Striatin Gene Variants Are Associated With Salt Sensitivity of Blood Pressure by Mechanisms That Differ in Women and Men.

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is a substantial risk factor for cardiovascular morbidity and mortality. Striatin (STRN) is critical for estrogen and aldosterone nongenomic signaling. However, the role of biological sex on the SSBP phenotype associated with STRN gene variants remains unexplored. METHOD: Data from 1306 subjects participating in the Hypertensive Pathotype (HyperPATH) Consortium were used to identify STRN gene single-nucleotide variants associated with SSBP. Haploblock analysis revealed a novel diplotype in the upstream regulatory region of STRN (rs888083 and rs6744560), with 31% of subjects being homozygous for the risk diplotype. RESULTS: Individuals homozygous for the risk diplotype had significantly greater SSBP than nonrisk diplotypes (P<0.009). While a significant genotype/SSBP association was present in both sexes, their potential mechanisms differed. Women, but not men homozygous risk diplotypes, had significantly greater aldosterone levels than nonrisk diplotypes (5.8±0.4 versus 3.2±0.7 ng/dl; P=0.01; liberal Na+ diet, adjusted). Men, but not women, homozygous risk diplotypes, had significantly reduced renal plasma flow response to Angiotensin II than nonrisk diplotypes (delta 95.2±5.2 versus 122.9±10.2 mL/min per 1.73 m2; P=0.01; liberal Na+ diet, adjusted). The single-nucleotide variants composing the risk diplotype were associated with lower STRN mRNA expression in human tissues (in silico). CONCLUSION: In women, the primary driver of SSBP is increased aldosterone, while in men, it is reduced renal plasma flow responses. Thus, despite a common hypertensive phenotype (SSBP) in both sexes, the specific treatment approaches might differ to increase therapeutic gain and mitigate adverse effects. These genetic- and sex-based observational results require confirmation in a prospective clinical study.

Elevated Blood Pressure and Aldosterone Dysregulation in Young Black Women Versus White Women on Controlled Sodium Diets.

CONTEXT: Black women have a higher prevalence of hypertension as compared to White women. Differences in dietary sodium intake have been implicated as a contributing factor for the disparities in hypertension. OBJECTIVE: Our objective was to understand whether young Black women would have higher systolic blood pressure (SBP) than White women even on controlled sodium diets and to determine whether SBP differences were due to differences in dietary sodium intake and/or aldosterone regulation. DESIGN: The analyses included 525 hypertensive and normotensive women (ages 18-71) from the International Hypertensive Pathotype consortium, who were maintained on liberal sodium (LIB; >200 mEq sodium/day) and restricted sodium (RES; 10 mEq sodium/day) diets. RESULTS: Multivariate regression analyses (adjusted for age, race, study site, body mass index) found that Black women (ages 18-50) had significantly higher SBP than White women on both sodium diets: +8.7 ± 2.7 mmHg (P-value = .002) on a LIB diet and +8.5 ± 2.5 mmHg (P-value = .001) on a RES diet. Even among 18- to 35-year-olds-who were normotensive and nonobese-Black women had higher SBP: +7.9 ± 2.4 mmHg (P-value = .001) on a LIB diet and +7.6 ± 2.7 mmHg (P-value = .005) on a RES diet. Younger Black women also had higher plasma aldosterone concentration to plasma renin activity ratio (ARR) on both LIB and RES diets as well as a higher sodium-modulated aldosterone suppression-stimulation index-an indicator of aldosterone dysregulation. In younger Black women-but not in White women-there was a significant association between SBP and ARR on both LIB and RES diets. CONCLUSION: Young Black women had increased SBP and ARR as compared to White women on LIB and RES diets, which offers insights into the possible mechanisms for the increased hypertension and cardiovascular disease risk in an at-risk and understudied population.

Mineralocorticoid Receptor Antagonism by Eplerenone and Arterial Inflammation in HIV: The MIRABELLA HIV Study.

Importance: The risk for atherosclerotic disease is increased 1.5- to 2.0-fold among persons with HIV (PWH). Increased activation of the renin-angiotensin-aldosterone system may contribute to increased arterial inflammation in this population. Objective: To determine the effects of eplerenone on arterial inflammation among well-treated PWH without known cardiovascular disease (CVD). Design, Setting, and Participants: Well-treated PWH who participated in the double-blinded, placebo-controlled, Mineralocorticoid Receptor Antagonism for Cardiovascular Health in HIV (MIRACLE HIV) study between February 2017 and March 2022 assessing the effects of eplerenone on myocardial perfusion were invited to participate in the Mineralocorticoid Receptor Antagonism By Eplerenone to Lower Arterial Inflammation in HIV (MIRABELLA) substudy if there was no current statin use. Participants were enrolled in the MIRABELLA study and underwent additional 18F-fludeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) imaging of the aorta and carotid arteries to assess arterial inflammation over 12 months of treatment with eplerenone vs placebo. Interventions: Eplerenone, 50 mg, twice a day vs identical placebo. Main Outcomes and Measures: The primary outcome was change in target to background ratio (TBR), a measure of arterial wall inflammation, in the index vessel after 12 months of treatment. The index vessel was defined as the vessel (aorta, left carotid artery, or right carotid artery) with the highest TBR at baseline in each participant. Results: A total of 26 participants (mean [SD] age, 54 [7] years; 18 male [69%]) were enrolled in the study. Treatment groups (eplerenone, 13 vs placebo, 13) were of similar age, sex, and body mass index. Eplerenone was associated with a reduction in TBR of the primary end point, the index vessel (eplerenone vs placebo: model treatment effect, -0.31; 95% CI, -0.50 to -0.11; P = .006; percentage change, -12.4% [IQR, -21.9% to -2.6%] vs 5.1% [IQR, -1.6% to 11.0%]; P = .003). We further observed a significant reduction of the TBR of the most diseased segment (MDS) of the index vessel (eplerenone vs placebo: -19.1% [IQR, -27.0% to -11.9%] vs 6.8% [IQR, -9.1% to 12.1%]; P = .007). A similar result was seen assessing the index vessel of the carotids (eplerenone vs placebo: -10.0% [IQR, -21.8% to 3.6%] vs 9.7% [IQR, -9.8% to 15.9%]; P = .046). Reduction in the TBR of MDS of the index vessel on 18F-FDG PET/CT correlated with improvement in the stress myocardial blood flow on cardiac magnetic resonance imaging (Spearman ρ = -0.67; P = .01). Conclusion and Relevance: In this small randomized clinical trial, eplerenone was associated with reduction in arterial inflammation among well-treated PWH without known CVD. In addition, reductions in arterial inflammation as measured by 18F-FDG PET/CT were related to improvements in stress myocardial perfusion. Further larger studies should explore whether eplerenone is a potential treatment strategy for inflammatory-mediated CVD in PWH. Trial Registration: ClinicalTrials.gov Identifier: NCT02740179.

CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals.

BACKGROUND: Disease-causing mutations in CACNA1D gene occur in aldosterone-producing adenomas and familial hyperaldosteronism. We determined whether single nucleotide polymorphisms in CACNA1D gene associate with higher aldosterone resulting in salt sensitivity of blood pressure (BP) and increased BP in men and women. METHODS: Data were obtained from the HyperPATH (International Hypertension Pathotypes) cohort, where participants completed a cross-over intervention of liberal and restricted sodium diets. Multi-Ethnic Genotyping Array identified 104 CACNA1D single nucleotide polymorphisms that met quality control. Single nucleotide polymorphism is rs7612148 strongly associated with systolic BP and was selected for study in 521 White participants in 3 scenarios ([1] hypertensives; [2] normotensives; [3] total population=hypertensives+normotensives) using multivariate regression analysis. RESULTS: In the total population and hypertensives, but not normotensives, risk allele carriers (CC, GC), as compared with nonrisk allele homozygotes (GG), exhibited higher salt sensitivity of BP and, on liberal sodium diet, higher systolic BP, lower baseline and angiotensin II-stimulated aldosterone, and lower plasma renin activity. On restricted sodium diet, BP was similar across genotypes, suggesting sodium restriction corrected/neutralized the genotype effect on BP. Because increased aldosterone did not seem to drive the increased salt sensitivity of BP and increased BP on liberal sodium diet, we assessed renal plasma flow. Renal plasma flow increase from restricted to liberal sodium diets was blunted in risk allele homozygotes in the total population and in hypertensives. A replication study in another cohort HyperPATH B (International Hypertension Pathotypes Cohort B) confirmed BP-genotype associations. CONCLUSIONS: CACNA1D rs7612148 risk allele associated with increased BP and salt sensitivity of BP, likely due to an impaired ability to increase renal plasma flow in response to a liberal sodium diet and not to excess aldosterone.

Effect of hypoglycemia on baroreflex sensitivity in individuals with type 2 diabetes: implications for autonomic control of cardiovascular function in diabetes.

PURPOSE: Hypoglycemia is associated with increased mortality, though the mechanisms underlying this association are not established. Hypoglycemia impairs the counterregulatory hormonal and autonomic responses to subsequent hypoglycemia. It is unknown whether hypoglycemia elicits a generalized impairment in autonomic control of cardiovascular function in individuals with type 2 diabetes. We tested the hypothesis that in individuals with type 2 diabetes, hypoglycemia impairs a key measure of cardiovascular autonomic homeostasis, baroreflex sensitivity. METHODS: Sixteen individuals with well-controlled type 2 diabetes and without known cardiovascular disease were exposed to two 90-min episodes of experimental hypoglycemia (2.8 mmol/L, 50 mg/dL) on the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). Baroreflex sensitivity was assessed using the modified Oxford method before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 min of hypoglycemia, and the following morning. A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on baroreflex sensitivity. The study is registered at ClinicalTrials.gov (NCT03422471). RESULTS: Baroreflex sensitivity during PM hypoglycemia was reduced compared to baseline, during AM hypoglycemia, and the next day. Insulin levels positively correlated with baroreflex sensitivity at baseline and during AM hypoglycemia. CONCLUSION: Exposure to hypoglycemia impairs a key measure of autonomic control of cardiovascular function and, thus, may increase the risk of cardiac arrhythmias and blood pressure lability in individuals with type 2 diabetes. This effect is attenuated in part by increased insulin levels.

Visceral Adiposity Index as a Measure of Cardiovascular Disease in Persons With Human Immunodeficiency Virus.

Background: Persons with well-treated human immunodeficiency virus (HIV) demonstrate a 2-fold higher risk of cardiovascular disease (CVD), which may be related to excess visceral adipose tissue (VAT). The visceral adiposity index (VAI) is a score to approximate VAT by combining biochemical measures with anthropometrics without quantification by imaging. We evaluated VAI in association with cardiometabolic factors among persons with HIV (PWH). Methods: Forty-five PWH on antiretroviral therapy and virologically controlled with increased abdominal VAT (VAT area >110 cm2 on CT) and no known CVD were included. VAI was calculated using standard sex-specific formulas. Coronary plaque was assessed using coronary CT angiography. Results: Participants were predominantly male (73%), white (53%), and non-Hispanic (84%), with a mean age of 55 (standard deviation, 7) years. Among PWH, median VAI was calculated to be 4.9 (interquartile range [IQR], 2.8-7.3). Log VAI correlated with log VAT (r = 0.59, P < .0001) and anthropometric measures (body mass index: r = 0.36, P = .02; waist circumference: r = 0.43, P = .004; waist-to-hip ratio: r = 0.33, P = .03). Participants with coronary plaque had a higher VAI compared to those without coronary plaque (median, 5.3 [IQR, 3.4-10.5] vs 2.8 [IQR, 1.8-5.0]; P = .004). VAI (area under the curve = 0.760, P = .008) performed better than the atherosclerotic CVD risk score to predict the presence of plaque in receiver operating characteristic analyses. Conclusions: VAI may be a useful biomarker of metabolic dysfunction and increased CVD risk that may occur with VAT accumulation in PWH. Clinical Trials Registration: NCT02740179.

Association Between Life's Simple 7 and Biomarkers of Cardiovascular Disease: Aldosterone, Interleukin-6, C-Reactive Protein.

Background To promote ideal cardiovascular health, the American Heart Association recommends adhering to Life's Simple 7 (LS7)-achieving healthy targets for body mass index, physical activity, dietary intake, blood pressure, fasting plasma glucose, and cholesterol, along with smoking abstinence. Poorer achievement of LS7 (lower score) has been associated with the development of hypertension and cardiovascular disease. However, less is known about the associations between LS7 and specific biomarkers linked to cardiovascular health: aldosterone, CRP (C-reactive protein), and IL-6 (interleukin-6). Methods and Results We analyzed 379 individuals (age 18-66 years) from the HyperPATH (International Hypertensive Pathotype), who were maintained on ≥200 mEq of sodium daily for 1 week. We calculated a 14-point summative LS7 score according to participants' baseline data. Based on the range of LS7 score in this population (3-14), we classified participants as "inadequate" (3-6), "average" (7-10), and "optimal" (11-14). Regression analyses found that a higher LS7 score group was associated with lower levels of serum and urinary aldosterone (Ptrend<0.001 and Ptrend=0.001, respectively), lower plasma renin activity (Ptrend<0.001), and a blunted increase in serum aldosterone with angiotensin II infusion (Ptrend=0.023). Being in the "optimal" LS7 score group was associated with lower serum CRP (Ptrend=0.001) and IL-6 (Ptrend=0.001). Conclusions A higher LS7 score was associated with a lower activity of the renin-angiotensin-aldosterone system and lower levels of the inflammatory markers CRP and IL-6. These findings offer a possible link between ideal cardiovascular health targets and biomarkers known to play a central role in the development of cardiovascular disease.

Randomized Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function Among Persons With Human Immunodeficiency Virus (HIV)-Results From the MIRACLE HIV Study.

BACKGROUND: Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. METHODS: Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI. RESULTS: Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/µL; P = .02) increased in the eplerenone- versus placebo-treated groups. CONCLUSIONS: RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. CLINICAL TRIALS REGISTRATION: NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II.

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

Protocol for a randomized placebo-controlled clinical trial using pure palmitoleic acid to ameliorate insulin resistance and lipogenesis in overweight and obese subjects with prediabetes.

Palmitoleic acid (POA), a nonessential, monounsaturated omega-7 fatty acid (C16:1n7), is a lipid hormone secreted from adipose tissue and has beneficial effects on distant organs, such as the liver and muscle. Interestingly, POA decreases lipogenesis in toxic storage sites such as the liver and muscle, and paradoxically increases lipogenesis in safe storage sites, such as adipose tissue. Furthermore, higher POA levels in humans are correlated with better insulin sensitivity, an improved lipid profile, and a lower incidence of type-2 diabetes and cardiovascular pathologies, such as myocardial infarction. In preclinical animal models, POA improves glucose intolerance, dyslipidemia, and steatosis of the muscle and liver, while improving insulin sensitivity and secretion. This double-blind placebo-controlled clinical trial tests the hypothesis that POA increases insulin sensitivity and decreases hepatic lipogenesis in overweight and obese adult subjects with pre-diabetes. Important to note, that this is the first study ever to use pure (>90%) POA with < 0.3% palmitic acid (PA), which masks the beneficial effects of POA. The possible positive findings may offer a therapeutic and/or preventative pathway against diabetes and related immunometabolic diseases.

Role of renin-angiotensin-aldosterone system activation and other metabolic variables in relation to arterial inflammation in HIV.

BACKGROUND: Arterial inflammation remains increased among persons with HIV (PWH) compared with persons without HIV (PWOH) even when controlling for traditional risk factors. We sought to understand whether increased renin-angiotensin-aldosterone system (RAAS) activation may be related to arterial inflammation in PWH and when compared with PWOH. DESIGN: Twenty PWH and 9 PWOH followed a controlled, standardized low and liberal sodium diet to simulate a RAAS-activated and RAAS-suppressed state, respectively. We measured serum lipoprotein-associated phospholipase A2 (LpPLA2) concentrations following both conditions to assess the physiologic dynamics of aldosterone in relation to arterial inflammation. RESULTS: LpPLA2 levels were significantly higher among PWH versus PWOH during both the RAAS-activated state[5.3(4.2, 6.1) versus 4.0(3.0, 4.8)nmol/L, median(interquartile range),p = .01]) and RAAS-suppressed state[4.4(3.9, 5.3) versus 3.8(3.4, 4.1)nmol/L,p = .01]. Among PWH, but not PWOH, LpPLA2 increased significantly with RAAS activation(p = .03). LpPLA2 levels measured during the RAAS-suppressed state among PWH remained relatively higher than LpPLA2 levels under both conditions among PWOH. Log LpPLA2 was related to log aldosterone during the RAAS-activated state(r = .39,p = .04) among all participants. Log LpPLA2 was correlated with visceral fat(r = .46,p = .04) and log systolic blood pressure(r = .57,p = .009) during a RAAS-activated state when an increase in aldosterone was stimulated in HIV. CONCLUSION: LpPLA2 is increased during a RAAS-activated state among PWH, but not among PWOH. Further, LpPLA2 was increased in both RAAS-activated and suppressed states in PWH compared with PWOH. These data suggest a biological link between increased aldosterone and arterial inflammation in this population. Future studies should test RAAS blockade on arterial inflammation as a targeted treatment approach in HIV.

Evaluation of Mineralocorticoid Receptor Antagonism on Changes in NT-proBNP Among Persons With HIV.

Subclinical myocardial dysfunction is prevalent among well-treated persons with HIV (PWH). We have previously demonstrated unique renin-angiotensin-aldosterone system physiology among PWH with metabolic dysregulation. Mineralocorticoid receptor blockade may be a targeted treatment strategy for subclinical heart disease in PWH. Forty-six PWH were randomized to receive either eplerenone 50 mg daily or placebo in a 6-month randomized, double-blinded, placebo-controlled trial. We assessed changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker of cardiac stretch, under controlled posture and dietary conditions. The eplerenone- and placebo-treated groups demonstrated a long duration of HIV with good immunological control. NT-proBNP levels were similar between the groups at baseline (41.1 [20.2, 97.9] vs 48.9 [29.2, 65.4] ng/L, P = .80) and decreased significantly more in the eplerenone- vs placebo-treated groups after 6 months (change NT-proBNP -9.6 [-46.8, 0.3] vs -3.0 [-17.0, 39.9] ng/L, P = .02 for comparison of change between groups). Decreases in NT-proBNP were independent of changes in systolic and diastolic blood pressure, and related to decreases in high-sensitivity C-reactive protein (ρ = 0.32, P = .05) and inversely to increases in serum aldosterone (ρ = -0.33, P = .04) among all participants. Treatment with eplerenone for 6 months vs placebo significantly decreases NT-proBNP levels among PWH, independent of eplerenone's known blood pressure-lowering effects. Further studies should elucidate whether lowering NT-proBNP in this at-risk metabolic population with subclinical heart disease will offer cardioprotection. CLINICAL TRIAL REGISTRATION: NCT01405456.

Daytime eating prevents internal circadian misalignment and glucose intolerance in night work.

Night work increases diabetes risk. Misalignment between the central circadian "clock" and daily behaviors, typical in night workers, impairs glucose tolerance, likely due to internal misalignment between central and peripheral circadian rhythms. Whether appropriate circadian alignment of eating can prevent internal circadian misalignment and glucose intolerance is unknown. In a 14-day circadian paradigm, we assessed glycemic control during simulated night work with either nighttime or daytime eating. Assessment of central (body temperature) and peripheral (glucose and insulin) endogenous circadian rhythms happened during constant routine protocols before and after simulated night work. Nighttime eating led to misalignment between central and peripheral (glucose) endogenous circadian rhythms and impaired glucose tolerance, whereas restricting meals to daytime prevented it. These findings offer a behavioral approach to preventing glucose intolerance in shift workers.

Effect of adrenocorticotropic hormone infusion on circulating sclerostin levels.

Glucocorticoid use is the most common cause of secondary osteoporosis. Poor skeletal health related to glucocorticoid use is thought to involve inhibition of the Wnt/ß-catenin signaling pathway, a key pathway in osteoblastogenesis. Sclerostin, a peptide produced primarily by osteocytes, is an antagonist of the Wnt/ß-catenin signaling pathway, raising the possibility that sclerostin is involved in glucocorticoids' adverse effects on bone. The aim of this study was to determine whether an acute infusion of cosyntropin (i.e. ACTH(1-24)), which increases endogenous cortisol, increases serum sclerostin levels as compared to a placebo infusion. This study was performed using blood samples obtained from a previously published, double-blind, placebo-controlled, randomized, cross-over study among healthy men and women who received infusions of placebo or cosyntropin after being supine and fasted overnight (ClinicalTrials.gov NCT02339506). A total of 17 participants were analyzed. There was a strong correlation (R2 = 0.65, P < 0.0001) between the two baseline sclerostin measurements measured at the start of each visit, and men had a significantly higher average baseline sclerostin compared to women. As anticipated, cosyntropin significantly increased serum cortisol levels, whereas cortisol levels fell during placebo infusion, consistent with the diurnal variation in cortisol. There was no significant effect of cosyntropin as compared to placebo infusions on serum sclerostin over 6-24 h (P = 0.10). In conclusion, this randomized, placebo-controlled study was unable to detect a significant effect of a cosyntropin infusion on serum sclerostin levels in healthy men and women.

Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway.

[Figure: see text].

Biological sex modifies aldosterone's secretion at a cellular level.

Inconsistencies have been reported on the effect of sex on aldosterone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues' levels. This study's goal was to determine whether ALDO's biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO's biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B2 expression or activity (ALDO levels). Activating the ZG's MR (thereby activating the ultrashort feedback loop) reduced CYP11B2's activity similarly in both sexes. Exvivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO's biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO's circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.

Myeloid Mineralocorticoid Receptor Transcriptionally Regulates P-Selectin Glycoprotein Ligand-1 and Promotes Monocyte Trafficking and Atherosclerosis.

Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex. Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity. Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation.

Associations of trauma and posttraumatic stress disorder with aldosterone in women.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with increased cardiovascular risk, however, underlying mechanisms have not been fully specified. PTSD is associated with stress-related hormones, including dysregulated glucocorticoid activity. Dysregulation of aldosterone, a mineralocorticoid activated by psychological stress and implicated in cardiovascular damage, may be a relevant pathway linking PTSD and cardiovascular risk. Few studies to date have evaluated the association between PTSD and aldosterone, none with repeated measures of aldosterone. We examined if trauma and PTSD were associated with altered aldosterone levels relative to women unexposed to trauma. METHODS: The association of trauma exposure and chronic PTSD with plasma aldosterone levels was investigated in 521 middle-aged women in the Nurses' Health Study II. Aldosterone was assessed at two time points, 10-16 years apart, and trauma exposure and PTSD were also ascertained for both time points. Regarding exposure assessment, women were characterized based on a structured diagnostic interview as: having chronic PTSD (PTSD at both time points; n = 174); being trauma-exposed (trauma exposure at first time point but no PTSD; n = 174); and being unexposed (no trauma exposure at either time point; reference group for all analyses; n = 173). Linear mixed models examined associations of trauma and PTSD status with log-transformed aldosterone levels, adjusting for covariates and health-related variables that may confound or lie on the pathway between PTSD and altered aldosterone levels. RESULTS: Across the sample, mean aldosterone concentration decreased over time. Adjusting for covariates, women with chronic PTSD had significantly lower aldosterone levels averaged over time, compared to women unexposed to trauma (ß = - 0.08, p = 0.04). Interactions between trauma/PTSD group and time were not significant, indicating change in aldosterone over time did not differ by trauma/PTSD status. Post-hoc exploratory analyses suggested that menopausal status partially mediated the relationship between chronic PTSD status and aldosterone level, such that postmenopausal status explained 7% of the effect of PTSD on aldosterone. CONCLUSIONS: These findings indicate that PTSD is associated with lower levels of aldosterone. Further work is needed to understand implications of this type of dysregulation in a key biological stress system for cardiovascular and other health outcomes previously linked with PTSD.

Acute effects of the food preservative propionic acid on glucose metabolism in humans.

INTRODUCTION: Propionic acid (PA) is a common food preservative generally recognized as safe by the US Food and Drug Administration; however, exogenous PA has effects on glucose metabolism that are not fully understood. Our preclinical studies demonstrated exogenous PA increases glucagon, norepinephrine, and endogenous glucose production (EGP). RESEARCH DESIGN AND METHODS: We performed a randomized, placebo-controlled, crossover study in 28 healthy men and women to determine the effect of PA (1500 mg calcium propionate) on these factors. Subjects had two study visits, each preceded by a 1 week, PA-free diet. During each visit, glucose, insulin, glucagon, norepinephrine, epinephrine, and EGP were assessed for 2 hours after oral administration of PA/placebo under resting conditions (protocol 1) and during either a euglycemic (~85-90 mg/dL) or hypoglycemic (~65-70 mg/dL) hyperinsulinemic clamp (protocol 2). RESULTS: PA, as compared with placebo, significantly increased: (1) glucagon and norepinephrine during protocol 1; (2) glucagon, norepinephrine, and epinephrine under euglycemic conditions in protocol 2; and (3) norepinephrine, epinephrine, and EGP under hypoglycemic conditions in protocol 2. CONCLUSION: Oral consumption of PA leads to inappropriate activation of the insulin counterregulatory hormonal network. This inappropriate stimulation highlights PA as a potential metabolic disruptor.