Identifying an acceptable number of ambulatory blood pressure measurements for accuracy of average blood pressure and nocturnal dipping status.

We aimed to identify the minimum number of ambulatory blood pressure (ABP) measures to accurately determine daytime and nighttime systolic blood pressure (BP) averages and nocturnal dipping status (i.e., relative daytime:nighttime change). A total of 43 midlife participants wore an ABP monitor for 24 h with measurements every 20/30 min during the daytime/nighttime, as identified by a sleep diary. We calculated daytime/nighttime systolic BP average and dipping status from all available measurements per participant (i.e., normative data). We then calculated daytime and nighttime BP per participant based on a random selection of 8-20 and 4-10 measurements and replicated random selections 1,000 times. We calculated accuracy by checking the proportion from 1,000 different randomly selected samples for a particular number of measurements that systolic BP was ±5 mmHg of normative data, and dipping status remained unchanged for each participant compared with the normative value. The best fit for the regression model estimated the minimal number of measurements for an accuracy of 95% in BP averages. For a 95% accuracy in estimating daytime and nighttime systolic BP, 11 daytime and 8 nighttime measurements were required. The highest accuracy for dipping status was 91.6 ± 13.4% using 20 daytime and 10 nighttime measures, while the lowest was (83.4 ± 15.1%) using 8 daytime and 4 nighttime measures. In midlife adults, 11 daytime and 8 nighttime measurements are likely enough to calculate average systolic BPs accurately. However, no minimum number is suggested to accurately calculate dipping status.NEW & NOTEWORTHY We found that a minimum of 11 blood pressure (BP) measures are necessary to calculate an accurate average daytime BP, and 8 nighttime measures are necessary to calculate an accurate nighttime average if 95% accuracy is acceptable. Regarding BP dipping status, the current recommendations (20 daytime/7 nighttime) inaccurately classified the dipping status 10.5% of the time, suggesting that guidelines may need to be updated to classify patients as nocturnal dippers or nondippers correctly.

Non-Dipping Blood Pressure or Nocturnal Hypertension: Does One Matter More?

PURPOSE OF REVIEW: Nocturnal hypertension and non-dipping are both associated with increased cardiovascular risk; however, debate remains over which is a better prognosticator of cardiovascular outcomes. This review explores current literature on nocturnal hypertension and non-dipping to assess their relationship to cardiovascular disease and implications for clinical practice. RECENT FINDINGS: While current data remain inconclusive, some suggest that nocturnal hypertension is a more reliable and clinically significant marker of cardiovascular risk than non-dipping status. Importantly, reducing nocturnal HTN and non-dipping through chronotherapy, specifically evening dosing of antihypertensives, has not been conclusively shown to provide long-term cardiovascular benefits. Recent data suggests that non-dipping, compared to nocturnal hypertension, may be falling out of favor as a prognostic indicator for adverse cardiovascular outcomes. However, additional information is needed to understand how aberrant nighttime blood pressure patterns modulate cardiovascular risk to guide clinical management.

Time-restricted feeding protects the blood pressure circadian rhythm in diabetic mice.

The quantity and quality of food intake have been considered crucial for peoples' wellness. Only recently has it become appreciated that the timing of food intake is also critical. Nondipping blood pressure (BP) is prevalent in diabetic patients and is associated with increased cardiovascular events. However, the causes and mechanisms of nondipping BP in diabetes are not fully understood. Here, we report that food intake and BP were arrhythmic in diabetic db/db mice fed a normal chow diet ad libitum. Imposing a food intake diurnal rhythm by time-restricted feeding (TRF; food was only available for 8 h during the active phase) prevented db/db mice from developing nondipping BP and effectively restored the already disrupted BP circadian rhythm in db/db mice. Interestingly, increasing the time of food availability from 8 h to 12 h during the active dark phase in db/db mice prompted isocaloric feeding and still provided robust protection of the BP circadian rhythm in db/db mice. In contrast, neither 8-h nor 12-h TRF affected BP dipping in wild-type mice. Mechanistically, we demonstrate that TRF protects the BP circadian rhythm in db/db mice via suppressing the sympathetic activity during the light phase when they are inactive and fasting. Collectively, these data reveal a potentially pivotal role of the timing of food intake in the prevention and treatment of nondipping BP in diabetes.

Long-term circadian disruption shortens life span and dampens blood pressure diurnal rhythms in stroke-prone spontaneously hypertensive rats.

Environmental cues such as light and timing of food intake influence molecular clocks that produce circadian rhythmicity of many biological functions. The master circadian clock is entrained by light input and synchronizes with peripheral clocks in every organ of the body. Careers that require rotating shift work schedules predispose workers to a constant desynchronization of these biological clocks and are associated with increased risk of cardiovascular disease. We used a stroke-prone spontaneously hypertensive rat model exposed to a known biological desynchronizer, chronic environmental circadian disruption (ECD), to test the hypothesis that it would accelerate the time to stroke onset. We then investigated whether time-restricted feeding could delay stroke onset and evaluated its usefulness as a countermeasure when combined with the constant disruption of the light cycle. We found that phase advancing of the light schedule accelerated stroke onset. Restricting food access time to 5 h/day regardless of lighting profoundly delayed stroke onset in both standard 12-h:12-h light/dark or ECD-lighting conditions compared with ad libitum feeding; however, acceleration by ECD versus control lighting conditions was still observed. Since hypertension is a precursor to stroke in this model, we assessed blood pressure in a small cohort longitudinally using telemetry. Mean daily systolic and diastolic blood pressure increased in a similar manner across rats in control and ECD conditions, thus hypertension was not grossly accelerated to cause earlier strokes. However, we observed intermittent dampening of rhythms after each shift of the light cycle reminiscent of a relapsing-remitting nondipping state. Our results suggest that constant disruption of environmental rhythms may be associated with an increased risk of cardiovascular complications in the presence of cardiovascular risk factors.NEW & NOTEWORTHY This stroke-prone spontaneously hypertensive rat model significantly delayed stroke onset with the timed food restriction intervention. Blood pressure recordings in this same model were continuous through the 3 mo and showed dampened systolic rhythms after each shift in the lighting schedule.

Defining the impact of continuous positive airway pressure therapy on diastolic function in adults with moderate-to-severe obstructive sleep apnea.

Although studies have shown that continuous positive airway pressure (CPAP) therapy to treat obstructive sleep apnea improves left ventricular diastolic function, modifiers of improvement are unknown. We explored race and pre-treatment 24-h non-dipping blood pressure status as modifiers of improved diastolic function. Participants (N = 220) with obstructive sleep apnea (apnea-hypopnea index ≥15 events/h) and hypertension were recruited to a cohort study that examined effects of 3-month CPAP therapy on 24-h blood pressure. Those who completed echocardiogram at baseline and follow-up were included in this analysis. Diastolic function parameters (E, A, e', E/A, E/e') were assessed. Race was categorised to African American versus others. Participants were categorised as nocturnal dippers (night-time blood pressure decrease by ≥10%) versus non-dippers. We compared changes in parameters of diastolic function by race and nocturnal dipping status. A total of 92 participants were included. They were men (86%), African American (67.4%), and current smoker (29.5%). Mean apnea-hypopnea index was 32.9 events/h. Mean CPAP usage was 3.15 h/day. After 3 months of CPAP treatment, there were significant improvements in measures of diastolic function: a median (interquartile range [IQR]) increase in E velocity by 4.00 (-5.75 to 13.75) cm/s, an increase in e' by 2.00 (0-4.00) cm/s, and a decrease in the E/e' ratio by 1.74 (-4.27 to 0.00) at follow-up (p < 0.05). These changes did not differ by race or nocturnal dipping status. Improvements in diastolic function after CPAP therapy did not differ by race or nocturnal dipping status. Further studies are needed to understand predictors of CPAP effects on diastolic function.

Neutrophil and monocyte ratios to high-density lipoprotein cholesterol as biomarkers in non-dipping hypertension.

OBJECTIVE: To investigate the level and significance of neutrophils to high-density lipoprotein cholesterol ratio (NHR) and monocytes to high-density lipoprotein cholesterol ratio (MHR) in patients with non-dipping hypertension. METHODS: A total of 228 patients were retrospectively enrolled in the study. They were divided into the dipping hypertension group (n = 76), the non-dipping hypertension group (n = 77) and the control group (n = 75) according to 24-h ambulatory blood pressure monitoring system (ABPM) recordings. NHR and MHR were calculated and compared statistically. Receiver operating characteristic (ROC) curve analyses were performed for NHR and MHR. Binary logistic regression analyses were introduced to investigate the independent associations of NHR and MHR with non-dipping hypertension. RESULTS: The NHR and MHR were significantly higher in the non-dipping hypertension group compared with the control group (p = .001, p < .001, respectively) and the dipping hypertension group (p = .039, p = .003, respectively). According to ROC curve analyses, NHR>73.35 and MHR>7.54 were regarded as high-risk groups. The area under the curve (AUC) was 0.642 (p < .001) for NHR and 0.718 (p < .001) for MHR. In multivariate analysis, compared with NHR, only MHR was still recognized as a marker for detection of non-dipping hypertension (odds ratio [OR]: 1.208, 95% confidence interval [CI]: 1.076 to 1.356, p = .001). CONCLUSIONS: Our data indicated that not NHR but MHR as new composite marker of inflammation and lipid metabolism may predict non-dipping hypertension to some extent.

Nondipping Blood Pressure: Predictive or Reactive Failure of Renal Sodium Handling?

Blood pressure follows a daily rhythm, dipping during nocturnal sleep in humans. Attenuation of this dip (nondipping) is associated with increased risk of cardiovascular disease. Renal control of sodium homeostasis is essential for long-term blood pressure control. Sodium reabsorption and excretion have rhythms that rely on predictive/circadian as well as reactive adaptations. We explore how these rhythms might contribute to blood pressure rhythm in health and disease.

Parathyroidectomy Is Associated With Reversed Nondipping Heart Rate That Impacts Mortality in Chronic Kidney Disease Patients.

OBJECTIVE: Nondipping heart rate (HR), defined as a night/day HR ratio >0.90, has been associated with increased mortality in epidemiologic studies. However, its prognostic value in stage 5 chronic kidney disease (CKD5) patients and the effects of parathyroidectomy (PTX) on nondipping HR remain unknown. METHODS: This case-control study of 162 healthy controls and 502 CKD5 patients was performed between 2011 and 2018, in which CKD5 patients were further divided into non-PTX (n = 186) and severe secondary hyperparathyroidism (SHPT) with PTX (n = 316) subgroups. Each participant underwent 24-hour Holter monitoring for HR ratio. Mortality was followed up in CKD5 patients (median time: 46.0 months). RESULTS: The HR ratio in CKD5 patients was higher than in controls (0.92 ± 0.08 vs 0.81 ± 0.08, P <.001), associated with a 44% increase in mortality risk per 0.1 increment (hazard ratio, 1.44; 95% CI: 1.02-2.03; P =.04), and was positively related to serum intact parathyroid hormone levels (P <.001). PTX reversed nondipping HR in SHPT patients (n = 50, median time: 6.3 months, P <.001). Survival probabilities for PTX (n = 294) were better than non-PTX (n = 47) (hazard ratio, 0.31; 95% CI: 0.14-0.67; P <.01) in SHPT patients (serum intact parathyroid hormone >500.0 pg/mL). CONCLUSION: CKD5 patients displayed a nondipping HR pattern, which is a prognostic marker of all-cause mortality. PTX for SHPT patients was associated with a reversal in nondipping HR ratio, which may mediate a better outcome.

Nocturnal non-dipping on 24-h Ambulatory Blood Pressure Monitoring in children and adolescents with obesity is associated with higher total cholesterol levels.

BACKGROUND: Few studies indicate the occurrence of abnormal nocturnal dipping of blood pressure (BP) in 35-50% of children and adolescents with obesity. The relation between that phenomenon and metabolic complications of obesity remains unclear. To evaluate the association between disorders of glucose and lipid metabolism, and nocturnal non-dipping in pediatric patients with obesity. METHODS: In 207 children (53.14% girls, mean age 14 (range 2-17), mean BMI Z-SCORE 4.38, range 2.07-10.74) standard 24-h Ambulatory Blood Pressure Monitoring was performed. Normal dipping was defined as a ≥ 10% decline in BP during the night. RESULTS: There were 106 (51.21%) cases of non-dippers. The mean 24-h nocturnal systolic BP (SBP) reduction (%) was 9.9 ± 5.5. The mean 24-h nocturnal diastolic BP (DBP) reduction (%) was 15.8 ± 8.5. There was a significant correlation between BMI Z-SCORE and mean day-time SBP (r = 0.14 P = .042). There are positive correlations between 24-h heart rate (beats/min) and BMI Z-SCORE (r = 0.15, P = .027), between fasting glucose and systolic BP Z-SCORE (r = 0.17, P = .03) and between mean diastolic BP and LDL cholesterol (r = 0.23, P = .004). Total cholesterol level was significantly higher in non-dippers (4.34 vs. 3.99 mmol/L, P = .034). There were no significant differences between non-dippers and dippers regarding fasting glucose (4.6 vs. 4.8 mmol/L), 120'post load glucose (5.7 vs. 5.9 mmol/L), insulin (19 vs. 20.2 µIU/mL), HOMA-IR (2.36 vs. 2.44), LDL cholesterol (2.64 vs. 2.51 mmol/L), HDL cholesterol (1.06 vs. 1.03 mmol/L) or triglycerides (1.36 vs. 1.34 mmol/L) levels. CONCLUSION: Nocturnal non-dipping is frequent in pediatric patients with obesity. It is associated with higher total cholesterol levels.

Concurrent Aerobic Plus Resistance Training Elicits Different Effects on Short-Term Blood Pressure Variability of Hypertensive Patients in Relation to Their Nocturnal Blood Pressure Pattern.

Background and Objectives: The purpose of this study was to investigate the effects of a 12-week concurrent training (CT) (i.e., aerobic plus resistance exercise) on short-term blood pressure variability (BPV) and BP values in hypertensive patients with non-dippper BP nocturnal pattern and underlying coronary artery disease. Material and Methods: The study included 72 consecutive patients who were divided into two groups according to the nocturnal BP pattern: dipping pattern (33 pts) and non-dipping (39 pts). Before starting CT and at 12 weeks, patients underwent the six minute walk test, ergometric test, assessment of 1-repetiton maximum (1 RM), and 24/h BP monitoring (24-h ABPM). Results: After CT, exercise capacity increased in both groups in a similar fashion. Twenty-four/h systolic BPV and daytime systolic BPV decreased significantly in the dipping group while they were unchanged in the non-dipping group (between groups changes: -1.0 ± 0.4 mmHg and -1.3 ± 0.9 mmHg; p = 0.02 and p = 0.006, respectively). Twenty-four/h systolic BP and daytime systolic BP decreased significantly in the dipping group while they were unchanged in the non-dipping group (between groups changes: -7.1 ± 2.6 mmHg and -7.8 ± 2.4 mmHg; p = 0.004 and p = 0.002, respectively). Nighttime systolic BP and BPV was unchanged in both groups. Twenty-four/h diastolic BP presented small but not significant changes in both groups. Conclusions: The effects of CT on BPV and BP were blunted in hypertensive subjects with a non-dipping BP pattern.

High prevalence of non-dipping patterns among Black Africans with uncontrolled hypertension: a secondary analysis of the CREOLE trial.

BACKGROUND: Dipping of blood pressure (BP) at night is a normal physiological phenomenon. However, a non-dipping pattern is associated with hypertension mediated organ damage, secondary forms of hypertension and poorer long-term outcome. Identifying a non-dipping pattern may be useful in assessing risk, aiding the decision to investigate for secondary causes, initiating treatment, assisting decisions on choice and timing of antihypertensive therapy, and intensifying salt restriction. OBJECTIVES: To estimate the prevalence and factors associated with non-dipping pattern and determine the effect of 6 months of three antihypertensive regimens on the dipping pattern among Black African hypertensive patients. METHODS: This was a secondary analysis of the CREOLE Study which was a randomized, single blind, three-group trial conducted in 10 sites in 6 Sub-Saharan African countries. The participants were 721 Black African patients, aged between 30 and 79 years, with uncontrolled hypertension and a baseline 24-h ambulatory blood pressure monitoring (ABPM). Dipping was calculated from the average day and average night systolic blood pressure measures. RESULTS: The prevalence of non-dipping pattern was 78% (564 of 721). Factors that were independently associated with non-dipping were: serum sodium > 140 mmol/l (OR = 1.72, 95% CI 1.17-2.51, p-value 0.005), a higher office systolic BP (OR = 1.03, 95% CI 1.01-1.05, p-value 0.003) and a lower office diastolic BP (OR = 0.97, 95% CI 0.95-0.99, p-value 0.03). Treatment allocation did not change dipping status at 6 months (McNemar's Chi2 0.71, p-value 0.40). CONCLUSION: There was a high prevalence of non-dipping among Black Africans with uncontrolled hypertension. ABPM should be considered more routinely in Black Africans with uncontrolled hypertension, if resources permit, to help personalise therapy. Further research is needed to understand the mechanisms and causes of non-dipping pattern and if targeting night-time BP improves clinical outcomes. Trial registration ClinicalTrials.gov (NCT02742467).

Which is responsible for target organ damage in masked hypertension? Is it an increase in blood pressure or a disruption of the circadian rhythm?

OBJECTIVE: Masked hypertension (MH) and non-dipping pattern are conditions associated with target organ damage and cardiovascular risk, which are frequently observed together. We aimed to show the relationship between the target organ damage observed in MH and the deterioration in the dipping pattern. METHODS: Patients who underwent ambulatory blood pressure monitoring (ABPM) and office blood pressure (BP) <140/90 mmHg were retrospectively screened. In ABPM data, those with daytime BP ≥135/85 mmHg and night BP ≥120/70 mmHg were included in the MH group, while the others were included in the normotensive group. The patients were grouped as dipper, non-dipper and reverse-dipper according to ABPM results. Left ventricular mass index (LVMI), glomerular filtration rate (GFR) and serum creatinine levels were used to determine target organ damage. RESULTS: 289 patients [mean age 46.6 ± 12.4 years, 136 (47.1%) males], 154 (53.3%) of whom had MH were included in our study. GFR value was found to be significantly lower, serum creatinine levels and LVMI were significantly higher in patients with MH compared to normotensives (p < .05, for all). When the subgroups were examined, it was found that this difference was associated with the disruption in the dipping pattern. In patients with MH, dipping pattern disruption without change in systolic BP was independently associated with an increase in LVMI (p < .05, for both). CONCLUSION: Target organ damage seen in MH may be due to the deterioration of the dipping pattern.

Assessment of salusin alpha and salusin beta levels in patients with newly diagnosed dipper and non-dipper hypertension.

OBJECTIVE: The pathophysiology of non-dipper hypertension has not been clarified. The relationship between salusins with atherosclerosis and hypertension has gained attention in recent years. The aim of this paper is to investigate whether salusins are associated with circadian blood pressure, left ventricular mass index, and diastolic functions in newly diagnosed hypertensives. METHODS: The study included 88 newly diagnosed hypertensive individuals. Twenty-four-hour ambulatory blood pressure monitoring and echocardiographic examinations were performed. The patients were assigned to dipper hypertension (n = 41) and non-dipper hypertension (n = 47) groups based on the ambulatory blood pressure monitoring results according to the presence of ≥ a 10% decrease in nighttime blood pressure values or not. Serum salusin α and ß levels were determined by electrochemiluminescence immunological test method. RESULTS: Compared to dipper hypertension, non-dipper hypertension group demonstrated lower salusin α levels (1818.71 ± 221.67 vs 1963 ± 200.75 pg/mL, p = .002), mitral E/A, septal E'/A' and higher salusin ß levels (576.24 ± 68.15 vs 516.13 ± 90.7 pg/ml, p = .001) and left ventricular mass index. Multivariate logistic regression analysis revealed salusin-α (OR 0.474, 95% CI 0.262 to 0.986, p = .001), salusin-ß (OR 2.550, 95% CI 2.123 to 2.991, p = .018), and left ventricular mass index (OR 2.620, 95% CI 2.124 to 2.860, p = .011) as independent predictors of non-dipper hypertension. As candidate markers to predict non-dipper hypertension, decreased salusin α, and increased salusin ß levels may mediate crosstalk between sympathetic and parasympathetic systems and indicate poor cardiovascular prognosis in hypertension.

Non-dipping phenomenon effects in monosymptomatic nocturnal enuresis treatment?

BACKGROUND: Monosymptomatic enuresis nocturna patients are shown to have disrupted blood-pressure regulation accompanying polyuria. In our study, we aimed to research the desmopressin response of enuresis patients with blood-pressure regulation problems. METHODS: The study included 175 patients, aged from 6-15 years, with a diagnosis of monosymptomatic enuresis nocturna. Before treatment, 24 h ambulatory blood-pressure monitoring (ABPM) was used to identify 52 non-dipper patients and 73 patients with normal results. The responses to desmopressin treatment and clinical and demographic characteristics affecting response were compared. RESULTS: The response to desmopressin treatment was found to be significantly low in the patients who were non-dippers on 24 h ABPM before treatment compared to those with normal ABPM results (P < 0.05). Similarly, the waking problems in the non-dipper group were found to be high by a significant degree (P < 0.05). In the non-dipper group, the systolic non-dipping rate was higher. CONCLUSIONS: Before desmopressin use, assessment of patients with a 24 h ABPM may be beneficial to select the method to be used for treatment.

Angiotensin II-mediated nondipping during sleep in healthy humans: effects on baroreflex function at subsequent daytime.

Blood pressure dipping at night is mediated by sleep-inherent, active downregulation of sympathetic vascular tone. Concomitantly, activity of the renin-angiotensin system is reduced, which might contribute to the beneficial effect of baroreflex downward resetting on daytime blood pressure homeostasis. To evaluate whether experimental nondipping mediated by angiotensin II during sleep would alter blood pressure and baroreflex function the next day in healthy humans, angiotensin-II or placebo (saline) was infused for a 7-h period at night, preventing blood pressure dipping in 11 sleeping normotensive individuals (5 males, balanced, crossover design). Baroreflex function was assessed about 1 h upon awakening and stop of infusion via microneurographic recordings of muscle sympathetic nerve activity (MSNA), showing that resting MSNA was significantly increased following angiotensin II nondipping compared with placebo (P = 0.029), whereas blood pressure and heart rate remained unchanged. Baroreflex sensitivity in response to vasoactive drug challenge was preserved, and neuroendocrine markers of fluid balance and electrolytes did not differ between conditions. Ambulatory blood pressure during subsequent daytime was not altered. Data were compared with analog experiments previously performed within the same subjects during awake daytime (ANCOVA). We conclude that angiotensin-II mediated nocturnal nondipping did not induce blood pressure elevation at subsequent daytime in healthy humans but was linked to increased vasoconstrictive sympathetic activity. This is in contrast to a prolonged increase in blood pressure in corresponding daytime experiments of the same individuals. Evidently, sleep strongly preserves normotensive blood pressure homeostasis in healthy humans.

Restoration of nocturnal blood pressure dip and reduction of nocturnal blood pressure with evening anti-hypertensive medication administration in pediatric kidney transplant recipients: A pilot randomized clinical trial.

Non-dipping and nocturnal hypertension are commonly found during ABPM in pediatric kidney transplant recipients. These entities are independently associated with increased cardiovascular disease risk in adults. Kidney transplant recipients aged 5-21 years with eGFR > 30 mL/min/1.73 m2 and ABPM demonstrating non-dipping status and normal daytime BP were randomized to intervention (short acting BP medication added in the evening) or control (no medication change) in this pilot, randomized, open-label, blinded end-point clinical trial. ABPM, echocardiography, and PWV were performed at baseline, 3 months, and 6 months. The trial included 17 intervention and 16 control participants. Conversion to dipper status occurred in 53.3% vs 7.7% (P = .01) at 6 months for intervention and controls, respectively. Systolic dip was greater in the intervention group compared to controls (10.9 ± 4.5 vs 4.2 ± 4.6, P = .001), and average systolic nighttime BP was significantly lower in the intervention group (106 ± 8.3 vs 114.9 ± 9.5 mm Hg, P = .01) at 6 months. There were no significant differences in LVMI, PWV, or eGFR between groups. Within-group changes in the intervention group demonstrated improvements in non-dippers, dipping, systolic nighttime BP and nighttime BP load. Restoration of nocturnal dip and improvement in nocturnal BP were observed in the population following chronotherapy. Future studies are needed with larger sample sizes over a longer period of time to delineate the long-term effect of improved nocturnal dip on target organ damage.

Knockout of the circadian clock protein PER1 results in sex-dependent alterations of ET-1 production in mice in response to a high-salt diet plus mineralocorticoid treatment.

Previously, we showed that global knockout (KO) of the circadian clock transcription factor PER1 in male, but not female, mice fed a high-salt diet plus mineralocorticoid treatment (HS/DOCP) resulted in nondipping hypertension and decreased night/day ratio of sodium (Na) excretion. Additionally, we have shown that the endothelin-1 (ET-1) gene is targeted by both PER1 and aldosterone. We hypothesized that ET-1 would exhibit a sex-specific response to HS/DOCP treatment in PER1 KO. Here we show that male, but not female, global PER1 KO mice exhibit a decreased night/day ratio of urinary ET-1. Gene expression analysis revealed significant genotype differences in ET-1 and endothelin A receptor (ETA) expression in male, but not female, mice in response to HS/DOCP. Additionally, both wild-type and global PER1 KO male mice significantly increase endothelin B receptor (ETB) expression in response to HS/DOCP, but female mice do not. Finally, siRNA-mediated knockdown of PER1 in mouse cortical collecting duct cells (mpkCCDc14) resulted in increased ET-1 mRNA expression and peptide secretion in response to aldosterone treatment. These data suggest that PER1 is a negative regulator of ET-1 expression in response to HS/DOCP, revealing a novel mechanism for the regulation of renal Na handling in response to HS/DOCP treatment.

Ivabradine reversed nondipping heart rate in rats with l-NAME-induced hypertension.

We hypothesized that decreasing elevated night-time heart rate (HR) in hypertension by administering a bradycardic agent (ivabradine) at bedtime could bring cardiovascular benefit. Since rats are nocturnal animals, they exhibit circadian rhythms phase-shifted relative to humans. Sixty-six Wistar rats were divided into non-diseased controls and rats with l-NAME-induced hypertension to compare the haemodynamic effects of daytime-dosed and night-time-dosed ivabradine. l-NAME-induced hypertension inverted the physiological 5.6% night-to-day HR dip to an undesirable HR rise by 11.1%. Ivabradine dosed at daytime (the rat's resting phase) reverted a night-to-day HR rise to HR dip by 14.2%. These results suggest a cardiovascular benefit of ivabradine dosed at the human's resting phase (night-time) for hypertensive patients with nondipping HR.

Nondipping heart rate and associated factors in patients with chronic kidney disease.

BACKGROUND: Nondipping heart rate (NHR) is a condition reported to be associated with cardiovascular events and cardiovascular mortality recently. We aimed to search whether there is difference among hypertensive patients with and without chronic kidney disease (CKD) in terms of NHR pattern and the factors associated with NHR in patients with CKD. METHODS: The study included 133 hypertensive patients with normal kidney functions, 97 hypertensive patients with predialysis CKD, and 31 hypertensive hemodialysis patients. Heart rate, blood pressure and pulse wave velocity (PWV) were measured by 24-h ambulatory blood pressure monitorization. NHR was defined as a decrease of less than 10% at night mean heart rate when compared with daytime values. RESULTS: NHR pattern was established as 26.3% in non-CKD hypertensive group, 43.3% in predialysis group and 77.4% in dialysis group. Among patients with CKD, when NHR group was compared with dipper heart rate group, it was seen that they were at older age, there were higher prevalence of diabetes mellitus and more female sex, and while the value of urea, creatinine, phosphorus, intact parathyroid hormone, and PWV were significantly higher, the value of hemoglobin, albumin and calcium were significantly lower. By multivariate analysis, hemoglobin [odds ratio (OR) 0.661; 95% CI 0.541-0.806; p < 0.001] and PWV (OR 1.433; 95% CI 1.107-1.853; p = 0.006) were established as independent determinants of NHR pattern. CONCLUSIONS: NHR pattern is significantly more frequently seen in hypertensive CKD patients than in hypertensive patients with non-CKD. Anemia and increased arterial stiffness are seen independently associated with NHR in CKD patients.

Ambulatory monitoring unmasks hypertension among kidney transplant patients: single center experience and review of the literature.

BACKGROUND: Disagreements between clinic and ambulatory blood pressure (BP) measurements are well-described in the general population. Though hypertension is frequent in renal transplant recipients, only a few studies address the clinic-ambulatory discordance in this population. We aimed to describe the difference between clinic and ambulatory BP in kidney transplant patients at our institution. METHODS: We compared the clinic and ambulatory BP of 76 adult recipients of a kidney allograft followed at our transplant center and investigated the difference between these methods, considering confounding by demographic and clinical variables. RESULTS: Clinic systolic BP (SBP) and diastolic BP (DBP) were 128 ± 13/79 ± 9 mmHg. Awake SBP and DBP were 147 ± 18/85 ± 10 mmHg. The clinic-minus-awake SBP and DBP differences were - 18 and - 6 mmHg, respectively. The negative clinic-awake ΔSBP was more pronounced at age > 60 years (p = 0.026) and with tacrolimus use compared to cyclosporine (p = 0.046). Sleep SBP and DBP were 139 ± 21/78 ± 11 mmHg. A non-dipping sleep BP pattern was noted in 73% of patients and was associated with tacrolimus use (p = 0.020). CONCLUSIONS: Our findings suggest pervasive underestimation of BP when measured in the kidney transplant clinic, emphasizes the high frequency of a non-dipping pattern in this population and calls for liberal use of ambulatory BP monitoring to detect and manage hypertension.