Unveiling Selected Influences on Chronic Kidney Disease Development and Progression.

Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood pressure, the pH of blood, and the water-electrolyte balance and by eliminating unnecessary metabolic waste products from blood. What is more, this disease does not show any specific symptoms at the beginning. The development of CKD is predisposed by certain conditions, such as diabetes mellitus or hypertension. However, these disorders are not the only factors promoting the onset and progression of CKD. The primary purpose of this review is to examine renin-angiotensin-aldosterone system (RAAS) activity, transforming growth factor-ß1 (TGF-ß1), vascular calcification (VC), uremic toxins, and hypertension in the context of their impact on the occurrence and the course of CKD. We firmly believe that a deeper comprehension of the cellular and molecular mechanisms underlying CKD can lead to an enhanced understanding of the disease. In the future, this may result in the development of medications targeting specific mechanisms involved in the decline of kidney function. Our paper unveils the selected processes responsible for the deterioration of renal filtration abilities.

The association between the urinary chromium and blood pressure: a population-based study.

BACKGROUND AND AIM: The impact of trace elements and heavy metals on human health has attracted widespread attention. However, the correlation between urinary chromium concentrations and blood pressure remains unclear and inadequately reported, and the aim of this study was to investigate the relationship between urinary chromium concentrations and blood pressure in adults in the United States (US). METHODS: We utilized data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 for this study. Multivariate logistic regression and multivariate linear regression were used to explore the association of urinary chromium concentrations with hypertension and blood pressure. Additionally, we also performed subgroup analysis and restricted cubic splines (RCS). RESULTS: A total of 2958 participants were enrolled in this study. The overall mean systolic blood pressure and diastolic blood pressure were 123.98 ± 0.60, 72.66 ± 0.57 mmHg, respectively. The prevalence of hypertension was found in 41.31% of the whole participants. In the fully adjusted model, we did not observe a correlation between urinary chromium concentrations and the risk of hypertension and systolic blood pressure. However, we found a negative association between urinary chromium concentrations and diastolic blood pressure. In subgroup analysis, we observed a positive association between urinary chromium and the risk of hypertension among participants older than 60 years of age and those who were Non-Hispanic Black. The interaction term highlighted the influence of age and race on this positive association. We also found a negative association of urinary chromium with diastolic blood pressure in male, participants who were current smokers, overweight, and other races, as well as those without alcohol use and anti-hypertensive drug use. However, the interaction term only revealed the influence of alcohol consumption on the negative association. CONCLUSION: Our study suggested that urinary chromium concentrations may show a negative association with diastolic blood pressure and this association was significantly dependent on alcohol consumption. Besides, a positive association between urinary chromium and the risk of hypertension was also found among participants older than 60 years of age and those who were Non-Hispanic Black.

Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment.

BACKGROUND: Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. OBJECTIVE: This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. METHODS: We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). RESULTS: Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21-0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20-0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25-0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11-4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03-4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15-0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). CONCLUSION: We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

Features of The Dynamics of Profibrotic Markers and Regression of Left Ventricular Hypertrophy After Renal Denervation in Patients With Resistant Hypertension and Stenosing Atherosclerosis of the Coronary Arteries.

AIM: To compare the changes in serum concentrations of matrix metalloproteinases (MMPs) and their tissue inhibitor (TIMP) to the dynamics of blood pressure (BP) and parameters of left ventricular hypertrophy (LVH) 6 months after renal denervation (RD) in patients with resistant arterial hypertension (RAH) and complicated coronary atherosclerosis. MATERIAL AND METHODS: In 22 RAH patients with complicated coronary atherosclerosis (revascularization and/or history of myocardial infarction (MI)), 24-hour BP monitoring, echocardiography, and measurement of blood MMPs and TIMP were performed at baseline and six months after RD. The comparison group consisted of 48 RAH patients without a history of coronary revascularization or MI. RESULTS: In 6 months after RD, BP was decreased comparably in both groups. In the group of complicated atherosclerosis, there were no significant changes in profibrotic markers or LVH parameters. Thus, at baseline and after 6 months, the values of the studied indicators were the following: left ventricular myocardial mass (LVMM) 233.1±48.1 and 243.0±52.0 g, LVMM index 60.6±14.5 and 62.8±10 .9 g/m2.7, proMMP-1 4.9 [2.1; 7.7] and 3.6 [2.0; 9.4]  ng/ml, MMP-2 290.4 [233.1; 352.5] and 352.2 [277.4; 402.9] ng/ml, MMP-9 220.6 [126.9; 476.7] and 263.5 [82.9; 726.2] ng/ml, TIMP-1 395.7 [124.7; 591.4] and 424.2 [118.2; 572.0] ng/ml, respectively. In the comparison group, on the contrary, there was a significant decrease in LVMM from 273.6±83.3 g to 254.1±70.4 g, LVMM index from 67.1±12.3 to 64.0±14.4 g/m2.7, proMMP-1 from 7.2 [3.6; 11.7] to 5.9 [3.5; 10.9] ng/ml, MMP-2 from 328.9 [257.1; 378.1] to 272.8 [230.2; 343.2] ng/ml, MMP-9 from 277.9 [137.0; 524.0] to 85.5 [34.2; 225.9] ng/ml, and the MMP-9/TIMP-1 ratio from 0.80 [0.31; 1.30] to 0.24 [0.07; 0.76]. The BP dynamics in this group was inversely correlated with MMP-2 at 6 months (r=-0.38), and the MMP-9/TIMP-1 ratio was correlated with LVMM and the LVMM index at baseline (r=0.39 and r=0.39) and at 6 months (r=0.37 and r=0.32). The change in TIMP-1 from 543.9 [277.5; 674.1] to 469.8 [289.7; 643.6] ng/ml was not significant (p=0.060). CONCLUSION: In RAH patients with complicated coronary atherosclerosis, the dynamics of profibrotic biomarkers and LVH parameters after RD was absent despite the pronounced antihypertensive effect, probably due to the low reversibility of cardiovascular remodeling processes or more complex regulatory mechanisms of the MMP system.

[Features of the Course of Arterial Hypertension in the Era of the COVID-19 Pandemic: Common Pathogenetic Links Between Hypertension and SARS-CoV-2].

The aim of this review was to present the mechanism of infection with severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) and its possible effect on the course of arterial hypertension. Another aim was to evaluate the relationship of the renin-angiotensin-aldosterone system with the pathogenetic stages of infection caused by SARS-CoV-2 virus.

[Changing Concepts About Optimal Target Blood Pressure and the Therapeutic Advantages of Azilsartan for Achieving it].

The article discusses current issues of the treatment of arterial hypertension. According to presented data, so-called therapeutic nihilism is becoming one of the main barriers to achieving target blood pressure (BP). This nihilism is that despite evidence of the effectiveness of achieving lower BP values, practitioners do not intensify antihypertensive therapy sufficiently to achieve such values. The article specially addresses new criteria for the effectiveness of antihypertensive therapy, which reflect the therapy sustainability. The most commonly used indicator is the duration of the period, during which systolic BP remains in the therapeutic range. The prognostic significance of such indicators is discussed. In these conditions, it is very important to use the most effective antihypertensive drugs for initial antihypertensive therapy, including as a part of combination therapy. This tactic provides more frequent achievement of BP goals without the need for dose adjustment. In this regard, a systematic review was performed, which included sufficiently large randomized studies of the antihypertensive effectiveness of azilsartan medoxomil. This systematic review will provide comprehensive information on a possible role of using the angiotensin II receptor blocker azilsartan as a basic drug for the treatment of a wide range of patients with high BP. Most of the studies included in the systematic review assessed the effectiveness of combination therapy including azilsartan.

Association between pulse pressure and carotid plaques in old adults with uncontrolled hypertension: results from a community-based screening in Hangzhou, China.

BACKGROUND: There is a broad pulse pressure (PP) and a high prevalence of carotid plaques in old adults. Previous studies have indicated that PP is strongly associated with carotid plaque formation. This study aimed to explore this association in old adults with uncontrolled hypertension. METHODS: 1371 hypertensive patients aged ≥ 60 years with uncontrolled hypertension were enrolled in a community-based screening in Hangzhou, China. Carotid plaques were assessed using ultrasonography. Logistic regression models were used to estimate the association between PP and carotid plaques by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Carotid plaques were detected in 639 (46.6%) of subjects. Multiple plaques were found in 408 (63.8%) and soft plaques in 218 (34.1%). Elevated PP was associated with a high prevalence of carotid plaques. After adjusting for traditional risk factors, compared to patients within the lowest tertile of PP, those within the highest tertiles had an increased risk of carotid plaques (OR 2.061, CI 1.547-2.745). For each 1-SD increase, the risk increased by 40.1% (OR 1.401, CI 1.237-1.587). There was a nonlinear association between PP and carotid plaques (P nonlinearity = 0.039). The risk increased rapidly after the predicted PP level reached around 60 mmHg. The associations were stronger among participants with multiple and soft plaques. CONCLUSIONS: Our findings suggested that PP was independently associated with carotid plaques in old adults with uncontrolled hypertension who have an increased risk of atherosclerosis.

Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers.

Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to ß-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1- phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD- and BB-induced vasodilatation. These findings may improve our understanding of the BP-lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP-lowering effects from these drugs.

Evaluation of blood pressure variation in recovered COVID-19 patients at one-year follow-up: a retrospective cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has various sequelae, one of which might be hypertension. We aimed to evaluate COVID-19's impact on blood pressure (BP) in non-hospitalized patients at one-year follow-up. METHOD: A total of 7,950 consecutive COVID-19 patients regularly visiting our cardiology clinic were retrospectively screened. Patients' electronic medical records including demographics, comorbidities, vital signs, treatments, and outcomes, were reviewed by two physicians. Individuals with at least one BP measurement in the three months preceding COVID-19 and one measurement in 12 months or more following recovery were included. BP levels before and after COVID-19 were compared using the paired t-test. RESULTS: 5,355 confirmed COVID-19 patients (mean age 55.51 ± 15.38 years) were included. Hypertension (56.9%) and diabetes mellitus (34%) were the predominant comorbidities, and 44.3% had prior major adverse cardiovascular events. Both systolic (126.90 ± 20.91 vs. 139.99 ± 23.94 mmHg, P < 0.001) and diastolic BP (80.54 ± 13.94 vs. 86.49 ± 14.40 mmHg, P < 0.001) were significantly higher post-COVID-19 vs. pre-COVID-19. Notably, 456 (14%) hypertensive patients experienced exacerbated hypertension, while 408 (17%) patients developed new-onset hypertension, overall 864 (16%) of patients had exacerbation or new hypertension. Linear regression analysis revealed that advanced age, smoking, previous cardiovascular events, hypertension, and diabetes mellitus predict increased BP following COVID-19 (P < 0.001). CONCLUSION: COVID-19 raised systolic and diastolic BP in the long term in non-hospitalized patients, with over one-sixth developing new-onset or exacerbated hypertension. All patients should be evaluated regarding BP, following COVID-19 recovery, particularly those with the mentioned predictive factors. (clinicaltrial.gov: NCT05798208).

Relationship between visit-to-visit blood pressure variability and depressive mood in Korean primary care patients.

BACKGROUND: High blood pressure variability (BPV) increases the risk of cardiovascular disease and may be better prognostic factor than blood pressure. Depressive mood is a common symptom among patients visiting primary care. This study aimed to investigate the association between depressive mood and high BPV among Korean primary care patients. METHODS: The Family Cohort Study in Primary Care (FACTS), conducted from April 2009 to November 2017, utilized a prospective cohort of Korean primary care patients, with a median follow-up period of 7.25 years. Depressive mood was assessed as a score of 21 points or more on the Korean-type Center for Epidemiologic Studies Depression scale. BP was measured at the initial visit and first and second follow-up visit. Visit-to visit SBP variability was analyzed using four metrics: intra-individual standard deviation, coefficient of variation, variation independent of mean, and average real variability. Logistic regression analysis was used to estimate the association of high BPV with depressive mood and other variables. RESULTS: Among 371 participants, 43 (11.6%) had depressive mood based on depression scores. Older age (odds ratio [OR]: 1.04, 95% confidence interval [CI]: 1.01-1.07) were associated with high SBP variability regardless of taking antihypertensive medication. Among participants taking antihypertensive medication, those with depressive mood had twice the risk of high SBP variability compared with those who did not (OR: 2.95, 95% CI: 1.06-8.20). CONCLUSIONS: Depressive mood was associated with high visit-to-visit SBP variability in primary care patients taking antihypertensive medication, potentially indicating increased cardiovascular risk. Primary care physicians should therefore closely monitor BPV in patients with depressive symptoms and provide appropriate interventions.

Association between intensity of physical activity and cognitive function in hypertensive patients: a case-control study.

Previous studies have shown that a higher intensity of physical activity (PA) is associated with a lower risk of cognitive impairment (CI), whereas hypertension is associated with higher CI. However, there are few studies on the association between PA intensity and cognitive function in hypertensive patients. This study investigated the association between PA intensity and cognitive function in hypertensive patients. A total of 2035 hypertensive patients were included in this study, including 407 hypertensive patients with CI and 1628 hypertensive patients with normal cognitive function matched 1:4 by age and sex. The International Physical Activity Questionnaire-Long Form and the Mini-mental State Examination were used to evaluate PA intensity, total metabolic equivalents, and cognitive function in patients with hypertension. Multivariate logistic regression was used to analyze the correlation between PA intensity and CI in hypertensive patients. The Spearman correlation coefficient was used to analyze the correlation between PA intensity and the total score of each component of the MMSE and the correlation between PA total metabolic equivalents and cardiac structure in hypertensive patients. After adjusting for all confounding factors, PA intensity was negatively associated with CI in hypertensive patients (OR = 0.608, 95% CI: 0.447-0.776, P < 0.001), and this association was also observed in hypertensive patients with education level of primary school and below and junior high school and above (OR = 0.732, 95% CI: 0.539-0.995, P = 0.047; OR = 0.412, 95% CI: 0.272-0.626, P < 0.001). The intensity of PA in hypertensive patients was positively correlated with orientation (r = 0.125, P < 0.001), memory (r = 0.052, P = 0.020), attention and numeracy (r = 0.151, P < 0.001), recall ability (r = 0.110, P < 0.001), and language ability (r = 0.144, P < 0.001). PA total metabolic equivalents in hypertensive patients were negatively correlated with RVEDD and LAD (r = - 0.048, P = 0.030; r = - 0.051, P = 0.020) and uncorrelated with LVEDD (r = 0.026, P = 0.233). Higher PA intensity reduced the incidence of CI in hypertensive patients. Therefore, hypertensive patients were advised to moderate their PA according to their circumstances.

Ideal cardiovascular health index and high-normal blood pressure in elderly people: evidence based on real-world data.

Limited information is available on the cardiovascular health (CVH) index and risk of high-normal blood pressure (HNBP) in elderly people. Randomized cluster sampling, multivariate logistic regression, and mediating effects analysis were used in this study analyze the relationship between CVH index and HNBP in the elderly. 1089 non-hypertensive residents aged 65 years or older completed the study. The positive rate of HNBP was 75.85% (male vs. female: 76.13% vs. 75.64%, P = 0.852); The ideal rate of CVH (ideal CVH index ≥ 5 items) was 14.51% (male vs. female: 15.91% vs. 13.46%, P = 0.256). Compared with people with 0-2 ideal CVH index, the risk of HNBP in people with 4 ideal indexes and ≥ 5 ideal indexes decreased by 50% and 63%, respectively, and their OR (95% CI) were 0.50 (0.31, 0.81) and 0.37 (0.21, 0.66), respectively. The results of the trend test showed that the risk of HNBP decreased by 32% for every increase in the ideal CVH index (trend P < 0.001) and TyG index does not play a mediating role in this relationship. That is, increasing the number of ideal CVH index may effectively reduce the risk of HNBP in elderly by one-third.

24-Hour Blood Pressure Variability Via Ambulatory Monitoring and Risk for Probable Dementia in the SPRINT Trial.

BACKGROUND: Blood pressure variability is an emerging risk factor for dementia, independent and oftentimes beyond mean blood pressure levels. Recent evidence from interventional cohorts with rigorously controlled mean blood pressure levels suggest blood pressure variability over months to years remains a risk for dementia, but no prior studies have investigated relationships with blood pressure variability over shorter time periods. OBJECTIVES: To investigate the potential effect of ambulatory blood pressure variability on the rate of cognitive outcomes under intensive vs standard blood pressure lowering. DESIGN: Post hoc analysis of the randomized, controlled, open-label Systolic Blood Pressure Intervention Trial clinical trial. SETTING: Multisite Systolic Blood Pressure Intervention Trial. PARTICIPANTS: 793 participants at increased risk for cardiovascular disease and without history of dementia at study randomization. INTERVENTION: Standard (<140 mmHg systolic blood pressure target) vs intensive (<120 mmHg systolic blood pressure target) lowering of mean blood pressure. MEASUREMENTS: 24-hour ambulatory blood pressure monitoring 27 months after treatment randomization (standard vs intensive) and follow-up cognitive testing. Intraindividual blood pressure variability was calculated as the average real variability over 24-hour, daytime, and nighttime periods. Participants were categorized into 3 adjudicated clinical outcomes: no cognitive impairment, mild cognitive impairment, probable dementia. Cox proportional hazards models examined the potential effect of ambulatory blood pressure variability on the rate of cognitive outcomes under intensive vs standard blood pressure lowering. Associations with mean blood pressure were also explored. RESULTS: Higher systolic 24-hour blood pressure variability was associated with increased risk for probable dementia in the standard group (adjusted hazard ratio [HR]: 2.56 [95% CI 1.16, 5.62], p = 0.019) but not in the intensive group (HR: 0.54 [95% CI 0.24, 1.23], p = 0.141). Similar findings were observed with daytime systolic blood pressure variability but not nighttime blood pressure variability. Mean blood pressure was not associated with cognitive outcomes. CONCLUSIONS: Higher systolic 24-hour and daytime blood pressure variability via ambulatory monitoring is associated with risk for dementia under standard blood pressure treatment. Findings support prior evidence that blood pressure variability remains a risk for dementia despite strict control of mean blood pressure levels.

Racial Disparities in Blood Pressure at Time of Acute Ischemic Stroke Presentation: A Population Study.

BACKGROUND: Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist. METHODS AND RESULTS: Adults with acute ischemic stroke presenting to an emergency department within 24 hours of last known normal during study epochs 2005, 2010, and 2015 within the Greater Cincinnati/Northern Kentucky Stroke Study were included. Demographics, histories, arrival BP, National Institutes of Health Stroke Scale score, and time from last known normal were collected. Multivariable linear regression was used to determine differences in mean BP between Black and White patients, adjusting for age, sex, National Institutes of Health Stroke Scale score, history of hypertension, hyperlipidemia, smoking, stroke, body mass index, and study epoch. Of 4048 patients, 853 Black and 3195 White patients were included. In adjusted analysis, Black patients had higher presenting systolic BP (161 mm Hg [95% CI, 159-164] versus 158 mm Hg [95% CI, 157-159], P<0.01), diastolic BP (86 mm Hg [95% CI, 85-88] versus 83 mm Hg [95% CI, 82-84], P<0.01), and mean arterial pressure (111 mm Hg [95% CI, 110-113] versus 108 mm Hg [95% CI, 107-109], P<0.01) compared with White patients. In adjusted subanalysis of patients <4.5 hours from last known normal, diastolic BP (88 mm Hg [95% CI, 86-90] versus 83 mm Hg [95% CI, 82-84], P<0.01) and mean arterial pressure (112 mm Hg [95% CI, 110-114] versus 108 mm Hg [95% CI, 107-109], P<0.01) were also higher in Black patients. CONCLUSIONS: This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.

Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension.

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.

Circulating angiotensin-(1-7) is decreased in patients with isolated nocturnal hypertension.

Isolated nocturnal hypertension (INHT), defined as nighttime elevated blood pressure (BP) with normal daytime BP assessed by ambulatory BP monitoring, is associated with higher cardiovascular morbidity and mortality. We hypothesized that an alteration in the circulating renin-angiotensin system (RAS) contributes to INHT development. We examined circulating levels of angiotensin (Ang) (1-7) and Ang II and ACE2 activity in 26 patients that met the INHT criteria, out of 50 that were referred for BP evaluation (62% women, 45 ±â€Š16 years old). Those with INHT were older, had a higher BMI, lower circulating Ang-(1-7) (P = 0.002) and Ang II levels (P = 0.02) and no change in ACE2 activity compared to those normotensives. Nighttime DBP was significantly correlated with Ang-(1-7) and Ang II levels. Logistic regression showed significant association in Ang-(1-7) and Ang II levels with INHT. Our study reveals differences in circulating RAS in individuals with INHT.

Salt Sensitivity of Blood Pressure.

The year 2024 marks the centennial of the initiation of the American Heart Association. Over the past 100 years, the American Heart Association has led groundbreaking discoveries in cardiovascular disease including salt sensitivity of blood pressure, which has been studied since the mid-1900s. Salt sensitivity of blood pressure is an important risk factor for cardiovascular events, but the phenotype remains unclear because of insufficient understanding of the underlying mechanisms and lack of feasible diagnostic tools. In honor of this centennial, we commemorate the initial discovery of salt sensitivity of blood pressure and chronicle the subsequent scientific discoveries and efforts to mitigate salt-induced cardiovascular disease with American Heart Association leading the way. We also highlight determinants of the pathophysiology of salt sensitivity of blood pressure in humans and recent developments in diagnostic methods and future prospects.