Diurnal Blood Pressure Rhythm Research Articles

Time Restricted Feeding Reverses Western Diet-Induced Disruptions in Diurnal Blood Pressure Rhythms and Aortic Media Thickening

Cardiovascular disease is one of the primary contributors to the global burden of disease. A poor diet commonly observed in the western world consisting of elevated fat, salt, and sugar is estimated to contribute to 14% of disability-associated life years and increased mortality. High fat fed animals have altered circadian rhythms and increased aortic and renal damage. As the timing of food intake is critical for establishing and maintaining proper circadian rhythms, and disruption of these rhythms is detrimental to cardiovascular health, we hypothesize that time restricted feeding, similar to intermittent fasting, will rescue western diet-induced cardiovascular disease. In this study, alongside normal diet (ND 10% kcal fat, 0.25% by weight salt. 0.7% kcal sucrose) controls, C57Bl/6J male mice were switched to a high fat (45% kcal), high salt (4% by weight), and high sugar (17% kcal) diet for 20 weeks. At 18 weeks, a portion of the western-diet (WD) mice were subjected to time-restricted feeding (TRF) where access to food was restricted to the active period, 6pm to 6am. A subset of mice were implanted with radiotelemeters 14 weeks into the study to measure 24hr conscious blood pressure. Body weight was measured throughout the study confirming increased weight gain in WD mice compared to ND mice and that TRF did not induce weight loss. By 10 weeks, WD fed animals showed increased pulse wave velocity indicative of vascular remodeling (p<0.05). Remarkably, WD mice exhibited a non-dipping phenotype of their blood pressure. Active blood pressures were similar across groups 137 to 142mmHg; however, WD mice exhibited an elevation in inactive blood pressure (124mmHg) compared to ND mice (108mmHg). TRF returned inactive blood pressure (110mmHg) to ND levels despite being on a WD. The mesor of a cosiner analysis of the diurnal pattern of blood pressure is elevated in WD mice which is rescued by TRF. WD and WD-TRF mice exhibited increased perirenal fat accumulation, serum insulin, renal mass, and albuminuria compared to ND mice. There was no difference between WD and WD-TRF mice in these endpoints. We also observed increased renal inflammation in WD and WD-TRF mice measured by flow cytometric analysis of immune infiltrates, yet no effect of TRF itself. Histological analysis of aortic sections by Masson’s trichrome revealed a significant thickening of the tunica media in WD mice (52.91±1.70μm, n=15) compared to ND mice (47.12±1.88μm, n=14, p<0.05) which was reversed by TRF treatment (44.97±1.22μm, n=14, p<0.01). These results demonstrate that western diet contributes to chronic renal inflammation and aortic remodeling. We present novel findings that TRF rescues WD-induced non-dipping blood pressure and tunica media thickening. AHA-DF837441, NIH-1T32AI138932-01A1, 1R01HL161212-01A1, 19EIA34480023, 19IPLOI34760558, NIH-5T32GM 8111-35, AHA-MRT827566 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract P232: Endothelin B Receptor Modulation Of Diurnal Blood Pressure Amplitude During High Salt Diet

High salt diet can alter baroreflex sensitivity. We have previously shown that rats deficient in endothelin B receptors (ET B -R) demonstrate an exaggerated diurnal blood pressure amplitude similar to that seen in rats with sinoaortic denervation fed a high salt diet. However, it remains unclear if ET B -R influence on baroreflex function is due to sensory or efferent mechanisms of autonomic blood pressure control. We employed selective ET B -R antagonism using A192621 in ET B -R deficient rats (ET B -def) that only express functional ET B -R on efferent nerves and transgenic controls (TG) to isolate the role of efferent vs sensory pathways. Rats with telemetry were fed a normal salt diet (0.49% NaCl) during baseline and osmotic minipump infusion of 10 mg/kg/day A192621 or vehicle. After one week of infusion, animals were fed a high salt (4.0% NaCl) diet. Selective ET B -R blockade increased 24 hr MAP in TG animals during normal salt diet (+16.4 ± 1.0 mmHg from baseline; n = 10; p < 0.001) but had no effect on ET B -def (-1.2 ± 1.8 mmHg; n = 7; p > 0.99 ). A192621 treated TG rats did not exhibit a further increase in pressure following high salt diet (+5.5 ± 1.3 mmHg; n = 6; p = 0.25), but both vehicle and A192621 treated ET B -def rats displayed a salt-sensitive increase in MAP (+15.9 ± 4.2 and +14.4 ± 4.5 mmHg; n = 3 and 4; p = 0.003 and 0.001, respectively). A192621 treatment had no significant effect on MAP amplitude (light-dark difference) in any group during normal salt diet. However, during high salt, A192621 treated TG animals had an increase in MAP amplitude (+9.7 ± 0.7 mmHg; n = 6; p = 0.002), and vehicle had no effect (+0.8 ± 0.8 mmHg; n = 5; p = 0.97). Both A192621 and vehicle treated ET B -def rats had a similar increase in amplitude following high salt diet (+9.3 ± 0.6 and +8.6 ± 1.4; n = 4 and 3; p = 0.001 and 0.018, respectively). In summary, antagonism of ET B -R increased MAP only in TG rats but did not have an effect on diurnal amplitude during normal salt in any group. Antagonism of ET B -R during high salt diet caused TG rats to exhibit a similarly high diurnal amplitude as ET B -def rats. These data suggest that blocking ET B -R on baroreflex sensory pathways are the mitigating cause for increased diurnal blood pressure rhythms during high salt diet.

Abstract 079: Long-term Circadian Disruption Via Food Availability Leads To Kidney Damage

Circadian disruption (CD) is a risk factor in cardiovascular disease although we know little about its effects on the kidney. Previous work from our group showed that short-term CD in mice by restricting food availability to the daytime is sufficient to invert diurnal blood pressure rhythms yet kidney excretory function remained aligned with the light-dark cycle. Thus, we hypothesize that long-term CD will result in kidney damage. After putting C57BL/6 mice on a regular 12:12 light:dark cycle were placed on an inactive time-restricted feeding (iTRF, 12h food access during the day/lights on) or ad libitum feeding protocol for 8 weeks. During the final week, male and female iTRF mice ate significantly less during the 24-hour day compared to ad lib feeding (male iTRF 6.1±1.4g/day vs. ad lib 9.1±0.9g/day, p<.0001, n=9 for both groups; female iTRF 6.4 ±0.7 g/day, vs. ad lib 8.3±1.5g/day, p<0.01, n=9 and 8, respectively). Both sexes had an inversion in their diurnal water intake rhythms but maintained normal diurnal urinary water excretion. Aldosterone (aldo) and endothelin-1 (ET-1) contribute to circadian timing of sodium transport systems in the collecting duct. While male iTRF mice maintained their diurnal rhythm of aldosterone excretion (2.0±1.4ng/hr in light, p=0.06; 7.8±3.1ng/hr in dark, p=0.37, n=6), female iTRF mice lost their diurnal rhythm (4.4±2.7ng/hr in light, p=0.85; 4.4±3.1ng/hr in dark, p=0.11, n=6). Male mice with iTRF had significantly lower ET-1 excretion, but maintained the diurnal variation. In contrast, female iTRF mice demonstrated an inverted ET-1 excretion pattern (18.5±6.3ng/hr in light vs. 7.3±2.9ng/hr in dark, p=0.03, n=3) compared to ad lib fed mice (18.9±2.1ng/hr in light vs. 33.7±5.6ng/hr in dark, p=0.01, n=3). Picrosirus red staining of kidneys revealed a striking increase in glomerular and interstitial fibrosis in iTRF male mice as compared to their ad lib counterparts. In contrast, iTRF female mice appeared to be completely protected from increased fibrosis. These results support our hypothesis that long-term CD due to timing of food intake exacerbates kidney damage. However, females were protected against renal fibrosis, perhaps due in part to an ability to better modulate kidney rhythms in response to food timing.

013 Associations Between Rest-Activity Rhythms and Nocturnal Blood Pressure are Sex-Dependent in Apparently Healthy Emerging Adults

Abstract Introduction Misalignment between endogenous circadian rhythms and environmental signals – an emerging risk factor for cardiovascular disease (CVD) – can disrupt diurnal blood pressure (BP) rhythms, resulting in higher nocturnal BP and less-pronounced BP dipping (i.e., % decline in nighttime systolic BP [SBP] relative to daytime values). Daily patterns of rest and activity (‘rest-activity rhythms’ [RAR]) are a proxy for estimating circadian disruption in free-living settings and have been independently associated with elevated CVD risk. However, the relation between RAR and nocturnal BP is unclear. Thus, we aimed to quantify the associations between RAR and nocturnal BP characteristics in male and female emerging adults (18-25y). Methods Fifty healthy emerging adults (20±1y; 20M/30F) underwent 24-h ambulatory BP monitoring following 14 consecutive days of continuous wrist actigraphy. RAR variables of interdaily stability (IS; day-to-day consistency in RAR), intradaily variability (IV; within-day fragmentation of RAR), and relative amplitude (RA; difference between trough vs. peak activity) were computed. Bivariate correlations were used to quantify associations between RAR variables and nocturnal BP characteristics for all participants, and separately for males and females. Linear regression models of mean nocturnal SBP, nocturnal diastolic BP (DBP), and SBP dipping were also generated to test main and interactive effects of sex and RAR. Potential confounders (variables associated with outcomes at p<0.10) of daytime BP, race, body mass index, physical activity, sleep duration, alcohol, caffeine, and sodium intake were also included as indicated. Results Overall, IS and RA positively correlated with % SBP dipping (IS: r=0.33, p=0.02; RA: r=0.35, p=0.01). Among females only, correlations strengthened (IS: r=0.50, p<0.01; RA: r=0.52, p<0.01) and an inverse association between RA and mean nocturnal SBP emerged (r=-0.46, p=0.01). Conversely, among males, no significant associations were apparent. Multivariate regressions revealed a significant sex*RAR interaction, such that in females, every 1-standard deviation increase in IS and RA were associated with an average decrease in nocturnal SBP of 5.4 mmHg (95% CI: -10.0, -0.73) and 4.8 mmHg (95% CI: -9.2, -0.34), respectively. Conclusion Findings suggest that consistent and high-amplitude RAR associate with more favorable nocturnal BP characteristics, particularly in emerging female adults. Support (if any) Supported in part by NIH P20-GM113125.

Circadian Regulation of Blood Pressure: of Mice and Men.

Blood pressure (BP) exhibits strong diurnal variations that have been shown to be important for normal physiology and health. In this review, we highlight recent advances in both basic and clinic research on how the circadian clock affects these BP rhythms. Tissue-specific and inducible knockout rodent models have provided novel ways to dissect how circadian clocks regulate BP rhythms and demonstrated that loss of these rhythms is associated with the development of disease. The use of circadian-specific research protocols has translated findings from rodent models to humans, providing insight into circadian control of BP, as well as how sleep, activity, and other factors influence diurnal BP rhythms. Circadian mechanisms play an important role in the regulation of diurnal BP rhythms. Future research needs to extend these findings to clinical populations and determine the extent to which circadian factors may play a role in the development of novel treatment approaches to the management of hypertension.

Diurnal rhythm of blood pressure in patients with polycythemia vera.

Polycythemia vera increases the risk of hypertension, but there is limited information about the effect on daily blood pressure fluctuations. This study aimed to demonstrate how diurnal blood pressure rhythm is affected in polycythemia vera patients. Fifty (50) patients (33 men; mean age 48 ± 15 years) with a diagnosis of polycythemia vera and 51 age and sex-matched healthy subjects for the control group were prospectively evaluated. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated by ambulatory blood pressure monitoring (ABPM) as average 24-hour, daytime and nighttime measures. Average 24-hour SBP and DBP, daytime SBP and DBP were similar in both groups. However, nighttime SBP and DBP were significantly higher in the polycythemia vera group compared with the control group (125.3 ± 17.2 and 73.7 ± 12.2 vs. 118.9 ± 12.2 and 69.5 ± 8.5; P = 0.034 and P = 0.044). Both nocturnal SBP fall and nocturnal DBP fall were blunted in the polycythemia vera group compared with the control group (-6.9 ± 8.9 and -11.3 ± 12.2 vs. -11.6 ± 7.7 and -16.3 ± 12.0, respectively). Both hemoglobin and hematocrit levels were positively correlated with nocturnal SBP fall (r = 0.306, P = 0.002 and r = 0.355, P < 0.001; respectively) in all patients. We found that the polycythemia vera group had significantly decreased nocturnal dipping compared with healthy controls. The SBP fall was also positively correlated with hemoglobin and hematocrit levels.

Diurnal rhythm of blood pressure among Nigerians with hypertension using 24-hour ambulatory blood pressure monitoring.

Introductionhypertension is the most common cardiac disease in Nigeria. There are very limited studies in Nigeria on the use of 24-hour ambulatory blood pressure monitoring (24-h ABPM) for evaluation of hypertensive patients. Twenty four-hour ABPM, unlike office blood pressure (OBP), can assess diurnal variation using parameters like awake blood pressure (BP), asleep (nocturnal) BP, mean 24-hour BP and dipping pattern. This can help in assessment of increased cardiovascular risk and management of hypertensive patients. We purposed to assess the diurnal rhythm of BP among Nigerians with hypertension.Methodsthis was a prospective cross-sectional study. Consecutive 77 hypertensive subjects were studied using Schiller MT-300 for 24-h ABPM.Resultsout of the 77 patients reviewed, 39 (50.6%) were females. The mean age was 50.9 years (SD 13.5). The mean awake systolic and diastolic BP were 135.6mmHg (SD 15.0) and 83.2mmHg (SD 10.0) respectively; mean asleep systolic and diastolic BP were 127.6mmHg (SD 17.9) and 76.2mmHg (SD 12.2) respectively; and mean 24-h systolic and diastolic BP were 133.6mmHg (SD 15.3) and 81.4mmHg (SD 10.2) respectively. Awake BP was elevated in 59.7% of study subjects. Elevated awake systolic BP and awake diastolic BP were present in 50.6% and 41.6% of the study population. Nocturnal (asleep) BP was elevated in 79.2%. Non-dipping pattern was the most prevalent pattern at 55.8%, followed by dipping (24.7%), reverse dipping (15.6%) and extreme dipping (3.9%).Conclusiona high proportion had nocturnal hypertension (79.2%) and non-dipping pattern was the most prevalent pattern (55.8%). Mean awake systolic BP, mean asleep systolic and diastolic BP and mean 24-h systolic and diastolic BP were elevated. The use of 24-h ABPM will enhance assessment of increased cardiovascular risk and management of Nigerians with hypertension.

Abstract P3037: Timing of Food Intake Controls Diurnal Blood Pressure Rhythm in Mice

Recent studies suggest that timing of food intake plays pivotal roles in regulating many physiological processes, such as lipid metabolism, immune responsiveness, and blood pressure (BP). Whether BP rhythms are altered by timing of food intake remains unknown. Here we sought to test the hypothesis that feeding during the inactive period (reverse feeding or RF) disrupts BP rhythms in mice. Male C57Bl/6J mice (WT, 12-16 wk old, n=11) and Bmal1 knockout mice (Bmal1KO, 12-16 wk old, n=7) were placed in metabolic cages maintained in normal 12 hr light/dark periods. Mice had free access to food and water for 3 days, followed by 6-days of RF with free access to water. Food and water intake were monitored twice per day at the beginning of active (lights off, 7pm-7am) and inactive (lights off, 7pm-7am) periods (AP and IP). As expected, mean arterial pressure (MAP via telemetry) was significantly higher in AP compared to IP when WT mice were fed ad libitum (113 ± 2 vs. 100 ± 2 mmHg, respectively, p&lt;0.01). Similar to previous reports, baseline MAP in Bmal1KO was comparable between AP and IP (95 ± 1 vs. 92 ± 3 mmHg, respectively, p=0.30). WT mice consumed the majority of their food during their active period (6.3 ± 0.7 vs. 2.1 ± 0.2 g, AP vs. IP, p&lt;0.01). In contrast, Bmal1KO mice consumed roughly the same amount of food throughout the day (3.6 ± 0.6 vs. 2.7 ± 0.4 g, AP vs. IP, p=0.25). RF led to an inversion of diurnal MAP in WT (99 ± 3 vs. 110 ± 3 mmHg, p&lt;0.01). Furthermore, RF induced a significant diurnal MAP rhythm in Bmal1KO (79 ± 3 vs. 95 ± 2 mmHg, p&lt;0.01). To eliminate the potential effect of light acting as a Zeitgeber (timing cue), we used WT mice to perform additional experiments in constant darkness. Mice were allowed ad lib food for several days before being divided into three groups: ad lib feeding, RF, and an offset feeding (OF) regimen (mice fed from 1pm-1am). Similar to normal lighting, RF in constant darkness led to an inversion of diurnal MAP (104 ± 3 vs. 112 ± 3 mmHg, fasting and feeding, respectively, p=0.055). OF resulted in a roughly 6-hour shift in diurnal MAP where again MAP was significantly higher when food was available from 1pm to 1am (104 ± 1 vs. 118 ± 3 mmHg, fasting and feeding, respectively, p&lt;0.001). These data demonstrate that timing of food intake controls diurnal blood pressure rhythm in mice.

The relationship between diurnal blood pressure abnormalities and target organ damage in normotensive subjects. Which is more important? Increased blood pressure levels or circadian blood pressure abnormalities

ABSTRACTObjective: Circadian blood pressure (CBP) abnormalities are well-known risk factors for many diseases such as cardiovascular, cerebrovascular, and chronic kidney disease. The object of this study was to evaluate the relationship between abnormalities in CBP rhythm and target organ damage (TOD) in normotensive non-dipper (non-DP) subjects.Methods: The 24-h ambulatory BP monitoring (ABPM) and echocardiography were performed and urinary albumin excretion (UAE) was measured in 127 normotensive dipper (DP) (42 males, 85 females) and 337 (89 males, 248 females) normotensive non-DP subjects.Results: When we compared DP and non-DP subjects; Pulse wave velocity (PWV) (7.12 ± 1.72 vs 7.57 ± 1.87 m/s, p = 0.02), the percentile of corrected PWV (cPWV) (7.1 vs. 20.2, p= 0.001) and the percentile of corrected augmentation index (cAIx) (23.5 vs. 33.9, p = 0.03), left ventricle mass index (LVMI) (78.00 ± 23.27 vs. 95.59 ± 18.29 g/m2, p = 0.01), relative wall thickness (RWT)(0.36 ± 0.13 vs 0.46 ± 0.09, p = 0.01), percentile of proteinuria (8.6 vs 29.2%, p = 0.00) were higher in non-DP group. In the correlation analyses, the PWV, LVMI, RWT were negatively correlated with the rate of systolic fall in nighttime (%)(−0.15, p = 0.01 vs. −0.23, p = 0.02 vs. −0.27, p = 0.00). It was observed that cPWV, cAIx, and UAE were independently associated with age and non-DP status (NDS), in logistic regression analysis.Conclusions: Our results suggested that normotensive persons with CBP abnormalities had TOD. In light of the data of this article, non-dipper status is detected in the early period and if the provision of diurnal blood pressure rhythm may reduce the incidence of future adverse events in nondipper normotensive subjects.

Evidence that Food Intake Controls Diurnal Blood Pressure Rhythm in Mice

Blood pressure exhibits a 24‐hour rhythm and peaks in the beginning of the active period in both human and rodents. Previous studies suggested that timing of food intake plays pivotal roles in regulating many physiological processes, such as lipid metabolism, sleep‐wake cycle, immune responsiveness, and even blood pressure. However, whether blood pressure and kidney function is altered by changing feeding time remains largely unknown. The current study was designed to test the hypothesis that feeding during the inactive period (reverse feeding or RF) disrupts blood pressure and kidney function in mice. Male C57Bl/6J mice (12–16 weeks old, n=6) were placed in metabolic cages and had free access to food and water for 3 days, followed by a 6‐day RF with free access to water. Food and water intake, as well as urine output were monitored twice per day at the beginning of active and inactive periods (AP and IP, respectively). Blood pressure was recorded via telemetry transmitters. As expected, we found that mean arterial pressure (MAP) was significantly higher in AP compared to IP when mice were fed ad libitum (114 ± 1 vs. 96 ± 1 mmHg, respectively, p&lt;0.01). However, RF led to an inversion of diurnal MAP (98 ± 5 vs. 112 ± 2 mmHg, p=0.02). Similar effects were observed in heart rate (ad libitum, 659 ± 12 vs. 548 ± 16 bpm, p=0.03; RF, 484 ± 48 vs. 613 ± 22 bpm, p=0.02). In contrast, RF did not alter diurnal rhythm in urine output (ad libitum, 1.0 ± 0.2 vs. 0.2 ± 0.1 ml/12hr, p&lt;0.01; RF, 1.4 ± 0.1 vs. 0.7 ± 0.1 ml/12hr, p&lt;0.01). However, diurnal rhythm in urinary sodium excretion was dampened after RF (ad libitum, 7.3 ± 0.8 vs. 1.0 ± 0.2 mEq/12hr, p&lt;0.01; RF, 6.5 ± 0.8 vs. 4.5 ± 0.7 mEq/12hr, p=0.08). Similarly, diurnal rhythm in urinary potassium excretion was abolished (ad libitum, 7.0 ± 0.9 vs. 0.8 ± 0.2 mEq/12hr, p&lt;0.01; RF, 4.8 ± 0.7 vs. 5.3 ± 0.7 mEq/12hr, p=0.97). We also measured urinary excretion of aldosterone by ELISA and found that its diurnal rhythm remained intact after RF (ad libitum, 990 ± 142 vs. 370 ± 38 pg/12hr, p=0.01; RF, 856 ± 181 vs. 204 ± 42 pg/12hr, p=0.01). These data suggest that RF inverts diurnal blood pressure rhythm and differentially modifies diurnal excretion of water and electrolytes in mice.Support or Funding InformationFunded by an AHA pre‐doctoral fellowship (18PRE33990345) to DZ and NHLBI P01 HL136267 to DMP. We appreciate Drs. Celso and Elise Gomez‐Sanchez's help with the aldosterone assay.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of circadian rhythm of diastolic blood pressure on diastolic function in elderly hypertensive patients

Objective To analyze the effects of 24-hour diurnal blood pressure rhythm (BPCR) changes on diastolic function in elderly hypertensive patients. Methods From February 2016 to February 2018, one hundred and twenty elderly patients with hypertension were divided into two groups according to their 24-hour ambulatory blood pressure status: dipper group with 65 cases (nocturnal blood pressure drop rate (>10%) and non-dipper group with 55 cases (nocturnal blood pressure drop rate<10%); ambulatory blood pressure and echocardiographic relaxation were detected.Posterior wall (PW), interventricular septum (IVS), left ventricular diameter (LVEDD), left ventricular mass index (LVM) and left ventricular mass index (LVMI) were examined.Fractional shortening (FS), stroke volume (SV), cardiac output (CO) and cardiac index (CI) were calculated, and peak flow time (A peak flow time total integration, ATVI) and peak flow velocity (A Pea) were measured.K flow rate ventricular (APFV); E peak flow time ventricular integral (ETVI), early Peak flow Velocity (EPFV) and left ventricular ejection fraction (LVEF) were detected. Results The 24 h DBP, 24 hSBP, nocturnal DBP, and nocturnal SBP in dipper group were (80.27±7.29) mmHg, (125.29±10.38) mmHg, (69.98±6.36) mmHg, (110.39±10.52) mmHg, which were lower than those of the noninvasive group ((83.82±7.51) mmHg, (130.89±10.71) mmHg, (79.81±6.84) mmHg, (126.83±10.92) mmHg), the differences were statistically significant (t=12.809, 13.954, 11.053, 13.289, P=0.042, 0.021, 0.014, 0.006). The EPFV in the dipper group was (65.02±11.83) cm/s, which was higher than that in the non-dipper group ((60.84±11.29) cm/s). The A/E, ATVI, and APFV in the dipper group were (1.03±0.58), (5.59±1.72) cm, (63.74±11.06) cm/s, respectively, lower than those in non-dipper group( (1.14±0.54), (6.11±1.68) cm, (68.82±11.17) cm/s), the differences were statistically significant (t=10.895, 11.643, 12.339, 10.854, P=0.032, 0.027, 0.013, 0.006). Left ventricular diastolic function was negatively correlated with daytime DBP (r=- 0.195, -0.217, -0.174, -0.173, P<0.05) and positively correlated with nighttime SBP(r=0.194, 0.171, 0.220, 0.206, P<0.05). Conclusion In elderly hypertensive patients, the left ventricular diastolic function and left ventricular hypertrophy are more serious in non-dipper patients, and it is necessary to strengthen the control of nocturnal blood pressure in elderly hypertensive patients. Key words: Blood pressure circadian rhythm; hypertension; elderly; diastolic function

Diurnal rhythm of central blood pressure during twenty-four-hour ambulatory monitoring

It’s known that ABPM is better in diagnosing hypertension than office-based measurements. Growing evidence supports that cBP is stronger predictor of cardiovascular risk than brachial BP. Dipping status of subjects can be assessed based on night-to-day BP ratio derived from ABPM. However, there is no data regarding diurnal rhythm of central hemodynamics. Arteriograph 24 is suitable for 24-hour monitoring of both central and brachial BP. The aim of our study was to compare the 24-hour pattern of peripherial and central BP in same patients.Patients and methods24-hour aortic BP-monitoring was performed with Arteriograph 24 in 46 subjects (30 male, 16 female). Measurements were carried out with Arteriograph 24 – a combination of a “single” Arteriograph and an ABPM. Mean age of patients were 55.36 years. Their dipper status was assessed according to the ESH-guidelines and the circadian variation of central hemodynamics was determined as the difference of peripherial and central BP during day and night.ResultsOnly 7 of 46 subjects were non-dipper according to their brachial BP. All of them had elevated central BP at night. In contrast we observed elevated AIx and higher cBP during nighttime in further 30 cases who had dipping of nighttime brachial BP.ConclusionscBP have diurnal rhythm but the circadian variation of cBP is not necessarily parallel with the corresponding peripherial values. Theoretically elevated peripherial vascular resistance during night helps to maintain the appropriate cBP to provide the cerebral, coronary and renal perfusion. If this observation is confirmed by further large-scale trials the clinical implications of dipping status could be reconsidered.

Abstract 089: Deletion of Circadian Clock Associated Gene, Rfwd2 , Alters Rhythm in Blood Pressure Timing Without Changes in Salt-Sensitivity

Healthy individuals display a diurnal blood pressure (BP) rhythm and salt-sensitivity increases the susceptibility for dysfunctional BP rhythms. Previously, bayesian modeling found that Rfwd2 gene was associated with circadian clock gene pathways in the Dahl Salt-sensitive rats (SS). SS rats lacking Rfwd2 were generated to test the hypothesis that Rfwd2 alters the circadian BP rhythm and salt-sensitivity in SS rats. Rfwd2 total knockout rats on the SS background are embryonic lethal, thus experiments utilized male Rfwd2 heterozygous SS ( Rfwd2 +/- ; n=6) and SS rats (n=8). All rats were maintained on Teklad (NIH-31) normal salt diet (NS; 0.4% NaCl) and then fed high salt diet (HS; 4% NaCl). BP was recorded via telemetry and systolic BP analyzed on days 4-7 of diet. On NS, the amplitude (difference between peak and mean) and mesor (rhythm-adjusted mean) were similar between genotypes. However, HS diet increased the amplitude (SS: 5.2 ± 0.4 to 9.3 ± 0.5, P&lt;0.0001; Rfwd2 +/- : 3.7 ± 0.5 to 9.0 ± 0.5, P&lt;0.0001) and mesor (SS: 147 ± 1.2 mmHg to 166 ± 1.7 mmHg, P&lt;0.0001; Rfwd2 +/- : 150 ± 1.6 mmHg to 177 ± 3.1 mmHg, P&lt;0.0001) in both genotypes. On HS, Rfwd2 +/- rats compared to SS had greater mesor (178 ± 3.1 mmHg vs. 166 ± 1.7 mmHg, P=0.003, respectively) and similar amplitude. Rfwd2 +/- had significant 1.4hr delay in trough (lowest value) SBP timing compared to SS within both salt diets (NS: P=0.005; HS: P=0.008). In addition, HS caused a delay in trough SBP timing in both genotypes. These results (figure) show that Rfwd2 has a role in trough BP timing, and the lack of this gene results in an exaggerated mesor on HS diet and a 1.4hr delay on NS and HS diets, which could potentially be coupled with renal injury.

Timing of Blood Pressure Rhythms Predict Risk of Renal Injury in the Dahl Salt‐Sensitive Rats

Salt‐sensitive individuals have higher susceptibility for dysfunctional diurnal blood pressure rhythms, development of hypertension and renal injury. The aim of this study was to elucidate genetic determinants of diurnal excretion of renal injury markers and timing of systolic BP (SBP) peak and trough patterns in 4 rat models of salt‐sensitivity. We utilized male Dahl salt‐sensitive (SS) rats, NADPH oxidase p67phox knockout in SS (SS.p67phox−/−), introgression of chromosome 13 from Brown‐Norway rats into SS (SS.BN13), and introgression of 16Mbp section of BN13 (SS.BN‐(D13Rat151‐D13Rat197)) in SS (SS.Line26). Male, 12–14 week old rats (n=7–14) were maintained on normal salt (NS; 0.4% NaCl) and then fed high salt (HS; 4% NaCl) diet for 7 days (Dyets, AIN‐76A). Telemetry was used to continuously measure SBP, heart rate and locomotor activity. On NS, 24‐hr SBP was 155.9 ± 0.2 mmHg (SS), 141.6 ± 0.3 mmHg (SSp67phox−/−), 145.5 ± 0.4 mmHg (SS.BN13), and 155.2 ± 0.2 mmHg (SS.Line26). The average 24‐hr SBP in rats on high salt diet was 173.3 ± 0.5 mmHg, 152.2 ± 0.5 mmHg, 158.5 ± 0.6 mmHg, and 171.0 ± 0.6 mmHg, respectively. Eating HS did not change the timing of peak and trough SBP rhythms within each genotype. Furthermore, there were no differences in timing of peak timing of SBP across genotypes on either diet. Similarly, there was no difference in timing of trough SBP across genotypes on NS. However, HS delayed the timing of trough SBP in SS (n=14) by 5.3 hours compared to SS.p67phox−/− (n=12, p&lt;0.001) and by 2.6 hours compared to SS.BN13 rats (n=7, p=0.036). Timing of trough SBP was similar between SS.Line26 (n=12) and SS rats. Heart rate and locomotor activity were not significantly different across genotypes or diets. On HS diet, SS.p67phox−/− (n=8) had lower proteinuria and albuminuria than SS (n=14) and SS.Line26 (n=12) during the active phase (p&lt;0.0001). On HS, proteinuria, albuminuria, and nephrinuria were highest in SS.Line26 compared to SS, SS.p67phox−/−, and SS.BN13 (n=7) during active phase (p&lt;0.01). Excretion of kidney injury marker 1, KIM1, was significantly higher in SS than SS.Line26, SS.BN13, and SS.p67phox−/− (p&lt;0.005). In summary, SS and SS.Line26 rats have delays in the inactive (trough) timing of SBP, which is associated with proximal tubular injury in SS and glomerular injury in SS.Line26 rats. These findings indicate that rat chromosome 13 has a role at least in part, in the timing of SBP and risk of kidney injury in the SS rat.Support or Funding InformationAmerican Heart Association Strategically Focused Research Network ‐ Hypertension (15SFRN2390002)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High prevalence of "non-dipping" blood pressure and vascular stiffness in HIV-infected South Africans on antiretrovirals.

BackgroundHIV-infected individuals are at increased risk of tissue inflammation and accelerated vascular aging (‘inflamm-aging’). Abnormal diurnal blood pressure (BP) rhythms such as non-dipping may contribute to an increased risk of cardiovascular and cerebrovascular events in HIV infected individuals. However, little data exists on ambulatory blood pressure (ABP) and measures of vascular stiffness in the black African HIV infected population.MethodsThis is a cross-sectional analysis of otherwise well, HIV infected outpatients on ART for >5 years. Study assessments included: 24hr ABP monitoring, pulse wave velocity (PWV) and central aortic systolic pressure (CASP) using a AtCor Medical Sphygmocor device, fasting lipogram, oral glucose tolerance test, high-sensitivity C-reactive protein (hsCRP) and anthropometric data. Patients completed a questionnaire of autonomic symptoms. CD4+ counts and viral loads were obtained from the National Laboratory results system.ResultsSixty seven black participants were included in the analysis of whom 91% (n = 61) were female with a mean age of 42.2 ± 8.6 years. The median duration on ART was 7.5 years (IQR = 6–10), 84% were virally supressed and the median CD4 count was 529.5cells/mm3 (IQR = 372.0–686.5). The majority (67%) were classified as overweight and 76% had an increased waist circumference, yet only 88% of participants were normotensive. A hsCRP level in the high cardiovascular risk category was found in 68% of participants. The prevalence of non-dipping BP was 65%. Interestingly, there was no association on multivariable analysis between dipping status and traditional risk factors for non-dipping BP, such as: obesity, autonomic dysfunction and older age.ConclusionThis relatively young cross-sectional sample of predominantly normotensive, but overweight black women on effective ART >5 years showed: a high prevalence of non-dipping BP, inflammation and vascular stiffness. Causality cannot be inferred but cardiovascular risk reduction should be emphasized in these patients.

NADPH Oxidase p67phox Subunit Contributes to the Maintenance of Diurnal Blood Pressure Rhythms in Dahl Salt‐Sensitive Rats

Loss of diurnal blood pressure (BP) rhythm, such as absence of dipping during the inactive phase is a known risk factor for cardiovascular disease. Salt‐sensitive individuals have higher susceptibility for dysfunctional diurnal BP rhythms as well as for developing hypertension. In this study, we hypothesized that NADPH oxidase, specifically the p67phox subunit, impairs diurnal BP rhythm and circadian clock gene mRNA expression in the Dahl salt‐sensitive (SS) rats. We utilized SS and p67phox knockout SS (SSp67phox−/−) rats (n=8 per group) to determine 24‐hr BP, heart rate and locomotor activity by telemetry while on normal (0.4% NaCl), low (0.04% NaCl) and high (4% NaCl) salt diets (Dyets, AIN‐76A). Our results show that SSp67phox−/− rats and SS rats have similar diurnal BP rhythms (average amplitude 3.43 vs. 3.13 mmHg, respectively) when on a normal salt diet. Cosinor analysis was used to calculate the amplitude, which is defined as the difference between peak and mean value of a 24‐hr oscillation. 24‐hr mean arterial pressure (MAP) was lower in SSp67phox−/− than SS (116 ± 1 vs. 129 ± 1 mmHg, respectively, p&lt;0.0001). Heart rate groups and locomotor activity did not differ across genotypes or diets. On one week of high salt diet, the increase in 24‐hr MAP from normal salt diet was larger in SS rats compared to SSp67phox−/− (+11.6 ± 0.8 vs. +7.0 ± 1.1 mmHg, respectively, p=0.017). The diurnal BP rhythm (day vs. night) in SS and SSp67phox−/− on high salt diet became more pronounced than on normal salt diet (average amplitude 7.99 and 6.11 mmHg, respectively). Low salt diet did not change 24‐hr MAP in either genotype, however diurnal BP rhythm was abolished in SS rats and maintained in the SSp67phox−/− rats (average amplitude 2.35 and 3.30 mmHg, respectively). We also measured 12‐hr urinary sodium (Na+) excretion via metabolic cages under normal, low and high salt diets. During the dark/active phase on high salt diet, SSp67phox−/− had less water intake and urine output compared to SS rats, while light/inactive phase measurements were similar. Urinary Na+ excretion was also lower in SSp67phox−/− compared to SS controls on high salt diet during the light/active phase, while Na+ excretion was similar during the light/inactive phase. Food intake was similar between genotypes, regardless of time of day. On normal and low salt diets, SSp67phox−/− and SS rats had similar urine output, food and water intake, and urinary Na+ excretion. To assess if core clock gene, Bmal1, was altered with salt diets, we examined Bmal1 mRNA expression in renal vessels at 12‐hr intervals under either low or high salt feeding. Bmal1 mRNA expression was higher at zeitgeber time 0 (ZT0) compared to ZT12 in renal vessel and buccal cells. In contrast to our prior findings using renal inner medullary tissue, neither salt diet or genotype changed the magnitude of Bmal1 mRNA expression. Taken together, these data suggest that NADPH oxidase p67phox expression contributes to the maintenance of diurnal BP rhythms in SS rats on low salt diet.Support or Funding InformationThis work was supported by the American Heart Association Strategically Focused Research Network grant (15SFRN2390002)

Loss of Bmal1 impairs the diurnal rhythm in sodium excretion that parallels the loss of circadian blood pressure rhythm

High salt intake correlates with elevated levels of blood pressure, leading to an increased risk of cardiovascular disease. Abnormal diurnal rhythm in sodium excretion is often found in patients that exhibit non‐dipping of blood pressure. Our recent findings suggest that high salt diet alters clock gene expression patterns. The current study was designed to test the hypothesis that the circadian gene Bmal1 regulates diurnal electrolyte excretion and blood pressure in response to different levels of dietary salt. We utilized Bmal1 knockout (Bmal1KO) (n=6) and wildtype (WT) mice in metabolic cages under normal (0.4%) and high salt (4%) diets and collected urine during active (lights‐off) and inactive (lights‐on) phases. We found that urinary sodium excretion in WT mice was higher during the active phase and lower during the inactive phase in response to normal or high salt diet (normal salt: 41±4μEq/12h vs. 21±5μEq/12h; high salt: 490±50μEq/12h vs. 100±20μEq/12h). Interestingly, in Bmal1KO mice the difference in sodium excretion was not significant between active and inactive phases (normal salt: 20±5μEq/12h vs. 11±4μEq/12h; high salt: 173±35μEq/12h vs. 101±19μEq/12h), indicating loss of diurnal Na+ excretion patterns. Similarly, we found that in WT mice, urinary potassium excretion was higher in the active phase and lower in the inactive phase (normal salt: 85±10μEq/12h vs. 29±12μEq/12h; high salt: 146±9μEq/12h vs. 74±8μEq/12h); however, Bmal1KO mice showed a similar potassium excretion pattern in active and inactive phases under normal salt diet, and an even higher urinary potassium in the inactive phase when challenged with high salt (23±4μEq/12h vs. 38±6μEq/12h). Finally, Bmal1KO mice exhibited a loss of diurnal blood pressure (measured by telemetry) rhythm on both diets. These data suggest that Bmal1 is important for maintaining the diurnal pattern in sodium excretion that mirrors the loss of circadian blood pressure rhythm.

Ambulatory Blood Pressure Monitoring in Individuals with HIV: A Systematic Review and Meta-Analysis.

IntroductionAbnormal diurnal blood pressure (BP) rhythms may contribute to the high cardiovascular disease risk in HIV-positive (HIV+) individuals. To synthesize the current literature on ambulatory BP monitoring (ABPM) in HIV+ individuals, a systematic literature review and meta-analysis were performed.MethodsMedical databases were searched through November 11, 2015 for studies that reported ABPM results in HIV+ individuals. Data were extracted by 2 reviewers and pooled differences between HIV+ and HIV-negative (HIV-) individuals in clinic BP and ABPM measures were calculated using random-effects inverse variance weighted models.ResultsOf 597 abstracts reviewed, 8 studies with HIV+ cohorts met the inclusion criteria. The 420 HIV+ and 714 HIV- individuals in 7 studies with HIV- comparison groups were pooled for analyses. The pooled absolute nocturnal systolic and diastolic BP declines were 3.16% (95% confidence interval [CI]: 1.13%, 5.20%) and 2.92% (95% CI: 1.64%, 4.19%) less, respectively, in HIV+ versus HIV- individuals. The pooled odds ratio for non-dipping systolic BP (nocturnal systolic BP decline <10%) in HIV+ versus HIV- individuals was 2.72 (95% CI: 1.92, 3.85). Differences in mean clinic, 24-hour, daytime, or nighttime BP were not statistically significant. I2 and heterogeneity chi-squared statistics indicated the presence of high heterogeneity for all outcomes except percent DBP dipping and non-dipping SBP pattern.ConclusionsAn abnormal diurnal BP pattern may be more common among HIV+ versus HIV- individuals. However, results were heterogeneous for most BP measures, suggesting more research in this area is needed.

Effect of nonsteroidal anti-inflammatory drugs on the indicators of cardiovascular risk in patients with acute nonspecific back pain

To evaluate the safety of etoricoxib in patients with acute nonspecific back pain associated with the high risk of cardiovascular events (CVE) in clinical practice. The open prospective follow-up by a simple randomization method included 80 patients, including 49 women and 31 men (mean 60.8±4.7 years). The patients were randomized into 4 groups of 20 persons each: 1) etoricoxib 90 mg/day; 2) nimesulide 100 mg/day; 3) diclofenac 100 mg/day; 4) meloxicam 15 mg/day. The investigation lasted 90±4.5 days. The interim evaluation criteria (study points) were pain changes using a visual analog scale (VAS); blood pressure (BP) changes; diurnal BP rhythm; and changes in coagulation hemostatic parameters and blood biochemical markers. The primary evaluation criteria (study endpoints) were the incidence of CVE in the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The patients with acute back pain were shown to have a high incidence of comorbidities during outpatient care. The administration of NSAIDs resulted in a significant reduction in the magnitude and intensity of pain syndrome according to VAS in all the groups just on day 3 of therapy with a more marked analgesia in patients receiving etoricoxib and diclofenac. All the groups exhibited an increase in average daily systolic and diastolic BP with the most favorable profile in Group 1 patients. The intake of etoricoxib and other NSAIDs provided no evidence for changes in hemostatic parameters and biochemical markers during 10 weeks. The safety of etoricoxib was comparable with that of NSAIDs in its effect on the plasma hemostatic system. Unlike nimesulide, diclofenac, and meloxicam, etoricoxib was characterized by a rapid steady-state analgesic effect with a less pronounced action on diurnal BP rhythm. Within 3 months after treatment, no acute CVE was recorded in the patients taking etoricoxib.

The effect of melatonin on circadian blood pressure in patients with type 2 diabetes and essential hypertension.

IntroductionThe aim of this study was to evaluate the effect of melatonin on blood pressure in patients with essential hypertension receiving medical treatment and with type 2 diabetes in good metabolic control.Material and methodsThe study lasted 8 weeks. Patients were equipped with a 24-hour ambulatory blood pressure monitor and took melatonin (3 mg a day in the evening) for 4 weeks. The patients were divided into four groups: group 1 (n = 32) including dippers, group 2 (n = 34) non-dippers treated with melatonin; and two control groups: group 3 (n = 28) including dippers and group 4 (n = 30) non-dippers treated without melatonin. After 4 weeks patients took melatonin for the next 4 weeks (5 mg a day). In each visit were analyzed: systolic, diastolic and mean blood pressure in both day and night time.ResultsWe observed that 29.5% non-dippers (n = 10) treated with melatonin in a dose of 3 mg/day achieved features of dippers compared to control group (p < 0.05). Five mg of melatonin per day restored normal diurnal blood pressure rhythm in 32.4% non-dippers (n = 11, p < 0.05). In non-dippers treated with melatonin significant decreases of diastolic, systolic and mean night blood pressure values (p < 0.05) were observed.ConclusionsMore than 30% of non-dippers with type 2 diabetes treated with melatonin were restored to the normal circadian rhythm of blood pressure. The effect of melatonin in both doses (3 mg and 5 mg) was significant for non-dippers only and included nocturnal systolic, diastolic and mean arterial pressure.