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.

Background: Elevated blood pressure (BP) is common during hospitalization. Despite recommendations to avoid routine changes in antihypertensive therapy, clinical practice remains variable. Prospective data on whether elevated in-hospital BP identifies patients with hypertension after discharge are limited. Methods: Adults hospitalized for non-cardiac conditions with asymptomatic routine in-hospital BP ?140 and/or ?90 mmHg on at least two occasions separated by ?24 hours were prospectively enrolled. Antihypertensive therapy was managed at the discretion of treating physicians. Routine in-hospital BP, standardized research BP, and changes in antihypertensive therapy were recorded. Four weeks after discharge, participants underwent 24-hour ambulatory BP monitoring (ABPM). Results: Among 50 participants, 42 (84%; 95% CI, 70.9 ? 92.8) had hypertension on follow-up ABPM. Among 21 participants without known hypertension, 18 (86%) had previously unrecognized hypertension on follow-up ABPM; among 29 participants with known hypertension, 24 (83%) had uncontrolled hypertension. Antihypertensive therapy was changed during hospitalization in 26 participants (52%), with de-escalation more frequent than intensification. Hypertension on follow-up ABPM was present in 88.5% of participants with and 79.2% without in-hospital therapy changes. Standardized research BP, but not routine in-hospital BP, correlated with follow-up ABPM. Conclusion: Asymptomatic elevated routine in-hospital BP identified a population with a high prevalence of hypertension four weeks after discharge, including patients with and without previously diagnosed hypertension. These findings support structured post-discharge BP reassessment rather than assuming that elevated in-hospital BP is transient. URL: www.ClinicalTrials.gov; Unique identifier: NCT06132451

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.

Introduction: The key role of maladaptive renal sympathetic activation in hypertension has led to the development of catheter-based renal denervation therapies. Unfortunately, the lack of practical physiological biomarkers impairs patient selection and prevents intraprocedural feedback for renal denervation. Methods: We tested whether renal arterial hemodynamic measures and the beat-to-beat variability of these measures reflect renal sympathetic innervation in two tightly controlled preclinical models of renal denervation. Bilateral renal hemodynamic data were obtained from ten conscious unilaterally denervated rabbits and ten anesthetized unilaterally denervated pigs that subsequently underwent stepwise catheter-based radiofrequency denervation of the contralateral kidney. Renal arterial mechanics were assessed by quantification of wave speed and input impedance modulus and phase shift. Variability was quantified as the within-recording standard deviation of each metric when measured on a beat-to-beat basis. Results: Wave speed trended down after surgical denervation in rabbits (P = 0.054) but not swine (P = 0.57); wave speed variability was unchanged in both models. Renal arterial input impedance modulus was not significantly affected by surgical denervation. Surgical renal denervation increased input impedance phase shift in rabbits (P = 0.0048) but not in swine (P = 0.85). The beat-to-beat variability of modulus did not differ significantly between innervated and surgically denervated kidneys in either species. Surgical renal denervation decreased phase shift variability in swine (P = 0.0048) but not rabbits. The difference in phase shift variability between kidneys in swine was eliminated after a single round of branch-vessel ablation (P = 0.42). Discussion: Renal arterial wave speed, input impedance, and their beat-to-beat variability did not consistently or dose-dependently reflect renal sympathetic innervation in these models. These findings argue against their use as direct physiological surrogates for renal sympathetic outflow.

Introduction. Whether the arterial pressure waveform carries structural vascular information that brachial pressure does not, and whether its shape can be read from facial video, are both uncertain, and recording a continuous pressure reference with synchronised video in a hypertension clinic has not been reported. We sought to determine whether continuous finger arterial pressure recording with synchronised facial video, linked to existing coronary calcium imaging, is feasible in adults attending a hypertension clinic, whether a consumer camera recovers heart rate and pulse shape in that setting, and to generate exploratory estimates of association between waveform morphology and coronary calcium. Methods. BP-WAVE is a single-site prospective observational pilot study. The primary outcome was feasibility, pre-specified as recruitment, consent, completeness of waveform recording, imaging availability and data completeness. Secondary outcomes were waveform quality, device agreement, feature extraction, and recovery of heart rate and pulse shape from video. The exploratory outcome was the Spearman correlation of 14 waveform features with the Agatston calcium score, with exact permutation p values adjusted within each family of tests. Results. Nine of ten planned participants were recorded over 12 days (median age 55 years, range 40 to 74; five women); all nine completed the recording with video and had a calcium score (median 351, range 33 to 1816). Of 4,178 detected beats, 2,965 (71%) passed quality control. Video recovered heart rate within 0.4 to 4.1 beats per minute in eight of nine participants and pulse shape above a phase-randomised noise bound in six of nine (held-out r 0.48 to 0.76). Form factor had the strongest correlation with calcium (rho -0.68, exact p 0.050, q 0.68); no feature was associated with calcium after Benjamini-Hochberg adjustment within any of the nine families of 14 tests (126 tests in all; smallest q 0.17). Conclusion. In this single-site pilot of nine adults from a hypertension clinic, continuous finger arterial pressure recording with synchronised facial video and linkage to coronary calcium was feasible, a consumer camera recovered heart rate in eight and pulse shape in six participants, and no waveform feature was associated with coronary calcium after correction for multiple testing.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome integrates cardiac, renal, and metabolic abnormalities that drive multi-organ injury. In pulmonary arterial hypertension (PAH), CKM manifests as systemic metabolic derangements, right ventricular dysfunction, and renal compromise. Renal dysfunction strongly predicts mortality in PAH, yet current therapies provide little renal benefit. Moreover, the mechanisms driving PAH nephropathy remain poorly understood, limiting our ability to effectively treat PAH-CKM. Methods: Single-nucleus RNA sequencing identified cell-type-specific transcriptional alterations in autopsy-derived kidneys from control (n=5) and PAH (n=4) patients. Mitochondrial, cytoplasmic, and phosphoproteomic analyses profiled proteomic alterations. AlphaFold 3/ChimeraX modeling defined the predicted structural consequences of altered protein phosphorylation. Histological analysis assessed renal fibrosis, glomerular structure, immune cell infiltration, and nephron segment density. Results: 3 of 4 PAH patients exhibited renal impairment, with a cohort mean estimated glomerular filtration rate of 61 plus or minus 36 mL/min/1.73m squared. snRNA-seq identified a distinct cellular architecture in PAH kidneys, marked by an increase in thick ascending limb, proximal tubule, and immune cell nuclei and depletion of collecting duct nuclei. Transcriptional profiling demonstrated proximal tubule and thick ascending limb cells both upregulated fatty acid oxidation, ferroptosis, and cuproptosis pathways. PAH lymphocytes displayed heightened T87 cell receptor signaling, natural killer cell-mediated cytotoxicity, and Th17 differentiation. Histological analyses demonstrated increased perivascular fibrosis, glomerular T-cell infiltration, and a reduction in glomerular basement membrane density in PAH kidneys. Mitochondrial and cytoplasmic proteomics revealed broad metabolic dysfunction characterized by impaired {beta}-oxidation, TCA cycle activity, amino acid metabolism, transsulfuration, and urea cycle pathways. Phosphoproteomics predicted increased GSK3{beta}, STK, and casein kinase activity in PAH kidneys. Finally, using the totality of our data, we nominated multiple druggable targets that could be evaluated to counteract PAH nephropathy. Conclusions: Integrated multi-omic profiling demonstrates PAH nephropathy is defined by glomerular structural remodeling, proximal nephron ferroptotic and cuproptotic signaling, amino acid metabolic dysregulation, and innate and adaptive leukocyte activation. Future studies intervening on these pathways could lead to the development of novel therapeutics to augment renal function in PAH.

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.

Purpose: This study aimed to investigate the association between hypertension and anisometropia and determine whether interocular structural asymmetry mediates this relationship. Methods: In this cross-sectional study, nationally representative samples from the US (N = 12,749; NHANES 1999-2008) and Korea (N = 35,484; KNHANES 2008-2024) were analyzed. Associations between hypertension, blood pressure components (BPC), and anisometropia were examined using weighted multivariable logistic regression and restricted cubic splines. Mediation analysis assessed whether asymmetry in optical coherence tomography (OCT) structural parameters mediated the association between BPC and anisometropia. Results: Hypertensive individuals had higher odds of anisometropia in both cohorts (NHANES: OR = 1.32, 95% CI: 1.12-1.56, P = 0.001; KNHANES: OR = 1.12, 95% CI: 1.05-1.20, P < 0.001). Each 10 mmHg increase in systolic blood pressure (SBP) and pulse pressure (PP) was associated with 5% and 10% greater risk, respectively. Interocular differences in central macular and choroidal thickness partially mediated the association between BPCs and anisometropia. Time-course bulk RNA-seq identified Rock1 as a candidate gene downregulated under hypertensive conditions. Conclusions: Hypertension was associated with anisometropia across two national cohorts. Interocular differences in central macular and choroidal thickness partially mediated this association, suggesting a link between systemic hemodynamic alterations and ocular structural asymmetry. Translational Relevance: These findings suggest that interocular OCT structural asymmetry may serve as a clinically accessible imaging biomarker to identify individuals at increased risk of hypertension-associated anisometropia.

Pulmonary arterial hypertension (PAH) is characterized by the hyperproliferative phenotype of pulmonary arterial smooth muscle cells (PAVSMCs) and extensive extracellular matrix (ECM) remodeling. Vacuolar protein sorting 34 (VPS34), a Class III Phosphatidylinositol-3 Kinase (PI3K), regulates cell proliferation, but its specific function in pulmonary vascular remodeling remains poorly understood. We aim to determine the role of VPS34 activation and regulation in PAVSMC proliferation, matrix deposition, and the progression of PAH. First, we found a marked decrease in the inhibitory phosphorylation of VPS34 at Ser164 (P-S164-VPS34), indicative of constitutive VPS34 activation, in remodeled pulmonary arteries (PAs) from human PAH patients and male mice exposed to Sugen/Hypoxia (SuHx). In human PAH PAVSMCs, siRNA-mediated knockdown of VPS34 or pharmacological inhibition via the selective inhibitor SAR405 significantly blunted cell proliferation and reduced the production of fibronectin, a major component of the remodeled ECM. Mechanistically, we found that Akt activation in PAH PAVSMCs promotes VPS34 activation; Protein Phosphatase 1 Catalytic Subunit Alpha is a potential effector in VPS34 activation; and active VPS34 led to the activation of the mTOR/S6 signaling pathway with tuberous sclerosis complex 2 downregulation. Finally, in vivo treatment with SAR405 attenuated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in SuHx mice, while concurrently decreasing vascular fibronectin deposition. Our study demonstrates that VPS34 activation, driven by an Akt-mediated loss of the inhibitory P-S164, is crucial in PAVSMC proliferation and fibrotic vascular remodeling in PAH. Targeting the VPS34 axis represents a promising anti-remodeling therapeutic strategy for the treatment of PAH. Keywords: Pulmonary arterial hypertension, vacuolar protein sorting 34, pulmonary vascular remodeling, pulmonary arterial vascular smooth muscle

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: Hypertension prevalence rises sharply in females after menopause, exceeding that of age-matched males in later life, conferring greater relative cardiovascular disease risk in females than in males. However, the underlying mechanisms remain poorly understood. Method: We studied multi-tissue RNA-sequencing data from 193 CVD-free participants aged >55 years in the GTEx database and extended the findings to 1,605 age-matched Framingham Heart Study participants. Results: We identified a dominant female hypertension co-expression signature in blood, expressed at lower levels in females with uncontrolled high blood pressure than in males (sex-by-hypertension interaction) in both cohorts. Genes contributing to this signature were enriched for post-transcriptional modification and insulin signalling and regulated by ETS family transcription factors (TFs). Ten ETS TFs showed the same female-specific hypertension association and together explained the signature?s expression. Moreover, in females, but not males, lower blood signature scores were associated with a pro-inflammatory transcriptome in the artery and kidneys. Conclusions: Collectively, we identified the ETS-transcriptomic axis as a potential mechanism explaining sex differences in human hypertension.

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.

Background: Dietary sodium intake is a modifiable determinant of blood pressure, and impaired renal sodium handling is implicated in the pathogenesis of hypertension. Whether dietary sodium intake modulates renal tubular sodium transporter abundance among normotensive adults at risk for hypertension is unknown. Methods: Forty-six normotensive adults with normal kidney function at risk of developing hypertension were prospectively enrolled to complete a very low sodium (LS) diet followed by a high sodium (HS) diet. Urinary extracellular vesicle (uEV) proteins were quantified from a 24-hour urine collection at the end of each diet. We compared normalized uEV protein concentrations between diets and tested whether diet modified uEV protein associations with serum aldosterone, urinary aldosterone, and serum cortisol-cortisone ratio under either diet using Wilcoxon rank sums and linear mixed effects models, respectively. Results: Participants achieved median [IQR] urine sodium 13.2 [7.7-19.9] mEq/24h on the LS diet and 244.0 [197.1-297.0] mEq/24h on the HS diet. LS intake induced greater renin activity, greater plasma and urinary aldosterone, and lower urinary cortisol, when compared to HS intake. In parallel, NCC, ENaC, SGLT2, OXSR1, and Pendrin uEV concentrations were significantly higher during LS intake than HS intake (p<0.05 for all), whereas TRPV5 and AQP2 uEV concentrations were lower during LS intake than HS intake (p<0.001 for both). Conclusions: Controlled dietary sodium modulation induced nephron-segment specific changes in uEV protein abundance. These findings demonstrate the ability of uEVs to serve as a non-invasive tool to probe in vivo renal sodium, water, and electrolyte handling.

Context Current guidelines for primary aldosteronism (PA) recommend screening all patients with hypertension. Given low screening rates, an automated artificial intelligence (AI)-based risk-stratified approach may facilitate guideline implementation. Objective To develop an AI-based prescreening tool using electronic health record (EHR) data to identify at-risk patients. Design Model development retrospective cohort study. Ensemble architecture using eXtreme Gradient Boosting, random forest, and extremely randomized trees was trained on EHR data (1986-2025) and evaluated on a test set of patients with hypertension. Setting Single institution system spanning community clinics and tertiary/quaternary centers reported via Mayo Clinic Platform. Patients Adults with hypertension, International Classification of Disease (ICD) diagnosis of PA, or had plasma renin/aldosterone testing. Main Outcome Measures Predicting PA diagnosis (disease) or negative workup (control) using age, sex, ICD diagnoses, vitals, labs, and medications by area under receiver operating characteristic (AUROC), estimated calibration error (ECE), and specificity. Results Of 22,264 patients (1,833 disease and 20,431 controls), median time from initial encounter to screening was 5.0 years (IQR 0.5-12.6). The model demonstrated AUROC 0.709 (95% CI 0.688-0.730) with ECE 0.037. At a 0.5 cut-off threshold, the model had high specificity (71.6%) and low false positivity (28.4%). In a test cohort of 1,279,455 adults with hypertension, the model identified 5,295 (0.4%) for first-pass screening. Conclusions A high-specificity model can provide a pre-screening PA pathway using routine EHR data to identify and prioritize patients for PA screening. This AI-based approach can risk-stratify patients, guide sequencing of testing/referrals, and pragmatically facilitate adoption of current guidelines into practice.

BackgroundAldosterone promotes endothelial dysfunction and cardiovascular injury through mineralocorticoid receptor (MR) activation. Autophagy is essential for endothelial homeostasis, yet its role in aldosterone-mediated vascular dysfunction remains unclear. We tested whether aldosterone impairs autophagic flux and whether restoring autophagy via Beclin1 (BCN1) activation protects vascular and cardiac function. MethodsEndothelial and vascular responses to aldosterone were assessed in wild-type mice, BCN1 gain-of-function mice (Becn1), and mice treated with spermidine or a BCN1- activating TB-peptide. Vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis were evaluated using wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology. ResultsAldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and disrupted autophagic flux in an MR-dependent manner, indicated by LC3 accumulation and reduced p62 and BCN1 expression. Spermidine restored endothelial function and normalized NO and ROS levels. BCN1 gain-of-function mice were protected from aldosterone-induced endothelial dysfunction and exhibited reduced coronary and myocardial fibrosis. TB-peptide activation of BCN1 enhanced autophagic flux, improved vascular function, decreased cardiac fibrosis, and rescued endothelial migration impaired by aldosterone. ConclusionsAldosterone induces endothelial dysfunction by suppressing autophagic flux through MR activation. Genetic or pharmacologic enhancement of BCN1-dependent autophagy restores endothelial homeostasis and prevents vascular and cardiac injury, identifying autophagy activation as a promising therapeutic approach for cardiovascular diseases associated with mineralocorticoid excess.

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 Randomized outcome trials have shown the benefit of antihypertensive treatment, but subgroup analyses exploring treatment responses in relation to patient characteristics are usually based on single factors rather than comprehensive patient profiles. We hypothesized that a combination of individual predictors better identifies patients who are more or less likely to achieve blood pressure (BP) control. Methods To test our hypothesis, we reanalysed the data from the double-blinded VALUE-outcome trial (n=15,313). The patient population was divided into an exploratory cohort (2/3) and a validation cohort (1/3). We constructed composite patient profiles by combining four proven predictors of BP control: age, severity of hypertension, comorbidity and previous treatment status. Logistic regression and Cox proportional hazard models were used to test whether BP control and cardiovascular event rates differed among these profiles, and whether profiling conferred additional predictive information beyond the individual factors alone. Results BP control rates differed significantly between patient profiles, regardless of treatment (likelihood ratio test, p<0.001). Results from the exploratory cohort were reproducible in the validation cohort. Profiling predicted BP control significantly better than any individual factor (p<0.001 for all comparisons). In addition, there were significant associations between profiles and the incidence of cardiovascular events. Adverse events, however, were not related to profiles. Conclusions We conclude that composite patient profiles may predict BP responses to antihypertensive treatment more accurately than single factors. These findings may help to better individualize antihypertensive therapy.

Background: Pulmonary arterial hypertension (PAH) manifests by pulmonary vascular remodeling, caused by hyper-proliferation and apoptosis resistance of resident PA cells, elevated right ventricular (RV) afterload, and death of RV failure. The goal of this study is to determine the role and mechanisms of action of mitotic spindle-associated microtubule regulator DLG associated protein 5 (DLGAP5) in pulmonary vascular remodeling in PAH. Methods: DLGAP5 expression was assessed in human PAH transcriptomic datasets, PAH patients' lung tissues, pulmonary artery smooth muscle cells (PASMCs), and pulmonary artery adventitial fibroblasts (PAAFs). Loss-of-function, molecular, functional, RNAseq, and network analyses were performed. Smooth muscle (SM)-specific DLGAP5 knockdown using adeno-associated virus serotype 6 (AAV6) in mice with SU5416/hypoxia-induced PH was performed. Results: DLGAP5 was overaccumulated in small muscular PAs, PASMCs, and PAAFs from PAH lungs. siRNA DLGAP5 down-regulated cyclin A2, suppressed hyper-proliferation, increased pro-apoptotic BIM, and induced apoptosis in human PAH PASMCs and PAAFs. DEP domain containing 1 (DEPDC1) was identified and validated as a downstream effector of DLGAP5 in PAH PASMCs responsible for hyper-proliferation and apoptosis resistance of human PAH PASMCs. SM-specific DLGAP5 knockdown with AAV6-enTagln-shDLGAP5 reversed DEPDC1 overaccumulation in small muscular PAs, reduced PA medial thickness, RV systolic pressure, mean PA pressure, and RV hypertrophy in mice with SuHx-induced PH. Conclusions: DLGAP5 supports proliferation and survival of human PAH PASMCs and PAAFs through up-regulation of cyclin A2, DEPDC1, and suppression of BIM, and promotes PA remodeling and PH in mice. DLGAP5 could serve as a potential molecular target to attenuate pulmonary vascular remodeling in PAH.

Introduction: The inability to measure renal sympathetic outflow clinically poses a significant problem for patient identification and intraprocedural feedback for renal denervation. Sympathetic vasomotion is a novel physiologic measure of rhythmic vascular control that reflects renal sympathetic nervous system activity, but previous measurements of sympathetic vasomotion relied on 15-minute data recordings, which may be impractical in many clinical settings. We therefore tested whether shorter data segments can provide reliable sympathetic vasomotion assessment to enhance decision making for renal denervation. Methods: Ten swine that had previously undergone unilateral surgical renal denervation underwent four rounds of catheter-based denervation of the contralateral kidney. Sympathetic vasomotion was quantified from the time-varying arterial pressure-resistive renal blood flow transfer function of recordings obtained before and after each round of ablation. Randomly placed 1- to 14-minute data segments were scored and compared with the corresponding 15-minute sympathetic vasomotion scores across 100 passes using correlation, intraclass correlation, error, and Bland-Altman agreement metrics, and by whether they reproduced the denervation decisions made from the full recordings. Results: Agreement with the 15-minute reference score improved steeply with recording length up to approximately four minutes and slowly thereafter, with the point of diminishing returns at four minutes for every group-level measure. Four-minute data segments showed an intraclass correlation coefficient of 0.94, reproduced the group-level statistical results across ablations, and preserved intraprocedural denervation decisions. Bland-Altman analysis revealed that individual-level precision continued to improve with recording length; the proportion of scores falling within a quarter of the average difference between innervated and denervated kidneys at baseline was 65 percent at four minutes and 96 percent at ten minutes. Discussion: Four-minute data segments provide a feasible minimum recording duration when the question is a group comparison or a paired, within-individual decision, such as intraprocedural confirmation that an innervated kidney has shifted toward a denervated state. When a single score must be interpreted on its own, as in preprocedural patient selection, ten-minute recordings provide greater precision. Further studies are needed to prospectively evaluate sympathetic vasomotion in clinical settings and determine whether this technology can support procedural feedback and inform patient selection.

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.