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The pathogenesis of hypertension is known to involve a diverse range of contributing factors including genetic, environmental, hormonal, hemodynamic and inflammatory forces, to name a few. There is mounting evidence to suggest that the gut microbiome plays an important role in the development and pathogenesis of hypertension. The gastrointestinal tract, which houses the largest compartment of immune cells in the body, represents the intersection of the environment and the host. Accordingly, lifestyle factors shape and are modulated by the microbiome, modifying the risk for hypertensive disease. One well-studied example is the consumption of dietary fibers, which leads to the production of short-chain fatty acids and can contribute to the expansion of anti-inflammatory immune cells, consequently protecting against the progression of hypertension. Dietary interventions such as fasting have also been shown to impact hypertension via the microbiome. Studying the microbiome in hypertensive disease presents a variety of unique challenges to the use of traditional model systems. Integrating microbiome considerations into preclinical research is crucial, and novel strategies to account for reciprocal host-microbiome interactions, such as the wildling mouse model, may provide new opportunities for translation. The intricacies of the role of the microbiome in hypertensive disease is a matter of ongoing research, and there are several technical considerations which should be accounted for moving forward. In this review we provide insights into the host-microbiome interaction and summarize the evidence of its importance in the regulation of blood pressure. Additionally, we provide recommendations for ongoing and future research, such that important insights from the microbiome field at large can be readily integrated in the context of hypertension.

Periods of fasting and refeeding may reduce cardiometabolic risk elevated by Western diet. Here we show in the substudy of NCT02099968, investigating the clinical parameters, the immunome and gut microbiome exploratory endpoints, that in hypertensive metabolic syndrome patients, a 5-day fast followed by a modified Dietary Approach to Stop Hypertension diet reduces systolic blood pressure, need for antihypertensive medications, body-mass index at three months post intervention compared to a modified Dietary Approach to Stop Hypertension diet alone. Fasting alters the gut microbiome, impacting bacterial taxa and gene modules associated with short-chain fatty acid production. Cross-system analyses reveal a positive correlation of circulating mucosa-associated invariant T cells, non-classical monocytes and CD4+ effector T cells with systolic blood pressure. Furthermore, regulatory T cells positively correlate with body-mass index and weight. Machine learning analysis of baseline immunome or microbiome data predicts sustained systolic blood pressure response within the fasting group, identifying CD8+ effector T cells, Th17 cells and regulatory T cells or Desulfovibrionaceae, Hydrogenoanaerobacterium, Akkermansia, and Ruminococcaceae as important contributors to the model. Here we report that the high-resolution multi-omics data highlight fasting as a promising non-pharmacological intervention for the treatment of high blood pressure in metabolic syndrome patients., Nutritional modification including fasting has been shown to reduce cardiometabolic risk linked to western diet. Here the authors show implementation of fasting resulted in alterations to the intestinal microbiota, and circulating immune cells, improving blood pressure and body weight in patients with metabolic syndrome.

CKD is characterized by a sustained proinflammatory response of the immune system, promoting hypertension and cardiovascular disease. The underlying mechanisms are incompletely understood but may be linked to gut dysbiosis. Dysbiosis has been described in adults with CKD; however, comorbidities limit CKD-specific conclusions.We analyzed the fecal microbiome, metabolites, and immune phenotypes in 48 children (with normal kidney function, CKD stage G3-G4, G5 treated by hemodialysis [HD], or kidney transplantation) with a mean±SD age of 10.6±3.8 years.Serum TNF-Gut barrier dysfunction and microbial metabolite imbalance apparently mediate the proinflammatory immune phenotype, thereby driving the susceptibility to cardiovascular disease. The data highlight the importance of the microbiota-immune axis in CKD, irrespective of confounding comorbidities.

High salt intake ranks among the most important risk factors for noncommunicable diseases. Western diets, which are typically high in salt, are associated with a high prevalence of obesity. High salt is thought to be a potential risk factor for obesity independent of energy intake, although the underlying mechanisms are insufficiently understood. A high salt diet could influence energy expenditure (EE), specifically diet-induced thermogenesis (DIT), which accounts for about 10% of total EE. We aimed to investigate the influence of high salt on DIT. In a randomized, double-blind, placebo-controlled, parallel-group study, 40 healthy subjects received either 6 g/d salt (NaCl) or placebo in capsules over 2 weeks. Before and after the intervention, resting EE, DIT, body composition, food intake, 24 h urine analysis, and blood pressure were obtained. EE was measured by indirect calorimetry after a 12 h overnight fast and a standardized 440 kcal meal. Thirty-eight subjects completed the study. Salt intake from foods was 6 g/d in both groups, resulting in a total salt intake of 12 g/d in the salt group and 6 g/d in the placebo group. Urine sodium increased by 2.29 g/d (p < 0.0001) in the salt group, indicating overall compliance. The change in DIT differed significantly between groups (placebo vs. salt, p = 0.023). DIT decreased by 1.3% in the salt group (p = 0.048), but increased by 0.6% in the placebo group (NS). Substrate oxidation indicated by respiratory exchange ratio, body composition, resting blood pressure, fluid intake, hydration, and urine volume did not change significantly in either group. A moderate short-term increase in salt intake decreased DIT after a standardized meal. This effect could at least partially contribute to the observed weight gain in populations consuming a Western diet high in salt.

Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17. producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4(+) cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A-driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.

Supplemental Digital Content is available in the text., Background: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes. Methods: Using Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichia coli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo. Results: Extracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of and respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. Conclusions: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.

Sensitive and precise serology assays are needed to measure the humoral response to antigens of respiratory syncytial virus (RSV) following natural infection or vaccination. We developed and evaluated a collection of electrochemiluminescent (ECL) serology assays using four RSV antigens (F, N, Ga and Gb). To assess the merits of ECL technology, the four ECL serology assays were evaluated using a well-characterized "gold standard" panel of acute and convalescent serum samples from fifty-nine RSV-positive and thirty RSV-negative elderly subjects (≥65 years old). The combined results from the four ECL assays demonstrated good concordance to the "gold standard" diagnosis, reaching 95% diagnostic sensitivity and 100% diagnostic specificity. Additionally, a combination of ECL assays provided higher diagnostic sensitivity than a commercially available diagnostic ELISA or cell-based microneutralization assay. In summary, these data demonstrate the advantages of using ECL-based serology assays and highlight their use as a sensitive diagnostic approach to detect recent RSV infection in an elderly population.

SummaryCotransins are cyclic heptadepsipeptides that bind the Sec61 translocon to inhibit cotranslational translocation of a subset of secreted and type I transmembrane proteins. The few known cotransin-sensitive substrates are all targeted to the translocon by a cleavable signal sequence, previously shown to be a critical determinant of cotransin sensitivity. By profiling two cotransin variants against a panel of secreted and transmembrane proteins, we demonstrate that cotransin side-chain differences profoundly affect substrate selectivity. Among the most sensitive substrates we identified is the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). Like all type II transmembrane proteins, TNF-α is targeted to the translocon by its membrane-spanning domain, indicating that a cleavable signal sequence is not strictly required for cotransin sensitivity. Our results thus reveal an unanticipated breadth of translocon substrates whose expression is inhibited by Sec61 modulators.

To compare the ovarian and endometrial effects of anastrozole and clomiphene when used with gonadotropins in a combination protocol.Prospective randomized trial.Academic infertility center.Fifty infertile women.Women were randomized to receive either 1 mg anastrozole or 100 mg clomiphene citrate for 5 days (cycle days 3-7) followed by FSH injections (days 7-11) for ovulation induction. A subset participated in a crossover arm of the study.Ovarian follicle number and size, E(2) levels, endometrial thickness, pregnancy, and cancellation rates.On cycle day 12, anastrozole cycles were associated with fewer total follicles (1.4 vs. 3.6, P=0.01), fewer mature follicles (0.6 vs. 1.6, P.01), lower serum E(2) (131 pg/mL vs. 613 pg/mL, P.01,) and the same endometrial stripe thickness compared with clomiphene citrate cycles. Cycle cancellation rates were similar between the two groups. On the day of hCG administration in noncancelled cycles, anastrozole cycles were associated with fewer total follicles (1.6 vs. 3.8, P.01), fewer mature follicles (1.3 vs. 2.1, P.01), and an equal endometrial stripe thickness compared with clomiphene citrate cycles. Pregnancy rates were similar between clomiphene (20%) and anastrozole (12%) cycles.Anastrozole when used in conjunction with gonadotropins results in lower E(2) levels and fewer follicles than clomiphene citrate. A combination protocol of anastrozole and gonadotropins may be a safer protocol for patients at higher risk of hyperstimulation and multiple births after infertility treatments.

Objective Polycystic ovary syndrome (PCOS) is associated with biochemical evidence of early atherosclerosis; however, data regarding vascular function are controversial. We hypothesized that resistance vessel function (mediated by the endothelium or smooth muscle) would be impaired in women with PCOS and aimed to determine the contribution of hyperandrogenism, obesity, or insulin resistance to vascular dysfunction. Design Prospective study. Setting University practice. Patient(s) Women with PCOS (n = 24) and age/weight-matched controls (n = 22). Intervention(s) Vascular function was assessed by measuring forearm vasodilatation in response to both endothelium-dependent (acetylcholine/bradykinin) and endothelium-independent dilators (nitroprusside/verapamil). Main Outcome Measure(s) Resistance vessel function. Result(s) Forearm vasodilatation to all four drugs was reduced (>50%) in obese PCOS compared to lean PCOS subjects. There was no significant difference in vascular function between obese or lean women with PCOS compared to corresponding controls. Androgen levels did not correlate with vascular function. Stepwise regression analysis showed that body mass index (BMI) contributed maximally to vascular dysfunction (R2 = 0.47). Conclusion(s) This comprehensive study demonstrates for the first time that obese women with PCOS have markedly reduced vascular smooth muscle function compared to lean subjects with PCOS. In our study obesity and insulin resistance, but not hyperandrogenism, appeared to be significant modulators of vascular function.

Objective To identify salient variables that influence decision making regarding multifetal reduction (MFR) and describe their effect on individuals over time. Design Prospective, exploratory, descriptive design, using qualitative and quantitative methods. Setting Midwestern tertiary care center. Participants A convenience sample of 11 consecutive consenting couples with triplet or higher-order pregnancies who elected to undergo MFR. Methods Semistructured audiotaped telephone interviews at three points: (a) 2 weeks postreduction, (b) 6 weeks postpartum, and (c) 6 months postpartum; a demographic and marital adjustment questionnaire. Main Outcome Measures Themes identified by content analysis and compared via matrix analysis between males and females and at three points in time; trends in marital adjustment. Results Dominant variables influencing MFR decision making were risks associated with higher-order pregnancies and preservation of infants’ and mothers’ health. Most participants identified emotional issues, including moral and ethical dilemmas, as the most difficult aspect of reduction. Over time, participants reported feeling more positive about their decision; nonetheless, negative feelings emerged progressively. Conclusions Risk aversion favored MFR decision making. Yet, both making and living with the decision were emotionally difficult for this sample. Interventions are needed to assist couples with this decision and its consequences.

Context: Polycystic ovary syndrome (PCOS) is associated with comorbidities that may contribute to increased risk of cardiovascular disease. PCOS is associated with increased risk of metabolic syndrome, dyslipidemia, and diabetes, but it remains unclear whether traditional cardiovascular (CV) risk factors can help predict coronary artery disease in this population. Objective: The objectives of the study were to detect early-onset subclinical coronary atherosclerosis (using coronary artery calcium as a marker) in young women with PCOS, compared with age- and body mass index-matched controls, and to compare traditional CV risk factors and inflammatory markers in the two groups. Design: This was a prospective case-control study. Setting: The study was conducted at a university hospital. Subjects: Twenty-four obese (body mass index ≥ 30 kg/m2) PCOS subjects and 24 obese controls participated. Outcome Measures: Coronary artery calcium, inflammatory markers (high-sensitivity C-reactive protein, IL-6, TNFα, adiponectin, leptin), fasting blood tests (glucose, lipids, insulin), and dual-energy x-ray absorptiometry scan for body fat distribution were measured. Results: Coronary artery calcium was detected in eight of 24 PCOS subjects (33%) and two of 24 controls (8%) (odds ratio 5.5, 95% confidence interval 1.03, 29.45, P < 0.03). Traditional CV risk factors did not differ significantly between the two groups, nor did markers of inflammation or adiposity, body fat distribution, or metabolic parameters with the exception of significantly lower quantitative insulin sensitivity check index (marker for insulin resistance) in the PCOS group (P < 0.05). Conclusions: Young, obese women with PCOS have a high prevalence of early asymptomatic coronary atherosclerosis, compared with obese controls. This increased risk is independent of traditional CV risk factors and novel markers of inflammation. These findings underscore the need to screen and aggressively counsel and treat these women to prevent symptomatic CV disease.

Polycystic ovary syndrome (PCOS) is associated with several metabolic complications. A few small studies have also suggested an increased risk of depression in women with PCOS. The goals of this study were to estimate the prevalence of depressive disorders in women with PCOS compared with controls and to evaluate the correlation between depression, hyperandrogenism, and other metabolic markers.Cohort study.University Hospital.Women with PCOS (Rotterdam criteria; n = 103). Women without PCOS seen during the same time period for an annual exam were used as control subjects (n = 103).Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ) and the Beck Depression Inventory.Depressive disorders.Women with PCOS were at an increased risk for depressive disorders (new cases) compared with controls (21% vs. 3%; odds ratio 5.11 [95% confidence interval (CI) 1.26-20.69]; P.03). The overall risk of depressive disorders in women with PCOS was 4.23 (95% CI 1.49-11.98; P.01) independent of obesity and infertility. Compared with the nondepressed PCOS subjects, the depressed PCOS subjects had a higher body mass index (BMI) and evidence of insulin resistance (P.02).We report a significantly increased risk of depressive disorders (as defined by the Diagnostic and Statistical Manual IV) in women with PCOS and recommend routine screening in this population.