Hypertension最新文献

Background: Proteomic signatures may enhance the prediction of cardiometabolic diseases for targeted prevention. We evaluated whether a proteomic risk score (ProtRS) improves the prediction of incident hypertension.

Methods: Within the UK Biobank Proteomics data set, participants at risk for incident hypertension were randomly split into derivation (n=25 158) and test (n=10 781) sets. A ProtRS was trained in the derivation cohort using least absolute shrinkage and selection operator penalized Cox regression and evaluated in the test set with sequential adjustment for demographics, clinical risk factors, and a polygenic risk score (PRS). External replication was performed in the Asklepios study (n=793).

Results: In UK Biobank Proteomics (2312 events), each 1-SD higher ProtRS was associated with incident hypertension after covariate adjustment (hazard ratio, 1.68 [95% CI, 1.59-1.78]; P<0.001). Adding the protein score to demographics, clinical variables, and PRS improved model fit (global χ² from 1733 to 2048, P<0.001), discrimination (C-index, 0.745-0.765), net reclassification improvement (19.0% [95% CI, 15.9-22.0]), and integrated discrimination improvement (2.9% [95% CI, 2.4-3.8]). In Asklepios (221 events), the ProtRS was associated with an increased risk of hypertension (hazard ratio, 1.32 [95% CI, 1.13-1.55]; P<0.001) after covariate adjustment, and improved global χ² (from 120.4 to 132.4; P<0.001), C-index (from 0.723 to 0.736) and discrimination (net reclassification improvement, 13.1% [95% CI, 1.2%-24.1%]). Pathway analysis highlighted neutrophil degranulation, insulin-like growth factor, PI3K signaling, and extracellular matrix remodeling.

Conclusions: A ProtRS improves prediction of incident hypertension beyond demographics, clinical, and genetic information in UK Biobank Proteomics, with supportive external replication. Proteomic information may enhance individualized hypertension risk stratification and provide biologic insights into disease development.

Background: Angiotensin-(1-7) lowers blood pressure and improves metabolic outcomes in animal models of obesity and hypertension. Whether central mechanisms are involved in these protective cardiometabolic effects is poorly understood. In this study, we hypothesized that angiotensin-(1-7) engages central neurocircuits originating in the arcuate nucleus of the hypothalamus under normal conditions and in diet-induced obesity.

Methods: Male mice were placed on a control diet or 60% high-fat diet for 12 weeks. Immunohistochemistry, in situ hybridization, electrophysiology, and physiological approaches were employed to determine whether angiotensin-(1-7) activates arcuate neurocircuits, characterizes the molecular identity of activated arcuate cells, and assesses the functional importance of this neurocircuit in blood pressure regulation.

Results: Under control diet conditions, systemic angiotensin-(1-7) administration (2 mg/kg, SC) increased the number of c-fos positive cells in the arcuate nucleus. Angiotensin-(1-7) mas receptors were highly localized to proopiomelanocortin neurons containing markers of gamma-aminobutyric acid transmission in the arcuate, with angiotensin-(1-7) increasing the firing activity of proopiomelanocortin neurons in a mas receptor-dependent manner. Acute intra-arcuate angiotensin-(1-7) administration lowered blood pressure. This effect was prevented by gamma-aminobutyric acid receptor antagonism in the downstream hypothalamic paraventricular nucleus, suggesting that angiotensin-(1-7) engages inhibitory arcuate-paraventricular circuits to lower blood pressure. Acute angiotensin-(1-7) could not activate proopiomelanocortin neurons or engage this arcuate-paraventricular neurocircuit in obese mice.

Conclusions: These findings suggest that angiotensin-(1-7) activates arcuate proopiomelanocortin neurons and engages arcuate-paraventricular inhibitory neurocircuits to lower blood pressure under normal conditions. In obesity, this circuit appears disrupted, which could contribute to the elevated blood pressure in this model.

Background: Preeclampsia is a pregnancy-specific disorder characterized by placental hypoxia and superficial invasion of trophoblast cells. However, the precise mechanisms by which hypoxia induces lactate and lactylation remain unclear.

Methods: Pan lysine lactylation levels were analyzed in the placentae of 36 patients with severe preeclampsia (sPE) and 36 normotensive pregnancies. A global lactylome analysis was performed, and BCAT2 (branched-chain aminotransferase 2)-K377 was selected for further investigation. The BCAT2-377R mutant was constructed to evaluate the effect on trophoblast migration, invasion, tube formation, and oxidative stress. The impact of the BCAT2-377R mutant on BCAT2 ubiquitination and degradation was further examined using MG132 and cycloheximide supplementation. Co-immunoprecipitation and double-immunofluorescence staining were conducted to identify the lactyltransferase of BCAT2. The specialized antibody was developed to validate BCAT2-K377la (branched-chain amino acid transaminase 2-lysine 377 lactylation) abundance in tissues and treated cells. A preeclampsia-like rat model was constructed to further verify whether the results were consistent with the clinical findings.

Results: Lactylation levels were elevated in the placentae of sPE. High lactate concentration enhanced Pan lysine lactylation and reduced BCAT2 protein levels while inhibiting cell migration, invasion, and tube formation. BCAT2-K377la impaired cell biological behaviors, increased oxidative stress, and promoted BCAT2 ubiquitination. The p300 acted as a lysine lactylation writer of BCAT2. BCAT2-K377la abundance was upregulated in sPE placentae and cells treated with hypoxia and lactate. In the rat model, elevated placental Pan lysine lactylation and BCAT2-K377la levels mirrored findings in clinical samples.

Conclusions: Our findings emphasized the role of nonhistone lactylation in sPE pathogenesis. Targeting BCAT2-K377la may serve as a potential intervention strategy for sPE.

Background: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular complications. We have shown that Ngal (neutrophil gelatinase-associated lipocalin)/lcn2 is involved in aldosterone-induced cardiac remodeling and inflammation. Here, we investigated the role of Ngal in the progression of cardiorenal syndrome.

Methods: CKD was induced in rats via 5/6 nephrectomy in wild-type and Ngal knockout rats. Cardiorenal functions were assessed 3 months after subtotal nephrectomy or sham operation. Cardiac fibroblasts were isolated from wild-type rats and incubated with or without rNgal (recombinant Ngal) and Gal-3 (galectin-3).

Results: Cardiac perfusion was less impaired in CKD Ngal knockout than in CKD wild type. Left ventricle interstitial fibrosis was more severe in CKD wild type than in sham but was blunted in CKD Ngal knockout rats. Levels of Gal-3, Col1 (collagen 1), Ccl2 (C-C motif chemokine ligand 2), and IL-6 (interleukin-6) were high in cardiac fibroblasts incubated with rNgal. A similar pattern was observed in cells treated with recombinant Gal-3. Both Ngal and Gal-3 induced activation of the Tlr4 (toll-like receptor 4)-Myd88 (myeloid differentiation primary response 88) pathway. The effects of rNgal were blunted by concomitant treatment with Gal-3 or Tlr4 inhibitors, suggesting that Gal-3 contributes to Ngal-induced cardiac fibrosis and inflammation by activating the Tlr4-Myd88 pathway. In both MEDIA-DHF (Metabolic Road to Diastolic Heart Failure) and BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) cohorts, elevated levels of Ngal and Gal-3 were associated with advanced diastolic dysfunction and adverse clinical outcomes, particularly among patients with impaired renal function.

Conclusions: In CKD rats, Ngal was involved in cardiac remodeling via a Gal-3/Tlr4-dependent pathway, increasing inflammation and fibrosis, and correlated to cardiac outcomes in the MEDIA-DHF and BIOSTAT-CHF cohorts.

Medical therapy for primary aldosteronism has been stagnant for decades, relying on mineralocorticoid receptor antagonists, which block downstream signaling of aldosterone rather than aldosterone production. This approach typically leads to reactive elevation of aldosterone production, and possible implications of its nongenomic effects. In addition, steroidal mineralocorticoid receptor antagonist use is limited by cross-reactivity with other nuclear receptors and concern for hyperkalemia, particularly in kidney insufficiency. These limitations have propelled a rising interest in therapies that suppress aldosterone production. Aldosterone synthase inhibitors directly target aldosterone synthase overexpression and aldosterone excess. This review presents the evolving landscape of primary aldosteronism therapies, including emerging aldosterone synthase inhibitor and nonsteroidal mineralocorticoid receptor antagonists, and it presents a perspective on expected benefits and limitations of these emerging classes.

Atrial fibrillation represents the most prevalent cardiac arrhythmia and is associated with substantial morbidity, including an increased risk for stroke and heart failure. The pathophysiology of atrial fibrillation involves electrical and structural remodeling of the atria, often referred to as atrial myopathy, that together increase the risk for arrhythmias. However, a specific approach to target the proarrhythmic substrate of atrial fibrillation is still lacking. Aldosterone and the mineralocorticoid receptor are well-known drivers of cardiac remodeling, and recent clinical and experimental studies indicate that they play a critical role in the pathogenesis of atrial fibrillation. Elevated aldosterone levels, for example, in primary aldosteronism, are associated with a higher risk for atrial fibrillation. Mineralocorticoid receptor antagonists reduce the onset of atrial fibrillation across various patient populations, including patients with hypertension, heart failure, chronic kidney disease, or undergoing cardiac surgery. In patients with preexisting atrial fibrillation, mineralocorticoid receptor antagonists may decrease atrial fibrillation recurrence when added to antiarrhythmic therapies. Experimental studies provide a direct link between aldosterone and atrial remodeling and arrhythmia. Mineralocorticoid receptor activation modulates several key cellular processes involved in atrial inflammation, fibrosis, and arrhythmogenesis, including fibroblast activation, cardiomyocyte dysfunction, and ion channel activity. Here, we review what is currently known about the role of aldosterone and the mineralocorticoid receptor in atrial fibrillation, summarize the mechanistic basis as supported by experimental studies, and discuss the potential of mineralocorticoid receptor antagonists in the prevention and treatment of atrial fibrillation.

Background: Endothelial dysfunction is recognized as a crucial initiating factor for hypertension and associated cardiovascular/renal injury. Although MYDGF (myeloid-derived growth factor) is mainly derived from bone marrow cells, recent studies have also found the expression of MYDGF in different parenchymal cells. However, the expression pattern and the role of endothelial MYDGF in hypertension remain unclear.

Methods: Endothelial-specific knockout of MYDGF mice and recombinant MYDGF were used to examine the role of MYDGF in hypertension and associated cardiovascular/renal injury.

Results: Endothelial MYDGF was significantly downregulated in hypertensive mice. MYDGF deficiency in the endothelium aggravated endothelial dysfunction and cardiovascular/renal injury in hypertensive mice, which was attenuated by the overexpression of MYDGF or recombinant MYDGF. Functionally, MYDGF maintained endothelial homeostasis via pleiotropic protective effects, including anti-inflammation, antiapoptosis, inhibiting aberrant endothelial permeability and senescence, and inducing NO generation. Mechanistically, MYDGF promoted the activation of HMOX1 (heme oxygenase-1) transcription by mediating STAT3 (signal transducer and activator of transcription 3) phosphorylation, thereby reestablishing endothelial homeostasis.

Conclusions: MYDGF governs endothelial homeostasis in hypertension through regulating HMOX1 expression. Targeting MYDGF may offer an innovative approach for treating hypertension and its cardiovascular complications.

Background: The latest updated 2025 and 2017 American College of Cardiology and the American Heart Association guidelines lowered the diagnostic threshold for hypertension to 130/80 mm Hg. Whether the new classification for hypertension has implications for reproductive outcomes remains uncertain.

Methods: This retrospective cohort study was conducted at the Reproductive Medicine Center of Shandong University in China. Women who underwent the initial embryo transfer of their first in vitro fertilization cycle were categorized into the normal blood pressure (BP), elevated BP, stage 1 hypertension, and stage 2 hypertension groups based on BP levels measured just before in vitro fertilization treatment. We examined associations of prepregnancy BP and reproductive outcomes.

Results: This study included 43 629 women who received in vitro fertilization treatment. The rate of live birth was lower in women with stage 1 and stage 2 hypertensions (46.1% and 41.4%, respectively) compared with women with normal BP (49.2%), with the adjusted relative ratios of 0.97 (95% CI, 0.937-0.996; P=0.027) and 0.91 (95% CI, 0.85-0.98; P=0.009), respectively. Compared with normal BP, both stage 1 and stage 2 hypertension were associated with higher risks of pregnancy loss, preeclampsia, and preterm delivery. Elevated BP was associated with a higher risk of gestational hypertension. Optimal BP cutoffs for adverse reproductive outcomes were consistent with the diagnostic threshold for stage 1 hypertension.

Conclusions: Compared with normal BP, prepregnancy stage 1 and stage 2 hypertension were associated with a lower rate of live birth after in vitro fertilization treatment and increased risks of pregnancy complications.

Background: This study aims to develop a prediction model to identify individuals at risk of hypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, by integrating epigenetic biomarkers and clinical factors in the first trimester of pregnancy.

Methods: A 2-stage nested case-control study, matched by age and body mass index, was conducted with 618 pregnant women in China, with peripheral blood samples collected in the first trimester to evaluate the average methylation levels of differentially methylated regions (DMRs) between controls and HDP cases. In stage 1 (discovery set), 24 controls and 27 cases were used to identify the differential DMRs. In stage 2, 294 controls and 273 cases were used to validate the previously identified DMRs. DMRs selected from the intersectional results of lasso regression, XGBoost, random forest, and Shapley Additive Explanations models were further combined with women's clinical risk factors to construct prediction models using logistic regression.

Results: In stage 1, 52 differential DMRs were identified with a false-positive rate <0.05. In stage 2, 12 differential DMRs were consistently observed, and 3 DMRs located in the CTSA, HMGB1, and miR1908/FADS2 genes were selected to construct a prediction model for HDPs. After combining the selected DMRs with clinical factors, the model achieved an area under the curve of 0.863 (95% CI, 0.826-0.901) in the training set and 0.757 (95% CI, 0.686-0.828) in the test set.

Conclusion: Findings of this study offer potential opportunities to identify high-risk patients with HDP in early pregnancy through DMRs identified in peripheral blood and provide new insights into the epigenetic cause of HDP.

Background: Home blood pressure (BP) monitoring (HBPM) is increasingly used as an alternative to office BP. However, factors influencing agreement between office and home BP among very old adults remain unclear.

Methods: During ARIC (Atherosclerosis Risk in Communities) visit 10, participants underwent 3 automated office BP (AOBP) measurements using an Omron HEM-907XL and performed HBPM twice daily for 8 days using an Omron BP7450. Discordance was defined as a systolic BP difference of ±10 mm Hg between mean AOBP and HBPM. Multivariable regression models evaluated demographic, anthropometric, and clinical factors associated with discordance.

Results: Among 792 participants (58% female; mean age, 84±3.7 years), mean systolic BP was 130.6 mm Hg (AOBP) and 129.6 mm Hg (HBPM). Despite a minimal average difference (1.0±15.7 mm Hg), 49% had ≥10 mm Hg systolic BP discordance. Higher AOBP was associated with greater discordance. Compared with females, males had lower AOBP relative to HBPM (-4.69 mm Hg [95% CI, -6.86 to -2.51]). Smaller arm circumference was associated with higher discordance (β=14.4 mm Hg [95% CI, 4.78-24.04]). Frail adults had lower AOBP relative to HBPM (β, -5.1 mm Hg [95% CI, -11.0 to 0.9]). Baseline AOBP systolic BP ≥140 mm Hg strongly predicted discordance ≥+10 mm Hg (odds ratio, 8.27 [95% CI, 5.52-12.40]). Participants aged 91 to 100 years had lower AOBP than those aged 78 to 80 years (β, -5.0 mm Hg [95% CI, -10.06 to 0.001]).

Conclusions: Among very old adults, substantial BP discordance between AOBP and HBPM was common and influenced by higher BP, age, male sex, arm circumference, and frailty.