Non-dipping Hypertension Research Articles

Could soluble ST2 levels be used to detect nondipper hypertensive subgroup in newly diagnosed hypertension patients.

ST2 receptor is a member of toll-like/interleukin-1 receptor family. After the activation of IL-33/ST2 signaling pathway clinically detectable amount of soluble form of ST2 (sST2) is released into the circulation. Previous studies showed that sST2 levels were significantly higher in hypertension patients than in controls. In this prospective study, we aimed to analyze this relation and test the predictive accuracy of the sST2 level in diagnosis of nondipping hypertension in newly diagnosed hypertension patients. Three hundred thirty-seven patients (150 normal, 187 hypertension) who presented with symptoms of hypertension were included in the study. All patients underwent 24-h ambulatory blood pressure monitoring and sST2 measurement. Of 187 hypertension patients, 92 of them had nondipping and 95 of them had dipping pattern. sST2 level was significantly higher in nondipping group compared to dipping group and control group (40.79 ± 7.77 vs. 32.47 ± 6.68; P < 0.0001 and 40.79 ± 7.77 vs. 20.09 ± 7.09; P < 0.0001 respectively). Binary logistic regression analysis revealed that; only sST2 level was an independent risk factor for hypertension [P < 0.0001, β: 1.258, odds ratio (OR) (95% confidence interval (CI)): 1.158-1.366]. and also nondipping hypertension [P < 0.0001, β: 1.208, OR (95% CI): 1.108-1.317]. Based on the present study it could be concluded that sST2 level is significantly associated with the newly diagnosed hypertension and nondipping hypertension. Hence it could reliably be used to diagnose hypertension and nondipping hypertension with high sensitivity and specificity.

The Role of bHLH Transcription Factor Bmal2 in Arterial Endothelial Circadian Rhythms and Remodeling: Sex Dependent Effects in Mice\r

Cardiovascular disease remains the number one cause of mortality in humans (Murphy, Kochanek, Xu, &amp; Arias, 2020). An important influence in the progression of artery disease is the long-term effect of disruptions in daily patterns or circadian rhythms. Not sleeping well at night and daytime sleepiness both associate with cardiovascular disease. In addition, a cardiovascular system that does not rest well at night is also bad. A blood pressure reading that does not decrease at night, called non-dipping hypertension, worsens cardiovascular disease. One important impact of broken rhythms is to cause disease in arteries. Thus, understanding the mechanisms that control 24-hour daily patterns is important. One key component gene of circadian rhythm is the transcription factor Bmal1. Vascular disease is a progression that begins as an adaptation to hypertension, diabetes, and hypercholesterolemia, whereby blood vessels change their structure in response to these changes in the bloodstream through a process called vascular remodeling. Remodeling is a process whereby arteries, arterioles, and even veins change their size and cellular structure (muscularity). Using mouse models of genetic disruption, our lab previously found that Bmal1 has an important role to control vascular remodeling, and when Bmal1 was disrupted, a vascular disease phenotype occurred. The lab also found that the endothelial cell layer of arteries contributes to the disease in Bmal1 knockout (KO) mice. These observations seemed the same in both males and females, thus, were sex independent. Bmal2, is a paralog of Bmal1. Bmal2 interacts with Bmal1 and is more selectively expressed in the endothelium. However, the role of Bmal2 in remodeling is not clear. To understand the role of Bmal2 in vascular disease, I have implemented a widely used experimental animal model of arterial ligation to induce vascular remodeling. I have ligated the left common carotid artery (LC) in two groups of mice, control wild-type (WT) mice (no genetic mutation) and the experimental Bmal2-KO (global knockout) mice. After two weeks, I isolated the LC and fixed the arteries in optimal cutting temperature (O.C.T.) compound and conducted histological processing (cut cross sections with a cryotome and staining with hematoxylin and eosin). I then quantified the changes in structure in the artery using the ImageJ program on digitized microscope images. My findings show that inward remodeling and wall-hypertrophy in male Bmal2- KO mice are similar to wild-type mice. The inward remodeling observed in the male WT and male Bmal2-KO mice is consistent with the normal response of what has been observed in this ligation model, inward accompanied by wall hypertrophy. However, I saw something different in the female Bmal2-KO mice undergoing the ligation for two weeks. Female Bmal2-KO mice exhibited robust inward remodeling that was accompanied by intimal hyperplasia. My data suggest that there are sex-specific differences in remodeling controlled by Bmal2.

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

ABSTRACT 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.

High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet.

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.

Association between international index of erectile function-5 scores and circadian patterns of newly diagnosed hypertension in erectile dysfunction patients.

By the beginning of this study in 2019, it was known that hypertension is a risk factor for erectile dysfunction, and also, there are circadian changes that occur in blood pressure. Further, non-dipping hypertension is known to be linked to poor cardiac outcomes and erectile functions, so the research described in this article was initiated with an aim to explore the potential relationship between erectile dysfunction and circadian patterns of newly diagnosed hypertension. Between April 2019 and May 2022, 583 patients aged 30-70 years were diagnosed with erectile dysfunction (ED) in our outpatient clinic. Applying our exclusion criteria to 583 patients, a group of 371 patients left with us; these patients were referred to the cardiology clinic for hypertension evaluation with consecutive ambulatory blood pressure monitoring (ABPM). Data were collected for the study prospectively. Of the 371 patients evaluated with ABPM, 125 had newly diagnosed hypertension (mean BP ≥135/85 mmHg in ABPM). These patients were divided into two groups according to the pattern of hypertension identified in ABPM: dippers (Group D) and non-dippers (Group ND). They were then compared using clinical and laboratory findings, including erectile function scores. While the number of patients in the ND group was 83, the number in the D group was 42. In the ND group, the mean age was higher (59 ± 10 vs. 54 ± 12, p=0.0024). IIEF-5 (international index of erectile function) scores were determined to be significantly lower in the ND group (14.4± 4.9 vs. 11.5± 4.6, p=0.001). Also, serum creatinine levels were higher in Group ND than in D (0.96± 0.12 vs. 1 ± 0.15, p=0.001). In our multivariate analysis, IIEF-5 scores (OR: 0.880, 95% CI: 0.811-0.955; p=0.002) and serum creatinine levels (OR: 1027, 95% CI: 1003-1052; p=0.025) were found to be independent risk factors of non-dipper HT. The cut-off value of the IIEF-5 score for non-dipper HT in a ROC curve analysis was 13.5 with 64.3% sensitivity and 66.1% specificity (area under curve value: 0.673 [95% CI: 0.573-0.772, p < 0.001]). This study showed that, in patients with ED, the non-dipper pattern was associated with poorer erectile function when HT was newly diagnosed. We also found that the severity of erectile dysfunction is an independent marker for non-dipper HT.

Effect of dipping and nondipping pattern of blood pressure on subclinical left ventricular dysfunction assessed by two-dimensional speckle tracking in hypertensive patients.

The aim of this study was to evaluate the left ventricular (LV) function by conventional two-dimensional speckle tracking echocardiography (2D STE) to detect subclinical LV systolic dysfunction in patients with dipper and nondipper hypertension. One hundred consecutive patients with hypertension were included in our study. Clinical evaluation, baseline laboratory investigations, 24 ambulatory blood pressure monitoring 2D echocardiographic examination and 2D STE were performed for all patients. Patients were classified as dippers and nondippers according to their nighttime MAP (mean arterial blood pressure) reduction rate of ≥10 or <10%, respectively. Of 100 patients, 71% were nondippers while 29% were dippers. Nondippers had a significantly lower global longitudinal strain (LS) value (-22.45 ± 3.26 vs. -18.2 ± 3.3, P < 0.001), global circumferential strain (CS) value (-24.23 ± 3.56 vs. -19.16 ± 8.25, P < 0.001) and global radial strain (RS) value (35.04 ± 11.16 vs. 29.58 ± 8.44, P = 0.009). It was found that nondipper status was associated with worsening of LS by 2.737, (P = 0.001), CS by 3.446, (P = 0.002), RS by -3.256, (P = 0.158) and DM also was found associated with worsening of LS by 1.849, (P = 0.062), CS by 3.284 (P = 0.018), RS by -2.499 (P = 0.381). The nondipping hypertension pattern is associated with subclinical LV systolic dysfunction as shown by the impaired global myocardial strain in all three directions.

Combination of Valsartan and Melatonin to Treat Non-Dipping Hypertension Rats via Circadian Clock System

Combination of Valsartan and Melatonin to Treat Non-Dipping Hypertension Rats via Circadian Clock System

Circadian Clock Factor PER1 is involved in Crosstalk between the Kidney and Adrenal Glands

Introduction Circadian clock proteins are transcription factors that play critical roles in the regulation of blood pressure, renal function, and hormone levels. Previously, we published that male mice with global knockout (KO) of the clock protein PER1 develop non-dipping hypertension in response to a high salt diet plus the mineralocorticoid DOCP (HSDOCP). HSDOCP treatment is a clinically relevant model of salt-sensitive hypertension. Global PER1 KO mice also exhibit inappropriately increased levels of aldosterone (Aldo) and decreased night:day ratio of urinary sodium (Na) excretion in response to HSDOCP. The objective of the present study was to examine the role of the kidney in PER1-mediated regulation of renal Na handling and Aldo levels. Hypothesis Kidney-specific KO of PER1 (KsPER1 KO) results in altered Aldo levels and decreased night:day rhythms of Na excretion in response to HSDOCP. Methods Ksp-cadherin Cre was used to generate KsPer1 KO mice. KO occurs in the distal nephron and collecting duct. KsPER1 KO (Cre +) mice were compared to control (CNTL) (Cre-) mice (all male; 2.5 months old). Baseline urine collections and plasma were collected on a normal salt diet (NS) and compared to similar samples collected after 3 days HS diet, followed by 3 days of HSDOCP treatment. Total RNA was isolated from adrenal glands (noon) for qPCR analysis. Results In contrast to global PER1 KO mice, the KsPER1 KO mice exhibited normal night:day urine Na excretion. However, KsPER1 KO mice exhibited increased Na retention vs CNTL (3.7 vs 2.7mEq, P<0.01). In response to HSDOCP, plasma Na significantly increased in KsPER1 KO (158 vs 164mM, P<0.05), but not in CNTL mice. HSDOCP treatment suppressed plasma Aldo in all mice, but KsPER1 KO mice displayed increased plasma Aldo vs. CNTL mice on both NS and HSDOCP treatment (NS: 21 vs. 12; HSDOCP: 4 vs. 2 pg/mL/gBW, P<0.01). Adrenal gland expression of the Aldo synthase gene, CYP11B2, was higher in KsPER1 KO vs CNTL (38%, P<0.05). Conclusions These results suggest that PER1 exerts kidney-specific action on renal Na handling independent of night:day effects. PER1 appears to be required for proper crosstalk between the kidney and adrenal gland to manage Aldo levels in response to HSDOCP. Given the prevalence of salt-sensitive hypertension in the general population, these findings have important implications for our understanding of how circadian clock proteins regulate homeostasis.

HIV-positive demonstrate more salt sensitivity and nocturnal non-dipping blood pressure than HIV-negative individuals

BackgroundHigh dietary salt and a lack of reduced blood pressure (BP) at night (non-dipping) are risk factors for the development of hypertension which may result in end-organ damage and death. The effect of high dietary salt on BP in black people of sub-Saharan Africa living with HIV is not well established. The goal of this study was to explore the associations between salt sensitivity and nocturnal blood pressure dipping according to HIV and hypertension status in a cohort of adult Zambian population.MethodsWe conducted an interventional study among 43 HIV-positive and 42 HIV-negative adults matched for age and sex. Study participants were instructed to consume a low (4 g) dietary salt intake for a week followed by high (9 g) dietary salt intake for a week. Salt resistance and salt sensitivity were defined by a mean arterial pressure difference of ≤5 mmHg and ≥ 8 mmHg, respectively, between the last day of low and high dietary salt intervention. Nocturnal dipping was defined as a 10–15% decrease in night-time blood pressure measured with an ambulatory blood pressure monitor.ResultsThe median age was 40 years for both the HIV-positive and the HIV-negative group with 1:1 male to female ratio. HIV positive individuals with hypertension exhibited a higher BP sensitivity to salt (95%) and non-dipping BP (86%) prevalence compared with the HIV negative hypertensive (71 and 67%), HIV positive (10 and 24%) and HIV-negative normotensive (29 and 52%) groups, respectively (p < 0.05). Salt sensitivity was associated with non-dipping BP and hypertension in both the HIV-positive and HIV-negative groups even after adjustment in multivariate logistic regression (< 0.001).ConclusionsThe results of the present study suggest that high dietary salt intake raises blood pressure and worsens nocturnal BP dipping to a greater extent in hypertensive than normotensive individuals and that hypertensive individuals have higher dietary salt intake than their normotensive counterparts. Regarding HIV status, BP of HIV-positive hypertensive patients may be more sensitive to salt intake and demonstrate more non-dipping pattern compared to HIV-negative hypertensive group. However, further studies with a larger sample size are required to validate this.

Effect of short-term exposure to indoor particulate matter on noctunal blood pressure dipping among hypertensive adults in ibadan: a pilot study

Abstract Introduction While blunted nocturnal blood pressure is a major risk factor for cardiovascular events, limited information exist on the association between indoor particulate and circadian blood pressure variation. We report the association of short-time exposure to PM2.5 and PM10 with blunted nocturnal blood pressure among hypertensive adults in Ibadan. Purpose This study was to determine the association between short time exposure to air particulates and blunted nocturnal blood pressure among people of African descent. Methods We conducted a cross-sectional study among fifty hypertensive cases attending our University College Hospital. A 24-hours blood pressure (BP) monitoring was carried out at the same time as indoor particulate matter monitoring in their homes. Exposure to indoor fine particles (PM2.5) and thoracic particles (PM10) was estimated using a real-time particle counter and compared to the World Health Organization (WHO) 24-hours threshold of 25 μg/m3 and 50 μg/m3 for PM2.5 and PM10 respectively. All monitoring was carried out over a 24-hours period during the wet season. Linear regression model was fitted to determine predictors of non-dipping hypertension. Results Of the 50 hypertensive patients studied, 5 (10.0%), 39 (78.0%), 6 (12.0%) were reverse dippers, non-dippers and dippers respectively. The mean indoor PM2.5 (44.17±19.18 μg/m3) and PM10 (60.10±27.13 μg/m3) among the non-dippers were significantly higher than values obtained among dippers (PM2.5 = 22.97±10.19 μg/m3; PM10 = 29.51±12.74 μg/m3); p&amp;lt;0.0001, and the WHO threshold limit. More non-dippers than dippers (54.5% vs 37.8%) used unimproved fuel such as firewood for cooking. PM10 was an independent predictors of non-dipping status in our regression analysis. Conclusion Short-term exposure to indoor PM air pollution was associated with blunted nocturnal blood pressure. Therefore air pollution reduction strategies through improved cooking pattern is advocated in order to prevent future cardiovascular events. Funding Acknowledgement Type of funding source: None

Whole blood viscosity predicts nondipping circadian pattern in essential hypertension.

Aim: We aimed to investigate the association between whole blood viscosity (WBV) and nondipping pattern in patients with essential hypertension. Materials & methods: A total of consecutive 530 patients who had been evaluated by ambulatory blood pressure monitoring were included. WBV was estimated by using hematocritand plasma total protein levels for both WBV in low shear rate(0.5 s-1) and WBV in high shear rate(208 s-1) according to the de Simone's formula. Results: In the multivariate analysis, low shear rate and high shear rate of WBV were associated independently with nondipping pattern in patients with essential hypertension. Conclusion: As a simple, inexpensive andnoninvasive tool, WBV seems to be a significant predictor of nondipping hypertension.

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.

The circadian clock is disrupted in mice with adenine-induced tubulointerstitial nephropathy

Chronic Kidney Disease (CKD) is increasing in incidence and has become a worldwide health problem. Sleep disorders are prevalent in patients with CKD raising the possibility that these patients have a disorganized circadian timing system. Here, we examined the effect of adenine-induced tubulointerstitial nephropathy on the circadian system in mice. Compared to controls, adenine-treated mice showed serum biochemistry evidence of CKD as well as increased kidney expression of inflammation and fibrosis markers. Mice with CKD exhibited fragmented sleep behavior and locomotor activity, with lower degrees of cage activity compared to mice without CKD. On a molecular level, mice with CKD exhibited low amplitude rhythms in their central circadian clock as measured by bioluminescence in slices of the suprachiasmatic nucleus of PERIOD 2::LUCIFERASE mice. Whole animal imaging indicated that adenine treated mice also exhibited dampened oscillations in intact kidney, liver, and submandibular gland. Consistently, dampened circadian oscillations were observed in several circadian clock genes and clock-controlled genes in the kidney of the mice with CKD. Finally, mice with a genetically disrupted circadian clock (Clock mutants) were treated with adenine and compared to wild type control mice. The treatment evoked worse kidney damage as indicated by higher deposition of gelatinases (matrix metalloproteinase-2 and 9) and adenine metabolites in the kidney. Adenine also caused non-dipping hypertension and lower heart rate. Thus, our data indicate that central and peripheral circadian clocks are disrupted in the adenine-treated mice, and suggest that the disruption of the circadian clock accelerates CKD progression.

P3563The influence of circadian patterand obstructive sleep apnean of blood pressure in nocturnal arrhythmias in hypertensive patients

Abstract Introduction There is growing evidence suggesting hypertension is related to the occurrence of arrhythmias. When occurring predominantly during the night, two potential entities commonly present in hypertensive patients could be related with increased arrhythmogenesis: (1) the lack of normal nocturnal dipping of blood pressure (BP) (non-dipping pattern of hypertension) or (2) obstructive sleep apnea (OSA). Thus, nocturnal arrhythmias (NAs) can identify hypertensive patients with OSA and/or non-dipping pattern, both related with adverse outcomes. Aims To determine if NAs are related with non-dipping hypertension, OSA or both. Methods We studied hypertensive patients who performed ambulatory blood pressure monitoring (ABPM) and also polysomnography and 24-hour Holter monitoring. Non-dipping pattern was considered when nocturnal BP reduction was inferior to 10%. Based on Holter monitoring, NAs were present when atrial fibrillation, frequent premature atrial contractions (PACs) (&gt;30 PACs/hour), runs of &gt;4 consecutive PACs, frequent premature ventricular contractions (PVCs) (&gt;30PVCs/hour) or runs of &gt;4 consecutive PVCs were present predominantly during sleeping hours. During polyssonography, apnoea/hypopnoea index (AHI) and oxygen saturation (SaO2) were analysed. Moderate to severe OSA was considered when AHI &gt;15. Results We studied 104 patients [median age 62 (54–70) years, 65% male): 42 (40%) had moderate to severe OSA (median AHI=11 (6–26), mean SaO2=94% (92–95)] and 64 (61%) were non-dippers. NAs occurred in 18 patients (17%) and they were independently associated with AHI (Odds Ratio (OR) for a one unit increase 1.04, 95% confidence interval (CI) 1.01–1.07, p=0.03) but not with SaO2 (OR 0.96, CI 0.78–1.19, p=0.73) nor non-dipping pattern (OR 1.23, CI 0.38–3.98, p=0.72). No interaction was found between OSA and non-dipping hypertension (p=0.35). In patients with dipping pattern (n=40), AHI was higher in NAs patients comparing with no NAs patients (median AHI 29 versus 10, p=0.04), while in those with non-dipping pattern (n=64), AHI was not statistically different between patients with and without NAs (21 versus 11, p=0.12) (figure). Figure 1 Conclusion In this population of hypertensive patients, the presence of NAs was associated with OSA severity (i.e AHI), but not with the non-dipping pattern of hypertension. The importance of obstructive events in arrhythmogenesis seemed to be more pronounced in dipping patients, suggesting the abnormal high blood pressure during the night may also have some impact on NAs in non-dipping patients. Overall, our results suggest that OSA screening should be considered when nocturnal arrhythmias are detected in hypertensive patients, but ABPM should not be forgotten since multiple mechanisms can be involved in nocturnal arrhythmogenesis.

Determinants of the circadian blood pressure pattern in hospitalized hypertensive patients

Background. Non-dipping hypertension might be associated with increased cardiovascular risk and multiple diseases. The aim of our study was to assess if there are parameters identified in 24-hour ECG-Holter monitoring (ECG-Holter), transthoracic echocardiography (TTE), ECG parameters or laboratory data that allow prediction of circadian blood pressure profile (CBPP). Material and methods. One hundred and three consecutive patients (male: 50.5%), who underwent 24-hour ambulatory BP measurement and ECG-Holter simultaneously were analyzed. We divided patients into 3 groups: dipping was defined as 10–20% (28.2%), non-dipping as < 10% (50.5%) fall in nocturnal BP and reverse-dipping as higher nocturnal than diurnal BP (21.4%). Additionally, we performed TTE and laboratory check-up in all patients. We built multivariable models for nocturnal fall in systolic BP (SBP) and CBPP. Results. Multivariable model based on clinical factors was: nocturnal fall in SBP (%) = [13.28 – 0.11 × age – 8.33 × (dilated cardiomyopathy) – 5.95 × PAD – 6.02 × a-adrenolytic]. Multivariable model based on laboratory, echocardiographic and electrocardiographic parameters was: nocturnal fall in SBP (%) = [–27.28 + 1.47 × hemoglobin – 0.14 × CK-MB + 0.14 × maximal heart rate]. Multivariable model for CBPP based on clinical factors included use of beta- or alpha-adrenolytics or torasemide. Conclusions. We proved that nocturnal fall in SBP and CBPP could be predicted based on ECG-Holter parameters, laboratory data and TTE results, as well as based on detailed medical history. These findings may have implications on care of patients with hypertension.

The Effects of Nocturnal Blood Pressure Paterns and Autonomic Alterations on Erectile Functions in Patients with Hypertension.

Hypertension (HT) is known to be of the main risk factors for erectile dysfunction (ED). But non-dipping (<%10 drop in the night) of HT is not investigated truly. The aim of this study was to test the hypothesis that the non-dipper hypertensive patients are more prone to develop erectile dysfunction. This was a cross-sectional clinical study. 70 HT patients diagnosed by Ambulatory blood pressure monitoring (ABPM) were classified into 3 groups (No ED, mild to moderate and severe) according to their International Index of Erectile Function (IIEF) scores. All three groups were compared for their dipping status by ABPM, heart rate variability (HRV) by holter monitoring. In our study non-dipper hypertensives had statistically more erectile dysfunction (P=0.004). Also severe ED patients with non-dipping pattern had decreased dipping blood pressure levels then those of ED(-) patients with non-dipping HT (P= .003)(Daytime Systolic/Nighttime Diastolic Blood Pressure= 0.8 ± 0.07 / 3.90 ± 1.5, respectively). LF/HF daytime/ nighttime in holter reflecting sympathetic overactivity (P< .001). Autonomic dysfunction especially sympathetic overactivity is associated with both non dipping pattern of HT and erectile dysfunction as a common pathologic pathway, besides there might be an association between ED and non dipping HT.

Characterization of gene expression in adrenal glands of mice lacking the circadian clock protein PER1

The circadian clock regulates a variety of physiological responses throughout a 24‐hour period. At a molecular level, the clock is governed by four core transcription factors, including PER1 and CRY, which are found in every cell in the human body. All reported circadian clock gene KO mice have a blood pressure (BP) phenotype. Aldosterone, a mineralocorticoid hormone and product of the renin‐angiotensin‐aldosterone system (RAAS), is secreted by the adrenal cortex and leads to increased sodium reabsorption by the kidneys in response to low BP or low blood volume. Previously we reported that 129/sv mice lacking the circadian clock gene Per1 had reduced BP and reduced plasma aldosterone levels associated with decreased expression of HSD3B1, a key enzyme in the steroid hormone synthesis pathway. Conversely, we found that male C57BL/6 Per1 KO mice have higher BP than control mice and develop non‐dipping hypertension (a lack of dip in BP during the rest period) on a high salt diet plus mineralocorticoid treatment. Non‐dipping hypertension has been associated with an increased risk for cardiovascular disease in humans. Interestingly, female Per1 KO mice do not develop non‐dipping hypertension on a high salt diet plus mineralocorticoid treatment. The goal of this study was to determine if expression of genes involved in the aldosterone synthesis pathway is altered in C57BL/6 Per1 KO mice. These deviances could explain the BP phenotype observed at the physiological level in male mice. We obtained adrenal glands from male and female WT and Per1 KO mice at noon (midpoint of the mouse rest phase), the same time at which serum was collected for aldosterone measurements. RNA was isolated from these tissues, converted to cDNA, and mRNA levels of genes involved in circadian rhythm and aldosterone synthesis were measured by quantitative real time PCR (qPCR). Preliminary data show that Cry1 is significantly down‐regulated in female Per1 KO mice by about 50% versus WT (n=5/6 per group, p&lt;0.05). Expression of aldosterone synthesis genes CYP11B and HSD3B1 did not appear to be significantly altered in the adrenal tissue of male or female Per1 KO mice compared to WT. In contrast to what was observed with 129/sv Per1 KO, plasma aldosterone levels did not differ between C57BL/6 Per1 KO vs. WT. The observed difference in Cry1 expression suggests that RAAS and the circadian clock may work together in the maintenance of homeostatic BP. In the future we expect to perform similar experiments using male and female WT and Per1 KO mice adrenal tissue collected at a midnight time point in order to further investigate the communication occurring at the molecular level between RAAS and the circadian clock.Support or Funding InformationNIH/NIDDK 1R01DK109570; The Gatorade Trust through the UF Department of MedicineThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Female C57BL/6J mice lacking the circadian clock protein PER1 are protected from nondipping hypertension.

The circadian clock is integral to the maintenance of daily rhythms of many physiological outputs, including blood pressure. Our laboratory has previously demonstrated the importance of the clock protein period 1 (PER1) in blood pressure regulation in male mice. Briefly, a high-salt diet (HS; 4% NaCl) plus injection with the long-acting mineralocorticoid deoxycorticosterone pivalate (DOCP) resulted in nondipping hypertension [<10% difference between night and day blood pressure (BP) in Per1-knockout (KO) mice but not in wild-type (WT) mice]. To date, there have been no studies that have examined the effect of a core circadian gene KO on BP rhythms in female mice. The goal of the present study was to determine whether female Per1-KO mice develop nondipping hypertension in response to HS/DOCP treatment. For the first time, we demonstrate that loss of the circadian clock protein PER1 in female mice does not significantly change mean arterial pressure (MAP) or the BP rhythm relative to female C57BL/6 WT control mice. Both WT and Per1-KO female mice experienced a significant increase in MAP in response to HS/DOCP. Importantly, however, both genotypes maintained a >10% dip in BP on HS/DOCP. This effect is distinct from the nondipping hypertension seen in male Per1-KO mice, demonstrating that the female sex appears to be protective against PER1-mediated nondipping hypertension in response to HS/DOCP. Together, these data suggest that PER1 acts in a sex-dependent manner in the regulation of cardiovascular rhythms.

Renal Na-handling defect associated with PER1-dependent nondipping hypertension in male mice

Many physiological functions have a circadian rhythm, including blood pressure (BP). BP is highest during the active phase, whereas during the rest period, BP dips 10-20%. Patients that do not experience this dip at night are termed "nondippers." Nondipping hypertension is associated with increased risk of cardiovascular disease. The mechanisms underlying nondipping hypertension are not understood. Without the circadian clock gene Per1, C57BL/6J mice develop nondipping hypertension on a high-salt diet plus mineralocorticoid treatment (HS/DOCP). Our laboratory has shown that PER1 regulates expression of several genes related to sodium (Na) transport in the kidney, including epithelial Na channel (ENaC) and Na chloride cotransporter (NCC). Urinary Na excretion also demonstrates a circadian pattern with a peak during active periods. We hypothesized that PER1 contributes to circadian regulation of BP via a renal Na-handling-dependent mechanism. Na-handling genes from the distal nephron were inappropriately regulated in KO mice on HS/DOCP. Additionally, the night/day ratio of Na urinary excretion by Per1 KO mice is decreased compared with WT (4 × vs. 7×, P < 0.001, n = 6 per group). Distal nephron-specific Per1 KO mice also show an inappropriate increase in expression of Na transporter genes αENaC and NCC. These results support the hypothesis that PER1 mediates control of circadian BP rhythms via the regulation of distal nephron Na transport genes. These findings have implications for the understanding of the etiology of nondipping hypertension and the subsequent development of novel therapies for this dangerous pathophysiological condition.

Associations of dipping and non-dipping hypertension with cardiovascular diseases in patients with dyslipidemia.

IntroductionDyslipidemia combined with hypertension increases the risk of cardiovascular disease (CVD). The current study aimed to investigate the association of dipping and non-dipping hypertension with CVD in patients with dyslipidemia.Material and methodsA total of 243 documented dyslipidemia patients with hypertension were enrolled. Clinical characteristics and clinic and 24-hour blood pressure (BP) parameters were compared between dipping and non-dipping groups based on 24-hour ambulatory blood pressure monitoring. Logistic regression analysis was performed to evaluate the association of dipping and non-dipping hypertension with CVD.ResultsCompared to the dipping group, patients in the non-dipping group were older, more likely to be male and smokers, had higher serum creatinine levels, and were more likely to have chronic kidney disease and CVD (p < 0.05 for all comparisons). No significant between-group differences in clinic systolic and diastolic BP (SBP and DBP) were observed. However, compared to the dipping group, 24-hour SBP, nighttime SBP and DBP, and night-day ratio of SBP and DBP were all significantly higher in the non-dipping group (p < 0.05 for all comparisons). In the dipping group, only night-day ratio of SBP was significantly associated with CVD, with an odds ratio (OR) of 1.09 (95% confidence interval (CI) of 1.02–1.34). In the non-dipping group, both night-day ratio of SBP and DBP were significantly associated with CVD, with an OR of 1.72 (95% CI: 1.33–2.06) and 1.23 (95% CI: 1.05–1.66), respectively.ConclusionsIn patients with dyslipidemia, non-dipping hypertension is more closely related to CVD compared to dipping hypertension.