Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy: Rationale and Design of the MAPEC Study

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post‐prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non‐dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non‐dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non‐dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow‐up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non‐dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP‐lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women ≥18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow‐up. The MAPEC study, now on its fourth year of follow‐up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic‐determined daytime or ABPM‐determined 24 h mean BP levels.     

Circadian rhythm of activity and sleep‐wakefulness in elderly institutionalized persons

Abstract

The circadian rhythms of blood pressure (BP) and heart rate (HR) were documented in 30 patients for a 24‐hour period before and during the 24 hours that included unilateral surgery for senile cataract or retinal detachment. The patients were premedicated with diazepam. Anaesthesia was induced at a fixed time (09.00) in all patients with thiopentone, and muscle relaxation was with pancuronium. Maintenance was with enflurane in 15 patients and with fentanyl and droperidol in the rest. Though the intraoperative changes in haemodynamic parameters were dissimilar with the two types of maintenance agents, but both types had a similar effect on the circadian rhythms of blood pressure and heart rate. Whereas preoperatively the BP and HR circadian rhythms were nearly in phase, with their peaks in the late morning to early afternoon, the postoperative rhythms underwent a dissociation to a phase shift in the BP 24‐h pattern. The phase effect may be hypothetically attributed to direct pharmacological actions or to masking effects.     

Modeling the circadian variability of ambulatorily monitored blood pressure by multiple-component analysis

The use of a set of new end points derived from ambulatory blood pressure monitoring (ABPM), in addition to the blood pressure (BP) values themselves, has been advocated to improve the sensitivity and specificity in diagnosing hypertension and to evaluate a person's response to treatment. An adequate estimation of rhythmic parameters depends, however, on the ability to describe properly the circadian pattern of BP variability. The purpose of this study was to identify a simple model that could characterize sufficiently well the circadian pattern of BP in normotensive healthy volunteers sampled by ambulatory monitoring. We studied 278 clinically healthy Spanish adults (184 men), 22.7±3.3 yr of age, without medical history of hypertension and mean BP from ambulatory profiles always below 135/85 mmHg for systolic/diastolic BP, who underwent sequential ABPM providing a total of 1115 series of BPs and heart rates (HRs), sampled on each occasion at 0.5h intervals for 48 h. Subjects were assessed while adhering to their usual diurnal activity and nocturnal sleep routine, without restrictions but avoiding the use of medication. The circadian rhythm in BP and HR for each subject was established by multiple-component analysis. A statistically significant 24h component is documented for 97% of the BP profiles, with a significant second (12h) harmonic documented in 65% of the profiles. Other ultradian harmonic components were significant in less than 20% of the profiles. A statistically significant increase in the coefficient of determination (percent of overall variability explained by the function fitted to the data) was only obtained after including the periods of 24 and 12 h for BP, and periods of 24, 12, and 6 h for HR in the model components. Although other ultradian components can be demonstrated as statistically significant in a small percent of subjects, a rather simple model including only the two first harmonics of the 24h period describes sufficiently well, at the specified sampling rate, the circadian pattern of BP in normotensive subjects. Departure from this model could characterize overt pathology, as recently demonstrated in the diagnosis of preeclampsia.     

Campodimele Study: Blood Pressure and Heart Rate Pattern in Clinically Healthy Elderly Subjects

Noninvasive ambulatory blood pressure (BP) monitoring is a developing method in clinical practice. Its interpretation needs reference standards stratified by age and gender. This study addresses ambulatory BP monitoring in elderly people with the purpose of quantifying the discrete and periodic variability of BP pattern over a 24-h period. The ABPM was performed in 92 clinically healthy subjects (45 men and 47 women) ranging in age from 76 to 102 years. The results refer to the time-qualified mean values with their dispersion, to the circadian rhythm with its parameters, and to the daily baric impact (BI) with its variability. The conclusion is drawn that BP preserves its nychtohemeral variability and circadian rhythmicity despite old age. The daily BP mean level and BI in older people in good health are comparable with those of young subjects, suggesting that humans surviving into old age are characterized by a eugenic control of their pressure regimen.     

Campodimele Study: Blood Pressure and Heart Rate Pattern in Clinically Healthy Elderly Subjects

Noninvasive ambulatory blood pressure (BP) monitoring is a developing method in clinical practice. Its interpretation needs reference standards stratified by age and gender. This study addresses ambulatory BP monitoring in elderly people with the purpose of quantifying the discrete and periodic variability of BP pattern over a 24-h period. The ABPM was performed in 92 clinically healthy subjects (45 men and 47 women) ranging in age from 76 to 102 years. The results refer to the time-qualified mean values with their dispersion, to the circadian rhythm with its parameters, and to the daily baric impact (BI) with its variability. The conclusion is drawn that BP preserves its nychtohemeral variability and circadian rhythmicity despite old age. The daily BP mean level and BI in older people in good health are comparable with those of young subjects, suggesting that humans surviving into old age are characterized by a eugenic control of their pressure regimen.     

24-Hour Profiles of Blood Pressure and Heart Rate in Cushing's Syndrome: Relationship Between Cortisol and Cardiovascular Rhythmicities

We monitored the circadian profiles of Cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushing's Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P< 0.001). The rhythmicity of BP was disrupted in patients affected by Cushing's Syndrome, whereas the 24-hr oscillation of HR was preserved (P < 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.     

Non-dipping blood pressure in the metabolic syndrome among Arabs of the Oman family study

Objective: The objective was to examine the circadian changes in blood pressure and their relation to the metabolic syndrome and its components in Omani Arabs. Research Methods and Procedures: Ambulatory blood pressure (ABPM) was recorded in 1124 subjects from 5 large, extended, consanguineous, and young Arab pedigrees. According to the International Diabetes Federation's definition, 264 subjects had the metabolic syndrome, a prevalence of 23%. Subjects were defined as non‐dippers when their nocturnal systolic blood pressure (SBP) fell by <10% from daytime SBP. Results: Non‐dippers with the metabolic syndrome were 131 of 264 (50%), compared with 265 of 860 (31%) without the metabolic syndrome. Of the non‐dippers, 99 of 131 (76%) were females and 32 of 131 (24%) were males. Daytime and nighttime SBP and DBP and nighttime pulse pressure were significantly higher in non‐dipper subjects with the metabolic syndrome. The important determinants of a non‐dipping BP in this cohort were high BMI and high serum triglycerides. Discussion: We hypothesize that obesity and nocturnal volume‐dependent hypertension may be involved in the pathophysiology of non‐dipping in the metabolic syndrome. This study showed that non‐dipping BP was common in subjects with the metabolic syndrome. Higher 24‐hour blood pressure load may add to the indices of the overall cardiovascular burden already associated with the metabolic syndrome.     

Association between Serum Leptin Levels and 24‐Hour Blood Pressure in Obese Women

Objective: To assess the relationship between serum leptin and 24‐hour blood pressure (BP) in obese women, according to body fat distribution. Research Methods and Procedures: A cross‐sectional study was carried out in a population of 70 nondiabetic, normotensive, obese women (40 with android and 30 with gynoid type of obesity) and 20 nonobese healthy women as a control group. All subjects underwent 24‐hour ambulatory BP monitoring. Blood samples were collected for serum leptin and plasma insulin measurements. Total cholesterol and high‐density lipoprotein cholesterol were also measured. Results: Serum leptin levels were significantly higher in obese subjects than in controls, and they were more elevated in android obese women than in gynoid ones. Leptin levels were positively related to body mass index (BMI), insulin, and waist and hip circumferences in the android group. Among gynoid subjects, leptin levels showed positive associations with BMI and insulin. In women with android obesity, strong positive correlations (p < 0.001) were found between leptin levels and 24‐hour systolic BP (SBP), daytime SBP, nighttime SBP, 24‐hour diastolic BP (DBP), and daytime DBP. Multiple regression analyses, including age, insulin and leptin concentrations, BMI, and waist and hip circumferences on 24‐hour and daytime SBP and DBP, showed that only leptin levels contributed to the variability of BP. Conclusions: Our study shows that serum leptin levels are directly related to 24‐hour BP levels in normotensive women with android fat distribution, independently of BMI.     

24-hour profiles of blood pressure and heart rate in Cushing's syndrome: relationship between cortisol and cardiovascular rhythmicities

We monitored the circadian profiles of cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushing's Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P less than 0.001). The rhythmicity of BP was disrupted in patients affected by Cushing's Syndrome, whereas the 24-hr oscillation of HR was preserved (P less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.     

Impact of obesity in intima media thickness of carotid arteries

Objective: To explore differences in intima media thickness (IMT) of the carotid arteries induced by differences in BMI. Research Methods and Procedures: Data from 3173 consecutive subjects, who were referred to our Hypertension Center from 1998 to 2004, were reviewed. Criteria for patients to be considered for further analysis included no past or concurrent antihypertensive medication, no concurrent medication with the potential to raise blood pressure (BP) (e.g., prednisone), and no clinical signs or laboratory evidence of secondary causes of hypertension. Our population was divided into four groups according to NIH criteria for obesity: underweight, normal weight, overweight, and obese. BMI, mean IMT of internal carotid arteries, and 24‐hour BP values were available for all subjects. Five hundred thirty six subjects of the four groups, matched for age, gender, and mean 24‐hour BP values, were included in the analysis. Results: Mean IMT of internal carotid arteries was increased with increasing BMI. Mean IMT was significantly higher in obese subjects compared with normal‐weight (p < 0.01) and underweight (p < 0.001) subjects. Mean IMT was significantly higher in overweight subjects compared with normal‐weight ones (p < 0.05). Furthermore, multivariate regression analysis in obese subjects revealed that fasting serum glucose was independently associated with IMT. Discussion: Obesity may be an important factor for carotid atherosclerosis, and at least some of the effects of obesity are independent of the BP levels. Fasting serum glucose levels in obese subjects may play an important role in carotid atherosclerosis.     

Comparison of circadian rhythm characteristics of blood pressure and heart rate in patients before and after elective coronary artery bypass surgery

Coronary artery bypass grafting surgery (CABGS) is done to reperfuse the ischemic myocardium of coronary disease patients. This study was designed to analyze the circadian rhythm characteristics of blood pressure (BP) and heart rate (HR) of patients before and after CABGS. Fifty-one patients undergoing elective CABGS were studied; 21 patients received one, 12 two and 18 three or more grafts. BP was monitored for 24h before and after CABGS while patients were recumbent in the hospital. Systolic (S) and diastolic (D) BP and HR were assessed every 30 min. Of the 51 patients, 37 (73%) had nondipper 24h BP patterns (nocturnal decline in BP < 10% of daytime mean level) in the preoperative baseline assessment. The peak and MESOR (rhythm-adjusted 24h mean) values of the circadian rhythm in SBP, DBP, and pulse pressure (PP) significantly declined following surgery, while HR and rate-pressure product (RPP = SBP x HR) markedly increased. The double amplitude (peak-to-trough variation) of the circadian rhythm in SBP and DBP was significantly reduced postoperatively, and that of the rhythm in HR and RPP significantly increased. The slopes of the morning rise and evening dip in the 24h SBP profile were reduced significantly after bypass grafting. The corresponding slopes of the HR profile, in contrast, were markedly increased.     

Modeling the circadian variability of ambulatorily monitored blood pressure by multiple-component analysis

The use of a set of new end points derived from ambulatory blood pressure monitoring (ABPM), in addition to the blood pressure (BP) values themselves, has been advocated to improve the sensitivity and specificity in diagnosing hypertension and to evaluate a person's response to treatment. An adequate estimation of rhythmic parameters depends, however, on the ability to describe properly the circadian pattern of BP variability. The purpose of this study was to identify a simple model that could characterize sufficiently well the circadian pattern of BP in normotensive healthy volunteers sampled by ambulatory monitoring. We studied 278 clinically healthy Spanish adults (184 men), 22.7±3.3 yr of age, without medical history of hypertension and mean BP from ambulatory profiles always below 135/85 mmHg for systolic/diastolic BP, who underwent sequential ABPM providing a total of 1115 series of BPs and heart rates (HRs), sampled on each occasion at 0.5h intervals for 48 h. Subjects were assessed while adhering to their usual diurnal activity and nocturnal sleep routine, without restrictions but avoiding the use of medication. The circadian rhythm in BP and HR for each subject was established by multiple-component analysis. A statistically significant 24h component is documented for 97% of the BP profiles, with a significant second (12h) harmonic documented in 65% of the profiles. Other ultradian harmonic components were significant in less than 20% of the profiles. A statistically significant increase in the coefficient of determination (percent of overall variability explained by the function fitted to the data) was only obtained after including the periods of 24 and 12 h for BP, and periods of 24, 12, and 6 h for HR in the model components. Although other ultradian components can be demonstrated as statistically significant in a small percent of subjects, a rather simple model including only the two first harmonics of the 24h period describes sufficiently well, at the specified sampling rate, the circadian pattern of BP in normotensive subjects. Departure from this model could characterize overt pathology, as recently demonstrated in the diagnosis of preeclampsia.     

Blood pressure and heart rate variability are linked with hyperphosphatemia in chronic kidney disease patients

ABSTRACT

Hyperphosphatemia is a common complication of chronic kidney disease (CKD) and is associated with cardiovascular disease (CVD), which has contributed to an increase in mortality of CKD patients. The onset of CVD often varies by time-of-day. Acute myocardial infarction or ventricular arrhythmia occurs most frequently during early morning. Blood pressure (BP) and heart rate circadian rhythms account for the diurnal variations in CVD. Preservation of normal circadian time structure from the cardiomyocyte level to the whole organ system is essential for cardiovascular health and CVD prevention. Independent risk factors, such as reduced heart rate variability (HRV) and increased BP variability (BPV), are particularly prevalent in patients with CKD. Analysis of HRV is an important clinical tool for characterizing cardiac autonomic status, and reduced HRV has prognostic significance for various types of CVD. Circadian BP rhythms are classified as extreme dipper, dipper, non-dipper or riser. It has been reported that nocturnal riser BP pattern contributes to cardiovascular threats. Previous studies have indicated that the circadian rhythm of serum phosphate in CKD patients is consistent with the general population, with the highest diurnal value observed in the early morning hours, followed by a progressive decrease to the lowest value of the day, which occurs around 11:00 am. Rhythm abnormalities have become the main therapeutic target for treating CVD in CKD patients. It has been reported that high levels of serum phosphate are associated with reduced HRV and increased BPV in CKD patients. However, the mechanisms related to interactions between hyperphosphatemia, HRV and BPV have not been fully elucidated. This review focuses on the evidence and discusses the potential mechanisms related to the effects of hyperphosphatemia on HRV and BPV.     

Sympathovagal Balance,Nighttime Blood Pressure,and QT Intervals in Normotensive Obese Women

Objective : We describe associations among the heart‐rate‐corrected QT (QTc) interval, QTc dispersion (QTc‐d), circadian BP variation, and autonomic function in obese normotensive women and the effect of sustained weight loss. Research Methods and Procedures : In 71 obese (BMI = 37.14 ± 2.6 kg/m²) women, 25 to 44 years of age, circadian BP variations (24‐hour ambulatory BP monitoring), autonomic function (power spectral analysis of RR interval oscillations), and cardiac repolarization times (QTc‐d and QTc interval) were recorded at baseline and after 1 year of a multidisciplinary program of weight reduction. Results : Compared with nonobese age‐matched women (n = 28, BMI = 23 ± 2.0 kg/m²), obese women had higher values of QTc‐d (p < 0.05) and QTc (p < 0.05), an altered sympathovagal balance (ratio of low‐frequency/high‐frequency power, p < 0.01), and a blunted nocturnal drop in BP (p < 0.01). In obese women, QTc‐d and the QTc interval correlated with diastolic nighttime BP (p < 0.01) and sympathovagal balance (p < 0.01). Waist‐to‐hip ratio, free fatty acids, and plasma insulin levels correlated with QT intervals and reduced nocturnal drops in both systolic and diastolic BP and sympathovagal balance (p < 0.01). After 1 year, obese women lost at least 10% of their original weight, which was associated with decrements of QTc‐d (p < 0.02), the QTc interval (p < 0.05), nighttime BP (p < 0.01), and sympathovagal balance (p < 0.02). Discussion : Sustained weight loss is a safe method to ameliorate diastolic nighttime BP drop and sympathetic overactivity, which may reduce the cardiovascular risk in obese women.     

Blood Pressure Circadian Rhythm and Variability in Essential Hypertensives without End-organ Damage

The aim of the study was to evaluate the 24-hour Blood Pressure (BP) profile in essential hypertensives without end-organ damage using a two-step method proposed by Staessen and his group: the existence of a circadian rhythm is first tested using Siegel’s Runs-Test, then a Fourier multiple harmonic analysis allows an adequate parametrical representation of the 24-hour BP profile. Sixty-five newly diagnosed, untreated mild-to-moderate essential hypertensives without end-organ damage (HYP) were compared to 29 normal control subjects (NORM). No significant differences have been found between the two groups when considering the existence of a BP circadian rhythm and acrophase parameters, as distinct from amplitudes (p&lt;0.01). Furthermore, as expected, BP mean values were found higher in the HYP group as compared with the NORM group. In conclusion, according to our results, essential hypertensives without end-organ damage present a preserved BP profile, showing a circadian rhythm, but, as compared to normal subjects, increased BP variability (BPV) as expressed by amplitude values. The present study is consistent with the hypothesis that BPV, even though related, is not a consequence of end-organ damage.     

Valsartan chronotherapy reverts the non-dipper pattern and improves blood pressure control through mediation of circadian rhythms of the renin-angiotensin system in spontaneous hypertension rats

ABSTRACT

Background: Numerous clinical studies have evaluated valsartan and found more efficacious control of blood pressure (BP) variability when administered before sleep. The treatment leads to improved outcomes when compared to administration upon awakening. The mechanism underlying this etiology is not fully understood. The present study investigates the safety and efficacy of asleep administration of valsartan in spontaneously hypertensive rats (SHR) with a non-dipping blood pressure pattern compared to SHRs receiving administration during awake time. Materials and Methods: 84 Male SHRs and 28 male Wistar-Kyoto rats (WKY) were kept under a strict alternating 12-h light/dark cycle. WKYs were utilized as a non-disease control. Meanwhile, SHRs were randomly divided into three groups: untreated, Valsartan asleep administration (VSA) and Valsartan awake administration (VWA) respectively. The VSA group was treated with valsartan (30 mg/kg/d) after the light onset, while the VWA group was treated with valsartan (30 mg/kg/d) after light offset. Both groups were treated for 6 weeks. Tail artery blood pressure was measured every 4 h via a noninvasive tail cuff blood pressure measurement method. HE and Masson staining were used to evaluate any damage within the target organs. ELISA was used to determine the 24-h plasma renin-angiotensin system (RAS) concentration at 4-h intervals. Results: Based on our findings, VSA significantly reduced 24-h and evening mean BP and restored the abnormal circadian rhythm compared to VWA, which attenuated injuries in the majority of target organs except for the kidneys. Furthermore, VSA was found to activate RAS during the light cycle and inhibit it during the dark cycle. Conversely, VWA was found to deactivate RAS throughout the day which may be related to the circadian BP rhythm. Conclusion: VSA may be more efficacious than VWA in controlling BP, circadian BP rhythm and blood RAS rhythm. Recent cardiovascular outcome investigations substantiate that chronotherapy treatment might be a novel therapeutic strategy for hypertension therapy.

Abbreviations: Angiotensin-converting enzyme (ACE); Angiotensin converting enzyme inhibitors (ACEIs); Angiotensin II (ANG II); Analysis of variance (ANOVA); Angiotensin receptor blockers (ARBs); Blood Pressure (BP); Calcium Antagonists Calcium Channel Blockers (CCB); Chronic kidney diseases (CKD); Sodium carboxyl methyl cellulose (CMC-Na); Cardiac mass index (CMI); Cardiovascular diseases (CVD); Diastolic blood pressure (DBP); Enzyme-linked immunosorbent assay (ELISA); Hematoxylin-eosin (H&E); Kidney mass index (KMI); Liver mass index (LMI); Mean arterial blood pressure (MAP); Plasma renin concentration (PRC); Renin-angiotensin system (RAS); Rennin (REN); Systolic blood pressure (SBP); Student-Newman-Keuls q test (SNK-q test); Spontaneous hypertension rats (SHR); Valsartan asleep Administration (VSA); Valsartan awake Administration (VWA); Wistar-Kyoto (WKY); Mesor (M); Amplitude (A); Phase (φ).     

Longitudinal studies on the effect of hypertension on circadian hemodynamic and autonomic rhythms in telemetered rats

This study dealt with the long-term effects of hypertension on circadian rhythms of hemodynamic and cardiovascular autonomic functions in radiotelemetered rats. Blood pressure (BP), heart rate (HR), spontaneous locomotor activity, and respiration.were monitored in spontaneously hypertensive rats (SHRs), a model of human hypertension, from 14 to 27 weeks of age and in Wistar-Kyoto rats (WKY) as controls. Cardiovascular autonomic changes were determined by time-domain analysis of the variability of BP (standard deviation of mean arterial pressure, SDMAP) and HR (standard deviation of R-R intervals, SDRR, and the root mean square of successive differences in R-R intervals, rMSSD). Compared with WKY rats, the 24-hr MAP and SDMAP were higher at week 14 in SHRs and showed stepwise increases over the study duration, suggesting progressive increases in vasomotor sympathetic activity in hypertensive rats. Also, higher SDRR, rMSSD, and activity and lower HR and respiration were demonstrated in SHRs. Normal circadian rhythms (higher dark-time values) of MAP, HR, SDMAP, and SDRR were evident in WKY rats at week 20 and continued thereafter. Compared with WKY rats, the circadian BP and HR patterns were abolished and inverted, respectively, in SHRs. Lower dark-time, compared with light-time, SDMAP values were observed in SHRs that were associated with temporal increases in HR variability indices. These findings demonstrate that hypertension elicits significant alterations in circadian autonomic and hemodynamic profiles. Further, the steady increases in BP, average level and oscillations, in SHRs may explain the reported progressive age-related vascular and cardiac hypertrophy in these rats.     

Comparison of the Effects on Ambulatory Blood Pressure of Awakening versus Bedtime Administration of Torasemide in Essential Hypertension

Torasemide is a high‐ceiling loop diuretic frequently used in the treatment of congestive heart failure, renal failure, and hypertension. Low doses of torasemide (2.5 to 5 mg/day) do not elevate 24 h natriuresis, and they constitute effective monotherapy for mild‐to‐moderate uncomplicated essential hypertension according to results based on clinic blood pressure (BP). However, there has yet to be a proper evaluation of its 24 h efficacy or potential dependency of effects according to the circadian time of treatment. Accordingly, this trial investigated the administration time‐dependent efficacy of torasemide in uncomplicated essential hypertensive patients. We studied a total of 113 grade 1 and 2 hypertensive patients, 51.7±10.6 yrs of age, randomly assigned to receive torasemide (5 mg/day) as a monotherapy either upon awakening or at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours before and after six weeks of treatment. The efficacy of torasemide was significantly greater with bedtime dosing (i.e., 14.8 and 9.5 mmHg reduction in the 24 h mean systolic and diastolic BP, respectively) as compared with morning dosing upon awakening (i.e., 6.4 and 3.4 mmHg reduction in mean systolic and diastolic BP; p<0.001 between the two treatment‐time groups). The percentage of patients with controlled ambulatory BP after treatment was also higher after bedtime treatment (64 vs. 23%; p<0.001). Safety and tolerability were comparable between the two treatment‐time groups. A dose of 5 mg/day torasemide is more effective for BP reduction for uncomplicated essential hypertensive patients when ingested at bedtime than in the morning upon arising. The difference in antihypertensive efficacy as a function of the circadian dosing‐time of torasemide here documented should be taken into account when prescribing this loop diuretic to treat essential hypertensive patients.