Hypertension

Background: Primary aldosteronism (PA) is increasingly recognized as a common cause of hypertension. The 2025 Endocrine Society guideline introduced a simplified diagnostic framework, but its real-world clinical implications remain unclear. Methods: We conducted a multicenter retrospective cohort study of hypertensive patients undergoing PA testing in Taiwan. PA was defined biochemically according to the 2025 Endocrine Society criteria. Multivariable logistic regression identified factors associated with PA diagnosis and aldosterone-targeted therapy. Among patients with suppressed renin (?1 ng/mL/h), restricted cubic splines evaluated the adjusted association between renin and PA probability. Results: Among 18,766 patients undergoing PA testing, 6,760 (36.0%) met diagnostic criteria for PA. PA was associated with older age, female sex, lower potassium, resistant hypertension, and a higher antihypertensive medication burden. Among patients with suppressed renin, lower renin remained significantly associated with higher adjusted PA probability. However, only 39.0% of patients with PA received aldosterone-targeted therapy, including 28.2% who received mineralocorticoid receptor antagonist therapy within 6 months and 9.4% who underwent adrenalectomy during follow-up. Lower renin, higher aldosterone, lower potassium, and resistant hypertension were associated with aldosterone-targeted therapy, while younger patients with fewer comorbidities were more likely to undergo adrenalectomy. Conclusions: Using the updated diagnostic framework, PA was highly prevalent among hypertensive patients undergoing PA testing. Nevertheless, many patients who met these biochemical criteria did not receive aldosterone-targeted therapy in routine care. These findings highlight the potential treatment implications of broader PA recognition and support the development of practical pathways to guide MRA therapy, adrenalectomy referral, and individualized management.

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.

Background: Pediatric hypertension (HTN) remains underdiagnosed despite established guidelines. Prior studies evaluating social drivers of health (SDOH) relied on diagnostic codes or single-visit blood pressure (BP) measurements, limiting identification of persistent BP elevation. We evaluated longitudinal BP patterns and associated SDOH among children with continuity of care. Methods: We conducted a retrospective cohort study of children aged 6-17 years with [&ge;]3 primary care visits between 2017 and 2024 within a large healthcare network. BP was classified according to guidelines. Multivariable logistic regression evaluated associations between persistent abnormal BP ([&ge;]3 abnormal readings, would meet guideline-based diagnosis for HTN) and stage 1/2 HTN with demographic, clinical, and neighborhood-level factors, including Area Deprivation Index (ADI), Child Opportunity Index (COI), and insurance instability. Results: Among 71,683 children, 2,911 (4.2%) had persistent abnormal BP, whereas only 848 (1.2%) had a documented HTN diagnosis. Obesity, age [&ge;]13 years, male sex, prematurity, and insurance instability were associated with abnormal BP and stage 1/2 HTN. Higher ADI quartiles were associated with increased odds of abnormal BP (Q3: OR 2.48) and stage 1/2 HTN (Q3: OR 4.89). Higher COI socioeconomic opportunity was associated with lower odds of abnormal BP, whereas higher educational opportunity was associated with higher odds; these associations were not observed for stage 1/2 HTN. Conclusions: Among children with continuity of care, substantial gaps in HTN recognition persist despite repeated opportunities for diagnosis. SDOH factors remained associated with BP abnormalities, supporting the need for system-level and community-based strategies to improve HTN detection.

This study enrolled 152 hypertensive patients with an ARR > 3.7 to assess the relationship between the traditional hypokalemia cutoff (3.5 mmol/L) and primary aldosteronism (PA) screening, and to establish a new cutoff. Under the traditional cutoff, only 35.7% of PA patients presented with hypokalemia. ROC curve analysis identified a new cutoff of 4.22 mmol/L, which increased sensitivity from 35.7% to 77.5%, with a specificity of 91.1% and an AUC of 0.897. The findings indicate that the traditional cutoff is insufficiently sensitive, while the new cutoff markedly improves screening sensitivity and facilitates early detection of PA.

Background: Hypertension is a leading modifiable cardiovascular risk factor prominently influenced by health-related social needs (HRSN). Whether detailed information on HRSN can improve identification of hypertension among minoritized women is unknown. Methods: Black and Latina women aged 18-65 years completed the Centers for Medicare and Medicaid Services Accountable Health Communities Screening Tool, assessing 13 HRSN domains. Hypertension was ascertained by a validated EHR-based algorithm or self-report of hypertension. Logistic regression tested associations of HRSN with hypertension. LASSO regression with 10-fold cross-validation was used to derive a poly-social risk score in the training set (random 70%) and tested in the validation set (30%) against a sociodemographic model (age, race, income, education). Results: Among 1302 participants (mean [SD] age 40.1 [11.3] years, 70.4% Black, 44.3% Latina), higher cumulative burden of HRSN was associated with increased odds of hypertension (adjusted odds ratio [aOR] for each additional domain of HRSN: 1.07 [95% CI 1.01-1.14], P=0.02). Food insecurity (aOR 2.30 [1.37-3.87], P= 0.002), lapse in utilities (aOR 1.44 [1.04-1.96], P=0.02), poor concentration (aOR 1.57 [1.13-2.17], P=0.007), and social isolation (aOR 1.77 [1.14-2.73], P=0.01) were associated with hypertension. In the validation set, the poly-social risk score did not improve discrimination for hypertension vs. the sociodemographic model (AUC 0.76 [95% CI 0.71-0.81] vs. AUC 0.80 [0.75-0.85]). Conclusion: In this cross-sectional analysis of Black and Latina women, greater cumulative social disadvantage was associated with hypertension. While inclusion of HRSN did not improve hypertension prediction beyond conventional sociodemographic indices, findings may inform targeted interventions among minorities at cardiometabolic risk.

Background: Intraoperative hypotension is associated with cardiovascular complications and mortality, making accurate blood pressure monitoring essential. However, the accuracy of noninvasive oscillometric cuff blood pressure (Cuff BP) during hypotension is uncertain. We examined the association between intraoperative hypotension and Cuff BP inaccuracy. Methods: A single-center retrospective cohort included 22,812 adults undergoing noncardiac surgery from April 2013 through November 2023, with 159,782 simultaneous Cuff BP and invasive arterial blood pressure (Arterial BP) pairs. Pairs with arterial systolic BP >120 mmHg or diastolic BP >80 mm Hg were excluded to focus on hypotensive range. Hypotension was defined as arterial mean arterial pressure (MAP) <65 mmHg and categorized as mild (55 to <65), moderate (45 to <55), or severe (35 to <45 mmHg). Cuff BP inaccuracy was defined as an absolute MAP difference >10 mmHg from Arterial BP. Multivariable logistic regression estimated adjusted odds ratios (ORs) and 95% CIs. Results: Compared with normal MAP (?65 mmHg), hypotension was associated with greater odds of Cuff BP inaccuracy (adjusted OR, 1.45 [95% CI, 1.41?1.49]). Adjusted ORs increased with severity (P for trend <0.001): 1.23 (95% CI, 1.19?1.27) for mild, 2.36 (95% CI, 2.24?2.50) for moderate, and 7.39 (95% CI, 6.34?8.62) for severe hypotension. Sensitivity for correct MAP classification decreased from 87.1% for normal MAP to 32.0%, 19.6%, and 10.2% for mild, moderate, and severe hypotension. Conclusions: We found a significantly higher risk of Cuff BP inaccuracy in patients with intraoperative hypotension, supporting cautious interpretation of Cuff BP during intraoperative hypotension.

Ambulatory blood pressure monitoring (ABPM) is recommended for confirming hypertension and assessing out-of-office blood pressure (BP). However, patient burden and device tolerability may limit broader implementation. We compared participant experience with a traditional oscillometric ABPM device and a compact cuff-integrated ABPM. The PRO-BP Study was a pilot randomized crossover study of 20 adults in New York City. Participants completed two 24-hour ABPM periods over 7 days using the SpaceLabs 90227 and SOMNOmedics ABPM Pro devices. After each period, participants rated comfort, pain, sleep interference, embarrassment, noise, skin irritation, and interference with daytime activities. Both devices achieved guideline-based recording-quality thresholds. Compared with SpaceLabs, ABPM Pro was associated with greater comfort (median 7.0 [IQR, 5.0-8.5] vs 3.5 [IQR, 2.0-6.5]; P=0.004), less pain (1.5 [0-3.5] vs 5.0 [0.5-7.0]; P=0.003), and less embarrassment (0.5 [0-3.5] vs 3.0 [0-6.0]; P=0.01). Other experience ratings did not differ significantly. Participant experience should be considered alongside recording quality when evaluating validated ambulatory BP monitoring technologies.

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.

Objectives: To compare real-world cardiovascular outcomes and safety events in patients with resistant hypertension following initiation of transdermal clonidine (TC) or spironolactone. Methods: A retrospective analysis was performed using Merative MarketScan(R) Databases in the USA to identify cohorts with resistant hypertension initiating TC or spironolactone as a fourth-line agent between January 2012 and September 2024. Major Adverse Cardiovascular Events (MACE) and safety events were assessed during variable follow-up periods. Inverse probability of treatment weighting (IPTW) was applied to adjust for differences in baseline characteristics. Cox proportional hazard models were used to adjust for post-index beta-blocker utilization as a time-varying covariate for MACE outcomes. Results: The analysis included 3,113 patients in the TC cohort and 30,640 in the spironolactone cohort. After IPTW, baseline characteristics were well balanced between cohorts (standardized mean differences <0.10; mean age 60 years, 54% male). Mean follow-up was 7.1 and 10.5 months for the TC and spironolactone cohorts, respectively. After IPTW no differences in MACE outcomes were observed between the two cohorts (weighted rate ratio 1.27 [0.79-2.06]). Results were consistent after adjusting for post-index beta-blocker use. The risk of hyperkalemia was significantly lower in the TC cohort (weighted rate ratio, 0.48 [0.33-0.70]. Conclusions: In this real-world analysis, patients with resistant hypertension treated with TC have similar risk for MACE outcomes as with spironolactone, but with significantly lower risk of hyperkalemia. Thus, in patients with resistant hypertension TC appears to provide similar cardiovascular protection, with a more favorable safety profile.

Background Racial and ethnic minority populations face disproportionate rates of uncontrolled blood pressure (BP) and hypertension-related mortality. Remote hypertension monitoring (RHM) with active clinician-led medication titration has shown promise for improving BP control, but real-world evidence in majority-minority primary care settings remains limited. Methods This retrospective cohort study (January 2022-December 2024) enrolled adults with hypertension in a Bluetooth-integrated RHM program at a single urban academic primary care clinic. Of 550 patients enrolled, 503 with evaluable follow-up data were included. Patients transmitted daily home BP readings; clinicians reviewed readings monthly and titrated anti-hypertensive regimens per 2017 ACC/AHA guidelines. BP control was assessed at baseline and 3, 6, and 9 months. Factors associated with longitudinal BP control were examined using multivariable generalized estimating equations (GEE), with outcomes defined as strict control (<130/80 mmHg), at-least-moderate control (<140/90 mmHg), and uncontrolled (>140/90 mmHg). Results Among 503 participants (mean age 58.3 [SD 12.1] years; 63.6% African American; 52.9% male), BP control increased from 10.1% at baseline to 37.1% at 9 months. Each additional month of enrollment was associated with reduced odds of uncontrolled BP (adjusted odds ratio [aOR] 0.82; 95% CI, 0.80-0.85; P<.001). White race was associated with lower odds of uncontrolled BP versus African American race (aOR 0.57, at-least-moderate control; aOR 0.40, strict control; both P<.001). Male sex (aOR 1.46; P=.02) and congestive heart failure (aOR 2.09, strict control; aOR 2.05, at-least-moderate control; both P<.05) were associated with higher odds of uncontrolled BP. Conclusion Bluetooth-integrated RHM with active clinician-led medication titration was associated with a nearly 4-fold increase in BP control over 9 months in a majority-minority primary care population. Persistent within-program racial disparities underscore the need for equity-centered strategies beyond technology adoption alone. Prospective studies with concurrent usual-care comparators are needed to establish causal inference.

BackgroundMyogenic tone is a fundamental property of resistance arteries that stabilizes tissue perfusion by coupling intraluminal pressure to smooth muscle cell (SMC) depolarization, Ca2+ influx, and vasoconstriction. TRPM4 (transient receptor potential melastatin 4) cation channels are required for this response in cerebral arteries, but whether TRPM4-dependent mechanotransduction is conserved across the broader resistance vasculature has remained unknown. MethodsWe combined droplet digital PCR, a newly generated Trpm4-Cre transgenic reporter mouse line, native-cell patch-clamp electrophysiology, pressure myography, selective pharmacological inhibition, and novel SMC-specific Trpm4-knockout (Trpm4-smKO) mice to define the expression, regulation, and functional importance of TRPM4 in cerebral, mesenteric, and skeletal muscle resistance arteries. ResultsTrpm4 transcripts were detected in all three vascular beds, and genetic reporter-based mapping localized TRPM4 expression to SMCs in multiple organs. Using conventional whole-cell patch-clamp electrophysiology, we recorded cation currents activated by high intracellular [Ca2+] and sensitive to the selective TRPM4 blocker 4-chloro-2-(1-naphthyloxyacetamido) benzoic acid (NBA) in native SMCs from all three beds. In cells patch-clamped using the amphotericin B-perforated configuration, stretching the plasma membrane by applying negative pressure (-20 mmHg) through the patch pipette activated transient inward cation currents that were suppressed by NBA. The selective angiotensin II type 1 receptor (AT1R) blocker losartan also inhibited stretch-induced currents without affecting Ca2+-activated whole-cell TRPM4 currents, indicating that AT1R signaling is required for mechanotransduction in SMCs from all three vascular beds. In pressurized arteries with established myogenic tone, NBA produced reversible, concentration-dependent suppression of pressure-induced constriction of cerebral, mesenteric, and skeletal muscle arteries while sparing constriction induced by direct depolarization of SMCs with high (60 mM) extracellular [K+]. TRPM4-dependent whole-cell currents and stretch-induced cation currents were decreased in SMCs from Trpm4-smKO mice, and myogenic tone was essentially absent in all three vascular beds from these animals. ConclusionsThese findings show that TRPM4 is essential for pressure-induced SMC depolarization and myogenic constriction in the resistance vasculature.

Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.

Heightened sympathetic outflow is a major contributor to the development of hypertension. The hypothalamic paraventricular nucleus (PVN) and the rostral ventrolateral medulla (RVLM) are critical regions for generating and regulating sympathetic activity associated with hypertension. Although presympathetic neural circuitry in the healthy brain is well characterized, it remains unclear whether these pathways undergo alterations in hypertension. Here, we determined presympathetic neural circuits by injecting pseudorabies virus (PRV), a transsynaptic retrograde tracer, into the adrenal gland of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Adult SHR exhibited a significantly greater number of PRV-labeled neurons in the PVN and RVLM, but not in the spinal intermediolateral column, compared with WKY. In contrast, the numbers of PRV-labeled neurons in the PVN and RVLM were comparable between young, prehypertensive SHR and age-matched WKY. Remarkably, long-term treatment with losartan--a brain-penetrant angiotensin II AT1 receptor antagonist-- initiated in young, prehypertensive SHR blunted the age-dependent hypertension development and reversed the increase in neuronal labeling in both the PVN and RVLM. However, losartan treatment had no effects in WKY. Additionally, electrophysiological recordings showed an elevated frequency of miniature excitatory postsynaptic currents in PVN presympathetic neurons of SHR, which was also normalized by long-term losartan treatment. These findings reveal an age-dependent expansion of presympathetic neuronal connectivity from the hypothalamus and brainstem to the adrenal gland during hypertension development in SHR. Enhanced AT1 receptor activity contributes to hypertension by increasing active glutamatergic synaptic input and promoting the recruitment of additional presympathetic neurons in the hypothalamus and brainstem. Key Points1. The numbers of neurons labeled by PRV injected into the adrenal gland are increased in the PVN and RVLM, but not in the spinal cord IML, in adult SHR compared to normotensive WKY. 2. The numbers of neurons in the PVN, RVLM, and spinal cord labeled by PRV injected into the adrenal gland are comparable in young, prehypertensive SHR and age-matched WKY. 3. Losartan treatment, initiated at a young age, blunts the hypertension development and reverses the increased numbers of PRV-labeled neurons in the PVN and RVLM of adult SHR but has no such effects in WKY. 4. The active glutamatergic synapses in PVN presympathetic neurons are elevated in adult SHR, and this elevation is reversed by long-term losartan treatment.

Background Hypertension remains one of the most challenging healthcare problems in the community. It is a common, measurable, and treatable condition that is nonetheless responsible for millions of preventable deaths each year. Hypertension affects approximately 1.28 billion adults worldwide, yet fewer than half (46%) are aware of their condition. Undiagnosed hypertension is a critical public health gap, contributing to preventable cardiovascular morbidity through silent end-organ damage. Machine learning can enable community-level screening using routinely available, non-invasive data, without the requirement of laboratory investigations. Methods We conducted a cross-sectional ML study using the National Health and Nutrition Examination Survey (NHANES) 2017-2018 cycle. Adults aged [&ge;]18 years were included; those with a self-reported prior hypertension diagnosis (n=1,930) were retained as negative controls. Probable undiagnosed hypertension was defined as mean blood pressure [&ge;]130/80 mmHg among participants reporting no prior hypertension diagnosis, consistent with the ACC/AHA 2017 threshold. Three classifiers: Logistic Regression (LR), Random Forest (RF), and Extreme Gradient Boosting (XGBoost) were trained on eight non-invasive predictor variables. Performance was assessed using AUC-ROC, sensitivity, specificity, and F1 score with bootstrap 95% confidence intervals (CIs). Stratified 5-fold cross-validation was applied. Results Of 9,254 NHANES 2017-2018 participants, 5,237 adults were included after exclusion criteria were applied; 1,072 (20.5%) had probable undiagnosed hypertension. LR achieved the highest test AUC of 0.611 (95% CI: 0.571-0.652), with sensitivity 0.535 (95% CI: 0.473-0.600) and specificity 0.594 (95% CI: 0.560-0.626). RF demonstrated near-absent sensitivity (0.047) despite adequate AUC (0.607), while XGBoost performed intermediately (AUC: 0.599; sensitivity: 0.279). Diabetes status, sex, and age were the most influential predictors by permutation feature importance. Conclusion ML classifiers trained on eight non-invasive variables demonstrated modest but consistent discrimination for identifying probable undiagnosed hypertension, supporting the feasibility of laboratory-free community screening. External validation in diverse populations is warranted before clinical implementation.

Abstract Background:Patients with hypertension commonly exhibit reduced exercise capacity. Impedance cardiography (ICG) enables continuous, non-invasive assessment of exercise-derived hemodynamic parameters; however, the relative associations of different ICG-derived parameters with exercise capacity remain unclear. Methods:In this retrospective cross-sectional study, 211 patients with hypertension who completed both ICG assessment and the six-minute walk test (6MWT) were enrolled. Exercise-derived hemodynamic parameters, including maximum heart rate (HRmax), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR), were continuously measured using the PhysioFlow(R) system. Univariable and multivariable linear regression analyses were performed to evaluate the associations between ICG-derived parameters and six-minute walk distance (6MWD). HRmax tertile and subgroup analyses were subsequently conducted. Results:In the final multivariable model, age ({beta} = -2.76, 95% CI, -3.85 to -1.67, P < 0.001), male sex ({beta} = 33.50, 95% CI, 8.40-58.60; P = 0.009), and HRmax ({beta} = 1.26, 95% CI, 0.69-1.83; P < 0.001) were independently associated with 6MWD. 6MWD increased progressively across HRmax tertiles (P for trend < 0.001). The positive association between HRmax and 6MWD remained consistent across all prespecified and exploratory subgroups. Conclusions:Among multiple exercise-derived ICG hemodynamic parameters, HRmax demonstrated the strongest and most consistent independent association with exercise capacity in patients with hypertension. These findings suggest that HRmax may represent the most informative dynamic hemodynamic parameter during exercise and that combining ICG with the 6MWT may provide a simple and accessible complementary approach for evaluating exercise capacity.

Background: Despite the common use of local heating and intradermal microdialysis perfusion of acetylcholine (ACh) to probe cutaneous endothelium and nitric oxide (NO)-dependent dilation, sex differences in microvascular responsiveness to these stimuli in healthy young adults remain incompletely understood. Methods: Cutaneous vasodilation was assessed in response to local heating to 39{degrees}C and 42{degrees}C and graded perfusion of ACh (10-10 to 10-1 mol/L) alone or concurrently with 15 mM NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) using laser-Doppler flowmetry coupled with intradermal microdialysis in 80 young adults (40 females). Results: Local heating to 42{degrees}C elicited greater endothelium- and NO-dependent dilation than heating to 39{degrees}C in both groups (p<0.001), but no sex differences were observed at either temperature (p=0.65). ACh-induced endothelium-dependent dilation also was not different between sexes (p=0.08), but the NO-dependent component was greater in females than in males (p=0.01). In young females, menstrual cycle day (range: day 2-33) was not associated with endothelium- or NO-dependent dilation in response to any stimulus (all p[&ge;]0.19), regardless of hormonal contraceptive use. Conclusions: Taken together, these findings suggest that sex differences in microvascular NO bioavailability in healthy young adults depend on the stimulus used to elicit cutaneous vasodilation and, in females, microvascular endothelium- and NO-dependent dilation are not meaningfully influenced by menstrual cycle phase.

Hypertension is commonly defined as a binary condition despite substantial heterogeneity in diagnosis, treatment, and blood pressure (BP) control. We propose a three-axis state model integrating diagnosis status, treatment intensity, and BP control to better characterize hypertension phenotypes. The framework generates 27 possible states that can be condensed into seven clinically meaningful groups. We applied the model to 5,129,584 Japanese adults using the National Database of Health Insurance Claims and Specific Health Checkups. Hierarchical cluster analysis, sensitivity analysis excluding patients with cardiovascular diseases other than hypertension, and validation against antihypertensive medication use were performed. Overall, 64% of participants were classified as normotensive, whereas 36% belonged to hypertension-related groups, including 11% with unrecognized hypertension and 7% with diagnosed but untreated hypertension. Agreement with data-driven hierarchical cluster analysis was substantial (weighted {kappa}=0.87). The group distribution remained largely unchanged in the sensitivity analysis, supporting the robustness of the proposed classification. Hypertension diagnosis also showed high validity, with a sensitivity of 96.5%, specificity of 91.8%, and substantial agreement with antihypertensive medication use ({kappa}=0.78). This three-axis framework provides a robust and clinically interpretable approach for characterizing hypertension phenotypes, enabling systematic identification of care gaps and supporting research, clinical decision-making, and population health management.

Background: Cutaneous microvascular responses to local heating and acetylcholine perfusion are widely used to assess nitric oxide (NO)-mediated endothelium-dependent dilation in human health and disease. Despite the increasingly common usage of these approaches, no studies have directly compared responses to these stimuli within individuals. Therefore, we assessed endothelium- and NO-dependent dilation in 80 young adults (40 males/40 females; 22{+/-}3 years) to determine the extent to which microvascular responses to these endothelium-dependent stimuli are comparable within an individual. Methods: We examined cutaneous vascular conductance responses to (1) standardized local heating protocols to 39{degrees}C and 42{degrees}C, and (2) graded infusions of acetylcholine (10-10-10-1 M) alone or with 15 mM NG-nitro-l-arginine methyl ester (L-NAME; NO synthase inhibitor). Endothelium- and NO-dependent dilation were calculated and expressed in multiple ways based on commonly published analyses to allow for a thorough comparison within and between each stimulus. Results: Local heating-induced endothelium- and NO-dependent dilation were lower at 39{degrees}C compared with 42{degrees}C (P<0.001). The magnitude of local heating-induced endothelium-dependent dilation was significantly related to the NO-dependent contribution of that response at 39{degrees}C (R2= 0.79) and 42{degrees}C (R2= 0.56). Local heating-induced NO-dependent dilation at 39{degrees}C was not related to that at 42{degrees}C (P>0.05). Acetylcholine-induced endothelium- and NO-dependent dilation were not related to local heating-induced responses (all P>0.05). Conclusions: These data demonstrate that while local heating and acetylcholine perfusion produce robust endothelium- and NO-dependent cutaneous vasodilation, these responses are not comparable within an individual.

Background: Hypertension is the leading modifiable cardiovascular risk factor globally, with the fastest-growing burden in low- and middle-income countries. This study aimed to estimate national hypertension prevalence, map provincial patterns, assess spatial clustering, and identify individual and community-level determinants among Zambian adults using the 2017 WHO STEPS survey. Methods: This cross-sectional study used data from the 2017 WHO STEPS survey, a nationally representative sample of 4,301 adults aged 18-69 years. Hypertension was defined as systolic BP [&ge;]140 mmHg, diastolic BP [&ge;]90 mmHg, or current antihypertensive use. Spatial autocorrelation was assessed via Moran's I and LISA. Four nested generalised linear mixed models with PSU-level random intercepts identified individual and community-level determinants. Results: Overall weighted hypertension prevalence was 24.0%. Lusaka recorded the highest prevalence (30.2%), followed by Southern (29.9%) and Muchinga (28.3%) provinces; Western Province had the lowest (12.4%). Spatial clustering was statistically significant but modest (Moran's I = 0.0247, p < 0.001). Between-cluster variation reduced from ICC = 5.9% to 1.8% in the full model, indicating geographic differences were largely explained by individual characteristics. Age was the strongest predictor; adults aged 60-69 had nearly sevenfold higher odds than those aged 18-29 (AOR 6.92, 95% CI: 4.95-9.66). Women had lower odds than men (AOR 0.64, 95% CI: 0.52-0.79). Obesity (AOR 2.34), overweight (AOR 1.65), high cholesterol (AOR 1.40), diabetes (AOR 1.35), and single marital status (AOR 1.34) were independently significant. Western Province showed consistently lower odds than Central Province (AOR 0.48). Conclusion: Hypertension affects one in four Zambian adults, driven primarily by age, sex, obesity, dyslipidaemia, and diabetes. Geographically prioritised interventions, including community health worker-led screening programmes in Lusaka and Southern Province, would maximise population-level impact. Population-level salt reduction and alcohol policies represent cost-effective complementary strategies. Longitudinal studies with finer spatial resolution are needed to clarify causal pathways underlying observed geographic clustering and inform SDG Target 3.4 progress.

BACKGROUNDChronic renin-angiotensin system (RAS) inhibition activates renin cells and induces afferent arteriolar hypertrophy, a maladaptive vascular response that may contribute to nephrosclerosis-like renal injury. Although genetic or cell ablation approaches have shown that renin cells are required for this remodeling, no pharmacological strategy to restrain hyperactivated renin cells while preserving RAS inhibition benefits has been established. Natriuretic peptides (NPs) counteract RAS; however, whether NP signaling modulates renin cell activation and afferent arteriolar remodeling remains unclear. METHODSWe examined direct effects of atrial natriuretic peptide (ANP) on As4.1 renin-producing cells using reverse transcription-quantitative PCR, ELISA, and RNA sequencing (RNA-seq). We established a mouse model of long-term RAS inhibition using valsartan, an angiotensin II receptor blocker (ARB), and compared it with sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI). Valsartan was matched between the ARB and ARNI groups. Renin cell activation, afferent arteriolar remodeling, and renal injury were evaluated using biochemical assays, histology, immunostaining, single-nucleus RNA-seq, and region-specific photo-isolation chemistry RNA-seq of afferent arteriolar/juxtaglomerular regions. RESULTSANP suppressed Ren1 expression and renin secretion in As4.1 cells; this effect was attenuated by a natriuretic peptide receptor A antagonist. RNA-seq demonstrated that ANP induced receptor-dependent remodeling of renin cell gene programs. In mice, long-term ARB treatment induced renin cell hyperactivation, expansion of renin-positive juxtaglomerular regions, afferent arteriolar hypertrophy, renal dysfunction, tubular injury markers, and fibrosis. ARNI increased plasma ANP levels and attenuated these pathological changes, despite a comparable blood pressure reduction. Single-nucleus transcriptomics revealed attenuation of tubular injury-associated cellular states and altered renin cell-associated mesenchymal programs with ARNI. Region-specific transcriptomics further demonstrated distinct molecular states in afferent arteriolar/juxtaglomerular regions between ARB- and ARNI-treated kidneys. Integrated transcriptomic analysis suggested that NP signaling converges on vascular regulatory programs in hyperactivated renin-expressing cells. CONCLUSIONSNP signaling acts as a pharmacologically augmentable modulator of maladaptive renin cell activation. ARNI attenuates renin cell hyperactivation, afferent arteriolar hypertrophy, and renal injury during long-term RAS inhibition, suggesting that neprilysin inhibition may preserve RAS blockade benefits while limiting renin cell-driven renal vascular remodeling.