Hypertension

Modulation of renal nerves to improve blood pressure (BP) control has become a topic of intense investigation over the last 10-15 years. Given that renal innervation is composed of mixed nerve fibers containing both afferent (sensory) and efferent (sympathetic) fibers, subsequent preclinical studies have been investigating their respective roles in hypertension pathobiology in different genetic and salt-sensitive rat models. Here we set out to investigate how renal afferent and efferent nerves regulate hypertension development in the chronic mild stress model (CMS). We show that in male CMS rats, ablation of afferent renal nerves (ARDNx) and all renal nerves (TRDNx) resulted in similar BP (104 {+/-} 2 mmHg vs. 101 {+/-} 3 mmHg, respectively), both reduced compared to the SHAM group (118 {+/-} 1 mmHg, p = 0.003 and p < 0.001, respectively) arguing for a prominent role of afferent renal nerves in CMS hypertension. Additionally, we show a reduction of vasopressin (AVP) V1b but not V1a receptor abundance in ARDNx CMS males but not females, suggesting that afferent renal nerves are involved in increase in BP via V1b AVP receptor. We additionally show that despite normal BP, female CMS rats display increased renal sympathetic nerve activity (RSNA; 2.39 {+/-} 0.23 bursts/beat vs. 1.44 {+/-} 0.12 bursts/beat, p < 0.005) measured directly with implanted telemetry in conscious rats over one week and aortic stiffness, as evidenced by increased aortic pulse wave velocity (173.2 {+/-} 50.9 mm/s vs. - 10.7 {+/-} 54.6 mm/s in controls, p = 0.0393). NEW & NOTEWORTHYWe show that renal denervation mitigates the rise in blood pressure (BP) in a model that is not genetic nor diet-dependent, the chronic mild stress model (CMS). Specifically, we demonstrate the role of afferent, rather than efferent, renal nerves in mediating the rise in BP in male CMS rats. Finally, we report that renal sympathetic nerve activity, but not BP, is elevated in female CMS rats measured by telemetry over seven days in conscious rats.

Primary aldosteronism (PA) is a common cause of secondary hypertension. To investigate its genetic basis, we perform a trans-ancestry genome-wide association study (GWAS) meta-analysis, with subtype-specific analyses for aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). Subsequently, we conduct genetic mediation analysis to partition PA effects on cardiovascular outcomes into blood pressure (BP)-mediated and BP-independent components. We further use a genetic risk score (GRS) to assess whether polygenic susceptibility to PA is associated with aldosterone-related traits in both population-based and PA case cohorts. We report 19 PA loci, including 13 new loci. While PA shares a broad polygenic framework across ancestries, subtype-specific heterogeneity exists, most notably at TARID/TCF21, which is preferentially associated with APA. A substantial proportion of the association between PA and cardiovascular disease is independent of systolic BP, particularly for heart failure and ischemic stroke. In population-based cohorts, a higher PA GRS is associated with higher systolic BP, lower serum potassium, and higher aldosterone levels, whereas in PA cases, particularly BAH, a higher GRS is linked to more severe aldosterone excess. Our results suggest that subclinical autonomous aldosterone excess exists along a continuous genetic spectrum across the population and that PA drives cardiovascular disease through substantial BP-independent pathways.

BackgroundHypertension, the persistent elevation of blood pressure (BP), is characterized by chronic low-grade inflammation and systemic cytokine release. Circulating cytokines contribute to the development of hypertension and end-organ damage. However, the specific immune profile associated with the progression of hypertension remains unclear. We hypothesize that a plasma cytokine signature reflects early BP changes in older adults. MethodsSeventy participants aged 57-81 years were categorized as normotensive (n = 17), elevated BP (n = 10), or hypertensive (n = 43) based on 24-hour ambulatory BP monitoring and antihypertensive treatment status. Plasma IL-1{beta}, IL-6, IL-10, IL-17A, IL-21, IL-22, IL-23, and TNF- were quantified using immunoassays. Partial Pearson correlations adjusted for demographic and biochemical covariates were used to assess associations between cytokines, BP, and cytokine-cytokine networks. ResultsIn untreated hypertensive individuals, plasma IL-23 was positively correlated with 24-hour diastolic BP. Antihypertensive treatment was associated with reduced IL-17A concentrations, which are negatively associated with 24-hour systolic BP. In the elevated BP group, IL-21 concentrations were higher than in normotensive individuals. To further characterize the cytokine signature, cytokine-cytokine correlations were examined. IL-23 and IL-17A were positively correlated with most interleukins, whereas TNF- showed few associations. IL-1{beta} exhibited strong correlations with both IL-23 and IL-17A, particularly in untreated participants. ConclusionIL-23 and IL-17A are associated with BP status and are broadly interconnected with other inflammatory cytokines, highlighting the potential importance of the IL-23/IL-17A axis in the hypertension of development. Early alterations in IL-21 in elevated BP may reflect immune changes that precede the onset of hypertension.

Background: Electrocardiographic (ECG) markers of atrial cardiopathy (AC) are associated with stroke mortality, but whether this association is modified by blood pressure (BP) is unknown. Methods: We analyzed 7,191 adults free of cardiovascular disease from the Third National Health and Nutrition Examination Survey who underwent baseline ECG. AC was defined by three ECG markers: prolonged P-wave duration 120 ms), abnormal P-wave axis (<0{degrees} or >75{degrees}), and deep terminal negativity of the P wave in V1 (<100 V). AC burden (per additional AC marker) and AC presence (1 vs. 0 markers) were examined in relation to stroke mortality using Cox proportional hazards models. Participants were stratified by BP as normal/elevated (<130/80 mmHg), stage 1-2 hypertension (130-159/80-99 mmHg), or severe hypertension (160/100 mmHg). Interaction by BP category was assessed. Results: During a median follow-up of 13.8 years, 183 stroke deaths occurred. In multivariable adjusted model, AC burden was associated with a 41% higher risk of stroke mortality (HR (95%CI): 1.41 (1.13-1.77)). This association was significantly modified by BP (interaction P=0.003). The HRs (95% CIs) per additional AC marker were 0.88 (0.52-1.49), 1.39 (1.03-1.88), and 2.94 (1.82-4.75) for normal/elevated BP, stage 1-2 hypertension, and severe hypertension, respectively. A similar pattern of associations was observed for AC presence, although the interaction with BP was not statistically significant. Conclusions: ECG-defined AC burden was independently associated with stroke mortality, with substantially stronger associations among individuals with severe hypertension, supporting BP as an important modifier of its prognostic significance.

Background. The imprecision of current metrics to capture the complex genetic admixture and racial identity among Hispanic/Latino individuals in the United States [US] is a concern. We examined the relationship of self-reported race and genetic ancestry with hypertension [HTN] among Hispanics/Latinos. Methods. Cross-sectional study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), including 10,586 Hispanic/Latino unrelated adults. Genetic ancestry: West African [AA], Amerindian [AI], and European [EA]. Self-reported race: White, Black, Native American, or Multiple/Missing (More than one race or Unknown/Not reported/Refused). HTN: systolic (SBP) [&ge;]130 mmHg, diastolic blood pressure (DBP) [&ge;]80 mmHg, and/or use of HTN medications. Age- and sex adjusted models were used. Results. Self-reported race was White (38{middle dot}6%), Black (3{middle dot}6%), Native American (4{middle dot}1%), and Multiple/Missing (53{middle dot}7%), with Unknown/Not reported/Refused representing 32{middle dot}7%. Black and White Hispanics/Latinos had the greatest AA (55{middle dot}7%) and EA (69{middle dot}3%) ancestries, respectively. Each 10% AA increase was associated with OR 1{middle dot}15, SBP beta +0{middle dot}9 mmHg, and DBP beta +0{middle dot}7 mmHg. Conversely, each 10% AI increase was associated with OR 0{middle dot}83, SBP beta -0{middle dot}4 mmHg, and DBP beta -0{middle dot}6 mmHg. HTN prevalence was highest among those with Black race or in the highest AA quantile (45{middle dot}6% and 48{middle dot}0%, respectively), and lowest among those with Native American race or in the highest AI quantile (37{middle dot}6% and 26{middle dot}7%, respectively). Conclusion. One-third of Hispanics/Latinos did not self-report race. Black or White self-reporting race did somewhat relate to AA or EA ancestry, respectively. HTN profiles were related to self-reported race and genetic ancestry in this admixed population.

Objectives: To characterize how completely and promptly summary results are reported for registered hypertension trials on ClinicalTrials.gov, and whether reporting correlates with the observable obligation to report. Methods: Cross-sectional analysis of completed or terminated interventional trials for hypertension, retrieved through the ClinicalTrials.gov API version 2. Trials required a primary completion date of type ACTUAL at least 12 months before extraction. Reporting was timed from primary completion to first results submission and classified as timely at 365 days or fewer. Applicability was approximated requiring interventional design, phase 2 or later, a United States site, and an FDA-regulated drug or device, assigned flag-confirmed or inferred. Proportions are reported with Wilson 95% confidence intervals, time to reporting by Kaplan-Meier, and adjusted associations by logistic regression clustered on lead sponsor. Results: Of 5,851 trials, 5,396 were due to report. Timely reporting was 9.1% (95% CI 8.3-9.9) and any-time reporting 28.8% (95% CI 27.6-30.0). Reporting was graded by applicability, with flag-confirmed trials reporting timely at 36.9% (95% CI 31.6-42.5) and non-applicable trials at 6.3% (95% CI 5.6-7.1). A United States site carried the strongest adjusted association with timely reporting (OR 4.03, 95% CI 2.99-5.42). Among unreported trials, 7.8% had a sponsor-tagged publication and 36.4% under a broader definition. Conclusion: Prompt registry reporting of hypertension trial results remains uncommon, and reporting is most closely associated with the observable obligation to report.

Intracranial aneurysms (IA) and their rupture (subarachnoid haemorrhage, SAH) are a rare but serious complication of autosomal dominant polycystic kidney disease (ADPKD). Both genetic and environmental risk factors contribute to the pathogenesis of IA and SAH, but specific information on risk factors in the ADPKD population are limited and international clinical guidelines mainly recommend screening for ADPKD patients with a family history of IA or SAH. We assessed the associations of monogenic variants, polygenic risk, and clinical factors with the diagnosis of IA or SAH in 2,200 adult ADPKD patients from three cohorts: the Irish Kidney Gene Project (IKGP, n=475), FinnGen (n=826), and Genomics England (GEL, n=899). Polygenic risk scores (PRS) for IA, hypertension, and smoking intensity were derived from previously published GWAS summary statistics and additionally conditioned using mtCOJO to account for their genetic correlation. IA or SAH was diagnosed in 158 of 2,200 patients (7.2%; mean age at diagnosis 51.1 years). Female sex (HR 2.21, 95% CI 1.50-3.25, p=6.52x10^-5) and smoking (HR 2.06, 95% CI 1.43-2.96, p=9.49x10^-5) were associated with IA or SAH in univariate Cox proportional hazards models, while diabetes was protective (HR 0.39, 95% CI 0.22-0.70, p=1.37x10^-3). Monogenic variant status was not found to associate with increased risk of IA or SAH. Polygenic score for IA was associated with increased risk of IA or SAH, with a 1 standard deviation increase in PRS associated with a pooled hazard ratio (HR) of 1.30 (95% CI 1.09-1.57, p=4.66x10^-3), and the association of the conditioned IA PRS remained in multivariate Cox proportional hazards models accounting for clinical factors and monogenic variants (HR 1.26, 95% CI 1.03-1.55, p=0.02). The addition of polygenic scores added significant prognostic information for IA or SAH beyond clinical risk factors in FinnGen (p=3.61x10^-3) and GEL (p=8.84x10^-3) but not in IKGP, as assessed by the likelihood ratio test. Overall, our study shows that the strongest risk factors for IA or SAH in ADPKD patients are smoking history, female sex, and polygenic risk for IA. Hypertension was not associated with IA (HR 0.50, 95% CI 0.24-1.00, p=0.051), likely due to the high prevalence of hypertension in this population across cohorts (69.6-85.3%). While family history may be considered a proxy of genetic risk, this study suggests that family history itself may be of limited utility in discriminating individuals with ADPKD at risk of IA or SAH. Keywords: Intracranial Aneurysms, subarachnoid haemorrhage, Autosomal Dominant Polycystic Kidney Disease, Polygenic Risk Scores, Hypertension, Family History

BackgroundHydrogen sulfide (H2S) is an important endothelial-derived vasodilator, but the signaling mechanism remains incompletely understood. We previously demonstrated that H2S-mediated vasodilation requires transient receptor potential vanilloid type 4 (TRPV4) channels. Because H2S has been reported to enhance heme oxygenase (HO) activity and HO-derived carbon monoxide (CO) regulates endothelial signaling, we hypothesized that H2S-mediated vasodilation requires HO-2-derived CO. MethodsPressure myography was performed in isolated rat mesenteric arteries to determine the contribution of HO, TRPV4, eBK, and SK/IK channels to H2S-mediated vasodilation. HO-2 sulfhydration was assessed using a maleimide assay, and spatial association among HO-2 and TRPV4 was examined using proximity ligation assays in human aortic endothelial cells. ResultsH2S Selicited concentration-dependent vasodilation that was abolished by HO inhibition. Repletion of CO restored H2S-mediated vasodilation in the presence of HO inhibition. CO-mediated vasodilation was abolished by TRPV4 and SK/IK inhibition but was unaffected by eBK inhibition. H2S increased HO-2 sulfhydration and enhanced HO activity. In endothelial cells, HO-2 and TRPV4 exhibited close spatial association. ConclusionsThese findings support a model in which H2S stimulates HO-2-derived CO production, leading to TRPV4-dependent endothelial signaling, SK/IK activation, and vasodilation. Together, the data support the existence of an endothelial HO-2/TRPV4/SK/IK signaling domain that contributes to H2S-mediated vascular reactivity.

TRPV4 ion channels in vascular smooth muscle cells (SMCs) are crucial regulators of blood pressure, and their functional effects are differentially shaped by their signaling partners. However, the mechanisms by which TRPV4 channels are compartmentalized into distinct signaling nanodomains with opposite impacts on blood pressure remain unclear. Here, we identify the scaffolding proteins that compartmentalize TRPV4 channels into discrete nanometer-scale signaling domains at the SMC plasma membrane and define how these nanodomains produce opposing effects on vasoconstriction and blood pressure. We show that AKAP5 anchors a nanodomain linking 1-adrenergic receptors, protein kinase C and TRPV4 channels, thereby driving sympathetic vasoconstriction and blood pressure elevation. In contrast, caveolin-1 promotes a mechanosensitive nanodomain comprising Piezo1, TRPV4, and BK channels that mediates vasodilation and a decrease in blood pressure. In hypertension, AKAP5-dependent constrictor nanodomains are hyperactive, whereas caveolin-1-based dilator nanodomains are hypoactive, shifting the balance toward pathological vasoconstriction. These findings reveal fundamental mechanisms that organize smooth muscle TRPV4 channels into spatially and functionally distinct nanodomains regulating blood pressure and show how disruption of this organization contributes to blood pressure elevation in hypertension.

The urinary bladder functions to store and release urine, yet how the sensation of bladder fullness is conveyed and perceived to the central nervous system is not understood. During bladder filling, the detrusor smooth muscle (DSM) generates phasic contractions, resulting in pressure fluctuations within the bladder. These transient pressure events drive bursts of afferent nerve activity, yet the underlying mechanism leading to rhythmic contractions remains unclear. Here, we examined the role of Gq protein-coupled receptor (GqPCR) activity on DSM excitability and contractility. Using ex vivo pressurized urinary bladder preparations and sharp microelectrode experiments on bladder strips from mice, we evaluated whole bladder transient pressure events, whole bladder DSM Ca2+ activity, and membrane potential in bladder strips. We found that global inhibition of urinary bladder GqPCR activity with YM-254890 abates phasic contractility and transient pressure events through a reduction in DSM Ca2+ activity and propagation of Ca2+ waves. Further, we found inhibition of GqPCR significantly hyperpolarizes DSM, reducing action potentials and decreasing excitability, and activation of protein kinase C restores membrane potential to baseline levels. These findings highlight that GqPCR activity mediates DSM excitability and contractility in such a way as to result in phasic detrusor contractions and transient pressure events.

Background Hypertension is a major global health challenge with well-established cardiovascular risks, yet its relationship with bone mineral density and the skeletal relevance of antihypertensive-related targets remain unclear. Methods Based on individual-level data from 366,443 European-ancestry participants in the UK Biobank, this study adopted restricted cubic spline models to explore linear and nonlinear associations between systolic/diastolic blood pressure (SBP/DBP) and heel estimated bone mineral density (BMD). We stratified participants by median DBP to conduct systematic biomarker analyses covering renal, endocrine, inflammatory and metabolic indicators. Drug-target Mendelian randomization (MR) combined with colocalization and mediation analyses was further performed to identify and validate causal antihypertensive-related target genes associated with BMD. Results A significant inverted U-shaped association was identified between DBP and BMD (P non-linear=3.23e-9), with peak BMD observed at a DBP of 80-90 mmHg, while SBP showed a trend of nonlinear correlation. Biomarker analyses revealed that renal biomarker cystatin C and endocrine biomarker IGF-1 exhibited DBP-dependent associations with BMD, mediating the nonlinear DBP-bone density relationship. Drug-target MR demonstrated that genetically proxied MMP9 expression (ACE inhibitor-related) was negatively correlated with BMD (beta=-0.036, P=5.29e-6), whereas CACNA1G expression (T-type calcium channel blocker target) was positively associated with BMD (beta=0.042, P=1.57e-9). Conclusion The inverted U-shaped association between blood pressure and bone mass might partly reflected by renal dysfunction. Antihypertensive pathways mediated by MMP9 and CACNA1G exert opposing effects on bone mass, implying that skeletal health should be considered when selecting antihypertensive agents for vulnerable older populations.

Objectives To validate two computational fluid dynamics (CFD) models derived from computed tomography angiography (CTA) for estimating trans-stenotic pressure gradients, using invasive intra-arterial pressure measurements as the reference standard in patients with renal artery stenosis (RAS). Background We assessed whether non-invasive assessment of the pressure gradient using CFD could be a reliable alternative to intra-arterial measurements for identifying hemodynamically significant RAS. Methods We performed intra-arterial measurements at rest and during dopamine-induced hyperemia to assess the trans-stenotic pressure gradient in 28 patients with RAS. A pre-intervention CTA scan was used to simulate the pressure gradient with a CFD model using a strategy based on Murray's law (CFD-Mu) and cortical volume (CFD-C). The agreement between the simulated and measured pressure gradients was assessed using intraclass correlation coefficients (ICC), Bland-Altman analysis and diagnostic agreement on the presence of a hemodynamically significant stenosis. Results In 20 patients, successful measurements and simulations were obtained. The ICC between measured pressure gradient and the CFD pressure gradient was 0.78 and 0.94 during baseline and 0.86 and 0.72 during hyperemia, for CFD-Mu and CFD-C, respectively. The sensitivity of CFD-Mu and CFD-C was 70% for both models at rest and 100% compared to the hyperemic measurements, whereas the specificity was 90% and 70% at rest and 79% and 72% during hyperemia, respectively. Conclusions The results support the use of individualized CFD simulations for hemodynamic assessment of RAS using CTA as input. The CFD models demonstrated high accuracy for the identification of a hemodynamically significant stenosis.

Background: Hyperkalemia is a clinically relevant disorder across the cardiorenal continuum. In Central America and the Dominican Republic, there are no published systematic descriptions of real-world clinical practices or the degree of alignment of these practices with the most recent hyperkalemia management guidelines. Objective: To characterize physicians perceptions and therapeutic behaviors regarding hyperkalemia, including diagnostic thresholds, criteria for intervention and referral, management strategies, and access to potassium monitoring. Methods: A cross-sectional study was conducted using an online survey administered between April and June 2025 to physicians from multiple specialties across seven countries. Absolute and relative frequencies were calculated overall and stratified by specialty and country. Results: A total of 362 responses were collected. Participants were primarily from Costa Rica (32.3%), Honduras (27.9%), and Guatemala (21.0%). 37.8% of respondents reported hyperkalemia in 10% to 30% of their patients, with the most reported diagnostic threshold being serum potassium 5.5 mEq/L. Outpatient intervention was most frequently initiated at 5.5 mEq/L (55.2%), while referral to the emergency department was reported at a potassium level of 6.0 mEq/L (35.6%). Regarding management strategies, 67.0% favored an electrocardiogram prior to deciding on intervention; 93.0% reported reduction or discontinuation of drug causing hiperkalemia; and 74.0% prescribed therapies increasing potassium excretion. Access to potassium monitoring differed substantially by setting reported as 55.5% in the public versus 90.3% in the private sector. Among cardiologists, frequently used strategies for hyperkalemia in heart failure were reduction or discontinuation of mineralocorticoid receptor antagonists and increased use of loop diuretics. Nephrologists favored strict dietary modifications, loop diuretics, and the use of cation-exchange resins. Conclusions: Substantial heterogeneity was observed in hyperkalemia definitions, action thresholds, and referral criteria, along with frequent modification of renin-angiotensin-aldosterone inhibitors, and reduced access to potassium monitoring in the public sector.

Introduction: Severe hypercholesterolemia has four primary causes: monogenic familial hypercholesterolemia (FH), polygenic hypercholesterolemia (PRS), severely elevated Lp(a) concentration, and hypercholesterolemia due to environmental/lifestyle/behavioral factors (i.e., no known genetic etiology). Here, we explore patient and clinician perspectives about the identification and management of each of these causes. Methods: Patients with severe hypercholesterolemia with a primary language of English or Spanish and clinicians (primary care, genetic counseling, cardiology) across two health systems (Geisinger, Mount Sinai) participated in semi-structured interviews. Analysis was completed using an a priori codebook informed by Proctor?s implementation outcomes to identify themes influencing the identification and management of the underlying causes of severe hypercholesterolemia. Results: A total of 28 patients and 25 clinicians participated. Patients emphasized the importance of receiving results directly from their clinician, requested take-home resources that mirrored the information from their clinician, were motivated to seek multidisciplinary care, and anticipated all results would be actionable, but that high-risk PRS and elevated Lp(a) may require more support (e.g., specialists, education) to act on. Clinicians stressed the importance of integrating workflows (e.g., test ordering) with the electronic health record, highlighted LDL-C levels and multidisciplinary care coordination as key to management, explained how they would tailor care to individual patients, and expressed a more limited understanding of Lp(a) and PRS result types based on their clinical experiences and, therefore, hesitation about the recommended clinical actions. Conclusions: Patients and clinicians identified complementary determinants influencing the identification and management of the underlying cause of severe hypercholesterolemia. Participants welcomed risk information and requested a higher level of informational support and specialty expertise to appropriately manage high Lp(a) and PRS results. Integrating genomic information into risk assessments will require a partnership between general practitioners and specialists to provide a multidisciplinary approach to the identification and management of the underlying causes of severe hypercholesterolemia.

Background. In Europe, first-trimester combined screening with the Fetal Medicine Foundation (FMF) algorithm identifies women at increased risk of preeclampsia who may benefit from personalized aspirin prophylaxis. However, a substantial proportion of early-onset preeclampsia (EOPE) remains undetected at clinically acceptable specificity. Objective. To evaluate the first-trimester performance of MaiRa for early-onset preeclampsia (EOPE) risk stratification by benchmarking it against FMF screening in the same women, characterizing discordant patient-level classification profiles and exploring potential implementation strategies. Study Design. This secondary case-control analysis was nested within the prospective, multicentre PREMOM cohort [NCT04990141], which enrolled women with singleton pregnancies across 14 tertiary hospitals in Spain. First-trimester MaiRa and FMF risk estimates were evaluated in the same 126 pregnant women, comprising 99 uncomplicated controls and 27 EOPE cases, defined by disease onset before 34 weeks. Discrimination was compared using a stratified paired bootstrap analysis of the areas under the receiver-operating-characteristic curves. Performance was assessed at prespecified clinical thresholds, and detection rates were evaluated at fixed false-positive rates. Universal and contingent MaiRa implementation strategies were also evaluated. Results. MaiRa showed greater first-trimester discrimination for EOPE than FMF combined screening (AUC, 0.974 vs 0.900; P=.040) and consistently achieved higher detection rates across fixed false-positive rates. At false-positive rates of 5% and 10%, MaiRa detected 85.2% and 92.6% of EOPE cases, compared with 44.4% and 70.4% for FMF, respectively. Patient-level analysis demonstrated that MaiRa identified 12 of 27 EOPE cases (44.4%) classified as low risk by FMF; these pregnancies generally exhibited less abnormal conventional first-trimester profiles, including fewer maternal risk factors, lower mean arterial pressure and lower uterine artery pulsatility index, yet 8 of 12 (66.7%) subsequently developed severe EOPE. Exploratory implementation analyses showed that universal MaiRa screening achieved the highest EOPE detection, whereas a contingent strategy using FMF for triage and reflex MaiRa testing reduced molecular testing to 35.7% of pregnancies while maintaining 77.8% sensitivity and 97.0% specificity. Conclusion. MaiRa provided greater first-trimester discrimination for EOPE than conventional combined screening and detected additional pregnancies that later developed severe disease despite less abnormal conventional screening profiles. The findings suggest that maternal plasma cfRNA profiling captures biological alterations not fully reflected by combined first-trimester screening and support further prospective evaluation in an independent, unselected obstetric population. Key words: early-onset preeclampsia; first-trimester screening; cell-free RNA; liquid biopsy; Fetal Medicine Foundation algorithm; combined screening; risk stratification; aspirin prophylaxis.

The Hippo signaling pathway is increasingly recognized as a key regulator of endothelial cell (EC) proliferation, migration and vascular development. However, the roles of its upstream scaffold proteins remain poorly understood. Although WWC family proteins are widely regarded as functionally redundant activators of LATS1/2 kinases, the human genome contains a third family member, WWC3, that is absent from mice, raising the possibility of species-specific regulation of endothelial Hippo signaling. Here, we assessed the roles of WWC2 and WWC3 in human ECs using siRNA-mediated knockdown. Surprisingly, we found that WWC3 is the predominant regulator of canonical Hippo signaling, with a substantially greater effect than WWC2 on LATS1/2 phosphorylation, YAP/TAZ localization and expression of Hippo target genes. Loss of WWC3 also altered endothelial morphology and induced a partial endothelial-to-mesenchymal transition-like (EndoMT-like) phenotype. By contrast, WWC2 had a lesser effect on canonical Hippo signaling, but it was required for normal VEGF signaling dynamics. Despite these distinct molecular functions, depletion of either WWC2 or WWC3 impaired EC proliferation, migration, and cord formation in vitro. Together, our findings demonstrate that WWC family proteins perform overlapping but distinct functions in human ECs, with WWC3 acting as the predominant canonical Hippo regulator, whereas WWC2 more efficiently modulates VEGF signaling. These results reveal unexpected functional specialization among WWC proteins and suggest that regulation of Hippo signaling in human ECs differs from that inferred from mouse studies.

Preeclampsia is a pregnancy complication characterized by hypertension, proteinuria, and end-organ dysfunction. Abnormal placentation leading to reduced placental perfusion may contribute to its development. Previous studies demonstrated that the activation of the apelin receptor (APJ) system has hypotensive, renoprotective, and antioxidant effects in preeclamptic rat models. Apelin and elabela (ELA) can stimulate the proliferation of trophoblast cells, suggesting a role in embryonic development. However, the mechanisms underlying the actions of apelin or ELA in trophoblast cells are not well understood, particularly in hypoxic settings. The immortalized HTR-8/SVneo trophoblastic cells were treated with cobalt chloride (CoCl2) at 0.2 mM for 24 hours to mimic hypoxic conditions. RT-qPCR, ELISA or Western blotting was used to measure mRNA or protein levels of apelin, elabela, and the components of IL-6 signaling in cell lysates or conditioned media. The exposure to CoCl2 increased total apelin and elabela content approximately 2-fold in the conditioned media but did not affect APJ levels. CoCl2 upregulated proinflammatory cytokine concentrations: soluble fms-like tyrosine kinase 1 (sFlt-1), soluble gp130 (sgp130), interleukin-6 (IL-6), and sIL-6 receptor (IL-s6R). Both apelin and elabela downregulated IL-6 mRNA but had no effect on sFlt-1 mRNA. Apelin attenuated sgp130, while ELA decreased the membrane form of IL-s6R. Apelin also decreased the pSTAT3/STAT3 ratio. CoCl2-induced hypoxia upregulated the pro-inflammatory milieu in HTR-8/SVneo cells. Local activation of this peptidergic system may be a compensatory response of the trophoblast cells to hypoxia as exogenous apelin and elabela treatment ameliorated the hypoxia-induced pro-inflammatory milieu.

Background: Severe aortic stenosis is associated with systemic and splanchnic hemodynamic disturbances that may alter gut microbial metabolism and host inflammatory responses. Objectives: We aimed to determine whether TAVI remodels the gut microbiome-derived metabolome and whether post-procedural SCFA dynamics are associated with the inflammatory cytokine response. Methods: We conducted a prospective paired single-center study of patients undergoing elective TAVI at Bern University Hospital. Stool and blood samples were collected before and three months after the procedure. Gut microbial composition was profiled by full-length 16S rRNA sequencing, circulating short-chain fatty acids (SCFAs) by targeted metabolomics, and inflammatory mediators by multiplex cytokine analysis, and integrated with hemodynamic and clinical data. Results: Forty patients were enrolled. Following TAVI, microbial richness declined without significant restructuring of overall community composition. In contrast, circulating SCFA profiles were significantly remodeled, driven by selective reductions in butyrate and isovalerate. A greater decline in circulating butyrate was inversely associated with IL-18 elevation (rho=0.668, p<0.001, n=36), independent of aortic valve calcification burden, hemodynamic improvement, and cardiovascular medications. Baseline isovalerate was nominally associated with 1-month adjudicated adverse events (AUC 0.77; exploratory). Conclusions: TAVI is associated with selective changes in gut microbiome-derived metabolic output rather than broad alterations in microbial community structure. Declining circulating butyrate identifies a gut-metabolite-immune axis linked to IL-18 dynamics and represents a potential biomarker of inflammatory recovery following valve intervention.

Objective Women with a history of Pelvic Inflammatory Disease (PID) face elevated risks of health complications and mortality. This study examined the association between cardiovascular health (CVH) and PID among U.S. women. Methods We conducted a cross-sectional analysis of NHANES 2013-2023 (n=6,382). The LE8 scores were categorized into four groups based on quartiles: Q1 (<25), Q2 (25-49), Q3 (50-74) and Q4 ([&ge;]75). We calculated adjusted ORs (95% CIs) via logistic regression to evaluate LE8-PID associations. Results Compared to the highest LE8 quartile ([&ge;]75), adjusted ORs for PID were 1.66 (95%CI:1.03-2.67) for Q3, 1.71(1.10-2.67) for Q2, and 1.99(1.13-3.50) for Q1. The inverse association was consistent across health behavior and health factor components, with sleep, smoking, blood pressure, and BMI showing the strongest effects, particularly among younger women. Conclusions Higher LE8 scores are inversely associated with PID prevalence, particularly in younger women. Promoting cardiovascular health may help reduce PID burden.

Chromaffin cells synthesize and secrete catecholamines to coordinate systemic stress responses and regulate diverse neuroendocrine and metabolic functions. However, the molecular mechanisms governing chromaffin-cell differentiation and their disruption in pheochromocytoma (PC) remain incompletely understood. Here, through integrated analyses of human developmental atlases, patient-derived transcriptomic datasets, genetically engineered mouse models, and chromaffin organoids, we identify TEAD1 signaling as a critical regulator of chromaffin-cell differentiation and function. In vivo studies using a chromaffin cell-specific TEAD1 overexpression mouse model demonstrated that suppression of TEAD signaling markedly compromises chromaffin-cell differentiation and endocrine function. Additionally, compared with other TEAD family members, TEAD1 transcriptional activities are readily affected by sequences near the binding motif. To identify therapeutically actionable regulators of TEAD1 signaling, we established a TEAD activity-based screening platform and identified the serotonin receptor HTR5A antagonist SB699551 as a potent modulator of chromaffin-cell state. SB699551 suppressed PC-cell proliferation in vivo, and remodeled catecholamines synthesis in primary human PC cells. Additionally, application of SB699551 to human PC tumor revealed a subpopulation of primary chromaffin cells sensitive to this compound. Mechanistically, CXXC5 and L1CAM were identified as downstream SB699551-TEAD1 signaling effectors mediating chromaffin-cell proliferation and differentiation. Overall, we demonstrate that TEAD1 signaling is a fundamental mechanism regulating chromaffin cell differentiation and that modulation of TEAD1 signaling via SB699551 offers a new area of investigation in chromaffin cell biology.