided according to gender and stature with a parameter test. RESULTS: Show a statistically significant circadian rhythm in cortisol secretion for all groups studied (P < 0.001 in all cases). A comparison of circadian parameters indicated similar characteristics between subjects of short, very short and normal stature. Despite a borderline statistically significant difference in rhythm-adjusted mean and amplitude of GH between nondeficient and GH-deficient children, there was no difference in the circadian pattern of cortisol secretion between these two groups. No correlation was found in circadian mean, amplitude, average, standard deviation, standard error, minimum or maximum between GH and cortisol for any of the groups of children. CONCLUSIONS: Any possible relation between GH and cortisol remains unclear. Moreover, GH-deficient children are not necessarily characterized by either hyper- or hypocortisolaemia.

Blood pressure excess for the early identification of gestational hypertension and preeclampsia.

We have examined prospectively whether the combined approach of establishing tolerance intervals for the circadian variability of blood pressure (BP) as a function of gestational age, and then determining the so-called hyperbaric index (area of BP excess above the upper limit of the tolerance interval) by comparison of any patient's BP profile (obtained by ambulatory monitoring) with those intervals provides a high sensitivity test for the early detection of pregnant women who subsequently will develop gestational hypertension or preeclampsia. We analyzed 657 BP series from 92 women with uncomplicated pregnancies and 378 series from 60 women who developed gestational hypertension or preeclampsia. BP was sampled for about 48 hours once every 4 weeks after the first obstetric consultation. Circadian 90% tolerance limits were determined as a function of trimester of gestation from 497 series previously sampled from a reference group of 189 normotensive pregnant women. The hyperbaric index was then determined for each individual BP series in the validation sample. Sensitivity of this test for diagnosing gestational hypertension was 93% for women sampled during the first trimester of gestation and increased up to 99% in the third trimester. The positive and negative predictive values were above 96% in all trimesters. Despite the limitations of ambulatory monitoring, the approach presented here, now validated prospectively, represents a reproducible, noninvasive, and high sensitivity test for the very early identification of subsequent gestational hypertension and preeclampsia, on the average, 23 weeks before the clinical confirmation of the disease.

Diagnosing gestational hypertension and preeclampsia with the 24-hour mean of blood pressure.

The use of ambulatory blood pressure monitoring has provided a method of blood pressure assessment that may compensate for some of the limitations of isolated measurements. Here we aim to examine prospectively the effectiveness of the commonly used 24-hour mean as a potential screening test for the identification of gestational hypertension and preeclampsia. We analyzed 503 blood pressure series from 71 healthy pregnant women and 256 series from 42 women who developed gestational hypertension or preeclampsia. Forty-eight-hour blood pressure monitoring was done once every 4 weeks after the first obstetric consultation. Sensitivity and specificity of the 24-hour mean of blood pressure were computed for each trimester of pregnancy by comparing distributions of values obtained for healthy and complicated pregnancies, without assuming an a priori threshold for diagnosing gestational hypertension on the basis of mean blood pressure. Sensitivity ranges from 31.8% for diastolic blood pressure in the second trimester to 84.1% for systolic blood pressure in the third trimester. However, specificity is as low as 6.9% for diastolic blood pressure in the first trimester. The positive predictive value does not reach 55% for any variable in any trimester. The higher relative risk was consistently obtained for systolic blood pressure (4.9 in the third trimester). Despite the highly statistically significant differences in blood pressure found between healthy and complicated pregnancies in all trimesters, the daily mean of blood pressure does not provide a proper and stable individualized test for diagnosing hypertensive complications in pregnancy. Other indexes obtained from the blood pressure series have been shown, however, to identify early in pregnancy those women who subsequently will develop gestational hypertension or preeclampsia, rendering ambulatory blood pressure monitoring a useful, but still costly, technique in pregnancy.

Influence of aspirin usage on blood pressure: dose and administration-time dependencies.

This study investigates the possible effects of acetylsalicylic acid (ASA; aspirin) on systolic (S) and diastolic (D) blood pressure (BP) in healthy and mildly hypertensive subjects receiving ASA at different times according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 73 healthy young adult volunteers and 18 previously untreated subjects with mild hypertension. The BP of each subject was automatically monitored every 30 minutes for 48h before the trial and at the end of a one-week course of placebo and a one-week course of ASA. Healthy volunteers were randomly assigned to one of six groups, defined according to the dose of ASA (either 500 mg/day, the usual commercial dose; or 100 mg/day) and timing of ASA and placebo (within 2h after awakening, Time 1; 7h to 9h after awakening, Time 2; or within 2h of bedtime, Time 3). Subjects with mild hypertension received the low dose of 100 mg/day ASA, as well as one week of placebo, and were randomly assigned to one of the same three groups defined above according to the time of treatment. A small (approximately 2 mmHg in the 24h mean of SBP), but statistically significant, BP reduction was found when 500 mg/day ASA was given to healthy volunteers at Time 2. With 100 mg/day, the effect of ASA in healthy subjects was comparable to the BP reduction found with the higher dose for Time 2; there was again no effect on BP at Time 1, but we found a statistically significant effect at Time 3 (2.3 mmHg reduction in the 24h mean of SBP), larger than for Time 2. For hypertensive patients, the BP reduction was again statistically significant for Time 2 and, to a greater extent, for Time 3 (approximately 4.5 mmHg for both SBP and DBP); all patients in these two groups showed a BP reduction after one week of ASA. The effect was about three times as large as the BP reduction obtained in healthy subjects treated with 100 mg/day ASA. Results indicate a statistically significant time- and dose-dependent effect of ASA on BP. In any meta-analysis of ASA effects, inquiries about the time when subjects took the drug are indicated and may account for discrepancies in the literature. Moreover, the influence of ASA on BP demonstrated here indicates the need to identify and control for ASA effects in patients using ASA before and during their participation in antihypertension medication trials.