Harford TJ, Singh KD, Pardhi TR
… +7 more, Desnoyer R, Ravi T, Jara ZP, Zalavadia A, Stenson K, Naga Prasad SV, Karnik SS
Hypertension
· 2026 Mar · PMID 41568432
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BACKGROUND: Plasma accumulation of the gut microbial metabolite 4-ethylphenylsulfate (4EPS), derived from dietary amino acid, tyrosine, has been associated with cardiovascular, renal, metabolic, and neurological disorder...BACKGROUND: Plasma accumulation of the gut microbial metabolite 4-ethylphenylsulfate (4EPS), derived from dietary amino acid, tyrosine, has been associated with cardiovascular, renal, metabolic, and neurological disorders. AngII (angiotensin II) infusion increases circulating 4EPS in mice, suggesting a potential mechanistic role. We hypothesized that 4EPS modulates AngII-regulated pathophysiology and disease progression by directly inhibiting AT1R (angiotensin II type 1 receptor). METHODS: This hypothesis was tested by combining AT1R pharmacology, cell signaling assays, ex vivo vascular studies, an AngII-induced aortic aneurysm growth model, and plasma proteomics analysis. RESULTS: in vitro, 4EPS reduced the binding of both AngII and the antagonist candesartan to AT1R and suppressed AngII-induced calcium signaling. Ex vivo, 4EPS attenuated AngII-mediated vasoconstriction. In vivo, high-fat diet-fed ApoE-null mice coinfused with AngII and 4EPS showed significant blunting of blood pressure elevation and a marked reduction in aortic aneurysm-related mortality compared with mice infused with AngII alone. Analysis of aortic remodeling revealed increased elastin preservation and decreased thickening of the intimal and medial layers in 4EPS-treated animals. Plasma proteomics indicated alterations in actin-cytoskeletal signaling pathways consistent with reduced activation of ERK (extracellular-regulated kinase) 1/2, filamin-A, and proteins involved in vascular smooth muscle cell motility. CONCLUSIONS: These findings identify 4EPS as a benign, endogenous AT1R antagonist that diminishes AngII-mediated hemodynamic and vascular pathology. By suppressing cytoskeletal signaling associated with vascular remodeling, 4EPS provides significant protection against hypertension and aortic aneurysm progression in mice, revealing a previously unrecognized protective role for a gut microbial metabolite in modulating renin-angiotensin system activity.
Becher C, Groeneveld EJ, Quarck R
… +10 more, Neep B, Pan X, Szulcek R, Tu L, Guignabert C, Bogaard HJ, Yu PB, de Man F, Sanchez-Duffhues G, Goumans MJ
Hypertension
· 2026 Feb · PMID 41564150
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BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder involving disrupted BMP (bone morphogenetic protein) signaling, pulmonary inflammation, and endothelial-to-mesenchymal transition (EndMT). We hy...BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder involving disrupted BMP (bone morphogenetic protein) signaling, pulmonary inflammation, and endothelial-to-mesenchymal transition (EndMT). We hypothesized that IL (interleukin)-33 signaling contributes to PAH progression by inducing EndMT and interacting with BMP9, a key modulator of inflammation and vascular remodeling. METHODS: IL-33 expression was assessed in lung tissues from Sugen/hypoxia and control mice, as well as in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with PAH and healthy donors. EndMT and signaling pathways were analyzed in PAECs and microvascular endothelial cells (MVECs) exposed to IL-33, BMP9, and sST2 (soluble supression of tumorigenicity 2) using quantitative polymerase chain reaction, Western blotting, ELISA, and immunostaining. Plasma BMP9 and sST2 levels were quantified in patients with PAH. RESULTS: Immunofluorescent analysis revealed elevated IL-33 expression in pulmonary endothelial cells of Sugen/hypoxia mice compared with controls, consistent with findings in PAECs from patients with PAH. BMP9 significantly upregulated sST2 expression in human PAEC and microvascular endothelial cells, inhibited IL-33 target gene expression, and effectively suppressed IL-33-induced EndMT. Notably, BMP9 demonstrated greater efficacy in preventing EndMT compared with rsST2 (recombinant soluble ST2) or ST2L-neutralizing antibodies. Circulating BMP9 and sST2 levels in the plasma of patients with PAH were positively correlated in specific patient groups stratified by sex, age, and New York Heart Association functional class, suggesting a protective role of BMP9 in modulating IL-33-induced EndMT. CONCLUSIONS: BMP9 plays a protective role against IL-33-induced EndMT in PAECs by upregulating sST2 expression and neutralizing IL-33, suggesting that targeting the IL-33 signaling pathway may represent a promising therapeutic strategy to mitigate EndMT in PAH.
Hypertension
· 2026 Apr · PMID 41549941
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BACKGROUND: Congestive heart failure (CHF) is characterized by the activation of neurohumoral drive concomitant with avid fluid retention. Renal denervation alleviates this fluid retention. SGLT2 (sodium-glucose cotransp...BACKGROUND: Congestive heart failure (CHF) is characterized by the activation of neurohumoral drive concomitant with avid fluid retention. Renal denervation alleviates this fluid retention. SGLT2 (sodium-glucose cotransporter 2) inhibitors have shown remarkable improvement in patients with cardiovascular diseases. We have recently demonstrated a relationship between enhanced renal sympathetic nerve activity and SGLT2 expression as well as function during CHF; however, the precise molecular mechanisms involved in the expression and translocation of SGLT2 and associated scaffolding proteins to the luminal membrane remain to be examined. METHODS: CHF was induced by coronary artery ligation followed by bilateral renal denervation 4 weeks later, in rats. Western blot analysis and immunohistochemistry were performed to evaluate changes in the expression of SGLT2, MAP17 (membrane-associated protein 17), PDZK1 (PDZ domain containing 1), and activation of ERK (extracellular signal-regulated kinase)/NF-KB (nuclear factor κB) in renal cortex. Human adult proximal tubular cells were used to determine the direct effect of norepinephrine on the expression of SGLT2-MAP17-PDZK1 and activation of the ERK/NF-KB pathway. RESULTS: Rats with CHF exhibited significantly enhanced expression of SGLT2, MAP17, and PDZK1 with a concomitant significant activation of ERK and NF-KB in the renal cortex. In rats with CHF, renal denervation mitigated enhanced expression of SGLT2-MAP17-PDZK1 as well as activation of ERK and NF-KB. Direct action of norepinephrine on human adult proximal tubular cells triggered enhanced expression of SGLT2-MAP17-PDZK1 by the activation of the ERK/NF-KB pathway. CONCLUSIONS: Enhanced basal renal sympathetic nerve activity in CHF activates the ERK/NF-KB pathway, which in turn facilitates the enhanced expression and translocation of the SGLT2-MAP17-PDZK1 scaffolding protein complex to the luminal membrane, augmenting sodium reabsorption in CHF.
Cho SMJ, Ruan Y, Lee HH
… +11 more, Koyama S, Juraschek SP, Allen NB, Yang E, McEvoy JW, Secemsky EA, Honigberg MC, Fahed AC, Patel AP, Hornsby WE, Natarajan P
Hypertension
· 2026 Mar · PMID 41532316
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BACKGROUND: Suboptimal blood pressure (BP) control remains a major cardiovascular disease risk factor. Whether genetically predicted BP independently predicts long-term BP control is unknown. We examined the associations...BACKGROUND: Suboptimal blood pressure (BP) control remains a major cardiovascular disease risk factor. Whether genetically predicted BP independently predicts long-term BP control is unknown. We examined the associations of BP polygenic scores (PGSs) with long-term BP control and treatment-resistant hypertension. METHODS: We identified 22 456 Mass General Brigham Biobank participants with hypertension. Longitudinal BP control was defined as the percentage of time above-target systolic BP (SBP) ≥130 mm Hg or diastolic BP (DBP) ≥80 mm Hg over 5 years. Using multivariable regression, we assessed the associations of BP PGS with duration above-target BP and lifetime treatment-resistant hypertension incidence. Incremental prognostic utility of BP PGSs was assessed based on the discrimination C-index, Brier score, and net reclassification index. Validation was performed in the population-based UK Biobank cohort using the SBP/DBP ≥140/90 mm Hg threshold. RESULTS: Among 10 853 (48.3%) were female, the mean SBP/DBP (SD) at index date was 132 (18)/75 (11) mm Hg, and 4126 (18.4%) developed treatment-resistant hypertension over lifetime. In reference to the low (<20th percentile) PGS group, the high (≥80th percentile) BP PGS was associated with 8.01 (95% CI, 6.68%-9.34%) longer duration with above-target SBP and 6.19 (95% CI, 5.05%-7.33%) with high DBP. Each high SBP and DBP PGS conferred 2.36 (95% CI, 2.07-2.68) and 1.75 (95% CI, 1.55-1.99)-fold higher odds of treatment-resistant hypertension. Adding BP PGSs to traditional risk factors improved treatment-resistant hypertension prediction from C-index (95% CI), 0.74 (0.73-0.75) to 0.78 (0.77-0.79). BP PGSs consistently predicted longitudinal BP management to a comparable extent in the UK Biobank. CONCLUSIONS: Harnessing BP PGSs may inform anticipated trends in BP control to warrant vigilant monitoring and augment prioritization of intensive therapy.
Williams K, Grobman B, Larbi Kwapong F
… +11 more, Col H, Turkson-Ocran RN, Ngo LH, Zhang M, Daya NR, Selvin E, Lutsey PL, Coresh J, Windham BG, Wagenknecht L, Juraschek SP
Hypertension
· 2026 Mar · PMID 41532301
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BACKGROUND: Higher relative risk for cardiovascular disease (CVD) events at lower blood pressure (BP) thresholds in female versus male adults suggest that hypertension thresholds should be sex-specific. METHODS: We used...BACKGROUND: Higher relative risk for cardiovascular disease (CVD) events at lower blood pressure (BP) thresholds in female versus male adults suggest that hypertension thresholds should be sex-specific. METHODS: We used the ARIC study (Atherosclerosis Risk in Communities) visit 1 (1987-1989) to compare the BP distribution, estimated risk (via the 10-year Predicting Risk of Cardiovascular Disease Events score), absolute risk, and relative risk of CVD according to BP thresholds, stratified by sex and hypertension treatment status, in participants without prior CVD. RESULTS: Of 13 418 participants (56% women, mean age [54±5.7 years]), 25% were treated for hypertension. Males had higher average 10-year CVD risk scores regardless of treatment. The distribution of BP and prevalence of CVD risk factors was similar for male and female adults. Incidence rates (per 10 000 person-years) comparing a systolic BP threshold of ≥140 versus <140 mm Hg for coronary heart disease were 30.9 and 12.0 among untreated male and female adults (=0.07) and 27.4 versus 16.5 among treated male and female adults (=0.63). HRs comparing a systolic BP threshold of ≥140 versus <140 mm Hg for coronary heart disease were 1.49 and 1.72 among untreated male and female adults (=0.16) and 1.30 versus 1.40 among treated male and female adults (=0.93). CONCLUSIONS: In this middle-aged population, there were no consistent differences in BP distribution, risk factor burden, absolute risk, or relative risk of CVD between male and female adults. These findings do not support a sex-specific threshold for hypertension.
Hypertension
· 2026 Mar · PMID 41521926
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BACKGROUND: A later age at menopause (≥55 years) is associated with lower cardiovascular disease risk compared with a normal age at menopause (45-54 years) in postmenopausal women (PMW). Aortic stiffening increases cardi...BACKGROUND: A later age at menopause (≥55 years) is associated with lower cardiovascular disease risk compared with a normal age at menopause (45-54 years) in postmenopausal women (PMW). Aortic stiffening increases cardiovascular disease risk, but the impact of late-onset menopause on aortic stiffness is unknown. METHODS: Total aortic stiffness (carotid-femoral pulse wave velocity [PWV]) was measured in 40 late-onset and 86 normal-onset PMW. Structural- and load/blood pressure-dependent PWV were calculated with exponential models; the percent of total PWV attributable to each was determined. Elastic modulus was assessed in aortic rings from female C57BL/6 N mice (3-6 months) exposed to 5% PMW serum. Lipidomics and triglyceride-related metabolite exposure of aortas with/without the mitochondrial antioxidant MitoQ identified lipid drivers of mitochondrial reactive oxygen species-related stiffness. RESULTS: PWV was 128 cm/s lower in late-onset (835±24 cm/s) versus normal-onset (963±24 cm/s) PMW. The difference in PWV remained >100 cm/s in multivariable models adjusted for age and education, cardiovascular disease risk factors, and medication use. Systolic and diastolic blood pressure were 10 and 6 mmHg lower in late-onset PMW. Some (<20%) of the attenuated PWV in late-onset PMW was related to lower load-dependent PWV. However, the majority (≈85%) was attributable to lower structural-dependent PWV. Elastic modulus was 35% lower in aortas exposed to serum from late- versus normal-onset PMW because of less mitochondrial reactive oxygen species-dependent stiffness. Triglyceride (16:0) was a driver of the effects of serum. CONCLUSIONS: Our findings suggest attenuated aortic stiffening via lower structural-dependent factors may be one mechanism by which late-onset menopause lowers cardiovascular disease risk.
Sconfienza E, Riancho J, Gebara N
… +7 more, Ferrão D, Burrello J, de Freminville JB, Deflorenne E, Lorthioir A, Azizi M, Amar L
Hypertension
· 2026 May · PMID 41521906
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BACKGROUND: Spironolactone is recommended as first-line therapy for patients with idiopathic primary aldosteronism. The aim of this study is to evaluate the impact of low and high doses of spironolactone on arterial bloo...BACKGROUND: Spironolactone is recommended as first-line therapy for patients with idiopathic primary aldosteronism. The aim of this study is to evaluate the impact of low and high doses of spironolactone on arterial blood pressure control, potassium levels, and the incidence of drug-related adverse effects. METHODS: We retrospectively included 394 patients with primary aldosteronism receiving spironolactone. Patients were divided into 2 groups, according to the median prescribed dose in our population (50 mg, 25-75): subjects treated with doses ≤50 mg versus >50 mg. RESULTS: The median follow-up after the introduction of spironolactone was 12 months, and 128 patients experienced adverse effects, with a proportion higher in men than in women (44.70% versus 15.70%). The most frequently reported adverse effect was gynecomastia, followed by sexual dysfunction. Subjects receiving a dose >50 mg of spironolactone displayed a higher prevalence of adverse effects (39.1%) compared to the ≤50 mg group (29.3%); this effect was significantly different only in men (=0.002). Patients in the low-dose group were treated with a higher number of antihypertensive drugs, especially diuretics. No significant differences were seen between the 2 subgroups in blood pressure control, potassium and renin levels, and occurrence of cardiovascular events at follow-up. CONCLUSIONS: Treatment with low doses of spironolactone, in association with other antihypertensive drugs, is effective in achieving an appropriate blood pressure control in primary aldosteronism, while it improves adherence with lower adverse effects. These findings could help the clinician choose the best therapeutic option for each patient.
Bach ML, Enggaard C, Thangaraj SS
… +4 more, Heinl A, Svenningsen P, Palarasah Y, Jensen BL
Hypertension
· 2026 Mar · PMID 41503724
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BACKGROUND: uPA (urokinase-type plasminogen activator) inhibitors mitigate salt retention, plasmin, and complement activation in acute proteinuric kidney diseases. We hypothesized that in chronic kidney injury with album...BACKGROUND: uPA (urokinase-type plasminogen activator) inhibitors mitigate salt retention, plasmin, and complement activation in acute proteinuric kidney diseases. We hypothesized that in chronic kidney injury with albuminuria, uPA contributes to hypertension and complement-dependent tissue inflammation and injury. METHODS: Wild-type and uPA KO (knockout) mice underwent either sham surgery or unilateral nephrectomy, followed by insertion of deoxycorticosterone acetate (DOCA)- or sham pellets and a high (4%) or control (0.5%) sodium chloride diet for 21 days. Glomerular filtration rate was estimated by transcutaneous fluorescein-isothiocyanate-sinistrin, and arterial blood pressure was recorded continuously by indwelling femoral catheters. Urine was analyzed for albumin, plasmin(ogen), electrolytes, kidney injury markers (neutrophil gelatinase-associated lipocalin), and complement proteins (C3, C3a). Kidney tissue was examined for neutrophil gelatinase-associated lipocalin, epithelial sodium channel, C3, C3a, C5a, cytokines, inflammation, and macrophage polarization markers (CD16CD32, CD163). RESULTS: DOCA-salt increased diuresis, Na excretion, albuminuria, tubular injury markers, and single-kidney glomerular filtration rate, with no genotype-dependent differences. Blood pressure increased by ≈30 mm Hg within 2 days and then stabilized, with no genotype difference for up to 15 days. DOCA-salt wild-type mice showed elevated urinary protease activity, plasmin, C3, and C3a, while these were mitigated in KO mice. In the kidney, DOCA-salt increased IL-6 (interleukin 6), MCP-1 (monocyte chemoattractant protein-1), MIP-1α (macrophage inflammatory protein 1 alpha), and TNF (tumor necrosis factor), while TNF and IP-10 (interferon gamma-induced protein-10) were reduced in KO mice. CD16CD32 macrophages predominated over CD163 macrophages in DOCA-salt kidney tissue across genotypes. CONCLUSIONS: While not essential for filtration barrier injury, glomerular filtration rate decline, and hypertension in DOCA-salt-induced kidney injury, uPA, through plasmin, generates anaphylatoxins with effects on specific cytokines.
Cheng YB, An DW, Zhang DY
… +29 more, Yu YL, Melgarejo JD, Boggia J, Martens DS, Hansen TW, Asayama K, Ohkubo T, Stolarz-Skrzypek K, Huang QF, Malyutina S, Casiglia E, Lind L, Maestre GE, Wang JG, Kikuya M, Kawecka-Jaszcz K, Dolan E, Sandoya E, Rajzer M, Nawrot TS, Narkiewicz K, Yang WY, Verhamme P, Filipovský J, Graciani A, Banegas JR, Li Y, Staessen JA, International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes Investigators
Hypertension
· 2026 Mar · PMID 41503706
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BACKGROUND: The ambulatory arterial stiffness index (AASI) is increasingly used in clinical research and practice. This individual-participant meta-analysis aims to consolidate the prognostic accuracy of AASI in the gene...BACKGROUND: The ambulatory arterial stiffness index (AASI) is increasingly used in clinical research and practice. This individual-participant meta-analysis aims to consolidate the prognostic accuracy of AASI in the general population and to derive an end point-based AASI risk threshold. METHODS: In 12 558 individuals enrolled in 14 population studies (48.8% women; mean age, 59.3 years), AASI was derived by regressing 24-hour diastolic on systolic blood pressure (mm Hg/mm Hg). Using Cox regression, the risk-carrying AASI threshold was established by examining stepwise increasing AASI levels and by determining the AASI level, yielding a 10-year risk similar to an office systolic pressure of 140 mm Hg. RESULTS: Over 10.7 years (median), 3027 all-cause deaths and 2183 cardiovascular end points occurred. In all participants, multivariable-adjusted hazard ratios expressing the all-cause deaths and cardiovascular end point risk per 1-SD AASI increment were 1.08 (95% CI, 1.04-1.13) and 1.13 (95% CI, 1.07-1.18). In a randomly defined subset of 8189 individuals, the risk-carrying AASI thresholds converged to 0.50 with hazard ratios (≥0.50 versus <0.50) of 1.14 (95% CI, 1.04-1.26) for all-cause deaths and 1.13 (95% CI, 1.01-1.26) for cardiovascular end point. In the replication sample (n=4369), these hazard ratios were 1.13 (95% CI, 1.01-1.26) and 1.19 (95% CI, 1.04-1.35). AASI continuous or per threshold significantly improved model performance. Analyses of secondary end points and subgroups stratified by sex, age, hypertension status and treatment, history of cardiovascular disease, and nocturnal dipping were confirmatory. CONCLUSIONS: Over and beyond traditional risk factors, AASI improves risk stratification. Exceeding the risk-carrying 0.50 AASI threshold necessitates increased vigilance in managing risk factors before irreversible cardiovascular complications occur.
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for ≈50% of heart failure, and hypertension often coexists. Although strain imaging detects subclinical dysfunction, the relative diagnostic val...BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for ≈50% of heart failure, and hypertension often coexists. Although strain imaging detects subclinical dysfunction, the relative diagnostic value of left atrial (LA) versus left ventricular (LV) strain for identifying hypertensive HFpEF remains uncertain. We compared LA and LV strain using cardiac MR feature tracking to determine optimal markers for HFpEF detection. METHODS: A single-center, retrospective study included 191 participants: 71 with HFpEF and hypertension (HFpEF-HTN), 60 with essential hypertension, and 60 controls who underwent cardiac MR. Cardiac MR feature tracking quantified LV global strains and strain rates, and LA reservoir (εs), conduit (εe), and booster pump (εa) strain with corresponding strain rates. One-way ANOVA compared groups, logistic regression identified HFpEF-HTN predictors, and receiver operating characteristic analysis with area under the curve assessed diagnostic accuracy. RESULTS: All LA strain parameters showed stepwise impairment from controls to hypertension to HFpEF-HTN (all <0.05). LV global strains decreased in HFpEF-HTN versus controls, while hypertension exhibited only reduced global longitudinal strain (all <0.05). LA parameters demonstrated superior discriminatory performance over LV parameters. εs best distinguished HFpEF-HTN from hypertension (area under the curve, 0.802 [95% CI, 0.724-0.867]), while εe best discriminated hypertension from controls (area under the curve, 0.892 [95% CI, 0.823-0.942]). CONCLUSIONS: LA strain parameters, particularly εs, provided superior diagnostic performance over LV strain in distinguishing HFpEF-HTN from hypertension. These findings support the potential role of LA strain as a sensitive imaging biomarker for detecting HFpEF-HTN. Prospective validation is needed before clinical implementation.
Lekva T, Frøystad M, Michelsen AE
… +5 more, Khan Y, Aukrust P, Halvorsen B, Roland MCP, Ueland T
Hypertension
· 2026 Mar · PMID 41498149
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BACKGROUND: Preeclampsia is a hypertensive disorder affecting 2% to 8% of pregnancies. Women with a history of preeclampsia have an increased risk of cardiovascular disease. The long noncoding RNA is shown to regulate i...BACKGROUND: Preeclampsia is a hypertensive disorder affecting 2% to 8% of pregnancies. Women with a history of preeclampsia have an increased risk of cardiovascular disease. The long noncoding RNA is shown to regulate inflammatory responses linked to cardiovascular disease. is decreased in preeclampsia placentas and may have a cis-regulatory function on neighboring RNAs. METHODS: Expression of , , , , and was assessed in peripheral blood mononuclear cells, and in plasma and extracellular vesicles, at 22 to 24 and 36 to 38 weeks of gestation in healthy (n=214) and preeclampsia (n=37) women from the STORK cohort study (STORe barn og Komplikasjoner, translated as Large Babies and Complications) and at 5-year follow-up in women with and without history of preeclampsia (n=29; n=271). We investigated their associations with established markers of disease activity and later cardiometabolic risk. was silenced in lipopolysaccharide-stimulated THP-1 differentiated macrophages in vitro. RESULTS: , , , and are decreased in peripheral blood mononuclear cells during preeclampsia development. At follow-up in women with a previous preeclampsia diagnosis, and are decreased in peripheral blood mononuclear cells and show associations with cardiometabolic markers. Silencing in macrophages increased secretion of IL (interleukin)-6 and reduced MMP9 (matrix metalloproteinase-9) and VEGF (vascular endothelial growth factor) A levels. CONCLUSIONS: Given the association of and neighboring RNAs with preeclampsia during pregnancy and at follow-up, as well as with cardiometabolic markers and results from silencing experiments, these transcripts may be potential targets for preeclampsia development and cardiometabolic risk in women with previous preeclampsia.