Relationship Between Metabolic Syndrome,Circadian Treatment Time,and Blood Pressure Non-Dipping Profile in Essential Hypertension

There is a strong association between metabolic syndrome (MS) and increased cardiovascular risk. Moreover, elevated nighttime blood pressure (BP) and non-dipping (subjects with <10% decline in the asleep relative to the awake BP mean) have been also linked to increased cardiovascular morbidity and mortality. We investigated the relation between MS, circadian time of hypertension treatment, and impaired nighttime BP decline in a cross-sectional study on 3352 (1576 men/1776 women) non-diabetic hypertensive subjects, 53.7?±?13.1 (mean?±?SD) yrs of age. Among them, 2056 were ingesting all their prescribed hypertension medication upon awakening, and 1296 were ingesting at least one of their BP medications at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours to substantiate reproducibility of the dipping pattern. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate mean BP when awake and asleep for each subject. MS was present in 52.6% of the subjects. The prevalence of an altered non-dipper BP profile was significantly higher among subjects with MS (52.0% vs. 39.5% in subjects without MS, p < .001). Non-dipping was significantly more prevalent among subjects ingesting all BP-lowering medications upon awakening (56.8%) than among those ingesting at least one of their BP medications at bedtime (29.1%; p < .001). Subjects with MS had significantly higher values of uric acid (6.0 vs. 5.3?mg/dL, p < .001), plasma fibrinogen (331 vs. 315?mg/dL, p < .001), and erythrocyte sedimentation rate (14.8 vs. 12.4?mm, p < .001). Non-dipping was significantly associated with the presence of MS and treatment upon awakening in a multiple logistic regression model adjusted by significant confounding factors, including age, creatinine, erythrocyte sedimentation rate, and cigarette smoking. This cross-sectional study documents a significant increase of a blunted sleep-time BP decline in treated hypertensive subjects with MS. Even in the presence of MS, treatment at bedtime is significantly associated with lower prevalence of a high-risk non-dipper BP profile. (Author correspondence: rhermida@uvigo.es)     

Ambulatory Blood Pressure Monitoring for the Early Identification of Hypertension in Pregnancy

Gestational hypertension and preeclampsia are major contributors to perinatal morbidity and mortality. The diagnosis of gestational hypertension still relies on conventional clinic blood pressure (BP) measurements and thresholds of ≥140/90?mm Hg for systolic (SBP)/diastolic (DBP) BP. However, the correlation between BP level and target organ damage, cardiovascular disease risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinic BP measurement. Accordingly, ABPM has been suggested as the logical approach to overcoming the low sensitivity and specificity of clinic BP measurements in pregnancy. With the use of ABPM, differing predictable BP patterns throughout gestation have been identified for clinically healthy and hypertensive pregnant women. In normotensive pregnancies, BP steadily decreases up to the middle of gestation and then increases up to the day of delivery. In contrast, women who develop gestational hypertension or preeclampsia show stable BP during the first half of pregnancy and a continuous linear BP increase thereafter until delivery. Epidemiologic studies have also consistently reported sex differences in the 24-h patterns of ambulatory BP and heart rate. Typically, men exhibit a lower heart rate and higher BP than women, the differences being larger for SBP than DBP. Additionally, as early as in the first trimester of gestation, statistically significant increased 24-h SBP and DBP means characterize women complicated with gestational hypertension or preeclampsia compared with women with uncomplicated pregnancies. However, the normally lower BP in nongravid women as compared with men, additional decrease in BP during the second trimester of gestation in normotensive but not in hypertensive pregnant women, and significant differences in the 24-h BP pattern between healthy and complicated pregnancies at all gestational ages have not been taken into consideration when establishing reference BP thresholds for the diagnosis of hypertension in pregnancy. Several studies reported that use of the 24-h BP mean is not a proper test for an individualized early diagnosis of hypertension in pregnancy defined on the basis of cuff BP measurements, thus concluding that from such an awkward approach ABPM is not useful in pregnancy. The 24-h BP pattern that characterizes healthy pregnant women at all gestational ages suggests the use for diagnosis of a time-specified reference limit reflecting that mostly predictable BP variability. Once the time-varying threshold, given, for instance, by the upper limit of a tolerance interval, is available, the hyperbaric index (HBI), as a determinant of BP excess, can be calculated as the total area of any given subject's BP above the threshold. This tolerance-hyperbaric test, where diagnosis of gestational hypertension is based on the HBI calculated with reference to a time-specified tolerance limit, has been shown to provide high sensitivity and specificity for the early identification of subsequent hypertension in pregnancy, as well as a valuable approach for prediction of pregnancy outcome. ABPM during gestation, starting preferably at the time of the first obstetric check-up following positive confirmation of pregnancy, provides sensitive endpoints for use in early risk assessment and guide for establishing prophylactic or therapeutic intervention, and should thus be regarded as the required standard for the diagnosis of hypertension in pregnancy. (Author correspondence: rhermida@uvigo.es)     

Circadian Time-Qualified Tolerance Intervals for Ambulatory Blood Pressure Monitoring in the Diagnosis of Hypertension

The large-amplitude circadian pattern in blood pressure of healthy subjects of both genders suggests that the constant threshold currently used to diagnose hypertension should be replaced by a time-specified reference limit reflecting the mostly predictable blood pressure variability during the 24 h. Accordingly, we derived circadian time-specified reference standards for blood pressure as a function of gender. We studied 743 normotensive Caucasian volunteers (400 men and 343 women), 45.7 ± 16.5 (mean ± SD) years of age. Blood pressure was measured by ambulatory monitoring at 20-min intervals during the day and at 30-min intervals at night for 48 consecutive hours. Data from each blood pressure series were synchronized according to the rest-activity cycle of each individual in order to avoid differences among subjects in actual times of daily activity. Data were then used to compute 90% circadian tolerance intervals for each gender separately. 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 reflect expected changes in the tolerance limits as a function of gender and circadian sampling time, as well as upper blood pressure limits below the thresholds currently used for diagnosing hypertension, especially for women. The use of these time-dependent tolerance limits for the computation of a hyperbaric index as a measure of blood pressure excess has already been shown to provide a reproducible and high-sensitivity test for the diagnosis of hypertension, which can also be used to evaluate treatment efficacy.     

Prevalence and Clinical Characteristics of Isolated-Office and True Resistant Hypertension Determined by Ambulatory Blood Pressure Monitoring

Hypertension is defined as resistant to treatment when a therapeutic plan including ≥3 hypertension medications failed to sufficiently lower systolic (SBP) and diastolic (DBP) blood pressures (BPs). Most individuals, including those under hypertension therapy, show a “white-coat” effect that could cause an overestimation of their real BP. The prevalence and clinical characteristics of “white-coat” or isolated-office resistant hypertension (RH) has always been evaluated by comparing clinic BP values with either daytime home BP measurements or the awake BP mean obtained from ambulatory monitoring (ABPM), therefore including patients with either normal or elevated asleep BP mean. Here, we investigated the impact of including asleep BP mean as a requirement for the definition of hypertension on the prevalence, clinical characteristics, and estimated cardiovascular (CVD) risk of isolated-office RH. This cross-sectional study evaluated 3042 patients treated with ≥3 hypertension medications and evaluated by 48-h ABPM (1707 men/1335 women), 64.2?±?11.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 522 (17.2%) had true isolated-office RH (elevated clinic BP and controlled awake and asleep ambulatory BPs while treated with 3 hypertension medications), 260 (8.6%) had false isolated-office RH (elevated clinic BP, controlled awake SBP/DBP means, but elevated asleep SBP or DBP mean while treated with 3 hypertension medications), and the remaining 2260 (74.3%) had true RH (elevated awake or asleep SBP/DBP means while treated with 3 medications, or any patient treated with ≥4 medications). Patients with false, relative to those with true, isolated-office RH had higher prevalence of microalbuminuria and chronic kidney disease (CKD), significantly higher albumin/creatinine ratio (p <?.001), significantly higher 48-h SBP/DBP means by 9.6/5.3?mm Hg (p?<?.001), significantly lower sleep-time relative SBP and DBP decline (p?<?.001), and significantly greater prevalence of a non-dipper BP profile (96.9% vs. 38.9%; p?<?.001). Additionally, the prevalence of the riser BP pattern, which is associated with highest CVD risk, was much greater, 40.4% vs. 5.0% (p?<?.001), among patients with false isolated-office RH. The estimated hazard ratio of CVD events, using a fully adjusted model including the significant confounding variables of sex, age, diabetes, chronic kidney disease, asleep SBP mean, and sleep-time relative SBP decline, was significantly greater for patients with false compared with those with true isolated-office RH (2.13 [95% confidence interval: 1.95–2.32]; p?<?.001). Patients with false isolated-office hypertension and true RH, however, were equivalent for the prevalence of obstructive sleep apnea, metabolic syndrome, obesity, diabetes, microalbuminuria, and chronic kidney disease, and they had an equivalent estimated hazard ratio of CVD events (1.04 [95% confidence interval: .97–1.12]; p?=?.265). Our findings document a significantly elevated prevalence of a blunted nighttime BP decline in patients here categorized as either false isolated-office RH and true RH, jointly accounting for 82.8% of the studied sample. Previous reports of much lower prevalence of true RH plus a nonsignificant increased CVD risk of this condition compared with isolated-office RH are misleading by disregarding asleep BP mean for classification. Our results further indicate that classification of RH patients into categories of isolated-office RH, masked RH, and true RH cannot be based on the comparison of clinic BP with either daytime home BP measurements or awake BP mean from ABPM, as so far customary in the available literature, totally disregarding the highly significant prognostic value of nighttime BP. Accordingly, ABPM should be regarded as a clinical requirement for proper diagnosis of true RH. (Author correspondence: rhermida@uvigo.es)     

Mice Show Circadian Rhythms of Blood Pressure During Each Wake-Sleep State

A daily rhythm of blood pressure (BP), with maximum values in the activity period, carries important prognostic information. The extent to which this rhythm depends on behavioral factors remains debated. Mice are the species of choice for functional genomics. In mice, episodes of wakefulness and sleep are not restricted to particular daily periods, allowing BP in each wake-sleep state to be measured at each time of day. The aim of this study was to investigate whether a circadian rhythm of BP is manifest in each wake-sleep state in mice. Mice with B6 genetic background (n?=?26) were implanted with a telemetric BP transducer and electrodes to discriminate wake-sleep states and recorded while housed under a 12:12?h light-dark period. For each mouse, 8 values of BP were obtained in each wake-sleep state (wakefulness, non-rapid-eye-movement sleep, and rapid-eye-movement sleep) by averaging over successive 3-h time bins. Analysis of variance evidenced a significant time effect in each wake-sleep state as well as a significant wake-sleep state?×?time interaction effect. In an additional group of mice (n?=?3) recorded in constant darkness, the Lomb-Scargle periodogram also revealed a significant circadian rhythm of BP in each wake-sleep state. These findings demonstrate that during each wake-sleep state, mice show daily and circadian rhythms of BP in conditions of entrainment to the light-dark cycle and in free-running conditions of constant darkness, respectively. (Author correspondence: giovanna.zoccoli@unibo.it)     

Influence of Age and Hypertension Treatment-time on Ambulatory Blood Pressure in Hypertensive Patients

Some studies based on ambulatory blood pressure (BP) monitoring (ABPM) have reported a reduction in sleep-time relative BP decline towards a more non-dipping pattern in the elderly, but rarely have past studies included a proper comparison with younger subjects, and no previous report has evaluated the potential role of hypertension treatment time on nighttime BP regulation in the elderly. Accordingly, we evaluated the influence of age and time-of-day of hypertension treatment on the circadian BP pattern assessed by 48-h ABPM. This cross-sectional study involved 6147 hypertensive patients (3108 men/3039 women), 54.0?±?13.7 (mean?±?SD) yrs of age, with 2137 (978 men/1159 women) being ≥60 yrs of age. At the time of study, 1809 patients were newly diagnosed and untreated, and 4338 were treated with hypertension medications. Among the later, 2641 ingested all their prescribed BP-lowering medications upon awakening, whereas 1697 ingested the full daily dose of ≥1 hypertension medications at bedtime. Diagnosis of hypertension in untreated patients was based on ABPM criteria, specifically an awake systolic (SBP)/diastolic (DBP) BP mean ≥135/85?mm Hg and/or an asleep SBP/DBP mean ≥120/70?mm Hg. Collectively, older in comparison with younger patients were more likely to have diagnoses of microalbuminuria, chronic kidney disease, obstructive sleep apnea, metabolic syndrome, anemia, and/or obesity. In addition, the group of older vs. younger patients had higher glucose, creatinine, uric acid, triglycerides, and fibrinogen, but lower cholesterol, hemoglobin, and estimated glomerular filtration rate. In older compared with younger patients, ambulatory SBP was significantly higher and DBP significantly lower (p?<?.001), mainly during the hours of nighttime sleep and initial hours after morning awakening. The prevalence of non-dipping was significantly higher in older than younger patients (63.1% vs. 41.1%; p?<?.001). The largest difference between the age groups was in the prevalence of a riser BP pattern, i.e., asleep SBP mean greater than awake SBP mean (19.9% vs. 4.9% in older vs. younger patients, respectively; p?<?.001). The sleep-time relative SBP decline was mainly unchanged until ～40 yrs of age, and then significantly and progressively decreasing with increasing age at a rate of .28%/yr (p?<?.001), reaching a minimum value of 4.38%?±?.47% for patients ≥75 yrs of age. Treated compared with untreated patients showed lower awake and asleep SBP means, although the predictable changes of SBP and DBP with age were equivalent in both groups. As a consequence, there were no significant differences between untreated and treated patients in the changes of the sleep-time relative SBP and DBP declines with age. Additionally, the asleep SBP and DBP means were significantly lower and the sleep-time relative SBP and DBP declines significantly higher at all ages in patients ingesting ≥1 BP-lowering medications at bedtime as compared with those ingesting all medications upon awakening. Our findings document a significantly elevated prevalence of a blunted nighttime BP decline with increasing age ≥40 yrs. The prevalence of a riser BP pattern, associated with highest cardiovascular risk among all possible BP patterns, was 4 times more prevalent in patients ≥60 yrs of age than those <60 yr of age. Most important, there was an attenuated prevalence of a blunted nighttime BP decline at all ages when ≥1 hypertension medications were ingested at bedtime as compared with when all of them were ingested upon awakening. These findings indicate that older age should be included among the conditions for which ABPM is recommended for proper cardiovascular risk assessment. (Author correspondence: rhermida@uvigo.es)     

Chronotherapy With Valsartan/Hydrochlorothiazide Combination in Essential Hypertension: Improved Sleep-Time Blood Pressure Control With Bedtime Dosing

Administration of angiotensin receptor blockers at bedtime results in greater reduction of nighttime blood pressure than dosing upon awakening, independent of the terminal half-life of each individual medication. To obtain blood pressure (BP) target goals most patients require treatment with more than one hypertension medication. However, the potential differing effects on BP regulation of combination therapy depending on the time-of-day of administration have scarcely been investigated. Accordingly, the authors prospectively evaluated the administration-time-dependent BP-lowering efficacy of valsartan/hydrochlorothiazide (HCTZ) combination therapy. The authors conducted a randomized, open-label, blinded-endpoint trial on 204 subjects with essential hypertension (95 men/109 women), 49.7?±?11.1 (mean?±?SD) yrs of age. The BP of participants in this trial was not properly controlled with respect to published ambulatory BP criteria after initially randomized to valsartan monotherapy (160?mg/day), whether routinely ingested upon awakening by one group or at bedtime by another group for 12 wks. Thus, HCTZ (12.5?mg/day) was added to valsartan as a single-pill formulation, maintaining the original treatment-time, i.e., upon awakening or at bedtime, of participants of the two groups, for another 12 wks. BP was measured by ambulatory monitoring for 48?h at inclusion and after each 12-wk span of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately define the beginning and end of daytime activity and nocturnal sleep so that the respective BP means for every participant at each evaluation could be precisely determined. Combination therapy resulted in a similar statistically significant reduction of the 48-h BP mean from baseline for both treatment-time groups (17.0/11.5?mm Hg in systolic/diastolic BP after combination therapy on awakening; 17.9/12.1?mm Hg reduction after combination treatment at bedtime; p?>?.542 between groups). The awake BP mean was reduced to a comparable extent in both treatment-time groups (p?>?.682). However, bedtime compared to morning dosing better reduced the asleep means of systolic BP (20.1 vs. 16.0?mm Hg; p?=?.015) and pulse pressure (6.5 vs. 4.0?mm Hg; p?=?.007 between groups). Accordingly, the proportion of subjects with a baseline non-dipper BP profile was significantly reduced from 59% to 23% only after bedtime combination treatment (p?<?.001). Moreover, the proportion of subjects with properly controlled ambulatory BP after combination therapy was significantly greater with bedtime than upon-awakening treatment (55 vs. 40%, p?=?.037). The improved efficacy in lowering the asleep BP mean, increased sleep-time relative BP decline, and greater proportion of controlled patients suggest that valsartan/HCTZ combination should be preferably administered at bedtime for treatment of subjects with essential hypertension requiring combination therapy to achieve proper BP control. (Author correspondence: rhermida@uvigo.es)     

血压昼夜节律特征及其分子调控机制

正常血压具有典型的昼夜节律特征。血压昼夜节律异常与高血压靶器官损害和心血管事件发生呈明显相关关系,是独立于血压水平的重要致病因素。血压昼夜节律的产生和维持与时钟基因的周期性表达有关。时钟基因bmal1、per2是体内生物钟系统运行的关键基因,其表达水平和节律变化直接调节血压的昼夜节律。     

Circadian Rhythm of Blood Pressure: Internal and External Time Triggers

Diurnal blood pressure (BP) fluctuations are superimposed by a 24-h rhythm with usually lower levels during the night and higher levels during the day. In contrast to other rhythmic bioparameters, the diurnal BP rhythm is largely dependent on activity and sleep rather than on clock time. This has been demonstrated by the BP characteristics after shifted sleeping and working phases, during transition from sleep to wakefulness, and by the influence of sleep and activities on the 24-h BP curve during normal daily routines. Whereas the circadian rhythm of BP is predominantly governed by external time triggers, endogenous rhythmic-ity can only be detected by time microscopic analysis or in conditions where effects of external time triggers are almost excluded.     

Chronobiologic Evaluation of Blood Pressure in School Children

Blood pressure (BP) and heart rate (HR) data were collected over 24 h with an ambulatory BP monitor to (a) determine the existence of 12-, 24-, and combined 12- and 24-h BP patterns in children as previously noted for adults; (b) provide MESOR (an acronym for midline estimating statistics of rhythm), amplitude, and acrophase data for subgroups of students by race and gender; and (c) determine the influence of HR (as an estimate of activity) on BP and BP patterns for 100 normal, healthy students 9-12 years of age. We found no statistically significant differences between various racial groups or between gender for MESOR, amplitude, acrophase, or degree of sinusoidality of circadian rhythmicity (R² values) for BP; clinically interesting differences were observed, including lower MESOR BPs in Hispanic males when compared with their female counterparts and slightly higher MESOR BPs in blacks of both genders when compared with whites. In addition, we demonstrated subgroups of students who exhibited specific 24-h and combined 12- and 24-h patterns. Also, 67% of subjects showed stable or nonrhythmic BP patterns, perhaps related to BP sampling intervals. Differences in HR, as a surrogate measure of activity, accounted for 56% of the variation in systolic BP but only 26% in diastolic BP over the 24 h.     

Circadian Blood Pressure Rhythm in Primary and Secondary Hypertension

Circadian blood pressure variability was recorded in patients with primary hypertension and with different forms of secondary hypertension using ambulatory 24-h blood pressure measurement. A group of 20 patients with different forms of secondary hypertension was compared with a matched group of patients with primary hypertension. Although the mean 24-h blood pressure was not different between the two groups, the patients with secondary hypertension had significantly higher systolic blood pressure during sleep and higher systolic and diastolic blood pressure in the early morning, compared with the primary hypertension group. This nocturnal blood pressure fall was then investigated in various groups of patients with different forms of secondary hypertension and compared with normotensives and patients with primary hypertension. Patients with mild primary hypertension (n = 152) and with severe primary hypertension (n = 30) had the same blood pressure fall (14–16 mm Hg systolic and diastolic) during the night (23:OO–05:OO h) as normotensives (n = 20). However, in patients with renoparenchymal hypertension (n = 29), renovascular hypertension (n = 20), hyperaldosteronism (n = 6), and hyperthyroidism (n = 14), the nocturnal blood pressure fall was significantly (p < 0.01) reduced. One patient with coarctation ofthe aorta and nine patients with primary hyperparathyroidism and elevated blood pressure had a normal circadian blood pressure profile with a normal nocturnal blood pressure fall. The heart rate decrease during the night was equal in all patient groups. Ambulatory blood pressure measurement allows blood pressure recording under everyday conditions, including nighttime. In primary hypertension the blood pressure variability exhibits the same circadian variation as in normotension, showing a marked nocturnal fall. However, in different forms of secondary hypertension, blood pressure shows a blunted circadian curve. This could have important diagnostic and therapeutic implications.     

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 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 (?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 (?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 or during their participation in antihypertension medication trials. (Chronobiology International, 14(6), 619–637, 1997)     

Effects of Time-of-Day of Hypertension Treatment on Ambulatory Blood Pressure and Clinical Characteristics of Patients With Type 2 Diabetes

Generally, hypertensive patients ingest all their blood pressure (BP)-lowering agents in the morning. However, many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in BP-lowering efficacy, duration of action, and safety of most classes of hypertension medications, and it was recently documented that routine ingestion of ≥1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Non-dipping (<10% decline in asleep relative to awake BP mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and is associated with increased CVD risk. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and analytical parameters of hypertensive patients with type 2 diabetes evaluated by 48-h ABPM. This cross-sectional study involved 2429 such patients (1465 men/964 women), 65.9?±?10.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM. Among the participants, 1176 were ingesting all BP-lowering medications upon awakening, whereas 1253 patients were ingesting ≥1 medications at bedtime. Among the latter, 336 patients were ingesting all BP-lowering medications at bedtime, whereas 917 were ingesting the full daily dose of some hypertension medications upon awakening and the full dose of others at bedtime. Those ingesting ≥1 medications at bedtime versus those ingesting all medications upon awakening had lower likelihood of metabolic syndrome and chronic kidney disease (CKD); had significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; and had higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. Moreover, patients ingesting all medications at bedtime had lowest fasting glucose, serum creatinine, uric acid, and prevalence of proteinuria and CKD. Ingestion of ≥1 medications at bedtime was also significantly associated with lower asleep systolic (SBP) and diastolic BP (DBP) means than treatment with all medications upon awakening. Sleep-time relative SBP and DBP decline was significantly attenuated in patients ingesting all medications upon awakening (p?<?.001). Thus, the prevalence of non-dipping was significantly higher when all hypertension medications were ingested upon awakening (68.6%) than when ≥1 of them was ingested at bedtime (55.8%; p?<?.001 between groups), and even further attenuated (49.7%) when all of them were ingested at bedtime (p?<?.001). Additionally, prevalence of the riser BP pattern, associated with highest CVD risk, was much greater (23.6%) among patients ingesting all medications upon awakening, compared with those ingesting some (20.0%) or all medications at bedtime (12.2%; p?<?.001 between groups). The latter group also showed significantly higher prevalence of properly controlled ambulatory BP (p <?.001) that was achieved by a significantly lower number of hypertension medications (p?<?.001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP mean and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, and improved metabolic profile in patients with type 2 diabetes ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for type 2 diabetes. (Author correspondence: rhermida@uvigo.es)     

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure,Heart Rate,and Motility: A Telemetric Study in Rats

In male Wistar rats [light (L): 07:00–19:00 h, dark (D): 19:00–07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED₅₀ values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.     

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure, Heart Rate, and Motility: A Telemetric Study in Rats

In male Wistar rats [light (L): 07:00-19:00 h, dark (D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED₅₀ values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.     

Circadian Rhythm of Blood Pressure and Heart Rate in Healthy Persons and Kidney Transplant Patients: Correlations with Activity

Fourteen diurnally active (07: 00–22: 39 h) normotensive healthy control subjects and 14 kidney transplant patients were studied by ambulatory blood pressure monitoring and wrist actigraphy simultaneously during one 24-h period. In the control group, circadian rhythms in systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressure, heart rate (HR), and wrist activity were documented by cosinor analysis with comparable afternoon peak times. In contrast, circadian rhythms with afternoon acrophases were detected only in HR and wrist activity in the patient group. The correlation of wrist activity with HR in controls and patients was comparable. Wrist activity and blood pressure were associated (r = 0.65 DBP and 0.54 SBP; p < 0.05) in controls, while in patients the relationship was weak or absent (r ranging from 0.02 SBP to 0.22 DBP). In 6 of 14 patients, BP and wrist activity were negatively correlated, reflecting the existence of nocturnal hypertension. In eight others, the correlation was small but positive. The 24-h pattern in BP and wrist activity in controls was comparably phased; however, this was not the case for the transplant patients, indicating the day-night pattern in blood pressure in this group is strongly dependent on pathologic phenomena rather than activity level and pattern.     

对原发性高血压患者进行健康教育的临床意义

目的：探讨对原发性高血压患者进行健康教育的临床意义。方法：选取2012年1月至2012年12月期间入住我干休所的原发性高血压患者252例,随机分为两组。其中观察组128例,在常规疗法的基础上对其进行健康教育;对照组124例则自行服药治疗。观察两组患者治疗前后的血压变化,对高血压知识的了解程度,膳食状况,体育锻炼,遵医服药的情况,自我检测及心理健康状况等。结果：观察组患者在接受健康教育后的平均得分明显高于对照组,差异有显著意义（P〈0.05）;观察组患者的血压状况,膳食状况,体育锻炼,服药情况等相关指标在接受健康教育后具有明显差异（P〈0.05）。结论：对原发性高血压患者实施积极有效的健康教育,不但能够有效提升患者对高血压相关知识的了解程度,优化患者的相关行为,提升治疗效果,更有助于提升患者的健康状况和生活质量。     

感觉神经损伤性盐敏感性高血压大鼠左心室肥厚与血压的关系

目的研究感觉神经损伤性盐敏感性高血压大鼠左心室肥厚与血压的关系。方法建立感觉神经损伤性盐敏感性高血压大鼠模型,计算左心室相对重量,观察左心室组织病理学形态特点。结果感觉神经损伤性盐敏感性高血压大鼠CAP-HS组收缩压明显升高,左心室明显增重,心肌细胞肥大,肌纤维排列紊乱,心肌间质纤维化,其左心室重量指数明显升高（P〈0.01）;CON-HS组大鼠左心室重量指数也有升高（P〈0.05）。结论感觉神经损伤性盐敏感性高血压大鼠左心室增重,心肌组织病理学改变与血压升高和摄入高盐有关。     

Administration-Time Differences in Effects of Hypertension Medications on Ambulatory Blood Pressure Regulation

Specific features of the 24-h blood pressure (BP) pattern are linked to progressive injury of target tissues and risk of cardiovascular disease (CVD) events. Several studies have consistently shown an association between blunted asleep BP decline and risk of fatal and nonfatal CVD events. Thus, there is growing focus on ways to properly control BP during nighttime sleep as well as during daytime activity. One strategy, termed chronotherapy, entails the timing of hypertension medications to endogenous circadian rhythm determinants of the 24-h BP pattern. Significant and clinically meaningful treatment-time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications, and their combinations, are now known. Generally, calcium channel blockers (CCBs) are more effective with bedtime than morning dosing, and for dihydropyridine derivatives bedtime dosing significantly reduces risk of peripheral edema. The renin-angiotensin-aldosterone system is highly circadian rhythmic and activates during nighttime sleep. Accordingly, evening/bedtime ingestion of the angiotensin-converting enzyme inhibitors (ACEIs) benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril exerts more marked effect on the asleep than awake systolic (SBP) and diastolic (DBP) BP means. Likewise, the bedtime, in comparison with morning, ingestion schedule of the angiotensin-II receptor blockers (ARBs irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with the additional benefit, independent of drug terminal half-life, of converting the 24-h BP profile into a more normal dipping pattern. This is the case also for the bedtime versus upon-awakening regimen of combination ARB-CCB, ACEI-CCB, and ARB-diuretic medications. The chronotherapy of conventional hypertension medications constitutes a new and cost-effective strategy for enhancing the control of daytime and nighttime SBP and DBP levels, normalizing the dipping status of their 24-h patterning, and potentially reducing the risk of CVD events and end-organ injury, for example, of the blood vessels and tissues of the heart, brain, kidney, and retina. (Author correspondence: rhermida@uvigo.es)