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Low dose-eplerenone treatment decreases aortic stiffness in patients with resistant hypertension.

ABSTRACT: Vascular damage is aggravated in animal models of hypertension with mineralocorticoid (MR) excess and in hypertensive patients with primary hyperaldosteronism. MR antagonism has shown to provide effective blood pressure (BP)-control in patients with treatment resistant hypertension (TRH), but the concurrent effects on the vasculature have not been examined. In a randomized, double-blinded, placebo-controlled parallel-group study, 51 patients with TRH received either eplerenone 50 mg or placebo for 6 months together with additional antihypertensives titrated to achieve a BP target of <140/90 mm Hg. Pulse wave velocity (PWV), augmentation index (AIx), augmentation pressure (AP), AP normalized to a heart rate of 75/min (AP@HR75), renal resistive index (RRI), intima-media thickness (IMT) and urinary albumin excretion rate (UAER) were assessed before and after treatment. PWV was reduced only with eplerenone (from 11.3±3.6 to 9.8±2.6 m/s, P˂.001), but not with placebo (10.3±2.0 to 10.1±1.8 m/s, P=.60), despite similar reductions in BP (-35±20/-15±11 mm Hg vs -30±19/-13±7 mm Hg, n.s.). Further, reductions in AP and AP@HR75 were greater with eplerenone, while changes in AIx, RRI, IMT and UAER were similar. Our data show that eplerenone beneficially affects markers of arterial stiffness and wave reflection in patients with TRH, independently of BP lowering. These data add to the evidence that MR antagonism should be the preferred treatment option in TRH.

SUBMITTER: Kalizki T

PROVIDER: S-EPMC8031041 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Spironolactone Reduces Aortic Stiffness in Patients With Resistant Hypertension Independent of Blood Pressure Change.

Project description:Background Aortic stiffness is an independent predictor of cardiovascular events in patients with arterial hypertension. Resistant hypertension is often linked to hyperaldosteronism and associated with adverse outcomes. Spironolactone, a mineralocorticoid receptor antagonist, has been shown to reduce both the arterial blood pressure (BP) and aortic stiffness in resistant hypertension. However, the mechanism of aortic stiffness reduction by spironolactone is not well understood. We hypothesized that spironolactone reduces aortic stiffness in resistant hypertension independently of BP change. Methods and Results Patients with uncontrolled BP (≥140/90 mm Hg) despite use of ≥3 antihypertensive medications (including diuretics) were prospectively recruited. Participants were started on spironolactone at 25 mg/d, and increased to 50 mg/d at 4 weeks while other antihypertensive medications were withdrawn to maintain constant mean BP. Phase-contrast cardiac magnetic resonance imaging of the ascending aorta was performed in 30 participants at baseline and after 6 months of spironolactone treatment to measure aortic pulsatility, distensibility, and pulse wave velocity. Pulse wave velocity decreased (6.3±2.3 m/s to 4.5±1.8 m/s, P<0.001) and pulsatility and distensibility increased (15.9%±5.3% to 22.1%±7.9%, P<0.001; and 0.28%±0.10%/mm Hg to 0.40%±0.14%/mm Hg, P<0.001, respectively) following 6 months of spironolactone. Conclusions Our results suggest that spironolactone improves aortic properties in resistant hypertension independently of BP, which may support the hypothesis of an effect of aldosterone on the arterial wall. A larger prospective study is needed to confirm our findings.

| S-EPMC8649301 | biostudies-literature

Eplerenone for hypertension.

Project description: Not available

| S-EPMC6464701 | biostudies-literature

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells.

Project description:Testosterone replacement therapy has benefits for aging men and those with hypogonadism. However, the effects of exogenous testosterone on Leydig cells are still unclear and need to be clarified. In this report, we demonstrate that testosterone supplementation can reduce oxidative damage in Leydig cells. The TM3 Leydig cell line was used as an in vitro cell model in this study. Cytoprotective effects were identified with 100-nmol l⁻¹ testosterone treatment, but cytotoxic effects were found with ≥ 500-nmol l⁻¹ testosterone supplementation. Significantly reduced reactive oxygen species (ROS) generation, lipid peroxide contents and hypoxia induction factor (HIF)-1α stabilization and activation were found with 100-nmol l⁻¹ testosterone treatment. There was a 1.72-fold increase in ROS generation in the 500-nmol l⁻¹ compared to the 100-nmol l⁻¹ testosterone treatment. A 1.58-fold increase in steroidogenic acute regulatory protein (StAR) expression was found in 50-nmol l⁻¹ testosterone-treated cells (P < 0.01). Chemically induced hypoxia was attenuated by testosterone supplementation. Leydig cells treated with low-dose testosterone supplementation showed cytoprotection by decreasing ROS and lipid peroxides, increasing StAR expression and relieving hypoxia stress as demonstrated by HIF-1α stabilization. Increased oxidative damage was found with ≥ 500-nmol l⁻¹ testosterone manipulation. The mechanism governing the differential dose effects of testosterone on Leydig cells needs further investigation in order to shed light on testosterone replacement therapy.

| S-EPMC3739334 | biostudies-other

Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study.

Project description:BackgroundIntravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium.AimsTo explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine.MethodSeven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed.ResultsTreatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission.ConclusionsThese results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.

| S-EPMC8693908 | biostudies-literature

Iron Stores, Hepcidin, and Aortic Stiffness in Individuals with Hypertension.

Project description:Background & aimsIron accumulation within the arterial wall has been hypothesized to promote atherosclerosis progression. Aim of this study was to evaluate whether the hormone hepcidin and iron stores are associated with arterial stiffness in subjects with essential hypertension.MethodsCirculating hepcidin, ferritin, and mutations in the hemochromatosis gene were compared between subjects included in the first vs. third tertile (n=284 each) of carotid-femoral pulse wave velocity (PWV) in an unselected cohort of patients with arterial hypertension.ResultsAt univariate logistic regression analysis, high PWV was associated with higher ferritin levels (p=0.010), but lower hepcidin (p=0.045), and hepcidin ferritin/ratio (p<0.001). Hemochromatosis mutations predisposing to iron overload were associated with high PWV (p=0.025). At multivariate logistic regression analysis, high aortic stiffness was associated with older age, male sex, lower BMI, higher systolic blood pressure and heart rate, hyperferritinemia (OR 2.05, 95% c.i. 1.11-3.17 per log ng/ml; p=0.022), and lower circulating hepcidin concentration (OR 0.29, 95% c.i. 0.16-0.51 per log ng/ml; p<0.001). In subgroup analyses, high PWV was associated with indices of target organ damage, including micro-albuminuria (n=125, p=0.038), lower ejection fraction (n=175, p=0.031), cardiac diastolic dysfunction (p=0.004), and lower S wave peak systolic velocity (p<0.001). Ferritin was associated with cardiac diastolic dysfunction, independently of confounders (p=0.006).ConclusionsIn conclusion, hyperferritinemia is associated with high aortic stiffness and cardiac diastolic dysfunction, while low circulating hepcidin with high aortic stiffness.

| S-EPMC4526526 | biostudies-literature

Next-Step Treatment Considerations for Patients With Treatment-Resistant Depression That Responds to Low-Dose Intravenous Ketamine.

Project description:Numerous short-term randomized trials support the acute-phase efficacy of low-dose intravenous (IV) ketamine for patients with treatment-resistant unipolar or bipolar depression. Ketamine's antidepressive effects generally have limited duration, highlighting the need for maintenance treatment after an acute-phase response. It is increasingly likely that psychiatrists will be called upon to manage the care of patients with treatment-resistant unipolar or bipolar depression who have responded acutely to ketamine and to recommend or initiate next-step treatments. However, there is a paucity of controlled evidence to guide best practices for managing treatment of patients with treatment-resistant unipolar or bipolar depression who have had a positive initial response to ketamine. This article reviews the available evidence supporting specific strategies for extending and maintaining acute antidepressive responses to low-dose IV ketamine in patients with treatment-resistant unipolar or bipolar depression and provides some preliminary considerations for clinical practice.

| S-EPMC7587874 | biostudies-literature

Aortic stiffness

Project description:BACKGROUND: Previous genomic studies with human tissues have compared differential gene expression between 2 conditions (ie, normal versus diseased) to identify altered gene expression in a binary manner; however, a potentially more informative approach is to correlate the levels of gene expression with quantitative physiological parameters. METHODS AND RESULTS: In this study, we have used this approach to examine genes whose expression correlates with arterial stiffness in human aortic specimens. Our data identify 2 distinct groups of genes, those associated with cell signaling and those associated with the mechanical regulation of vascular structure (cytoskeletal-cell membrane-extracellular matrix). Although previous studies have concentrated on the contribution of the latter group toward arterial stiffness, our data suggest that changes in expression of signaling molecules play an equally important role. Alterations in the profiles of signaling molecules could be involved in the regulation of cell cytoskeletal organization, cell-matrix interactions, or the contractile state of the cell. CONCLUSIONS: Although the influence of smooth muscle contraction/relaxation on arterial stiffness could be controversial, our provocative data would suggest that further studies on this subject are indicated. Keywords: other

2003-08-28 | GSE420 | GEO

Treatment with low dose fasudil for acute ischemic stroke in chronic hypertension.

Project description:We investigated the effect of Rho kinase inhibition on changes in cerebral blood flow (CBF), brain injury and vascular function after ischemic stroke in spontaneously hypertensive rats (SHR). Changes in core MCA and collateral perfusion were measured by a validated laser Doppler method. Animals underwent 2 h tMCAO and 2 h reperfusion. Fasudil (0.1 mg/kg, i.v.) or vehicle was given at 30 min ischemia (n = 9/group; mean (SD)). Brain injury was determined by 2,3,5-triphenyltetrazolium chloride staining. To determine the effect of fasudil on vascular function, fasudil was given 10 min before reperfusion and parenchymal arterioles studied isolated (n = 6/group; mean(SD)). Collateral perfusion was low in vehicle-treated SHR (-8(32)%) that changed minimally with fasudil (6(24)%, p > 0.05, effect size: 0.47;95% CI-0.49-1.39). Reperfusion CBF was below baseline in vehicle (-27(26)%) and fasudil (-32(25)%, p > 0.05, effect size: 0.19; 95% CI-0.74-1.11) groups, suggesting incomplete reperfusion in both groups. Fasudil had little effect on brain injury volume (28(13)% vs. 36(7)% in vehicle, p > 0.05, effect size: 0.75; 95% CI-0.24-1.66). In isolated parenchymal arterioles, myogenic tone was similar between groups (37(6)% vs. 38(10)% in vehicle, p > 0.05, effect size: 0.09; 95% CI-1.05-1.21). There were no differences with fasudil treatment vs. vehicle in perfusion, brain injury and vascular function that may be related to the low dose that had minimal blood pressure lowering effect.

| S-EPMC5584704 | biostudies-literature

Antialbuminuric effect of eplerenone in comparison to thiazide diuretics in patients with hypertension.

Project description:This study investigated the effects and safety of eplerenone or thiazide diuretics in patients with hypertension and albuminuria (pretreatment urinary albumin/creatinine ratio ≥10 mg/gCr) treated with an angiotensin II receptor blocker. The primary end point was the mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks. An efficacy analysis was performed in 195 patients (98 in the eplerenone group and 97 in the thiazide group). Systolic and diastolic blood pressures at 48 weeks were similar in the two groups. The mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks was similar in the two groups (P=.804). In the safety analysis, the withdrawal rates for adverse events were similar in both groups. The antialbuminuric effects and safety of eplerenone therapy were similar to those of thiazide diuretics when combined with an angiotensin II receptor blocker in patients with hypertension and albuminuria.

| S-EPMC8031246 | biostudies-literature

Hypertension and arterial stiffness in heart transplantation patients.

Project description:Post-transplantation hypertension is prevalent and is associated with increased cardiovascular morbidity and subsequent graft dysfunction. The present study aimed to identify the factors associated with arterial stiffness as measured by the ambulatory arterial stiffness index.The current study used a prospective, observational, analytical design to evaluate a group of adult heart transplantation patients. Arterial stiffness was obtained by monitoring ambulatory blood pressure and using the ambulatory arterial stiffness index as the surrogate outcome. Multivariate logistic regression analyses were performed to control confounding.In a group of 85 adult heart transplantation patients, hypertension was independently associated with arterial stiffness (OR 4.98, CI 95% 1.06-23.4) as well as systolic and diastolic blood pressure averages and nighttime descent.Measurement of ambulatory arterial stiffness index is a new, non-invasive method that is easy to perform, may contribute to better defining arterial stiffness prognosis and is associated with hypertension.

| S-EPMC5004574 | biostudies-other

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