Arsenic Exposure-Related Hypertension in Bangladesh and Reduced Circulating Nitric Oxide Bioavailability.

BACKGROUND: Hypertension is a major cause of death worldwide. Although arsenic exposure has been associated with the risk of hypertension, this association appears nonuniform due to inconsistent results from studies conducted in different populations. Moreover, hypertension is a complex condition with multiple underlying mechanisms and factors. One factor is impaired production and bioavailability of vascular nitric oxide (NO). However, the implications of the effects of arsenic exposure on circulating NO and its association with hypertension in humans are largely unknown. OBJECTIVE: We investigated the dose-response relationship between arsenic exposure and hypertension with vascular NO levels as a potential mediator of arsenic-related hypertension in individuals exposed to a broad range of arsenic. METHODS: A total of 828 participants were recruited from low- and high-arsenic exposure areas in Bangladesh. Participants' drinking water, hair, and nail arsenic concentrations were measured by inductively coupled plasma mass spectroscopy. Hypertension was defined as a systolic blood pressure (SBP) value of ≥140 and a diastolic (DBP) value of ≥90 mmHg. Serum NO levels reflected by total serum nitrite concentrations were measured by immunoassay. A formal causal mediation analysis was used to assess NO as a mediator of the association between arsenic level and hypertension. RESULTS: Increasing concentrations of arsenic measured in drinking water, hair, and nails were associated with the increasing levels of SBP and DBP. The odds of hypertension were dose-dependently increased by arsenic even in participants exposed to relatively low to moderate levels (10-50µg/L) of water arsenic [odds ratios (ORs) and 95% confidence intervals (CIs): 2.87 (95% CI: 1.28, 6.44), 2.67 (95% CI: 1.27, 5.60), and 5.04 (95% CI: 2.71, 9.35) for the 10-50µg/L, 50.01-150µg/L, and >150µg/L groups, respectively]. Causal mediation analysis showed a significant mediating effect of NO on arsenic-related SBP, DBP, and hypertension. CONCLUSION: Increasing exposure to arsenic was associated with increasing odds of hypertension. The association was mediated through the reduction of vascular NO bioavailability, suggesting that impaired NO bioavailability was a plausible underlying mechanism of arsenic-induced hypertension in this Bangladeshi population. https://doi.org/10.1289/EHP13018.

Tonic action of endothelin type B and dopamine D3 receptors in spontaneously hypertensive and deoxycorticosterone acetate-salt hypertensive rats: effects of intrarenally applied selective antagonists.

Endothelins and renal dopamine contribute to control of renal function and arterial pressure in health and various forms of experimental hypertension, the action is mediated by tonic activity of specific receptors. We determined the action mediated by endothelin type B and by dopamine D3 receptors (ETB-R, D3-R) in anaesthetized spontaneously hypertensive (SHR) and in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In rats of both hypertension models infused during 60 min into the interstitium of in situ kidney were either ETB-R antagonist, BQ788 (0.67 mg kg-1 BW h-1) or D3-R antagonist, GR103691 (0.2 mg kg-1 BW h-1). Arterial pressure (MAP), renal artery blood flow (RBF, transonic probe) and renal medullary blood flow (MBF, laser-Doppler) were measured along with sodium, water and total solute excretion (UNaV, V, UosmV). Experiments with ETB-R blockade confirmed their tonic vasodilator action in the whole kidney (RBF) and medulla (MBF) in both hypertension models. In SHR only, the first evidence was provided that ETB-R specifically increases transtubular backflux of non-electrolyte solutes. In DOCA-salt rats ETB-R blockade caused an early decrease in water and salt transport whereas an increase was often reported from many previous studies. The most striking effect of D3-R blockade in SHR was a selective increase in MBF, which strongly suggested tonic vasoconstrictor action of these receptors in the renal medulla; this speaks against prevailing opinion that D3 receptors are virtually inactive in SHR. In our model variant of DOCA-salt rats of D3-R blockade clearly caused a rapid major increase in MAP in parallel with depression of renal haemodynamics.

Prescribing cascades of antigout medications from thiazide diuretics in gout-naïve hypertensive adults receiving first-line pharmacological management.

Prescribing cascade is a significant clinical problem but is often overlooked. We explore the incidence of the prescribing cascades of antigout medications related to thiazide treatment in gout-naïve hypertensive adults newly exposed to the pharmacological treatment. This population-based, retrospective cohort study used the Taiwan National Health Insurance Registry Database. Gout-naïve hypertensive adults who were newly dispensed first-line antihypertensive drugs between January 1, 2000, and December 31, 2016, were enrolled. Patients were divided into the thiazide group (n = 4192) and the non-thiazide group (n = 81,083). The non-thiazide group included patients who received an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blocker, or beta-blocker. The study utilized propensity score matching and multivariable Cox regression models to investigate the prescribing cascade of antigout agents following antihypertensive treatment, adjusting for factors like age, sex, comorbidities, and concurrent medications. After propensity score matching, each group consisted of 4045 patients, with the thiazide group exhibiting a higher risk of being prescribed antigout medications across different time intervals post-treatment initiation. Specifically, adjusted hazard ratios (aHRs) for the thiazide group were 2.23, 2.07, and 2.41 for < 30 days, 31-180 days, and > 180 days, respectively, indicating a sustained and significant risk over time. Comparative analyses revealed thiazide diuretics were associated with a higher risk of antigout medication prescriptions compared to other antihypertensive classes, particularly evident after 180 days. Subgroup analyses across various demographics and comorbidities consistently showed an increased risk in the thiazide cohort. Gout-naïve hypertensive adults newly dispensed thiazide had a higher risk of subsequently adding antigout agents than those taking other first-line antihypertensive medications. The awareness and interruption of these prescribing cascades are critical to improving patient safety.

Phthalate exposure and blood pressure in U.S. children aged 8-17 years (NHANES 2013-2018).

BACKGROUND: Current evidence from epidemiologic studies suggested that phthalate metabolites might be associated with blood pressure (BP) changes. However, the special relationship between phthalate metabolites and BP changes in children has not been clearly elucidated in existing researches. OBJECTIVES: We investigated the links between phthalate metabolites and various BP parameters, including systolic/diastolic BP, mean arterial pressure (MAP), and the presence of hypertension. METHODS: The population sample consisted of 1036 children aged 8 to 17 years from the 2013-2018 NHANES in the United States. High performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to measure urinary concentrations of 19 phthalate metabolites. Systolic/diastolic BP were derived from the average of three valid measurements, and MAP was calculated as (systolic BP + 2 × diastolic BP)/3. Hypertension was defined as mean systolic BP and/or diastolic BP that was ≥ 95th percentile for gender, age, and height reference. Linear regression, logistic regression, and weighted quantile sum (WQS) regression models were employed to assess the associations between phthalate exposure and systolic/diastolic BP, MAP, and hypertension. RESULTS: Ten of 19 phthalate metabolites including MCNP, MCOP, MECPP, MBP, MCPP, MEP, MEHHP, MiBP, MEOHP, and MBzP had detection frequencies > 85% with samples more than 1000. MCNP, MCOP, MECPP, MBP, MCPP, MEHHP, MiBP, MEOHP, and MBzP were generally negatively associated with systolic/diastolic BP and MAP, but not protective factors for hypertension. These associations were not modified by age (8-12 and 13-17 years) or sex (boys and girls). The above-mentioned associations were further confirmed by the application of the WQS analysis, and MCOP was identified as the chemical with the highest weight. CONCLUSION: Phthalate metabolites were associated with modest reductions in systolic/diastolic BP, and MAP in children, while appeared not protective factors for hypertension. Given the inconsistent results among existing studies, our findings should be confirmed by other cohort studies.

Exploring the impact of prenatal perfluoroalkyl and polyfluoroalkyl substances exposure on blood pressure in early childhood: A longitudinal analysis.

Previous research investigating the correlation between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and subsequent blood pressure (BP) in offspring has yielded limited and contradictory findings. This study was conducted to investigate the potential relationship between maternal PFAS levels during pregnancy and subsequent BP in early childhood. A total of 129 expectant mothers from the Shanghai Birth Cohort were included in the study. Using high-performance liquid chromatography/tandem mass spectrometry, we measured ten PFAS compounds in maternal plasma throughout the pregnancy. When the children reached the age of 4, we examined their systolic BP (SBP) and diastolic BP (DBP), along with mean arterial pressure (MAP) and pulse pressure (PP). Data interpretation employed multiple linear and logistic regression models, complemented by Bayesian kernel machine regression (BKMR).We found that the majority of PFAS concentrations remained stable during pregnancy. The linear and BKMR models indicated a positive relationship between the PFAS mixture in maternal plasma and offspring's DBP and MAP, with perfluorohexanesulphonic acid (PFHxS) having the most significant influence (PFHxS and DBP [first trimester:ß=3.03, 95%CI: (1.01,5.05); second trimester: ß=2.35, 95%CI: (0.94,3.75); third trimester: ß=2.57, 95%CI:(0.80,4.34)]; MAP [first trimester:ß=2.55, 95%CI: (0.64,4.45); second trimester: ß=2.28, 95%CI: (0.95,3.61); third trimester: ß=2.35, 95%CI:(0.68,4.01)]). Logistic regression highlighted an increased risk of prehypertension and hypertension in offspring with higher maternal PFHxS concentrations during all three trimesters [first trimester: OR=2.53, 95%CI:(1.11,5.79), second trimester: OR=2.05, 95%CI:(1.11,3.78), third trimester: OR=3.08, 95%CI:(1.40,6.79)]. A positive correlation was identified between the half-lives of PFAS and the odds ratio (OR) of prehypertension and hypertension in childhood (ß=0.139, P=0.010). In conclusion, this research found maternal plasma PFAS concentrations to be positively associated with BP in offspring, with PFHxS showing the most significant influence. This correlation remained consistent throughout pregnancy, and this effect was proportional to the half-lives of PFAS.

Date (Phoenix dactylifera L. Mill) fruit enhances sexual performance via modulation of oxido-inflammatory mediators and purinergic signaling in hypertensive male rats.

INTRODUCTION: The present study aimed at investigating the effect of dietary supplementation of Phoenix dactylifera, an important component of aphrodisiac supplements, on sexual performance, oxido-inflammatory mediators and purinergic signaling system in hypertensive rats. MATERIAL AND METHODS: Hypertension was induced via oral administration of 40 mg/kg L-NAME. Thereafter, the sexual performance of the experimental animals was determined and the hypertensive rats with impaired sexual activities were placed on P. dactylifera-supplemented diet for 21 days, and the effects of the treatment on the overall sexual behavior, antioxidant status, oxido-inflammatory biomarkers, and enzyme activity of the purinergic system were assessed. RESULTS: Hypertensive rats showed a significant (p < 0.05) decrease in sexual performance, elevated level of oxido-inflammatory mediators, and altered purinergic enzymes activity when compared with the control. However, sub-chronic feeding with P. dactylifera-supplemented diet improved sexual performance, significantly lowered oxido-inflammatory biomarkers, and enhanced the activity of purinergic enzymes in hypertensive rats. CONCLUSION: Findings presented in this study suggest that dietary inclusion of P. dactylifera could be useful in managing erectile dysfunction (ED) commonly observed in subjects with hypertension. Findings highlighted in this study thus provide the scientific basis supporting the folkloric use of P. dactylifera as a key ingredient in aphrodisiac supplements.

Joint effects of air pollution and neighborhood socioeconomic status on cognitive decline - Mediation by depression, high cholesterol levels, and high blood pressure.

Air pollution and neighborhood socioeconomic status (N-SES) are associated with adverse cardiovascular health and neuropsychiatric functioning in older adults. This study examines the degree to which the joint effects of air pollution and N-SES on the cognitive decline are mediated by high cholesterol levels, high blood pressure (HBP), and depression. In the Emory Healthy Aging Study, 14,390 participants aged 50+ years from Metro Atlanta, GA, were assessed for subjective cognitive decline using the cognitive function instrument (CFI). Information on the prior diagnosis of high cholesterol, HBP, and depression was collected through the Health History Questionnaire. Participants' census tracts were assigned 3-year average concentrations of 12 air pollutants and 16 N-SES characteristics. We used the unsupervised clustering algorithm Self-Organizing Maps (SOM) to create 6 exposure clusters based on the joint distribution of air pollution and N-SES in each census tract. Linear regression analysis was used to estimate the effects of the SOM cluster indicator on CFI, adjusting for age, race/ethnicity, education, and neighborhood residential stability. The proportion of the association mediated by high cholesterol levels, HBP, and depression was calculated by comparing the total and direct effects of SOM clusters on CFI. Depression mediated up to 87 % of the association between SOM clusters and CFI. For example, participants living in the high N-SES and high air pollution cluster had CFI scores 0.05 (95 %-CI:0.01,0.09) points higher on average compared to those from the high N-SES and low air pollution cluster; after adjusting for depression, this association was attenuated to 0.01 (95 %-CI:-0.04,0.05). HBP mediated up to 8 % of the association between SOM clusters and CFI and high cholesterol up to 5 %. Air pollution and N-SES associated cognitive decline was partially mediated by depression. Only a small portion (<10 %) of the association was mediated by HBP and high cholesterol.

Characterization of Diclofenac-induced Renal Damage in Normotensive and Hypertensive Rats: A Comparative Analysis.

BACKGROUND: Diclofenac is the non-steroidal anti-inflammatory drug (NSAID) mostly prescribed worldwide, but it is highly associated with hypertension and acute kidney injury. Despite that, little information is available about the renal effects of diclofenac in hypertensive individuals, which led us to carry out this comparative study between the renal effects of this NSAID in normotensive (NTR) and spontaneously hypertensive rats (SHR). METHODS: Male Wistar NTR and SHR were orally treated with vehicle (V: 10 mL/kg) or diclofenac sodium (D: 100 mg/kg) once a day for 3 days. Urine volume, electrolytes excretion (Na+, K+, Cl-, and Ca2+), urea, creatinine, pH, and osmolarity were evaluated. Furthermore, blood samples and renal tissue were collected to perform biochemical and histological analysis. RESULTS: Diclofenac increased the renal corpuscle and bowman's space in the SHR, while no microscopic changes were observed in the renal tissue of NTR. Regarding the urinary parameters, diclofenac reduced urine volume, pH, osmolarity, and all electrolytes excretion, followed by decreased urea and creatinine levels in both lineages. Moreover, it also induced hyponatremia, hypokalemia, and hypocalcemia in SHR, while reduced glutathione-S-transferase activity, lipid hydroperoxides, and nitrite levels in renal tissue. CONCLUSIONS: The data presented herein demonstrated that diclofenac induces renal damage and impaired renal function in both NTR and SHR, but those effects are exacerbated in SHR, as seen by the histological changes and electrolytes balance disturbance, therefore, reinforcing that diclofenac may increase the risks of cardiovascular events in hypertensive patients.

Air pollution, APOE genotype and risk of dementia among individuals with cardiovascular diseases: A population-based longitudinal study.

Individuals with cardiovascular disease (CVD) are particularly vulnerable to dementia, but it remains unclear whether air pollution exposure links with higher risk of dementia among those with CVD. The data were derived from the UK Biobank study (UKB). Dementia-free participants with CVD at baseline were included. Air pollution exposure was assessed through land use regression models, including particulate matter (PM2.5, PM2.5-10, and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOX). A Cox proportional hazards model was used to investigate the associations between air pollution exposure and incident dementia among individuals with CVD. Air pollution was associated with dementia among individuals with CVD, and the hazard ratios of dementia associated with each interquartile range (IQR) µg/m3 increase in air pollution were 1.07 (95% CI: 1.02, 1.12) for PM2.5, 1.10 (95% CI: 1.04, 1.15) for PM10, 1.08 (95% CI: 1.03, 1.14) for NO2 and 1.05 (95% CI: 1.00, 1.09) for NOx. Associations between air pollution and all-cause dementia were found to be significant among individuals with hypertension. Adverse effects of air pollution were also observed for Alzheimer's dementia (AD) and vascular dementia (VaD), with a higher effect for AD. Observed associations remained similar in subgroups of APOE ε4 carriers and noncarriers, although there was a higher risk difference across different air pollution concentration among these individuals carrying APOE ε4. Air pollution emerges as a critical risk factor for dementia among individuals with CVD, regardless of genetic susceptibility indicated by the APOE genotype. Notably, individuals with hypertension might be susceptible to the adverse effects of air pollution, leading to a higher incidence of dementia. Understanding these impacts on dementia among individuals with CVD may promote better targeted prevention and clinical management strategies.

Personalized Antihypertensive Treatment Optimization With Smartphone-Enabled Remote Precision Dosing of Amlodipine During the COVID-19 Pandemic (PERSONAL-CovidBP Trial).

BACKGROUND: The objective of the PERSONAL-CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID-19 Pandemic) trial was to assess the efficacy and safety of smartphone-enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID-19 pandemic. METHODS AND RESULTS: This was an open-label, remote, dose titration trial using daily home self-monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5-7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10-12)/7 (95% CI, 6-7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events. CONCLUSIONS: Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App-assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long-term care. REGISTRATION: URL: clinicaltrials.gov. Identifier: NCT04559074.

Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE.

BACKGROUND: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions. METHODS: We performed post-hoc analyses to evaluate the association in 3124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n = 346) and SBP ≥ 180 mmHg (hypertensive crisis) (n = 69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis. RESULTS: Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10-9; OR = 5.2). CONCLUSION: Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity.

Sex- and Gender-Based Reporting in Antihypertensive Medication Literature Informing Hypertension Guidelines.

BACKGROUND: Hypertension is the leading modifiable cardiovascular risk factor with recognized sex- and gender-based differences. We assessed the incorporation of sex and gender reporting in the antihypertensive medication literature informing hypertension guidelines. METHODS AND RESULTS: Literature cited in the International Society of Hypertension (2020), European Society of Cardiology/European Society of Hypertension (2018), American College of Cardiology/American Heart Association (2017), Latin American Society of Hypertension (2017), Pan-African Society of Cardiology (2020), and Hypertension Canada (2020) guidelines was systematically reviewed. Observational studies, randomized controlled trials, and systematic reviews involving antihypertensive medications were included. Studies with participants of a single sex, guidelines, and commentaries were excluded. Data on study participation-to-prevalence ratio by sex, analysis of baseline demographics and study outcomes by sex, and stratification of adverse events by sex were extracted. Of 1659 unique citations, 331 studies met inclusion criteria. Of those, 81% reported the sex of participants, and 22% reported a male-to-female participation-to-prevalence ratio of 0.8 to 1.2. Three percent of studies stratified baseline characteristics by sex, and 20% considered sex during analysis through statistical adjustment or stratification. Although 32% of studies reported adverse events, only 0.6% stratified adverse events by sex. Most (58%) studies reporting sex/gender used sex and gender terms interchangeably. CONCLUSIONS: Incorporation of sex- and gender-based considerations in study population, analysis, or reporting of results and adverse events is not common in the antihypertensive medication literature informing international hypertension guidelines. Greater attention to sex- and gender-based factors in research is required to optimally inform management of hypertension.

Immune-related cardiovascular toxicities of PD-1/PD-L1 inhibitors in solid tumors: an updated systematic review and meta-analysis.

Purpose: The objective of this study was to investigate the risk of cardiovascular toxicities related to PD-1/PD-L1 inhibitors in solid tumors. Methods: A literature search was performed following the participants, interventions, comparisons, outcomes, and study design (PICOS) principles, and the study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analysis was conducted using Review Manager version 5.4. Results: This meta-analysis included 69 randomized controlled trials (RCTs) divided into five groups based on the treatment regimens: PD-1/PD-L1 + chemotherapy versus chemotherapy, PD-1/PD-L1 versus chemotherapy, PD-1/PD-L1 versus placebo, PD-1/PD-L1 + CTLA-4 versus PD-1/PD-L1 and PD-1/PD-L1 + CTLA-4 versus chemotherapy. Compared to chemotherapy treatment alone, PD-1/PD-L1 +chemotherapy significantly increased the risk of hypertension [all-grade (OR = 1.27, 95% CI [1.05, 1.53], p = 0.01); grade 3-5 (OR = 1.36, 95% CI [1.04, 1.79], p = 0.03)], hypotension [all-grade (OR = 2.03, 95% CI [1.19, 3.45], p = 0.009); grade 3-5 (OR = 3.60, 95% CI [1.22, 10.60], p = 0.02)], arrhythmia [all-grade (OR = 1.53, 95% CI [1.02, 2.30], p = 0.04); grade 3-5 (OR = 2.91, 95% CI [1.33, 6.39], p = 0.008)] and myocarditis [all-grade (OR = 2.42, 95% CI [1.06, 5.54], p = 0.04)]. The risk of all-grade hypotension (OR = 2.87, 95% CI [1.26, 6.55], p = 0.01) and all-grade arrhythmia (OR = 2.03, 95% CI [1.13, 3.64], p = 0.02) significantly increased when treated with PD-1/PD-L1 inhibitors compared to the placebo. The risks of cardiovascular toxicities are significantly higher with PD-1+CTLA-4 compared to PD-1 alone (OR = 2.02, 95% CI [1.12, 3.66], p = 0.02). Conclusion: PD-1/PD-L1 inhibitor leads to an increased risk of cardiovascular toxicities, especially hypertension, hypotension, arrhythmia, and myocarditis.

Causal Relationship Between Branched-Chain Amino Acids and Hypertension: A Mendelian Randomization Study.

BACKGROUND: This study aimed to investigate the causal relationships between branched-chain amino acids (BCAAs) and the risks of hypertension via meta-analysis and Mendelian randomization analysis. METHODS AND RESULTS: A meta-analysis of 32 845 subjects was conducted to evaluate the relationships between BCAAs and hypertension. In Mendelian randomization analysis, independent single-nucleotide polymorphisms associated with BCAAs at the genome-wide significance level were selected as the instrumental variables. Meanwhile, the summary-level data for essential hypertension and secondary hypertension end points were obtained from the FinnGen study. As suggested by the meta-analysis results, elevated BCAA levels were associated with a higher risk of hypertension (isoleucine: summary odds ratio, 1.26 [95% CI, 1.08-1.47]; leucine: summary odds ratio, 1.28 [95% CI, 1.07-1.52]; valine: summary odds ratio, 1.32 [95% CI, 1.12-1.57]). Moreover, the inverse variance-weighted method demonstrated that an elevated circulating isoleucine level might be the causal risk factor for essential hypertension but not secondary hypertension (essential hypertension: odds ratio, 1.22 [95% CI, 1.12-1.34]; secondary hypertension: odds ratio, 0.96 [95% CI, 0.54-1.68]). CONCLUSIONS: The increased levels of 3 BCAAs positively correlated with an increased risk of hypertension. Particularly, elevated isoleucine level is a causal risk factor for essential hypertension. Increased levels of leucine and valine also tend to increase the risk of essential hypertension, but further verification is still warranted.

Central Artery Hemodynamics in Angiotensin II-Induced Hypertension and Effects of Anesthesia.

Systemic hypertension is a strong risk factor for cardiovascular, neurovascular, and renovascular diseases. Central artery stiffness is both an initiator and indicator of hypertension, thus revealing a critical relationship between the wall mechanics and hemodynamics. Mice have emerged as a critical animal model for studying effects of hypertension and much has been learned. Regardless of the specific mouse model, data on changes in cardiac function and hemodynamics are necessarily measured under anesthesia. Here, we present a new experimental-computational workflow to estimate awake cardiovascular conditions from anesthetized data, which was then used to quantify effects of chronic angiotensin II-induced hypertension relative to normotension in wild-type mice. We found that isoflurane anesthesia had a greater impact on depressing hemodynamics in angiotensin II-infused mice than in controls, which led to unexpected results when comparing anesthetized results between the two groups of mice. Through comparison of the awake simulations, however, in vivo relevant effects of angiotensin II-infusion on global and regional vascular structure, properties, and hemodynamics were found to be qualitatively consistent with expectations. Specifically, we found an increased in vivo vascular stiffness in the descending thoracic aorta and suprarenal abdominal aorta, leading to increases in pulse pressure in the distal aorta. These insights allow characterization of the impact of regionally varying vascular remodeling on hemodynamics and mouse-to-mouse variations due to induced hypertension.

Effects of allisartan-isoproxil-based combination antihypertensive regimen in hypertensive patients with microalbuminuria or hyperuricemia.

Microalbuminuria and hyperuricemia management are crucial for the integrated management of hypertensive patients. This retrospective post hoc analysis aims to evaluate the optimal allisartan-isoproxil-based combination regimen for hypertensive patients with microalbuminuria or hyperuricemia. A total of 460 hypertensive patients with microalbuminuria and 486 hypertensive patients with hyperuricemia were included in this study. All patients were initially treated with allisartan-isoproxil for 4 weeks. Thereafter, patients with blood pressure (BP) < 140/90 mmHg continued the monotherapy for 8 weeks; patients with BP ≥140/90 mmHg were randomly assigned in a 1:1 ratio to receive allisartan-isoproxil + amlodipine (Group A + C) or allisartan-isoproxil + indapamide (Group A + D) for 8 weeks. The changes of BP, urinary albumin and serum uric acid (UA) were measured. In patients with microalbuminuria, the urinary albumin/creatinine ratio (UACR) significantly decreased by 10.4 mg/g in Group A + C (vs. baseline p = .0035) and 24.2 mg/g in Group A + D (vs baseline p < .0001), intergroup p = NS. In patients with hyperuricemia, serum UA level decreased by 44.5 µmol/L in Group A + C (vs. baseline p = .0003), but increased by 27.2 µmol/L in Group A + D (vs. baseline p = .0167), intergroup p < .0001. The results suggest that for hypertensive patients with microalbuminuria, angiotensin receptor blocker (ARB) + calcium channel blocker (CCB) or ARB+ diuretic both are good choices based on their improvement of microalbuminuria and BP. But for patients with hyperuricemia, ARB + diuretic may further increase the level of UA.

Case report: a unique presentation of memantine overdose causing echolalia and hypertension.

BACKGROUND: Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023. CASE PRESENTATION: Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation. CONCLUSIONS: Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.

Soybean-derived antihypertensive hydrolysates attenuate Ang II-induced renal damage by modulating MAPK and NF-κB signaling pathways.

Hypertension-induced kidney injury is considered a vital consequence of long-term and uncontrolled hypertension, which is commonly associated with an excessive accumulation of angiotensin II (Ang II) from hyperactivated RAS. Antihypertensive peptides have a significant effect on blood pressure regulation, but few studies have focused on the ameliorative function of antihypertensive peptides on renal injury. This study explored the effects of soybean protein-derived hydrolysate (SPH) on SHR and Ang II-induced HK-2 cells. SPH significantly attenuated blood pressure and alleviated renal pathological injury in SHRs after oral gavage administration. According to the pathological results, the kidneys of SHRs showed inflammation and SPH attenuated inflammatory cell infiltration in the kidneys of SHRs. Immunohistochemical analysis further revealed that SPH inhibited MCP-1 expression and increased Nrf2 expression in the kidneys. An in vitro HK-2 cell model demonstrated that SPH exhibited optimal activity for reducing Ang II-induced inflammatory cytokines and ROS overproduction. Mechanistically, SPH was observed to regulate MAPK/JNK and NF-κB signaling pathways. These findings indicate that potent antihypertensive SPH significantly ameliorates hypertension-induced kidney damage.

First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors.

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy. RESULTS: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours. CONCLUSIONS: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.

Efficacy and safety of Ciprofol compared with Propofol during general anesthesia induction: A systematic review and meta-analysis of randomized controlled trials (RCT).

BACKGROUND: Ciprofol, a newer entrant with similarities to propofol, has shown promise with a potentially improved safety profile, making it an attractive alternative for induction of general anesthesia. This meta-analysis aimed to assess the safety and efficacy of ciprofol compared with propofol during general anesthesia induction. METHODS: A comprehensive literature search was conducted using PubMed, Clinical Trial.gov, and Cochrane Library databases from inception to July 2023 to identify relevant studies. All statistical analyses were conducted using R statistical software version 4.1.2. RESULTS: Thirteen Randomized Controlled Trials (RCTs) encompassing a total of 1998 participants, were included in our analysis. The pooled analysis indicated that Ciprofol was associated with a notably lower incidence of pain upon injection [RR: 0.15; 95% CI: 0.10 to 0.23; I^2 = 43%, p < 0.0000001] and was non-inferior to propofol in terms of anesthesia success rate [RR: 1.00; 95% CI: 0.99 to 1.01; I^2 = 0%; p = 0.43]. In terms of safety, the incidence of hypotension was significantly lower in the ciprofol group [RR:0.82; 95% CI:0.68 to 0.98; I^2 = 48%; p = 0.03]. However, no statistically significant differences were found for postoperative hypertension, bradycardia, or tachycardia. CONCLUSION: In conclusion, Ciprofol is not inferior to Propofol in terms of its effectiveness in general anesthesia. Ciprofol emerges as a valuable alternative sedative with fewer side effects, especially reduced injection pain, when compared to Propofol. SUMMARY: Propofol, frequently utilized as an anesthetic, provides swift onset and quick recovery. However, it has drawbacks such as a narrow effective dosage range and a high occurrence of adverse effects, particularly pain upon injection. Ciprofol, a more recent drug with propofol-like properties, has demonstrated promise and may have an improved safety profile, making it a compelling alternative for inducing general anesthesia. This meta-analysis compared the safety and effectiveness of Ciprofol with Propofol for general anesthesia induction in a range of medical procedures, encompassing thirteen Randomized Controlled Trials (RCTs) and 1998 individuals. The pooled analysis indicated that Ciprofol was associated with a notably lower incidence of pain upon injection [RR: 0.15; 95% CI: 0.10 to 0.23; I^2 = 43%, p < 0.0000001] and was non-inferior to propofol in terms of anesthesia success rate [RR: 1.00; 95% CI: 0.99 to 1.01; I^2 = 0%; p = 0.43]. In terms of safety, the incidence of hypotension was significantly lower in the ciprofol group [RR:0.82; 95% CI:0.68 to 0.98; I^2 = 48%; p = 0.03]. However, no statistically significant differences were found for hypertension, bradycardia, or tachycardia. In conclusion, ciprofol is equally effective at inducing and maintaining general anesthesia as propofol. When compared to propofol, ciprofol is a better alternative sedative for operations including fiberoptic bronchoscopy, gynecological procedures, gastrointestinal endoscopic procedures, and elective surgeries because it has less adverse effects, most notably less painful injections.