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.

BackgroundRisk stratification in hypertension remains challenging. The prognostic value of plasma renin in guiding therapy for hypertension is not well established. MethodsIn this multicenter retrospective cohort of 16,600 people with hypertension, we evaluated the association between plasma renin activity and major adverse cardiovascular events (MACE) defined as stroke, myocardial infarction, and all-cause death. Plasma renin was analyzed as a continuous variable using restricted cubic splines. A 6-month landmark analysis assessed treatment effects of mineralocorticoid receptor antagonists (MRA) as opposed to baseline renin-angiotensin system inhibitors. ResultsContinuous renin level showed a U-shaped association with MACE, with the lowest risk at 1.17ng/mL/h. In categorical analyses, low renin (<0.3 ng/mL/h; adjusted hazard ratio [HR]=1.29, 95% CI 1.15-1.45) and high renin (>3.0ng/mL/h; HR=1.19, 95% CI 1.06-1.33) were both associated with higher MACE risk. Initiation of MRA therapy after renin measurement was associated with a graded reduction in MACE risk where patients with low renin had the lowest risk (HR=0.75, 95%CI 0.60-0.92), and patients with high-renin had the highest risk (HR=1.41, 95%CI 1.03-1.94). In contrast, baseline use of renin-angiotensin system inhibitors was associated with a graded reduction in MACE risk where patients with high-renin had the lowest risk (HR=0.76, 95%CI 0.63-0.92) but those with low renin did not benefit (HR=0.87, 95%CI 0.72-1.04). ConclusionsPlasma renin is a prognostic biomarker for MACE and may serve as a guide for treatment selection. A renin-guided strategy that favors MRAs in patients with low renin may reduce MACE and support individualized hypertension care. Clinical PerspectiveO_ST_ABSWhat is News?C_ST_ABSO_LIIn this large multicenter cohort of 16,600 patients with hypertension, plasma renin activity demonstrated a U-shaped association with major adverse cardiovascular events, with increased risk observed at both suppressed and elevated renin levels. C_LIO_LIRenin-defined hypertensive phenotypes were associated with differential treatment responses that mineralocorticoid receptor antagonist initiation was associated with lower cardiovascular risk in patients with low renin, whereas baseline renin-angiotensin system inhibitor use was associated with lower risk in patients with higher renin. C_LIO_LIThese findings extend the clinical role of renin beyond screening for primary aldosteronism, suggesting that renin may serve as an accessible marker that links hypertension pathophysiology, cardiovascular risk, and treatment responsiveness. C_LI What Are the Clinical Implications?O_LIPlasma renin may help clinicians move beyond blood pressure levels alone and recognize biologically distinct forms of hypertension that may require different therapeutic strategies. C_LIO_LISuppressed renin may identify a broader phenotype of renin-independent aldosteronism or mineralocorticoid receptor activation, in which earlier consideration of mineralocorticoid receptor antagonist therapy may be appropriate even without a formal diagnosis of primary aldosteronism. C_LIO_LIA renin-guided treatment strategy may provide a practical framework for mechanism-based hypertension care, while prospective studies are needed to determine whether this approach improves long-term cardiovascular outcomes. C_LI

Background: Left atrial (LA) stiffness index is a non-invasive echocardiographic parameter reflecting left ventricular filling pressure; however, its prognostic significance in hypertension remains unclear. We aimed to assess the prognostic value of the longitudinal change in LA stiffness index in patients with hypertension. Methods: We analyzed 1,442 hypertensive patients from the STRATS-HHD registry who underwent echocardiography including LA and left ventricular (LV) strain at baseline and 6-18 months. Patients were categorized into four groups according to longitudinal changes in LA stiffness index: normal-normal, improved, aggravated, and persistently stiff. The primary outcome was a composite of hospitalization for heart failure (HHF) and cardiovascular death, and secondary outcomes included HHF and incident atrial fibrillation. Results: Among 1,442 patients, 996 (69.1%) were classified as normal-normal, 173 (12.0%) as improved, 91 (6.3%) as aggravated, and 182 (12.6%) as persistently stiff. Over 5 years, aggravated (adjusted hazard ratio [aHR] 2.175, 95% confidence interval [CI] 1.048-4.515, P=0.037) and persistently stiff (aHR 2.935, 95% CI 1.697-5.076, P<0.001) groups were associated with a higher risk of the primary outcome, whereas the improved group showed a similar risk to the normal-normal group. Similar trends were observed for HHF and for incident atrial fibrillation. Adding LA stiffness index into a model including clinical factors and LV mass index improved risk prediction for composite outcomes. Conclusions: LA stiffness index was associated with clinical outcomes in hypertensive patients, with longitudinal changes providing additional prognostic information. Assessment of its trajectory may further refine risk stratification in patients with hypertension.

Background: Primary aldosteronism (PA) testing is recommended for patients with resistant hypertension but remains underused, and evidence linking aldosterone-targeted therapy to improved cardiovascular and renal outcomes is limited. Methods: In a nationwide cohort of patients with resistant hypertension between 2001 and 2022, we assessed PA testing and subsequent mineralocorticoid receptor antagonist (MRA) use and adrenalectomy. Among tested patients, time-dependent Cox models were used to assess associations between treatment exposure and mortality, major adverse cardiovascular events (MACE) and renal outcomes. Results: Among 254,338 patients, only 2.0% were tested for PA. Tested patients had a higher prevalence of hypokalemia and cardiometabolic comorbidities. In the overall tested population, MRA use was not associated with lower risks of cardiovascular or renal outcomes. However, when testing resulted in an established PA diagnosis, the use of both MRA (hazard ratio [HR] 0.60, 95% CI 0.42-0.86) and adrenalectomy (HR 0.33, 95% CI 0.20-0.54) were associated with a reduced risk of MACE compared with no aldosterone-targeted therapy. Similar results were observed regarding mortality. Adrenalectomy was associated with lower risk of MACE (HR 0.55, 95% CI 0.30-0.99), all-cause mortality (HR 0.52, 95% CI 0.29-0.93) and renal outcomes (HR 0.37, 95% CI 0.17-0.80) compared with MRA in patients with a diagnosis of PA. Conclusions: PA remains markedly underrecognized in resistant hypertension. Among patients with resistant hypertension who did undergo PA testing with establishment of a PA diagnosis, aldosterone-targeted therapy resulted in lower risk of adverse cardiorenal outcomes and death when compared to conventional antihypertensive therapy.

Effective hypertension management depends on sustained engagement with primary care, and there is a need to understand the magnitude and determinants of follow-up loss in real-world primary care. We analyzed electronic health record (EHR) data from 26,541 patients with hypertension across primary care practices participating in the EvidenceNOW quality-improvement initiative. We characterized retention in care, longitudinal blood pressure (BP) control, and predictors of loss to follow-up using descriptive statistics, cumulative retention curves, and multivariable Cox proportional-hazards regression. At baseline, mean systolic and diastolic BP were 140.0 {+/-} 20.6 and 84.7 {+/-} 13.0 mmHg, respectively; only 10.7% (95% CI 10.4-11.1) of patients had controlled BP and 18.1% never returned for any follow-up visit. Among the 21,729 patients who had [&ge;]1 follow-up encounter, retention declined steeply over time--from 59.9% at 6 months to 16.3% at 36 months. Patients identifying as Black/African American (adjusted hazard ratio [aHR] 1.44; 95% CI 1.33-1.56), Hispanic/Latino (aHR 1.43; 1.35-1.52), or Other race/ethnicity (aHR 1.50; 1.41-1.59) had significantly higher hazards of being lost to follow-up than White patients, whereas older age, female sex, comorbid diabetes, heart failure, chronic kidney disease, stroke, and baseline BP control were each independently protective. Among patients retained for at least 12 months, BP control rose to 63.7% and remained near 64-66% through 36 months. These findings reveal a substantial and inequitable longitudinal care-engagement gap that is likely a principal driver of suboptimal hypertension control in the United States and identify actionable demographic and clinical targets for primary-care retention interventions.

Background: Comprehensive assessment of hypertension-mediated organ damage (HMOD) across multiple organ systems in sub-Saharan Africa is limited. We assessed the prevalence and correlates of multidomain HMOD in a geographically diverse population in Ghanaian adult. Methods: This cross-sectional secondary analysis of the Ghana Heart Study, which included 1,106 adults aged [&ge;]18 years from four Ghanaian regions between September 2016 and March 2017. Multidomain HMOD was determined using a pre-specified 9-domain composite score [&ge;]2, using an ESH/ESC 2018 guideline-informed selection of HMOD domain with baPWV instead of carotid-femoral PWV (cfPWV), due to device unavailability, and a threshold of [&ge;]14 m/s which was derived from analysis within the cohort. LODO sensitivity analyses were used to address issues of predictor-outcome circularity. We used logistic regression models to examine association between each predictor and multidomain HMOD, adjusted for age, systolic blood pressure, body mass index, presence of dyslipidaemia and smoking status. We also performed receiver operating characteristic (ROC) analysis to determine correlates of multidomain HMOD and compare the discriminative ability of each predictor against the others. Results: The mean age of participants was 46.9{+/-}17.2 years of which 58% were females. Multidomain HMOD was observed in 21.3% (235/1,106; zero-imputation lower bound 21.2%) of participants studied. There was a marked increase in the prevalence of multidomain HMOD with advancing age. Thus, while 8.6% (44/ 511) of adults<45years had multidomain HMOD, 20.6% (63/306) of 45- to 59-yr-olds and 44.4% (128/ 288) of individuals [&ge;]60 years had multidomain HMOD. HMOD-positive adults were older (59.1{+/-}8.4 vs 43.6{+/-}13.4y, p<0.001), had higher systolic BP (147{+/-}22 vs 123{+/-}21 mmHg, p<0.001), and had higher prevalence of hypertension (73% vs 28%, p<0.001) than their HMOD-negative counterparts. Using the primary (circular) specification, the strongest co-occurrence among all domains of HMOD was observed between peripheral artery disease and other HMOD (OR 41.2, 95% CI 20.7-81.6; p<0.001) followed by valvular burden and other HMOD (OR 14.4, 95% CI 4.8-43.8; p<0.001) and between ECG-LVH and other HMOD (OR 9.0, 95% CI 5.9-13.8; p<0.001) (S2 Table). After LODO correction to remove the self-inclusive co-occurrence between each predictor domain and the outcome (all p-values calculated in S2 Table), there was no significant association between the remaining 8 HMOD domains and the prevalence of multidomain HMOD (all p-values>0.05; S2 Table). This was not the case for baPWV, however. Thus, whereas the AUC of the best performing non-self-inclusive HMOD domain (ECG-CMD) only reached 0.688{+/-}0.016 (vs 0.827{+/-}0.008 for self-inclusive AUC calculated for the sake of interest only and provided as supplementary material), baPWV demonstrated good discriminative capacity (LODO-adjusted AUC = 0.702, 95% CI 0.654-0.751; S3 Fig). However, this AUC did not significantly exceed that for age alone (AUC = 0.752; {Delta}AUC = -0.050, 95% CI ?0.103 to 0.03; p=0.106; S3 Fig). Most importantly, after adjustment for SBP (a direct mediator in this pathway), the LODO AUC for baPWV did not exceed that for the single variable age (S3 Fig), indicating that baPWV does not possess independent discriminative power for multidomain HMOD above and beyond the information provided by SBP and age. Importantly, however, the adjusted OR for baPWV did not reach statistical significance (OR 1.094, 95% CI 0.986-1.213; p=0.091), suggesting that while circularity prevented validation of biological association, it did not prove the absence of association altogether. Sensitivity analysis (estimating total as opposed to direct effect) in which SBP was excluded from the regression model to estimate the total effect of baPWV on the prevalence of HMOD showed that, indeed, the OR for baPWV was significantly elevated (OR 1.261; 95% CI 1.150-1.382; p<0.001) in this specification. The effect of SBP, a direct mediator in this pathway, therefore apparently accounted for the non-significance in the original model entirely. Formal mediation analysis using the aforementioned specification yielded that SBP indeed mediated 69.9% (95% CI 41.3-128.8%) of the effect of baPWV on the prevalence of HMOD. Conclusions: One in five Ghanaian adults has hypertension-mediated organ damage in multiple HMOD domains. baPWV has good discriminative power for HMOD risk prediction in a Ghanaian adult population under the non-circular LODO estimand (LODO- adjusted AUC = 0.702; 95% CI: 0.654, 0.751) than the PCE (AUC = 0.496; 95% CI: 0.438, 0.555; {Delta}AUC = +0.206; p < 0.001). However, baPWV LODO AUC (0.702) was not statistically significantly greater than age alone (AUC = 0.752; 95% CI: 0.730, 0.774; {Delta}AUC = -0.050, p = 0.106). AUC for self- inclusive model was provided in supplementary materials for the reader's perusal, and that AUC (0.827; 95% CI: 0.794, 0.860) is circular. The prevalence of ECG-LVH was substantially higher (42%) than that of echocardiographic- LVH (5.9%) in this Black African population. These findings support further research on the role of baPWV for HMOD risk prediction in a Ghanaian adult population. Prospective validation of baPWV would be needed before clinical use.

Background and Aims Hypertension during pregnancy is a major cause of maternal and neonatal morbidity and mortality, yet the efficacy and safety of antihypertensive treatments in this setting remain uncertain. We evaluated the effects of antihypertensive drug targets on adverse pregnancy-related outcomes using genetic variants to instrument target perturbation. Methods We performed drug target Mendelian randomization to mimic pharmacological perturbation of targets from six commonly used antihypertensive drug classes, using data from up to 671,922 pregnant women. Genetic variants near drug target genes associated with systolic or diastolic blood pressure were selected as instruments. We estimated effects of target modulation on six primary and eight secondary pregnancy outcomes. Results Genetically instrumented downregulation of blood pressure through beta-blocker (BB) and calcium-channel blocker (CCB) targets, particularly ADRB1 and CACNB2, was associated with a reduced risk of hypertensive disorders of pregnancy, including preeclampsia. For example, CACNB2-instrumented lowering corresponded to a 7% (95% CI: 5-9%) reduction in preeclampsia risk per 1 mmHg decrease in blood pressure. For most other targets, estimates were directionally consistent but imprecise. Across additional outcomes, effects varied by target, with suggestive evidence for reduced risks of miscarriage, preterm birth, small-for-gestational-age birth, and labour induction, although these estimates were accompanied by substantial uncertainty. Conclusions These findings support a protective effect of BB and CCB targets on hypertensive disorders of pregnancy and highlight potential target-specific differences in safety. This work illustrates the value of Mendelian randomization in addressing clinical uncertainties where robust trial evidence is limited.

BackgroundPreeclampsia (PE) is a complex hypertensive disorder of pregnancy characterized by endothelial dysfunction, immune dysregulation, and systemic vascular injury. Multiple genome-wide association studies (GWAS) have revealed genetic signals shared with hypertension and blood pressure traits, potentially obscuring biological mechanisms that are more specific to PE pathogenesis. Furthermore, the functional consequences of most PE-associated variants remain poorly understood. In addition, GWAS relies on short-read sequencing and array-based analyses, limiting the ability to identify insertions, deletions, and other structural variants that may contribute to disease-associated regulatory mechanisms. In this study, we investigated the regulatory architecture of PE-specific genetic variants and evaluated their potential linkage disequilibrium (LD) with structural variants. MethodsWe integrated GWAS, transcriptomic, and long-read sequencing data to investigate the regulatory architecture of PE-specific genetic variants. Summary statistics for PE, hypertension, systolic and diastolic blood pressure were obtained from the GWAS Catalog, and variants uniquely associated with PE (P [&le;] 1x10-4) were prioritized. Cis-expression quantitative trait locus (cis-eQTL) analyses were performed in whole-blood RNA-sequencing data from 180 African American women. Significant associations were replicated in biologically relevant tissues from the GTEx Project, including vascular, renal, and immune-related tissues. Long-read sequencing-derived structural variants (SVs) were subsequently evaluated for LD with replicated eQTL loci. ResultsA total of 10,843 PE-specific variants, present in whole-genome sequencing data of the 180 women, were evaluated. Cis-eQTL analyses identified 480 significant eQTL-gene associations involving 277 unique variants and 192 genes (FDR [&le;] 0.05). Replication analyses supported 69 eQTL-gene associations across five GTEx tissues, involving 35 variants and 14 genes. Replicated signals were enriched in vascular tissues, particularly artery tibial and artery aorta. Several prioritized genes converged on immune and vascular pathways, including MICA, HLA-DPB1, SEMA4D, JUP, ZFP57, and TMEM204. Integration of GWAS and eQTL effects demonstrated consistent regulatory shifts associated with PE-risk alleles, including downregulation of immune-related loci and upregulation of select vascular-associated genes. Long-read sequencing analyses identified 66 high-LD (r2 [&ge;] 0.80) SNP-SV-gene associations, including 12 replicated eQTL variants, 8 candidate SVs, and 3 replicated genes, suggesting that structurally complex genomic regions may contribute to the observed regulatory signals. ConclusionsThe tissues enriched in the regulatory signal highlight the importance of systemic endothelial biology in PE susceptibility. The findings of this study support a model in which PE-specific genetic susceptibility converges predominantly on interconnected immune and vascular regulatory mechanisms. The integration of eQTL analyses with long-read structural variant discovery provides additional insight into the complex genomic architecture underlying PE and highlights candidate regulatory loci that may not be adequately captured through conventional GWAS approaches alone. The study also emphasizes the importance of conducting functional genomic analyses in diverse populations to improve understanding of disease biology and advance precision medicine efforts. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/728031v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1caf4a5org.highwire.dtl.DTLVardef@1839b4eorg.highwire.dtl.DTLVardef@14922c3org.highwire.dtl.DTLVardef@894040_HPS_FORMAT_FIGEXP M_FIG C_FIG Regulatory Genomics of Preeclampsia-Specific Risk Variants Highlights Immune and Endothelial Mechanisms. GWAS summary statistics for preeclampsia, hypertension, SBP, and DBP were integrated to identify 10,843 preeclampsia-specific variants that were subsequently evaluated in cis-eQTL analyses using whole-blood RNA-sequencing data from 180 African American women (left). Cis-eQTL analyses identified 480 significant associations involving 277 variants and 192 genes (FDR [&le;] 0.05), of which 69 eQTL-gene associations involving 35 variants and 14 genes replicated across five GTEx tissues, with strongest enrichment observed in vascular tissues, particularly artery tibial and artery aorta (center). Prioritized genes, including MICA, HLA-DPB1, SEMA4D, JUP, ZFP57, and TMEM204, converged on interconnected immune and endothelial pathways associated with systemic vascular dysfunction, impaired placentation, and inflammatory dysregulation in preeclampsia. Integration of long-read sequencing data further identified 66 high-LD SNP-SV-gene associations involving 12 replicated eQTL variants, 8 candidate structural variants, and 3 replicated genes, suggesting that structurally complex genomic regions may contribute to regulatory mechanisms not fully captured through conventional GWAS approaches alone. eQTL indicates expression quantitative trait locus; FDR, false discovery rate; GTEx, Genotype-Tissue Expression project; SBP, systolic blood pressure; DBP, diastolic blood pressure; LD, linkage disequilibrium; SV, structural variant.

Background: Comprehensive assessment of hypertension-mediated organ damage (HMOD) across multiple organ systems remains limited in sub-Saharan Africa. We aimed to determine the prevalence and predictors of multidomain HMOD in a geographically diverse Ghanaian adult population. Methods: This secondary analysis of the Ghana Heart Study included 1,106 adults from four regions. Multidomain HMOD was defined as a pre-specified 9-domain TOD composite score ?2, based on the ESH/ESC 2018 guidelines framework. Logistic regression and ROC analysis were used to identify predictors and compare discriminative performance. Results: Mean age was 46.9 (17.2) years and 58% were female. Multidomain HMOD prevalence was 21.2% (235/1,106) and increased steeply with age: 8.6% (<45 years), 20.6% (45?59 years), and 44.4% (?60 years). Hypertension prevalence was 73% in the HMOD group versus 28% in those without HMOD (p < 0.001). The strongest independent associations were peripheral artery disease (OR 41.2), valvular burden (OR 14.4), and ECG-LVH (OR 9.0). baPWV showed superior discriminative performance (AUC 0.827, 95% CI 0.794?0.860) compared with the ASCVD Pooled Cohort Equations (AUC 0.466; ?AUC +0.351, DeLong test p < 0.001). Conclusions: One in five Ghanaian adults has hypertension-mediated organ damage in ?2 organ systems. baPWV is the strongest predictor and substantially improves risk stratification beyond conventional scores. These findings support the use of baPWV to guide hypertension management and HMOD assessment in West Africa.

Background: Hypertensive disorders of pregnancy (HDP) are a risk factor for early cardiovascular disease in women, perhaps related to adverse cardiovascular reactivity to physiologic stress. Objectives: To evaluate the association of HDP subtypes with exercise stress echocardiography parameters. Methods: This retrospective cohort study linked exercise stress echocardiograms with delivery records. HDP was classified as none, gestational hypertension (GH), and preeclampsia (PEC). We compared features of treadmill exercise stress echocardiography among HDP groups, adjusted for maternal demographic characteristics, time between delivery and stress testing, resting blood pressure (BP), and exercise duration. Results: Among 885 women with matching delivery and exercise echocardiography records (41.4plus-or-minus sign7.4 years at exercise exam), 92 (10.4%) experienced GH and 39 (4.4%) experienced PEC. Women with PEC were referred for exercise stress testing 3.1 years earlier following delivery (p<0.001) and had shorter exercise duration (lower case Greek beta]=-69.6 seconds [95% CI -115.9, -23.4], p=0.003) than those without HDP. Women with GH had higher peak exercise systolic BP (lower case Greek beta=8.96 mmHg [95% CI 4.89, 13.04], p<0.001), diastolic BP (lower case Greek beta=2.67 mmHg [95% CI 0.24, 5.10], p=0.031), and pulse pressure (lower case Greek beta=8.25 mmHg [95% CI 4.11, 12.39], p<0.001) than those without HDP. Women with GH and PEC were twice as likely to have concentric remodeling and more adverse diastolic parameters on echocardiography than those without HDP (p<0.05). Conclusions: Exercise stress echocardiography may detect subclinical cardiovascular dysfunction in midlife women following HDP, with adverse findings differing by subtype: GH was associated with higher peak exercise BP and PEC with lower exercise capacity.

1. Background: With the rising prevalence of hypertension, especially among younger populations, there is a critical need to better assess health status and predict associated complications. This study developed a biological age model ("hypertension age") for hypertensive patients to predict the risk and timing of major complications. 2. Methods: Using South Korea's NHIS-NHID data, researchers analyzed 4,535,041 hypertensive patients who underwent health examinations between 2009 and 2010. Patients were followed for an average of 12.40 years (until 2022). Principal Component Analysis (PCA) was used to develop the biological age (cBA) model. The risk and onset timing of complications were analyzed using Cox proportional hazards and multiple regression models, adjusting for variables like medication use and baseline diseases. 3. Results: A 1-standard deviation (SD) increase in the age gap?where biological age exceeds chronological age (cBA - CA)?was significantly associated with an elevated risk for all major complications in both sexes (p < 0.001). Furthermore, a 1-SD increase in this gap significantly accelerated the time to complication onset for nearly all conditions (p < 0.001), with the exception of dementia in women. The impacts of medication use, hypertension duration, and baseline comorbidities varied by specific complication. 4. Conclusions: Lowering "hypertension age" relative to chronological age can significantly reduce the risk and delay the onset of major cardiovascular and related complications. Quantifying this biological age gap serves as a powerful motivational tool for personalized health management and complication prevention in hypertensive patients.

Background: Pathologic aldosteronism induces oxidative stress, tissue injury, and increases in hemoglobin. Conversely, aldosterone antagonist therapy decreases hemoglobin. Whether these effects are attributable to aldosterone-mediated changes in iron and oxygen metabolism is unknown. Methods: The plasma proteome of participants with overt primary aldosteronism (PA) (n=50) was compared with participants without overt PA (n=61). To isolate aldosterone-dependent effects, participants without overt PA underwent oral sodium suppression testing to quantify the magnitude of renin-independent aldosterone production, enabling monotonic dose-response analyses across the continuum of renin-independent aldosteronism (subclinical to overt PA). Differential abundance testing was performed using empirical Bayes linear modeling, followed by Reactome pathway enrichment analysis and covariate-adjusted sensitivity analyses. To validate clinical relevance, aldosterone dose-response trends with blood count parameters were examined in this cohort, and an independent population-based cohort of 5,713 people with hypertension. Results: 903 proteins in the peripheral circulation were differentially abundant in overt PA versus participants without PA. The most significantly increased protein in overt PA was CYBRD1, involved in iron reduction and absorption. Pathway enrichment identified 16 iron- and heme-related pathways, including erythropoietin signaling, heme biosynthesis and mitochondrial iron-sulfur cluster biogenesis, with increases in heme and erythroid proteins and decreases in mitochondrial iron-sulfur proteins. Linear aldosterone dose-dependent trend analyses across the PA continuum further supported this signature, identifying progressive increases in hemoglobin subunits (HBA1/HBB), heme-related proteins (HMBS, UROS, AMBP, HPX, GLO1) and erythrocyte oxygen handling enzymes (CA1/CA3), alongside progressive reductions in mitochondrial electron transport chain subunits (CYCS, ETFA). These proteomic changes corresponded with aldosterone dose-dependent increases in red blood cell count, hemoglobin, and hematocrit, in this cohort and another population-based cohort. Conclusion: The continuum of PA is characterized by a progressive shift away from mitochondrial oxidative phosphorylation and toward increased intestinal iron absorption, preferential iron transport over storage, and enhanced heme synthesis and recycling, possibly reflecting cellular pseudohypoxia and systemic adaptations to increase oxygen delivery. These findings provide a novel mechanistic basis for aldosterone-mediated tissue injury and the benefits of aldosterone-directed therapy.

BackgroundPreeclampsia (PE) is a hypertensive disorder of pregnancy characterized by systemic inflammation, oxidative stress, and endothelial dysfunction. Although maternal vascular dysfunction is well established in PE, the mechanisms underlying fetal vascular injury remain poorly understood. We investigated whether inflammatory signaling activates NADPH oxidase 5 (NOX5) and contributes to oxidative stress and dysfunction in human umbilical arteries from pregnancies complicated by PE. MethodsUmbilical arteries and serum samples were obtained from normotensive pregnant women (NP) and women with PE. Vascular reactivity, nitric oxide (NO) bioavailability, reactive oxygen species (ROS) generation, cytokine levels, and NOX isoform expression were evaluated in human umbilical arteries and EA.hy926 endothelial cells. Pharmacological inhibition of NOX5, TNF- neutralization, Ca{superscript 2} channel blockade, and siRNA-mediated NOX5 silencing were used to investigate mechanisms. ResultsPE umbilical arteries exhibited increased vasoconstrictor responses, oxidative stress, and NOX5 expression, accompanied by impairment of NO bioavailability. NOX5 inhibition reversed vascular hyperreactivity in PE vessels. Exposure of normotensive umbilical arteries to PE serum reproduced the PE vascular phenotype, characterized by enhanced ROS generation, reduced NO levels, and hypercontractility. In endothelial cells, PE serum induced TNF--dependent Ca{superscript 2} influx, oxidative stress, and reduced NO production. Both pharmacological and genetic inhibition of NOX5 prevented these alterations. ConclusionsPE promotes fetal vascular dysfunction through activation of a TNF-/Ca2+/NOX5 signaling pathway that amplifies oxidative stress and impairs NO bioavailability. These findings identify NOX5 as a previously unrecognized mediator of umbilical artery dysfunction in PE and suggest the TNF-/Ca2+/NOX5 axis as a potential therapeutic target in hypertensive pregnancies.

Sympathetic neuronal (SN) activity critically regulates the development and function of peripheral organs and tissues. Activity-dependent plasticity has been shown to modulate SN output, suggesting that compensatory forms of plasticity could contribute to maintaining stability of sympathetic circuits. Early SN hyperactivity drives the development of hypertension in humans and in the spontaneously hypertensive rat (SHR). In this study we used chemogenetic and pharmacological approaches, and took advantage of the enhanced activity of SHR SNs, to examine how long-term changes in activity impact synaptic properties in neonatal SN cultures. We showed that bidirectional changes in SN activity result in compensatory shifts in synaptic density that counteract long-term activity manipulations. These changes were mediated by satellite glial cells (SGCs), a non-neuronal cell in the sympathetic ganglia that has been shown to influence cholinergic synaptic sites during development. In the absence of SGCs there was no induction of homeostatic plasticity. Further, direct chemogenetic activation of SGCs was sufficient to drive compensatory plasticity, while glial inhibition blocked SN plasticity. We found that SGCs respond to cholinergic signaling by downregulating the expression of the synaptic regulators NGF and TNF, suggesting that neurons and glia interact to stabilize sympathetic output during long-term changes in circuit activity. Finally, we investigated whether these plasticity mechanisms are present in neonatal SHR SNs. We demonstrated that SHR SNs have an attenuated response to glia, both during synapse formation and activity-dependent plasticity. Taken together, this work outlines a novel homeostatic activity-dependent plasticity mechanism in the peripheral nervous system.

Cells deploy adaptive programs to maintain homeostasis under stress, yet mechanisms counteracting damage triggered by transmembrane signaling remain poorly defined. Using a hyperaldosteronism model, we examined how autophagy regulates aldosterone-mediated mineralocorticoid receptor (MR) activation. In human umbilical vein endothelial cells (HUVECs), aldosterone induced autophagy, as evidenced by elevated Beclin-1, an increased LC3-II/LC3-I ratio, and reduced SQSTM1/p62. Aldosterone also promoted MR translocation from the cytosol to the nucleus. Co-immunoprecipitation and immunofluorescence revealed direct interaction and colocalization between MR and Beclin-1, as well as enhanced MR-lysosome association. Domain mapping showed that the Beclin-1 middle domain (161-241 AA) binds the MR C-terminal region (601-984 AA). Bioinformatic prediction and ChIP-qPCR confirmed that MR occupies the promoters of IL-1{beta}, IL-6, and TNF- upon aldosterone stimulation. Beclin-1 overexpression attenuated MR nuclear translocation, promoter binding, and inflammatory cytokine expression, whereas Beclin-1 knockdown reversed these effects. In vivo, aldosterone-infused Beclin-1 transgenic (Becn1-tg) mice exhibited lower blood pressure, reduced aortic medial thickening, and attenuated cardiac hypertrophy relative to wild-type controls, with no difference in body weight. Our findings identify Beclin-1 as a critical negative regulator of aldosterone signaling through an autophagy-dependent negative feedback loop. By interacting with MR and directing it toward lysosomal sequestration, Beclin-1 limits MR nuclear translocation and transcriptional activity, thereby mitigating aldosterone-induced vascular inflammation and cardiovascular injury. HighlightsAldosterone activates autophagy and promotes MR-Beclin-1 interaction in HUVECs Beclin-1 binds the C-terminal MR domain and directs MR to lysosomal degradation Beclin-1 overexpression suppresses MR nuclear translocation and cytokine gene activation Beclin-1 transgenic mice are protected from aldosterone-induced cardiovascular injury

Background As dementia prevalence rises globally, it is critical to find preventions that target modifiable risk factors like blood pressure. Pulse pressure (PP), a marker of arterial stiffness, contributes independently to cognitive impairment. Yet, clinically interpretable thresholds for PP for cognitive decline remain undefined. We examined the independent association between PP and domain-specific cognitive trajectories and identified PP thresholds associated with greater cognitive decline across ethnically diverse regional populations. Methods Data were harmonized across three longitudinal cohorts (54,878 participants with up to 20 years follow-ups and 266,144 observations). Linear mixed-effects models identified a nonlinear association between PP and cognition (memory, orientation, and executive function), whereby cognitive decline accelerated after around 50 mmHg of pulse pressure, despite controlling for mean arterial pressure and dementia risk factors. Stratification based on PP thresholds (Low: PP <30; Normal: 30 to <50; Borderline: [&ge;]50; and High: [&ge;]60 mmHg), and tested for differences in memory decline across groups. Stratified analyses were similarly conducted across other blood pressure measures, racial, age and sex groups. Findings Non-linear associations indicated that memory decline was particularly noticeable for pulse pressure [&ge;]60 mmHg. Compared with normal pulse pressure, [&ge;]60 mmHg was associated with worse memory performance (pooled {beta} -0.062 SD; 95% CI -0.107 to -0.016) and greater memory decline with age (-0.026 SD/year; -0.036 to -0.015), including among normotensive individuals. Findings were consistent across diverse regional cohorts (UK, US and China), racial groups, age strata and sexes. Interpretation Pulse pressure over 60 mmHg is associated with elevated cognitive risk, independent of blood pressure measures, even among normotensive individuals. These findings support pulse pressure thresholds as clinically interpretable and complementary markers of cognitive risk.

AimMaternal iron deficiency (ID) during pregnancy induces cardiovascular adaptations, including reduced blood pressure and improved cardiac efficiency in hypertensive pregnancy. Iron is essential for mitochondrial function, particularly oxidative phosphorylation, where it serves as a cofactor within electron transfer complexes. Given the high metabolic demands of the maternal heart and irons central role in mitochondrial metabolism, we examined how maternal ID affects cardiac mitochondrial ultrastructure, respiration, dynamics, and redox status in pregnant spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Methods and ResultsFemale SHR and WKY rats were fed iron-replete or iron-restricted diets before and throughout gestation. On gestational day 21, cardiac mitochondrial ultrastructure was assessed by transmission electron microscopy (TEM), respiration by high-resolution respirometry, and the expression of proteins involved in fusion, fission, autophagy, and apoptosis markers by immunoblotting. Antioxidant gene expression was quantified by RT-qPCR. Data were analyzed by two-way ANOVA with Holm-Sidaks post hoc test. Maternal iron restriction reduced hemoglobin levels in both strains. TEM revealed enlarged, morphologically heterogeneous mitochondria with reduced and disrupted cristae architecture in ID dams of both strains. Iron restriction reduced succinate-supported respiration and tended to reduce NADH-supported respiration, in both strains. SHR dams exhibited reduced fusion signalling, reflected by a lower L-OPA1:S-OPA1 ratio. MFN1 expression was reduced by ID in both strains, whereas MFN2 expression was lower in SHR and further reduced by ID. In contrast, DRP1 phosphorylation increased selectively in ID-WKY dams. Iron restriction increased LC3-II:I ratio and BNIP3 in SHR, and increased PINK1 in both strains, while Parkin and p62 were unchanged. Antioxidant gene expression increased in ID-SHR but decreased in ID-WKY dams. Despite these alterations, markers of oxidative damage and apoptosis were unchanged by iron restriction. ConclusionMaternal ID induces marked remodeling of myocardial mitochondrial ultrastructure and selectively constrains iron-dependent respiration in hypertensive pregnancy without overt oxidative damage or apoptosis. These mitochondrial alterations occur alongside previously observed reductions in blood pressure and improved cardiac efficiency, suggesting favorable hemodynamic adaptations may coexist with underlying bioenergetic constraints in the maternal heart. Translational PerspectiveMaternal iron deficiency anemia (IDA) may alter the course of hypertensive pregnancy in ways not evident from hemodynamic indices alone. Here, IDA was associated with abnormal myocardial mitochondrial ultrastructure, selective reductions in respiratory capacity and stress response pathways, despite previously observed improvements in blood pressure and cardiac efficiency. These findings suggest that favourable hemodynamic changes may reflect reduced metabolic demand rather than enhanced bioenergetic capacity. If confirmed in human pregnancy, management of ID in women with underlying hypertension may need closer attention to cardiac metabolic health, as cardiovascular adaptions could coexist with myocardial stress and may vary with anemia severity and duration.

Hypertension represents the most prevalent chronic cardiovascular condition, typically culminating in pathological cardiac remodeling characterized by hypertrophy and extensive fibrosis. Although the cellular phenotypes associated with these changes are well-documented, the precise mechanisms by which hypertensive stress is sensed and transduced into a fibrotic program remain poorly defined. To elucidate these mechanisms, we investigated the role of Lysyl oxidase (LOX), an extracellular matrix (ECM)-modifying enzyme that is upregulated during hypertensive stress and associated with cardiovascular diseases. By employing cell-type specific Cre-Lox technology to conditionally delete Lysyl oxidase in either smooth muscle cells (SMCs) or fibroblasts, the primary ECM-secreting cell populations, we demonstrate that fibroblast-specific Lox deletion had no significant impact on the progression of cardiac fibrosis. Conversely, SMC-specific Lox deletion selectively inhibited the fibrotic response without affecting other remodeling parameters, such as cardiac hypertrophy. Notably, in the SMC-specific Lox knockout hearts, fibrosis was restricted to the perivascular niche and failed to propagate into the cardiac interstitium. We find that this transition is a mechanical, ECM-dependent process initiated by SMCs. Our results identify SMCs, rather than fibroblasts, as the primary sensors and initiators of the hypertensive fibrotic response. These findings demonstrate that fibrosis can be uncoupled from other hypertensive manifestations and identify SMC-mediated ECM modification as a potential therapeutic target for treating hypertensive heart disease.

Genome-wide association studies have identified rare and common mutations associated with increased risk of pulmonary arterial hypertension (PAH), but the mechanism by which impaired SOX17 expression increases PAH risk is not known. Notably, SOX17 plays a critical role in endothelial identity during development by suppressing RUNX1 through binding to its promoter and directing stem and progenitor cells toward an endothelial rather than a hematopoietic cell fate. RUNX1 functions as a key regulator of myeloid differentiation, aberrant angiogenesis and adverse cardiac remodeling. Previously, we found that RUNX1 inhibition reverses pulmonary hypertension (PH) in multiple animal models. Here, we hypothesize that impaired expression of SOX17 in PAH leads to endothelial cell (EC) dysfunction by failing to suppress RUNX1. METHODSHuman pulmonary artery endothelial cells (HPAECs) with stable SOX17 CRISPR/Cas9 knockout or RUNX1 overexpression were generated and examined for endothelial and hematopoietic gene expression, proliferation, migration, apoptosis, and angiogenesis. Immortalized lymphoblastoid cell lines (LCLs) from PAH patients with SOX17 mutations and healthy controls were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into ECs. The effect of RUNX1 inhibition on Sugen/hypoxia-PH was examined in rats, SOX17 enhancer knockout (SOX17enhKO) mice, and Cdh5-CreERT2;Runx1(flox/flox);SOX17enhKO triple transgenic mice. SOX17 and RUNX1 expression were analyzed in peripheral blood samples from PAH patients (n=359). RESULTSHPAECs with SOX17 deletion or RUNX1 overexpression exhibited decreased expression of EC markers, enhanced proliferation and migration, defective angiogenesis, and decreased apoptosis. RUNX1 siRNA knockdown or RUNX1 inhibition by Ro5-3335 partially restored the endothelial properties in SOX17 KO HPAECs. ECs differentiated from SOX17 mutant PAH patient iPSCs exhibited upregulated RUNX1 expression and loss of endothelial identity, which was also partially restored by RUNX1 siRNA or Ro5-3335. In addition, SOX17enhKO mice had increased RUNX1 expression and susceptibility to Sugen/hypoxia-induced PH (SuHx-PH). Treatment with RUNX1 inhibitors or inducible endothelial-specific deletion of RUNX1 rescued SuHx-PH susceptibility in SOX17enhKO mice. RUNX1 inhibitors Ro5-3335 and Ro24-7429 also reversed SuHx-PH in wild-type rats. In addition, plasma RUNX1 expression was higher in PAH patients lacking detectable SOX17 expression than in patients with detectable SOX17 expression. CONCLUSIONSImpaired SOX17 expression increases the risk of PAH through insufficient suppression of RUNX1, leading to pulmonary endothelial dysfunction. RUNX1 inhibition mitigates PH associated with SOX17 deficiency and may represent a novel therapeutic strategy for PAH, especially those with rare or common SOX17 mutations.

BACKGROUNDChronic thromboembolic pulmonary hypertension (CTEPH) is a severe and progressive condition characterized by dyspnea and fatigue. Our previous study reported cognitive impairment in pulmonary hypertension (PH) patients. However, balloon pulmonary angioplasty (BPA) capable of alleviating cognitive impairment in patients with CTEPH is largely unknown. METHODSThis was a prospective study involving a total of 131 patients with CTEPH who underwent BPA at the Shanghai Pulmonary Hospital. We collected Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) questionnaires and examined plasma A{beta} and phosphorylated-tau217 (p-tau217) levels to assess the cognitive function of patients with CTEPH between the pre-BPA and post-BPA stages. RESULTSFollowing BPA, patients exhibited improved cognitive performance, accompanied by reduced plasma levels of A{beta}1-42 and p-tau217. After the third BPA session, patients with a mean pulmonary arterial pressure (mPAP) of[&ge;]25 mmHg had significantly lower MMSE and MoCA scores compared to those with an mPAP of <25 mmHg. Linear regression analyses revealed that baseline and post-intervention MMSE or MoCA total scores were significant predictors of cardiac output (CO) levels measured after the last BPA procedure. Logistic regression analyses incorporating pre- and post-BPA clinical parameters identified three independent predictors of baseline cognitive dysfunction: lower educational attainment, higher baseline A{beta}1-42 levels, and elevated baseline p-tau217 concentrations. CONCLUSIONSOur findings suggest promising therapeutic effects of BPA, associated with improvements in cognitive dysfunction and reductions in plasma A{beta}1-42 and p-tau217 levels in patients with CTEPH. NOVELTY AND RELEVANCEO_ST_ABSWhat Is New?C_ST_ABSThis is the first study to demonstrate that balloon pulmonary angioplasty (BPA) improves cognitive function (MMSE/MoCA scores) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). And the first report that BPA reduces plasma levels of A{beta}1-42 and p-tau217-- key Alzheimers disease-related proteins--in CTEPH patients, establishing a peripheral biomarker for CTEPH-associated cognitive impairment. What Is Relevance?Cognitive impairment is common but underrecognized in CTEPH, BPA now addresses both cardiopulmonary and cognitive dysfunction, improving quality of life beyond hemodynamic recovery. Findings support the cardiopulmonary-brain axis in CTEPH: improved pulmonary hemodynamics and oxygenation reduce systemic pathological protein release, benefiting brain function. Clinical/Pathophysiological Implications?Our findings suggest promising therapeutic effects of BPA, associated with improvements in cognitive dysfunction and reductions in plasma A{beta}1-42 and p-tau217 levels in patients with CTEPH.