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.

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.

A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development.

The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.

GNAI2 polymorphic variance associates with salt sensitivity of blood pressure in the Genetic Epidemiology Network of Salt Sensitivity study.

Salt sensitivity of blood pressure (BP) increases hypertension risk and associated adverse cardiovascular outcomes. At present, there are no validated rapid tests or diagnostic markers to identify salt sensitivity of BP in clinical practice. Based on our prior animal studies that report a role for brain Gαi2 proteins in the salt sensitivity of BP and evidence that GNAI2 single nucleotide polymorphisms (SNPs) associate with hypertension risk, we investigated the hypothesis that GNAI2 SNPs associate with salt sensitivity of BP in humans. Our data provide the first evidence that a GNAI2 SNP ( rs10510755 ) positively associates with salt sensitivity of BP in the Genetic Epidemiology of Salt Sensitivity data set (continuous phenotype P = 0.049, case-control phenotype P = 0.039; n = 968), independently of subject sex or age. These observations suggest that genotyping at GNAI2 may be a useful biomarker in identifying individuals at risk for developing salt-sensitive BP and related complications or in identifying salt sensitivity within the hypertensive population.

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium.

The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway.

BACKGROUND: VEGF signaling pathway inhibitor (anti-VEGF) therapy is associated with hypertension, but little is known about predisposing clinical characteristics. This study describes the real-world association between baseline clinical characteristics, blood pressure (BP) response, and survival in patients prescribed anti-VEGF therapies. METHODS: Clinical data from Partners HealthCare in Massachusetts was obtained from adults treated with anti-VEGF therapies (2002-2013). Treatment-induced hypertensive response was defined as worsening of preexisting hypertension or new diagnosis of hypertension (if no prior hypertension history). RESULTS: Data from 1120 patients with renal cell carcinoma (32.2%), hepatocellular carcinoma (11.6%), gastrointestinal stromal tumors (12.5%), and other sarcomas (15.3%) were analyzed. Most patients received sunitinib (52%), sorafenib (25.9%), or pazopanib (18%). A treatment-induced hypertensive response was identified in 49.7% of treated patients. Preexisting hypertension, present in 65.4%, was an independent risk factor for BP elevation (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.27-1.92); other risk factors included age ≥60 years (OR, 1.26; 95% CI, 1.06-1.52), and body mass index (BMI) ≥25 kg/m(2) (OR, 1.26; 95% CI, 1.04-1.53). Race, sex, anti-VEGF therapy prescribed, and baseline antihypertensive class were not significant risk factors. The absolute observed mean increase in BP was 21 mm Hg (systolic)/15 mm Hg (diastolic), both in patients with and without preexisting hypertension. The development of hypertension predicted improved survival (hazard ratio, 0.76; 95% CI, 0.65-0.89). CONCLUSIONS: Preexisting hypertension, age, and BMI identify patients at risk for significant anti-VEGF therapy-induced BP elevation. Hypertension appears to be a clinical biomarker of efficacy of anti-VEGF therapies in a broad range of malignancies.

Merkel cells and touch domes: more than mechanosensory functions?

The touch dome (TD) is an innervated structure in the epidermis of mammalian skin. Composed of specialized keratinocytes and neuroendocrine Merkel cells, the TD has distinct molecular characteristics compared to the surrounding epidermal keratinocytes. Much of the research on Merkel cell function has focused on their role in mechanosensation, specifically light touch. Recently, more has been discovered about Merkel cell molecular characteristics and their cells of origin. Here we review Merkel cell and TD biology, and discuss potential functions beyond mechanosensation.

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.

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.

Eating during the biological night is associated with nausea.

OBJECTIVES: This study assessed whether there was a time-of-day effect on nausea reports in participants during studies employing circadian protocols. METHODS: Visual-analog-scales of nausea ratings were recorded from 34 participants (18-70years; 18 women) during forced desynchrony studies, where meals were scheduled at different circadian phases. Subjective nausea reports from a further 81 participants (18-35years; 36 women) were recorded during constant routine studies, where they ate identical isocaloric hourly snacks for 36-40 hours. RESULTS: Feelings of nausea varied by circadian phase in the forced desynchrony studies, peaking during the biological night. Nausea during the constant routine was reported by 27% of participants, commencing 2.9 ± 5.2 hours after the midpoint of usual sleep timing, but was never reported to start in the evening (4-9 PM). CONCLUSIONS: Nausea occurred more often during the biological night and early morning hours. This timing is relevant to overnight and early morning shift workers and suggests that a strategy to counteract that is to pay careful attention to meal timing.

Evaluating hormonal mechanisms of vitamin D receptor agonist therapy in diabetic kidney disease: the VALIDATE-D study.

BACKGROUND: Insufficient vitamin D status and increased renin-angiotensin system (RAS) activity have been associated with renal-vascular disease and nephropathy in diabetes. Accumulating evidence indicates that vitamin D receptor (VDR) activation lowers unfavorable RAS activity; however, more human intervention studies evaluating whether this mechanism could influence diabetic kidney disease are needed. We previously reported that both vitamin D levels and genetic variation at the VDR predict human RAS activity, and that vitamin D therapy can lower RAS activity in non-diabetics. The VALIDATE-D study is a randomized, placebo-controlled, intervention study designed to extend these findings by evaluating whether direct VDR activation in diabetes lowers circulating and local renal-vascular tissue RAS activity (Aims 1 and 2) in a manner similar to the action of ACE inhibitors (Aim 3). METHODS/DESIGN: Forty subjects with type 2 diabetes, microalbuminuria, and without chronic kidney disease will be recruited to undergo detailed assessment of the RAS before and after randomization to calcitriol 0.75 mcg/day or placebo. Primary analyses will evaluate whether calcitriol therapy reduces circulating and renal-vascular tissue-RAS activity in comparison to placebo. All subjects will thereafter be treated with lisinopril and followed for 3.5 months to evaluate whether combination therapy (calcitriol + lisinopril vs. placebo + lisinopril) additively or synergistically improves renal-vascular function, and lowers proteinuria. DISCUSSION: The VALIDATE-D study is the first human intervention study to evaluate whether direct VDR activation can lower the human RAS in diabetes, compared to the effect of an ACE inhibitor, and whether this mechanism can translate to clinically relevant endpoints for diabetic kidney disease. The outcomes of VALIDATE-D will have major implications for the recommendation of vitamin D supplementation for the primary prevention of kidney complications in diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01635062.

Targeting the hedgehog pathway to treat basal cell carcinoma.

The discovery of mutations that activate hedgehog (Hh) signaling in basal cell carcinoma (BCC) and other cancers has spurred the development of small molecule inhibitors that target the Hh pathway. High-throughput screens have identified a number of drug candidates that antagonize smoothened (SMO), an essential protein in the Hh signaling pathway. Clinical studies of the oral SMO inhibitor vismodegib (GDC-0449) in patients with inoperable or metastatic BCC have led to its recent approval by the US Food and Drug Administration. This review aims to give the clinician an overview of vismodegib and other Hh pathway inhibitors in the treatment of patients with advanced BCC and basal cell nevus syndrome. Issues of drug mechanism, efficacy, safety, tolerability, and tumor resistance are addressed.

Economic Evaluation of Artificial Intelligence Systems Versus Manual Screening for Diabetic Retinopathy in the United States.

BACKGROUND: The objective of this economic modeling study was to compare the cost effectiveness of fully automated retinal image screening (FARIS) to the current practice of universal ophthalmologist referral for diabetic retinopathy in the United States (US) health care system. METHODS: A Markov decision-analytic model was used to compare the automated versus manual screening and management pathway for diabetic patients with unknown retinopathy status. Costs (in 2021 US dollars), quality-adjusted life year (QALY) gains, and incremental cost-effectiveness ratios were calculated. Sensitivity analysis was performed against a $50,000/QALY willingness-to-pay threshold. RESULTS: FARIS was the dominant screening strategy, demonstrating cost savings of 18.8% at 5 years with equivalent net QALY gains to manual screening. Cost-effectiveness status was dependent on FARIS detection specificity, with a threshold value of 54.8%. CONCLUSION: Artificial intelligence-based screening represents an economically advantageous screening modality for diabetic retinopathy in the US, offering equivalent long-term utility with significant potential cost savings. [Ophthalmic Surg Lasers Imaging Retina 2023;54:272-280.].

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.

Longitudinal changes in blood pressure are preceded by changes in albuminuria and accelerated by increasing dietary sodium intake.

BACKGROUND: Dietary sodium is a well-known risk factor for cardiovascular and renal disease; however, direct evidence of the longitudinal changes that occur with aging, and the influence of dietary sodium on the age-associated alterations are scarce. METHODS: C57BL/6 mice were maintained for 13 months on a low (LS, 0.02 % Na+), normal (NS, 0.3 % Na+) or high (HS, 1.6 % Na+) salt diet. We assessed 1) the longitudinal trajectories for two markers of cardiovascular and renal dysfunction (blood pressure (BP) and albuminuria), as well as hormonal changes, and 2) end-of-study cardiac and renal parameters. RESULTS: The effect of aging on BP and kidney damage did not reach significance levels in the LS group; however, relative to baseline, there were significant increases in these parameters for animals maintained on NS and HS diets, starting as early as month 7 and month 5, respectively. Furthermore, changes in albuminuria preceded the changes in BP relative to baseline, irrespective of the diet. Circulating aldosterone and plasma renin activity displayed the expected decreasing trends with age and dietary sodium loading. As compared to LS - higher dietary sodium consumption associated with increasing trends in left ventricular mass and volume indices, consistent with an eccentric dilated phenotype. Functional and molecular markers of kidney dysfunction displayed similar trends with increasing long-term sodium levels: higher renovascular resistance, increased glomerular volumes, as well as higher levels of renal angiotensin II type 1 and mineralocorticoid receptors, and lower renal Klotho levels. CONCLUSION: Our study provides a timeline for the development of cardiorenal dysfunction with aging, and documents that increasing dietary salt accelerates the age-induced phenotypes. In addition, we propose albuminuria as a prognostic biomarker for the future development of hypertension. Last, we identified functional and molecular markers of renal dysfunction that associate with long-term dietary salt loading.

Lysine-specific demethylase 1 deficiency modifies aldosterone synthesis in a sex-specific manner.

Biologic sex influences the development of cardiovascular disease and modifies aldosterone (ALDO) and blood pressure (BP) phenotypes: females secrete more ALDO, and their adrenal glomerulosa cell is more sensitive to stimulation. Lysine-specific demethylase 1 (LSD1) variants in Africans and LSD1 deficiency in mice are associated with BP and/or ALDO phenotypes. This study, in 18- and 40-week-old wild type (WT) and LSD1+/- mice, was designed to determine whether (1) sex modifies ALDO biosynthetic enzymes; (2) LSD1 deficiency disrupts the effect of sex on these enzymes; (3) within each genotype, there is a positive relationship between ALDO biosynthesis (proximate phenotype), plasma ALDO (intermediate phenotype) and BP levels (distant phenotype); and (4) sex and LSD1 genotype interact on these phenotypes. In WT mice, female sex increases the expression of early enzymes in ALDO biosynthesis but not ALDO levels or systolic blood pressure (SBP). However, enzyme expressions are shifted downward in LSD1+/- females vs males, so that early enzyme levels are similar but the late enzymes are substantially lower. In both age groups, LSD1 deficiency modifies the adrenal enzyme expressions, circulating ALDO levels, and SBP in a sex-specific manner. Finally, significant sex/LSD1 genotype interactions modulate the three phenotypes in mice. In conclusion, biologic sex in mice interacts with LSD1 deficiency to modify several phenotypes: (1) proximal (ALDO biosynthetic enzymes); (2) intermediate (circulating ALDO); and (3) distant (SBP). These results provide entry to better understand the roles of biological sex and LSD1 in (1) hypertension heterogeneity and (2) providing more personalized treatment.

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.

Brief cognitive-behavioral treatment for avoidant/restrictive food intake disorder in the context of functional dyspepsia: Study protocol for a feasibility randomized controlled trial.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) symptoms are common (up to 40%) among adults with functional dyspepsia (FD), a disorder of gut-brain interaction characterized by early satiation, post-prandial fullness, epigastric pain, and/or epigastric burning. Using an 8-session exposure-based cognitive-behavioral treatment (CBT) for adults with FD + ARFID compared to usual care (UC) alone, we aim to: (1) determine feasibility, (2) evaluate change in clinical outcomes in, and (3) explore possible mechanisms of action. METHODS: We will randomize adults with FD who meet criteria for ARFID with ≥5% weight loss (N = 50) in a 1:1 ratio to CBT (with continued UC) or to UC alone. A priori primary benchmarks will be: ≥75% eligible participants enroll; ≥75% participants complete assessments; ≥70% participants attend 6/8 sessions; ≥70% of sessions have all content delivered; ≥70% participants rate Client Satisfaction Questionnaire scores above scale midpoint. We will also examine the size of changes in FD symptom severity and related quality of life within and between groups, and explore possible mechanisms of action. CONCLUSIONS: Findings from this trial will inform next steps with treatment development or evaluation-either for further refinement or for next-step efficacy testing with a fully-powered clinical trial.

Physical Activity and the Acute Hemodynamic Response to ACE Inhibition in Hypertension.

Introduction. Physical activity (PA) can reduce blood pressure (BP) in hypertensives through possibly interacting with the renin-angiotensin-aldosterone system (RAAS). We conducted a nested-cohort analysis to determine if self-reported PA was associated with BP responsiveness to acute angiotensin converting enzyme inhibition (ACEi). Methods. Data were extracted from the HyperPATH dataset, a cohort designed to identify mechanisms of cardiometabolic risk. Hypertensives that completed a self-assessed PA questionnaire, hormonal assessments (aldosterone [ALDO]), and BP to a single dose of an ACEi (captopril, 25 mg) were included. All participants (n = 144) were studied on a controlled diet for 7 days. PA was recorded as no PA, or little, moderate, or high amounts of exercise. Analyses were adjusted for age, sex, race, and body mass index. Results. Individuals who reported high amounts of PA displayed a greater BP lowering effect from ACEi compared to those who reported moderate (-14.8 ± 8.1 vs -8.4 ± 9.9 mm Hg, P < .01) or no additional PA (-14.8 ± 8.1 vs -2.6 ± 9.9 mm Hg, P < .001). Exploratory analyses indicated high amounts of PA were associated with a reduced heart rate (54 ± 8 vs 66 ± 10 bpm, P < .001) and blunted ALDO (ß = 0.44, 95% confidence interval = 0.19-0.70). Conclusions. Higher self-reported PA was associated with an augmented BP lowering effect to acute ACEi in hypertensive patients.