Role of Raptor Gene Variants in Hypertension: Influence on Blood Pressure Independent of Salt Intake in White Population.

BACKGROUND: The mTOR (mechanistic target of rapamycin) is an essential regulator of fundamental biological processes. mTOR forms 2 distinct complexes, mTORC1 (mTOR complex 1) when it binds with RAPTOR (Regulatory-associated Protein of mTOR) and mTORC2 (mTOR complex 2) when it associates with RICTOR (Rapamycin-insesitive companion of mTOR). Due to the previous link between the mTOR pathway, aldosterone, and blood pressure (BP), we anticipated that variants in the mTOR complex might be associated with salt-sensitive BP. METHODS: BP and other parameters were assessed after a one-week liberal Na+ (200 mmol/d) and a one-week restricted Na+ (10 mmol/d) diet in 608 White subjects from the Hypertensive Pathotype cohort, single-nucleotide variants in MTOR, RPTOR, and RICTOR genes were obtained for candidate genes analyses. RESULTS: The analysis revealed a significant association between a single nucleotide variants within the RPTOR gene and BP. Individuals carrying the RPTOR rs9901846 homozygous risk allele (AA) and heterozygous risk allele (GA) exhibited a 5 mm Hg increase in systolic BP on a liberal diet compared with nonrisk allele individuals (GG), but only in women. This single nucleotide variants effect was more pronounced on the restricted diet and present in both sexes, with AA carriers having a 9 mm Hg increase and GA carriers having a 5 mm Hg increase in systolic BP compared with GG. Interestingly, there were no significant associations between MTOR or RICTOR gene variants and BP. CONCLUSIONS: The RPTOR gene variation is associated with elevated BP in White participants, regardless of salt intake, specifically in females.

Mineralocorticoid receptor and aldosterone: Interaction between NR3C2 genetic variants, sex and age in a mixed cohort.

CONTEXT: Hypertension, a prevalent cardiovascular risk, often involves dysregulated aldosterone and its interaction with the mineralocorticoid receptor (MR). Experimental designs in animal models and human cohorts have demonstrated a sex and age dependency of aldosterone secretion that expands our pathophysiologic understanding. OBJECTIVE: This study explores the genetic variation of NR3C2, which encodes MR, in relation to aldosterone, considering age, sex, and race. METHODS: Incorporating 720 Caucasians and 145 Africans from the HyperPATH cohort, we investigated the impact of rs4835490, a single nucleotide risk allele variant, on aldosterone levels and vasculature. RESULTS: Notably, a significant association between rs4835490 and plasma aldosterone under liberal salt conditions emerged in individuals of European ancestry (P=0.0002). Homozygous carriers of the risk A allele exhibited elevated plasma aldosterone levels (AA=8.1±0.9 vs GG=4.9±0.5 ng/dl). Additionally, aldosterone activation through posture (P=0.025) and urinary excretion (P=0.0122) showed notable associations. Moreover, genetic interactions with race, sex, and age were observed. Caucasian females under 50 years displayed higher plasma aldosterone, urine aldosterone, and posture aldosterone with the AA genotype compared to females over 50 years, suggesting a potential connection with menopausal or estrogen influences. Interestingly, such age-dependent interactions were absent in the African cohort. CONCLUSIONS: our study highlights the significance of NR3C2 genetic variation and its interplay with age, sex, and race in aldosterone activation. The findings point towards an estrogen-modulating effect on MR activation, particularly in women underlining the role of aldosterone dysregulation in hypertension development. This insight advances our comprehension of hypertension's complexities and opens avenues for personalized interventions.

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.

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.

ERAP1 Shows Distinct Regulatory Mechanisms on Blood Pressure Modulation Between Males and Females.

The authors have withdrawn their manuscript owing to editing error. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

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.

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.

A candidate locus in the renalase gene and susceptibility to blood pressure responses to the dietary salt.

BACKGROUND: High dietary salt confers a risk of elevating blood pressure (BP) and the development of hypertension. BP to salt intake may be determined in part by individual genetic predisposition. Identifying these genetic underpinnings will enhance our understanding of the biological mechanisms of BP regulation. This study aims to assess the genetic association with salt sensitivity of BP (SSBP) within two well-phenotyped multinational cohorts. METHODS: A total of 720 white participants from the HyperPATH consortium program were selected and genotyped using a multiethnic genotyping array. Individuals consumed two study diets containing high (>200 mEq/day) and low (<10 mEq/day) sodium content, after which SSBP, aldosterone, and plasma renin activity (PRA) were assessed in a controlled inpatient research setting. RESULTS: A top signal (rs10887801; beta = 4.57, P  = 5.03E - 07) at the renalase gene ( RNLS ) region was significantly associated with SSBP. We also identified seven single nucleotide variants with linkage disequilibrium to the top signal at this region that comprised a significant haplotype (TCTTAGTT, P  = 0.00081). Homozygous carriers of the T-risk allele of the key single nucleotide variant had higher SSBP ( P  ≤ 0.00001) and lower PRA ( P  = 0.0076) compared with the nonrisk allele. CONCLUSION: We identified significant associations between genetic variants of the RNLS gene and BP responses to dietary salt intervention and PRA that suggest susceptibility to volume-driven hypertension. These findings may contribute to a better understanding of the genetic mechanisms underlying BP regulation, support the role of RNLS in the pathogenesis of SSBP, and identify individuals who may be at risk from excess dietary salt intake.

Aldosterone and cardiovascular diseases.

Aldosterone's role in the kidney and its pathophysiologic actions in hypertension are well known. However, its role or that of its receptor [minieralocorticoid receptor (MR)] in other cardiovascular (CV) disease are less well described. To identify their potential roles in six CV conditions (heart failure, myocardial infarction, atrial fibrillation, stroke, atherosclerosis, and thrombosis), we assessed these associations in the following four areas: (i) mechanistic studies in rodents and humans; (ii) pre-clinical studies of MR antagonists; (iii) clinical trials of MR antagonists; and (iv) genetics. The data were acquired from an online search of the National Library of Medicine using the PubMed search engine from January 2011 through June 2021. There were 3702 publications identified with 200 publications meeting our inclusion and exclusion criteria. Data strongly supported an association between heart failure and dysregulated aldosterone/MR. This association is not surprising given aldosterone/MR's prominent role in regulating sodium/volume homeostasis. Atrial fibrillation and myocardial infarction are also associated with dysregulated aldosterone/MR, but less strongly. For the most part, the data were insufficient to determine whether there was a relationship between atherosclerosis, stroke, or thrombosis and aldosterone/MR dysregulation. This review clearly documented an expanding role for aldosterone/MR's dysregulation in CV diseases beyond hypertension. How expansive it might be is limited by the currently available data. It is anticipated that with an increased focus on aldosterone/MR's potential roles in these diseases, additional clinical and pre-clinical data will clarify these relationships, thereby, opening approaches to use modulators of aldosterone/MR's action to more precisely treat these CV conditions.

Challenges and Approach to Identifying Individuals with Salt Sensitivity of Blood Pressure.

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is a trait observed in both humans and animals, characterized by an increase in blood pressure (BP) following salt loading or a drop in BP following salt depletion. SUMMARY: This "intermediate" phenotype has been reported in a sizable portion of individuals regardless of their hypertensive status; hypertensives (27-51%), normotensives (18-47%). Further, in epidemiological studies, this phenotype is associated with increased adverse cardiovascular outcomes, risk factors, and reduced survival rates. Herein, we review the challenges in the assessment of SSBP, heterogeneity in the assessment method and protocols, and how these differences could affect the results. Further, we review how to identify individuals with SSBP in the clinic by using clinical and genetic data. No clinical approach has yet provided sufficient sensitivity and specificity to identify those with SSBP. Thus, SSBP is not routinely identified in the clinic. Current genetic data suggest that genotyping may support such an office approach. To date, studies in 18 genes have provided sufficient evidence and reproducible data to identify potential mechanisms involved in subsets of subjects with hypertension and SSBP. KEY MESSAGE: Proof-of-concept clinical trials using genetic biomarkers to determine and treat individuals with SSBP are ongoing. Their results will provide critical evidence to support genetic-focused, mechanistically driven algorithms to identify and treat, specifically, individuals with SSBP - personalized medicine.

Enhanced Thrombotic Responses Are Associated With Striatin Deficiency and Aldosterone.

Background In addition to its role on blood pressure, aldosterone (ALDO) also affects the hemostatic system leading to increased experimental thrombosis. Striatin is an intermediate in the rapid, nongenomic actions of ALDO. Striatin heterozygote knockout (Strn+/-) mice have salt sensitivity of blood pressure and mildly chronically increased ALDO levels. In addition, in humans, striatin polymorphic gene variants are associated with increased salt sensitivity of blood pressure. Thus, we hypothesized that striatin deficiency would be associated with an increased prothrombotic response. Methods and Results Strn+/ - mice and wild-type littermates were maintained on a liberal sodium diet (1.6%). We measured in vivo thrombus formation following laser-induced injury in cremaster arterioles using intravital microscopy. Mice were randomized to intravenous administration of ALDO or its vehicle. Acutely, ALDO increased thrombotic responses in wild-type mice (P<0.01) versus controls within minutes as determined by increased platelet accumulation and fibrin deposition at the site of laser injury. We then compared thrombus formation without ALDO administration in Strn+/- and wild-type mice. Strn+/- mice showed highly significant increases in laser-induced thrombosis (P<0.001), as shown by increased platelet accumulation and fibrin deposition. Interestingly, the response in the Strn+/- mice basally was far greater than the wild-type mice with ALDO administration, and ALDO administration produced no additional effect on thrombus responses in Strn+/- mice. Conclusions These results demonstrate a novel protective role of striatin in experimental thrombosis. Such a protective effect may be reduced in human striatin risk allele carriers, given the similar salt sensitivity of blood pressure in these individuals and Strn+/- mice.

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.

Striatin genotype-based, mineralocorticoid receptor antagonist-driven clinical trial: study rationale and design.

OBJECTIVES: In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN - increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy - a mineralocorticoid receptor antagonist, eplerenone - as compared with a nonspecific anti-hypertensive therapy - amlodipine. METHODS: One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of <140/90 mmHg.Anticipated results We anticipate that STRN risk allele carriers will demonstrate a greater reduction in BP with eplerenone and will require a lower dose of eplerenone to reach goal BP as compared with amlodipine. CONCLUSION: This is a proof-of-concept clinical trial. Positive results support the feasibility of performing genetically-defined, mechanistically-driven trials in HTN. Clinically, it would suggest that genetic biomarkers can identify individuals highly responsive to specific treatment.

Interplay Between Statins, Cav1 (Caveolin-1), and Aldosterone.

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin's aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1-43.2) lower aldosterone level (P=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (P=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (P=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin's aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.

A clinical trial to evaluate the effect of statin use on lowering aldosterone levels.

BACKGROUND: Statins are the first-line pharmaceutical agent in the management of hypercholesterolemia and cardiovascular (CV) risk reduction, and the most commonly prescribed class of drugs worldwide. Studies describing CV risk reduction independent of LDL-cholesterol lowering have evoked an interest in the pleiotropic mechanisms of statins' benefits. We recently demonstrated that administration of statins in animal models lowers aldosterone levels and observed an association between statin use and reduced aldosterone levels in two human cohorts, with lipophilic statins displaying a greater effect than hydrophilic statins. Therefore, we designed a randomized, placebo-controlled, double-blinded intervention study to assess whether statin treatment lowers aldosterone in a type-dependent manner in humans, with simvastatin (lipophilic) showing a greater effect than pravastatin (hydrophilic). METHODS/DESIGN: One hundred five healthy participants will be recruited from the general population to enroll in a 12-week, randomized, placebo-controlled, double-blinded, 3-arm clinical trial. Ninety participants are anticipated to complete the protocol. After baseline assessment of aldosterone levels, participants will be randomized to daily simvastatin, pravastatin, or placebo. Aldosterone levels will be assessed after 2 days on study drug and again after 6 weeks and 12 weeks on study drug. Prior to each aldosterone assessment, participants will consume an isocaloric sodium and potassium-controlled run-in diet for 5 days. Assessments will occur on an inpatient research unit to control for diurnal, fasting, and posture conditions. The primary outcome will compare 12-week angiotensin II-stimulated serum aldosterone by study drug. Secondary outcomes will compare baseline and 12-week 24-h urine aldosterone by study drug. DISCUSSION: Results from this rigorous study design should provide strong support that statins lower aldosterone levels in humans. These results may explain some of the beneficial effects of statins that are not attributed to the LDL-lowering effect of this important class of medications. Results would demonstrate that statin lipophilicity is an important attribute in lowering aldosterone levels. The outcomes of this program will have implications for the design of studies involving statin medications, as well as for the differential use of classes of statins. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02871687 ; First Posted August 18, 2016.

Dietary sodium intake and cortisol measurements.

OBJECTIVES: To assess the influence of a dietary sodium intake intervention on cortisol measurements within the general population. DESIGN: Cross-over intervention. PATIENTS: Six hundred thirty adults without known Cushing syndrome, cardiovascular or renal disease completed a restricted dietary sodium diet (10 mmol/d, 230 mg/d) followed by cross-over to a liberalized dietary sodium diet (200 mmol/d, 4600 mg/d). Twenty-four-hour urine collection and biochemical investigations were performed at the end of each dietary intervention. RESULTS: Mean 24-hour urinary free cortisol increased with liberalized sodium intake when compared with restricted sodium intake (178.0 ± 89.7 vs 121.3 ± 65.6 nmol/d, P < .001). Nearly all participants (84%) had an increase in the urinary free cortisol following liberalized sodium intake. This translated to a substantial difference in the proportion of participants exceeding categorical thresholds of urinary cortisol on liberalized vs restricted sodium intake: 62% vs 27% for 138 nmol/d (50 mcg/d), 46% vs 17% for 166 nmol/d (60 mcg/d), 32% vs 10% for 193 nmol/d (70 mcg/d), 23% vs 6% for 221 nmol/d (80 mcg/d), 17% vs 4% for 248 nmol/d (90 mcg/d). In parallel, there was a small decrease in morning total serum cortisol with liberalized sodium intake (303.0 ± 117.3 vs 326.4 ± 162.5 nmol/L, P < .001). CONCLUSIONS: Increased dietary sodium intake increases urinary free cortisol excretion and may increase the risk for false-positive results. Variations in dietary sodium intake may influence the interpretations of cortisol measurements performed to evaluate for hypercortisolism.