BACKGROUND: Preeclampsia is associated with long-term cognitive dysfunction, potentially linked to cerebral iron deposition. This study investigated striatal iron alterations using quantitative susceptibility mapping and...BACKGROUND: Preeclampsia is associated with long-term cognitive dysfunction, potentially linked to cerebral iron deposition. This study investigated striatal iron alterations using quantitative susceptibility mapping and their relationship with cognitive function in patients with preeclampsia. METHODS: This cross-sectional study enrolled 321 participants, including nonpregnant and pregnant healthy controls, and patients with preeclampsia. Participants underwent the Montreal Cognitive Assessment, Trail Making Test, and 1.5 T brain magnetic resonance imaging. Striatal iron content was quantified using quantitative susceptibility mapping reconstructed with a morphology-enabled dipole inversion algorithm. RESULTS: Preeclampsia patients showed poorer executive function (Trail Making Test part [A+B]: partial η=0.170; part B: partial η=0.100) and elevated nucleus accumbens magnetic susceptibility (all <0.001). Age (=0.744, <0.001) and hematocrit (=0.846, =0.011) were independently associated with iron levels. In addition, significant interactions between nucleus accumbens susceptibility values and preeclampsia status were observed for log-transformed Trail Making Test completion times (part [A+B]: interaction =0.388, =0.006; part B: interaction =0.424, =0.003), indicating that elevated iron specifically exacerbates executive vulnerability in preeclampsia. CONCLUSIONS: Nucleus accumbens iron level is elevated in preeclampsia and correlates with executive performance. Although the cross-sectional design limits causal conclusions, these findings highlight nucleus accumbens iron deposition as a key pathological feature underlying preeclampsia-related cerebral involvement.
Dathan-Stumpf A, Martini E, Stepan H
… +2 more, Kolar R, Rauscher FG
Hypertension
· 2026 Jun · PMID 42366971
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BACKGROUND: Adaptive optics retinal imaging (rtx1e, Imagine Eyes, Orsay, France) enables high-resolution visualization of the retinal microvasculature, providing insights into systemic vascular health. Currently, no stud...BACKGROUND: Adaptive optics retinal imaging (rtx1e, Imagine Eyes, Orsay, France) enables high-resolution visualization of the retinal microvasculature, providing insights into systemic vascular health. Currently, no studies exist describing changes in wall-to-lumen ratio (WLR) during pregnancy, neither during the physiological course of pregnancy nor in pregnancy-associated complications. METHODS: This single-center, prospective study at the Leipzig University Hospital, Germany, examines changes in retinal microvasculature by employing adaptive optics to calculate the WLR of an arteriole within a few seconds. The study examined a well-phenotyped cohort of 460 primarily White healthy singleton pregnancies, with 543 measurements taken from the first to the third trimester. The WLR was automatically determined using the nnUNet deep learning model. RESULTS: Step-down selection mixed-effects modeling identified gestational week, maternal age, mean arterial pressure, and parity as significant contributors to WLR, whereas body mass index did not improve model fit. In the final model, advancing gestational week (<0.001), higher maternal age (0.012), and higher mean arterial pressure (<0.001) were independently associated with increased WLR, whereas multiparous women showed significantly lower WLR values compared with nulliparous women, with negligible multicollinearity (variance inflation factor ≈1). CONCLUSIONS: We identify WLR as a sensitive marker for imaging microvascular remodeling, serving as an indicator of adaptation to physiological pregnancy. Normal pregnancy is associated with an instant change of the retinal microvasculature indicated by an increase of WLR. Further studies are required to investigate the postpartum course of WLR and establish whether these changes are reversible. REGISTRATION:URL: https://www.drks.de; Unique identifier: DRKS00032530.
Voskamp LW, Rousian M, Daniels A
… +4 more, Wuhrer M, Danser AHJ, Steegers-Theunissen RPM, Verdonk K
Hypertension
· 2026 Jun · PMID 42359511
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BACKGROUND: Placenta-related complications are major contributors to maternal and neonatal morbidity. Glycosylation modulates immunoglobulin function by altering molecular structure and receptor affinity. During pregnanc...BACKGROUND: Placenta-related complications are major contributors to maternal and neonatal morbidity. Glycosylation modulates immunoglobulin function by altering molecular structure and receptor affinity. During pregnancy, IgG (immunoglobulin G) and IgA (immunoglobulin A) glycosylation normally shift toward a more anti-inflammatory profile. We hypothesized that this adaptation is attenuated in complicated pregnancies, resulting in altered glycosylation trajectories. METHODS: Women with singleton pregnancies were enrolled in the prospective Rotterdam Periconception Cohort (2017-2018). Serum samples were collected at 9, 11, 13, 22, and 32 weeks of gestational age. IgG and IgA glycosylation was measured using liquid chromatography-mass spectrometry, and summarized into glycosylation traits (galactosylation, sialylation, fucosylation, bisection). Placenta-related complications (preeclampsia, pregnancy-induced hypertension, preterm birth, or small-for-gestational-age) were identified from medical records. Longitudinal changes and group differences in Ig glycosylation were analyzed using linear mixed-effects models with false discovery rate correction. RESULTS: Among the included 193 pregnancies, 54 were complicated by at least 1 placenta-related disorder. In complicated pregnancies, galactosylation and sialylation were consistently lower, whereas fucosylation and bisection were higher. From 9 weeks of gestational age onwards, fucosylation was significantly elevated at IgA Asn327/Asn340 and Asn205 (-score difference: 0.45-0.52; =0.002-0.004 and 0.33-0.37; =0.038). Bisection increased more steeply at IgG1, IgA Asn144/Asn131, and IgA Asn327/Asn340 (=0.021-0.027). IgG galactosylation rose less across gestation (=0.021-0.024), and IgA galactosylation and sialylation declined more sharply at Asn144/Asn131, Asn205, and Asn327/Asn340 (q=0.000-0.026). CONCLUSIONS: Pregnancies with placenta-related complications exhibit more proinflammatory glycosylation profiles. These findings suggest a potential mechanistic link between immunoglobulin glycosylation and placental dysfunction, with specific glycopeptides as possible biomarkers. REGISTRATION:URL: https://onderzoekmetmensen.nl/en/trial/57880; Unique identifier: NL-OMON57880.
Qiao Y, Sun Z, Harshfield EL
… +3 more, Ji X, Markus HS, Zhao W
Hypertension
· 2026 Jun · PMID 42345116
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BACKGROUND: Blood pressure (BP) variability (BPV) is associated with cardiovascular risk beyond mean BP. Whether first-line antihypertensive regimens differentially affect BPV and cardiovascular outcomes remains uncertai...BACKGROUND: Blood pressure (BP) variability (BPV) is associated with cardiovascular risk beyond mean BP. Whether first-line antihypertensive regimens differentially affect BPV and cardiovascular outcomes remains uncertain. METHODS: We conducted a target trial emulation using pooled individual participant data from 2 randomized trials: ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial). Propensity score matching was used for pairwise comparisons of RAS (renin-angiotensin system) inhibitors, calcium channel blockers (CCBs), and diuretics, as monotherapy or in combination. Follow-up was initiated at a predefined baseline medication assessment. The primary outcome was visit-to-visit systolic BPV, assessed using variation independent of the mean. Secondary outcomes included major adverse cardiovascular events and its individual components. RESULTS: The final cohort included 5779 participants (median of 12 BP measurements and median follow-up of 3.5 years), among whom 2754 were included in the matched analysis. CCB-based regimens were consistently associated with significantly lower systolic BPV compared with both RAS inhibitor-based and diuretic-based regimens. This association was consistent across monotherapy (CCB versus RAS: β=-1.341 [95% CI, -1.930 to -0.752]; <0.001) and combination therapies (CCB+diuretic versus RAS+diuretic: β=-1.299 [95% CI, -1.852 to -0.747]; <0.001). In contrast, RAS inhibitor-based and diuretic-based regimens demonstrated comparable BPV profiles. 215 (3.7%) major adverse cardiovascular event events were observed in the overall cohort. No significant differences in major adverse cardiovascular event or individual components were observed across comparisons. CONCLUSIONS: Among high-risk hypertensive patients receiving target-driven BP management, CCB-based regimens were associated with lower visit-to-visit systolic BPV compared with RAS inhibitor-based and diuretic-based regimens. However, these differences were not accompanied by detectable differences in cardiovascular outcomes.
Ford CD, Cameron NA, Clark D
… +7 more, Derington CG, Hardy ST, Mattei J, Yarrington CD, Zoghby ZM, Garovic VD, American Heart Association Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology
Hypertension
· 2026 Jun · PMID 42345114
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Hypertension is a leading cause of cardiovascular morbidity and mortality. Individuals living in rural areas have a higher prevalence of hypertension and a lower prevalence of blood pressure control. Factors contributing...Hypertension is a leading cause of cardiovascular morbidity and mortality. Individuals living in rural areas have a higher prevalence of hypertension and a lower prevalence of blood pressure control. Factors contributing to the increased hypertension prevalence in rural populations include shortages of health care professionals, limited access to transportation and longer travel distances to care, lower health literacy, socioeconomic factors, and reduced access to pharmacies. Approaches to addressing barriers to effective hypertension management include expanding rural telehealth services, deploying mobile units, leveraging pharmacists, implementing remote blood pressure monitoring, and engaging community health workers. Health services need to be culturally tailored and address the unique challenges faced by rural communities. Further research is needed to identify effective methods for addressing health disparities experienced by rural populations related to hypertension management.
Hypertension
· 2026 Jun · PMID 42333473
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Mineralocorticoid receptor (MR) antagonists (MRAs) are first-line therapy for primary aldosteronism and guideline-recommended treatment for heart failure (HF). The cardiovascular benefits of MRAs exceed blood pressure re...Mineralocorticoid receptor (MR) antagonists (MRAs) are first-line therapy for primary aldosteronism and guideline-recommended treatment for heart failure (HF). The cardiovascular benefits of MRAs exceed blood pressure reduction, reflecting inhibition of inappropriate MR activation in cardiac and vascular tissues, and immune cells. Early preclinical studies demonstrated that aldosterone excess induces myocardial inflammation and fibrosis through MR-dependent pathways, and clinical trials established the efficacy of MRAs in reducing morbidity and mortality in HF. Nonsteroidal MRAs are now available, and aldosterone synthase inhibitors have commenced clinical testing; it is thus timely to revisit the mechanisms of MR activation in the heart and related cell types. This review will discuss key findings from preclinical and clinical studies of MRA use in HF and mineralocorticoid infusion, and update our understanding of MR actions in the normal myocardium and in the pathophysiology of primary aldosteronism and HF. Emerging data on aldosterone-mediated cardiovascular injury in patients with primary aldosteronism, including structural and functional cardiac changes and links to adverse outcomes, will be included, along with recent advances in MR-targeted pharmacology that offer improved selectivity and safety profiles. This review provides an updated understanding of MR-dependent pathways in the cardiovascular system and potential strategies for optimizing cardiovascular protection in both primary aldosteronism and HF.
Cutler HR, Hanssen H, Hauser C
… +11 more, Streese L, Sattwika PD, Kitt J, McCourt A, Suriano K, Kenworthy Y, Frost A, Krasner S, Lewandowski AJ, Lapidaire W, Leeson P
Hypertension
· 2026 Jun · PMID 42305089
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BACKGROUND: Women display retinal vessel caliber abnormalities after hypertensive pregnancy, but whether these predate or reflect vascular aging is unknown. METHODS: Retinal imaging was performed in 2 cohorts: 196 women...BACKGROUND: Women display retinal vessel caliber abnormalities after hypertensive pregnancy, but whether these predate or reflect vascular aging is unknown. METHODS: Retinal imaging was performed in 2 cohorts: 196 women at 6 to 12 months postpartum (167 hypertensive, 29 normotensive), and 105 women at 15 to 25 years postpartum (64 hypertensive, 41 normotensive), using identical imaging/analysis protocols (Imedos Health, GmbH). Central retinal arteriolar and venular equivalents were calculated, corrected for mean arterial pressure at the time of imaging, and compared across hypertensive and normotensive pregnancy groups using multivariable linear regression models adjusted for body mass index and time postpartum. tests were used to compare effect sizes across time points. RESULTS: At both time points, corrected central retinal arteriolar and venular equivalents were lower after hypertensive pregnancies compared with normotensive pregnancies (<0.001). Between-group differences were larger at 6 to 12 months than 15 to 25 years postpartum for both arteriolar (β=-0.53 versus -0.15; =-4.19; <0.001) and venular calibers (β=-0.50 versus β=-0.18, =-3.83; <0.001), consistent with age-related reductions after normotensive pregnancy. Arteriovenous ratio was significantly different at 6 to 12 months postpartum (<0.001), but not at 15 to 25 years postpartum. Differences were not explained by blood pressure at the time of imaging, but 6 to 12 months postpartum, related to early pregnancy blood pressure (β=0.01; <0.001). CONCLUSIONS: Hypertensive pregnancy is associated with retinal vessel changes up to 25 years postpartum that predate age-related reductions and are associated with early pregnancy blood pressure. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04273854 and NCT05434195.
Tsioufis K, Kyriakoulis KG, Vakka A
… +13 more, Stamataki N, Tatakis F, Konstantinidis D, Mihas C, Soulaidopoulos S, Kasiakogias A, Kordalis A, Thomopoulos C, Tsioufis P, Doumas M, Stergiou GS, Schlaich MP, Böhm M
Hypertension
· 2026 Jun · PMID 42299672
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BACKGROUND: Resistant hypertension remains a major clinical challenge. This systematic review/meta-analysis evaluated whether the addition of a single pharmacological or device-based intervention (renal denervation [RDN]...BACKGROUND: Resistant hypertension remains a major clinical challenge. This systematic review/meta-analysis evaluated whether the addition of a single pharmacological or device-based intervention (renal denervation [RDN]) can achieve effective blood pressure (BP) control in patients with true resistant hypertension. METHODS: A systematic search of MEDLINE/PubMed was performed to identify studies assessing the antihypertensive effects of adding a single pharmacological or device-based intervention in patients with true resistant hypertension. Primary analyses were conducted using a single-arm framework. RESULTS: Sixty-eight studies were included (n=6297; weighted mean age, 60 years; males 60%; diabetes 35%; smoking 16%; cardiovascular disease 27%). Participants received an average of 4.8 antihypertensive medications, with baseline office BP of 164/92 mm Hg and 24-hour ambulatory BP of 148/85 mm Hg. The median follow-up was 6 months. Meta-analysis of 58 studies (n=4579; 52% RDN) demonstrated a pooled mean 24-hour systolic ambulatory BP reduction from baseline of -11.3 mm Hg (95% CI, -12.3 to -10.2). Meta-analysis of 15 studies (n=2700; 15% RDN) showed a pooled hypertension control rate during follow-up of 35% (95% CI, 28-42). No significant differences were observed between RDN and pharmacotherapy or between randomized and nonrandomized studies. CONCLUSIONS: A single intervention-either pharmacological or RDN-on top of guideline-directed background therapy resulted in clinically meaningful BP reduction in patients with true resistant hypertension; however, only one-third of patients achieved BP control. Future clinical trials are needed to evaluate whether combination treatment strategies integrating optimized pharmacological regimens with RDN can provide more effective and durable BP control in this particularly challenging patient population.
Hunt K, Morgan GR, Sanchez Soriano C
… +13 more, Burke J, Giarratano Y, Hamid C, Keane R, Jenks R, Low S, Donaldson S, Magennis M, Dhillon B, Townsend RC, MacGillivray T, Bernabeu MO, Reynolds RM
Hypertension
· 2026 Jun · PMID 42299671
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BACKGROUND: There is an unmet need for biomarkers that can dynamically track maternal vascular health and guide interventions in disordered pregnancies. The retina and choroid provide a window into the systemic vasculatu...BACKGROUND: There is an unmet need for biomarkers that can dynamically track maternal vascular health and guide interventions in disordered pregnancies. The retina and choroid provide a window into the systemic vasculature. We aimed to characterize longitudinal trajectories of retinal and choroidal features during healthy pregnancy and explore differences associated with preeclampsia. METHODS: Overall, 251 pregnant women underwent multimodal retinal imaging with color fundus photography, scanning laser ophthalmoscopy, and optical coherence tomography at multiple antenatal (12±3 or 20±3 weeks' gestation and 36±3 weeks' gestation, n=183) or a single third-trimester (36±3 weeks' gestation, n=68) time point. Retinal and choroidal vascular features were extracted using an automated pipeline. We examined gestational trajectories of these features and their associations with blood pressure change and serum angiogenic factors. Trajectories were compared for women with preeclampsia and those without placental dysfunction. RESULTS: Significant reductions in measurements of retinal vessel caliber and density and of choroidal thickness, and increases in retinal thickness measurements, were seen over healthy pregnancy. These changes were not correlated with maternal blood pressure change. Third-trimester retinal arteriolar caliber and density were weakly correlated with placental growth factor (=0.32, <0.001 and =0.31, <0.001) and soluble fms-like tyrosine kinase 1 (=-0.21, =0.006 and =-0.33, <0.001) levels. Preeclampsia was associated with significantly greater reductions in retinal arteriolar caliber (=0.022 for right eye, =0.019 for left) and density (<0.001 for each eye) across gestation. CONCLUSIONS: Retinal and choroidal features change throughout pregnancy, and these trajectories are altered in preeclampsia. REGISTRATION:URL: xxx; Unique identifier: ISRCTN40843826.
Delmas P, Osorio N, Penalba V
… +2 more, Dignat-George F, Hache G
Hypertension
· 2026 Jun · PMID 42261674
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Arterial baroreceptors constitute the safeguard of cardiovascular homeostasis by translating vascular stretch into reflex control/ afferent firing. Recent advances have identified an unexpectedly diverse palette of candi...Arterial baroreceptors constitute the safeguard of cardiovascular homeostasis by translating vascular stretch into reflex control/ afferent firing. Recent advances have identified an unexpectedly diverse palette of candidate ion channels, including PIEZO1/2, TMEM150C, TRPV1, TRPC5 (transient receptor potential canonical 5), and epithelial sodium channels (ENaC), yet the molecular logic of their mechanosensory function remains unresolved. However, the field is mired in controversy: are PIEZOs truly indispensable barosensors, or do TRPs, ENaCs, and Tentonin3 provide parallel, context-dependent mechanotransduction? Equally contentious is the extent to which distinct baroreceptor morphologies, end-net versus flower-spray terminals, rapidly versus slowly adapting afferents, deploy specialized channel repertoires to encode dynamic versus steady-state pressure stimuli. Such heterogeneity challenges prevailing reductionist models and underscores baroreception as an emergent property of distributed molecular systems rather than a single-channel solution. Here, we critically appraise molecular, anatomic, and physiological evidence to advance an unifying framework in which baroreceptor diversity is both structural and functional, shaped by channel composition, terminal architecture, and afferent excitability.
Brubaker LH, Catov JM, Bairey Merz CN
… +19 more, Barnes S, Barone Gibbs B, Booker W, Chung JH, Greenland P, Grobman WA, Khan SS, Lane A, Levine LD, McNeil RB, Miller EC, Muldoon MF, Ray M, Saade GR, Scifres CM, Silver RMB, Simhan H, Yee LM, Hauspurg A
Hypertension
· 2026 Jun · PMID 42261656
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BACKGROUND: Isolated diastolic hypertension can precede combined systolic-diastolic hypertension, suggesting isolated diastolic hypertension may be a risk factor for adverse cardiovascular outcomes. Little is known about...BACKGROUND: Isolated diastolic hypertension can precede combined systolic-diastolic hypertension, suggesting isolated diastolic hypertension may be a risk factor for adverse cardiovascular outcomes. Little is known about the prevalence of hypertensive subtypes (isolated diastolic, isolated systolic, or combined systolic-diastolic hypertension) in the years after first pregnancy, and whether these differ after hypertensive disorder of pregnancy. METHODS: This is a secondary analysis (conducted 2023-2024) of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study. Nulliparas were enrolled at 8 US clinical sites from 2010 to 2013; participants who completed the Heart Health Study visit 2 to 7 years after pregnancy were eligible. Blood pressures were elevated at the visit if systolic was ≥130 mm Hg and diastolic ≥80 mm Hg. Multinomial logistic regression relative risk models were adjusted for age, body mass index, race, and time from pregnancy to visit. RESULTS: Four thousand three hundred two participants were included. Mean age at Heart Health Study visit was 30.7 years (SD, 5.6 years); 812 (19%) had elevated blood pressure. Isolated diastolic hypertension was most prevalent (n=627; 15%). Compared with normotensive pregnancy, hypertensive disorders of pregnancy were associated with combined systolic-diastolic (adjusted risk ratio, 3.09 [95% CI, 2.21-4.31]) and isolated diastolic hypertension (adjusted risk ratio, 1.65 [95% CI, 1.36-2.00]). CONCLUSIONS: Isolated diastolic hypertension is the most prevalent hypertensive subtype after first pregnancy. Women with hypertensive disorders of pregnancy had increased risk of combined systolic-diastolic and isolated diastolic hypertension. Given the high prevalence of isolated diastolic hypertension found in this cohort, postpartum women represent a subgroup with opportunity for cardiovascular risk reduction. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02231398.
Agarwal R, Correa-Rotter R, Navaneethan SD
… +14 more, Heerspink HJL, Weir MR, McGill JB, Mottl AK, Nangaku M, Rosenstock J, Rossing P, Vaduganathan M, Scott C, Li L, Brinker M, Kovesdy CP, Green JB, Mann JFE
Hypertension
· 2026 Jun · PMID 42244376
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BACKGROUND: This secondary analysis of the CONFIDENCE (combination effect of fInerenone and empagliflozin in participants with chronic kidney disease and type 2 diabetes using a UACR endpoint) trial (REGISTRATION:URL: h...BACKGROUND: This secondary analysis of the CONFIDENCE (combination effect of fInerenone and empagliflozin in participants with chronic kidney disease and type 2 diabetes using a UACR endpoint) trial (REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05254002) assessed systolic blood pressure (SBP) changes with empagliflozin/finerenone combination therapy versus monotherapy in people with chronic kidney disease and type 2 diabetes across baseline SBP categories. We assessed SBP response predictors and whether early (day 30) SBP changes mediate urinary albumin-to-creatinine ratio reductions. METHODS: Participants (n=800) were stratified by baseline SBP (<130 mm Hg; ≥130 mm Hg). Outcomes included SBP response (≥10 mm Hg reduction from baseline at day 180) and longitudinal SBP changes, analyzed by linear mixed-effects models and logistic regression. Causal mediation analysis, a secondary exploratory analysis, evaluated the effect of day 30 SBP change on day 180 urinary albumin-to-creatinine ratio reduction. RESULTS: At baseline, 532 (66%) participants had SBP ≥130 mm Hg; 268 (34%) had SBP <130 mm Hg. Combination therapy increased SBP response odds versus finerenone (odds ratio, 1.83 [95% CI, 1.21-2.76]; =0.004) or empagliflozin (odds ratio, 1.45 [95% CI, 0.97-2.17]; =0.07). The strongest predictor of response was baseline SBP (odds ratio, 2.04 per 10 mm Hg higher SBP; <0.0001). Combination therapy significantly reduced SBP versus monotherapies in the ≥130 mm Hg (<0.0001) but not in the <130 mm Hg group. SBP reduction mediated <10% of the total urinary albumin-to-creatinine ratio reduction. Acute kidney injury and hyperkalemia incidences were similar across SBP subgroups. CONCLUSIONS: Combination therapy reduced SBP more than monotherapies in participants with SBP ≥130 mm Hg. Urinary albumin-to-creatinine ratio reduction appeared largely independent of SBP changes at day 30; though this secondary analysis was limited by reliance on clinic blood pressure measurement. Prospective studies with ambulatory blood pressure monitoring are required.
Sun M, Gao M, Liu Y
… +12 more, Xia Z, Ma L, Shi N, Zhang Y, Sun S, Tao J, Bao M, Zhou M, Wang C, Yang T, Zhang Z, Yang Y
Hypertension
· 2026 Jun · PMID 42237910
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BACKGROUND: Metabolic reprogramming is increasingly recognized as a key driver of endocrine tumor biology, yet how dysregulated metabolism promotes aldosterone excess in aldosterone-producing adenomas remains largely unc...BACKGROUND: Metabolic reprogramming is increasingly recognized as a key driver of endocrine tumor biology, yet how dysregulated metabolism promotes aldosterone excess in aldosterone-producing adenomas remains largely unclear. METHODS: Multiomics profiling of human adrenal and blood specimens was performed to identify metabolic reprogramming. Dysregulated genes and accumulation of intermediates in the propionate metabolism were validated in aldosterone-producing adenomas. Functional effects on aldosterone production were assessed in adrenocortical cells and mice. Key downstream molecules and pathways were examined through transcriptomics, mass spectrometry, and targeted functional assays. RESULTS: Aldosterone-producing adenomas exhibited reprogrammed propionate metabolism and accumulation of its byproduct methylmalonic acid, associated with upregulation of the upstream enzyme PCCA (propionyl-CoA carboxylase subunit A). In adrenocortical cells, PCCA overexpression increased CYP11B2 (aldosterone synthase) expression and aldosterone production, while its silencing had the opposite effects. In both adrenocortical cells and female mouse adrenals, methylmalonic acid promoted CYP11B2 expression and aldosterone production. Mechanistically, methylmalonic acid elevated reactive oxygen species, which triggered -glutathionylation modification of the L-type calcium channel Ca1.2 at cysteines 106 and 621, as confirmed by mass spectrometry and site-directed mutagenesis. This redox-dependent modification enhanced Ca1.2 plasma membrane expression and intracellular calcium concentrations, thereby activating calcium/calmodulin signaling, upregulating CYP11B2 expression, and driving aldosterone production. CONCLUSIONS: These findings identify a methylmalonic acid-oxidative stress-Ca1.2 -glutathionylation axis that links metabolic rewiring to aldosterone production, uncovering potential therapeutic opportunities targeting redox-dependent metabolic signaling in primary aldosteronism.
Fayad M, Ismail D, Boulkroun S
… +2 more, Fernandes-Rosa FL, Zennaro MC
Hypertension
· 2026 Jun · PMID 42233185
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Detecting secondary forms of hypertension is key to targeted management and prevention of cardiovascular complications. Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, resulting fro...Detecting secondary forms of hypertension is key to targeted management and prevention of cardiovascular complications. Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, resulting from excess adrenal unilateral or bilateral aldosterone production. Its prevalence rises with hypertension severity, reaching 25% in treatment-resistant patients. Understanding the genetic basis of PA provides key insights into its pathophysiology and improves strategies for diagnosing and managing hypertension in the general population. Genetic studies performed over the last few years have unraveled the genetic spectrum of PA. Somatic and germline mutations have been identified in most aldosterone-producing adenomas and familial forms of the disease. Recent studies have also uncovered genetic loci that increase susceptibility to PA that are common to lateralized and bilateral forms of PA and shared with blood pressure loci. Together with the clinical and biochemical description of a continuum of aldosterone dysregulation in hypertension, these findings mark a shift in our understanding of disease pathogenesis, indicating that common genetic variants may contribute to dysregulated aldosterone production in hypertension and to the development of PA in extreme cases. Different genetic susceptibility and genotype-phenotype correlations may shape the demographic distribution and clinical recognition of PA, influencing both its apparent prevalence and the likelihood of timely diagnosis.
Hypertension
· 2026 Jun · PMID 42233183
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BACKGROUND: Preeclampsia is a multifactorial, pregnancy-related disorder characterized by new-onset hypertension and proteinuria, with distinct early- and late-onset forms. Although complement dysregulation has been impl...BACKGROUND: Preeclampsia is a multifactorial, pregnancy-related disorder characterized by new-onset hypertension and proteinuria, with distinct early- and late-onset forms. Although complement dysregulation has been implicated in the pathogenesis of preeclampsia, its causal role remains unclear. In mice, Crry (complement receptor 1-related protein Y) functions as a critical complement regulator at the fetal-maternal interface. Because complete Crry deficiency is embryonically lethal, direct in vivo investigation of complement activation in pregnancy has been challenging. METHODS: We generated a placenta-specific, doxycycline-inducible short hairpin RNA mouse model in which Crry expression can be downregulated in a dose-dependent manner. This system employs Cyp19-driven Cre recombinase and a tetracycline-inducible gene expression system regulatory cassette, enabling precise temporal and spatial control of Crry suppression and restricting complement activation specifically to the placenta. RESULTS: We found that early gestation placental complement activation impairs maternal cardiac and hepatic adaptation, reduces placental efficiency, and causes fetal growth restriction-features consistent with early-onset preeclampsia. Delayed complement activation produces a phenotype resembling late-onset preeclampsia, characterized by maternal hypertension without placental pathology. In the early-onset-like phenotype, fetal growth restriction is accompanied by placental glycogen storage deficiency and impaired endocrine function. Maternal glucose metabolism remains intact; however, compensatory changes in lipid metabolism occur, although these adaptations are insufficient to prevent fetal growth restriction. CONCLUSIONS: This model demonstrates that the timing of placental complement activation determines whether pregnancy develops early- or late-onset-like features. These findings provide mechanistic insight into how complement dysregulation contributes to the spectrum of preeclampsia pathology and establish a powerful experimental platform for studying disease mechanisms and evaluating therapeutic strategies.
Rangel Bousquet Carrilho T, Grandi SM, Bodnar LM
… +2 more, Hutcheon JA, Johansson K
Hypertension
· 2026 Jun · PMID 42233181
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BACKGROUND: We aimed to establish how weight gain patterns across successive pregnancies relate to longer-term maternal cardiometabolic health. METHODS: Obstetric records of all nulliparous pregnancies in Stockholm and G...BACKGROUND: We aimed to establish how weight gain patterns across successive pregnancies relate to longer-term maternal cardiometabolic health. METHODS: Obstetric records of all nulliparous pregnancies in Stockholm and Gotland (Sweden, 2008-2015) were linked with hospital discharges, outpatient visits, and prescription dispensations until 2019. Total pregnancy weight gain (kg) was standardized for gestational age and early pregnancy body mass index and classified as ≤ -1, > -1 and < +1 (reference), and ≥ +1 scores. Postpartum cardiometabolic conditions (type 2 diabetes, hypertension, cardiovascular diseases) were identified using , codes and medications. Hazard ratios were estimated using a Cox proportional hazards model. RESULTS: Among 58 333 individuals, 5.9% (n=3440) developed a cardiometabolic condition, with a median onset of 4 years [interquartile range, 2-6]. Hazard ratios were higher for those gaining ≥ +1 score (19.4 kg at 40 weeks in normal-weight individuals) in the first pregnancy (hazard ratio, 1.29 [95% CI, 1.19-1.40]). Among individuals developing conditions after the second pregnancy, risks were increased for those with high weight gain in the first pregnancy, but not the second (hazard ratios, 1.30 [95% CI, 1.13-1.50] versus 1.05 [95% CI, 0.88-1.26], respectively), compared with those gaining > -1 and < +1 score in both pregnancies. CONCLUSIONS: Individuals with high weight gain in their first pregnancy were 30% more likely to develop a cardiometabolic condition than those with lower weight gain. Preventing excessive weight gain in the first pregnancy may be key to reducing maternal cardiometabolic risk.