Hypertension最新文献

Background: Postprandial hypotension (PPH) may contribute to falls among older adults, particularly those taking antihypertensive medication. However, evidence on this association in community-dwelling populations is limited. Since ambulatory blood pressure (BP) monitoring captures BP during daily activities, it may provide accurate assessments of PPH outside the clinic setting.

Methods: This prospective cohort study examined the association between PPH and fall risk among community-dwelling adults aged ≥65 years taking antihypertensive medication. At baseline, participants underwent 24-hour ambulatory BP monitoring; subsequently, they completed monthly fall calendars during a 12-month follow-up. PPH by systolic BP (SBP; systolic PPH) was defined as a postprandial SBP decline, mean SBP during the hour before the meal minus the minimum SBP during the 2 hours after the meal, following any meal of ≥20 mm Hg, or a decrease to SBP ≤90 mm Hg when preprandial SBP was ≥100 mm Hg.

Results: Among 626 participants (mean±SD age, 74.6±6.2 years; 56.1% women), 442 (70.6%) experienced systolic PPH. The mean±SD number of meals was 2.6±0.8 during the ambulatory BP monitoring period. During the 12-month follow-up, falls occurred in 169 of 442 (38.2%) participants with systolic PPH and 70 of 184 (38.0%) participants without systolic PPH. Systolic PPH was not associated with fall risk (adjusted hazard ratio, 0.93 [95% CI, 0.69-1.26]). A restricted cubic spline analysis demonstrated no evidence of an association between the largest postprandial SBP decline across all meals and fall risk.

Conclusions: In this cohort study, PPH identified by ambulatory BP monitoring was common but not associated with risk of falls.

Background: Multifetal pregnancies have increased preeclampsia risk, but the underlying pathogenesis may differ from that of singletons. It remains unclear whether twin placentas show molecular signs of preeclampsia synchronously.

Methods: We performed RNA sequencing on 32 individual placental samples from twin gestations grouped by preeclampsia status: 24 dichorionic twin (DT) and 8 monochorionic twin gestations. Ten singleton placentas from preeclamptic pregnancies were also analyzed. A benchmark data set (GSE203507, GSE114691, and GSE1482410) and a test data set (GSE190973) comprised 71 early onset preeclampsia and 69 control singleton placentas. Differential abundance analysis was conducted, and machine learning was used to derive a novel 98-transcript classification signature (accuracy >0.97 in benchmark and test data sets).

Results: Across 7 groups, 2946 transcripts were differentially modulated (likelihood-ratio test; false discovery rate <0.05). Placental signature scoring distinguished normotensive from early onset preeclampsia in GSE203507 singletons (P<0.0001) although normotensive DTs did not differ from DTs with preeclampsia (Kruskal-Wallis/Dunn). Notably, some twin placentas without clinical preeclampsia exhibited preeclampsia-like profiles. Linear mixed-effects regression, which accounted for intertwin correlation structure, revealed increasing signature scores across singleton and DT groups (all P<0.01): normotensive singletons

Conclusions: These findings highlight the complexity of preeclampsia pathology in twins. In DT pregnancies complicated by preeclampsia, placental involvement may be asymmetrical, suggesting that disease may arise from a single affected placenta; however, these results require replication.

Background: Hypertension is a leading risk factor for negative health outcomes due to end-organ effects that include small vessel disease in the brain. Low-renin hypertension is understudied at the blood pressure (BP), microvascular, and mechanistic level, and in relation to biological sex. This study examined the effects of low-renin hypertension, produced by activation of the brain renin-angiotensin system in a deoxycorticosterone acetate (DOCA) salt model.

Methods: C57BL/6J mice were treated with DOCA (or sham) and given tap H₂O and H₂O with 0.15 mol/L NaCl for 3 to 4 weeks followed by assessment of the microvasculature. Mean arterial pressure and BP variability were measured using radiotelemetry.

Results: Baseline and diurnal changes in mean arterial pressure, increases in mean arterial pressure, and BP variability during DOCA salt, were greater in male than female mice. Compared with sham treatment, endothelial function of cerebral arterioles in vivo was reduced by >70% by DOCA salt in males, dysfunction that could be reversed by local inhibition of AT1R (angiotensin II type 1 receptor), MR (mineralocorticoid receptor), or Rho kinase. DOCA salt increased arteriolar cross-sectional area and wall stiffness in male, but not female mice. In males (but not females), performance on a novel object recognition test was selectively impaired.

Conclusions: Activation of the central renin-angiotensin system has sex-specific effects on BP, diurnal changes in BP, BP variability, arteriolar structure, and stiffness. Marked endothelial dysfunction was present in males (with several contributing mechanisms). These findings provide new insight into BP-related and small vessel disease-related phenotypes, mechanisms that contribute to endothelial dysfunction, and sex-specific differences in BP traits in a preclinical model of low-renin hypertension.

Background: Endothelial mechanosensing is essential for controlling vascular tone. LRRC8A (leucine-rich repeat-containing protein 8A) was previously identified as a core subunit of the mechanoresponsive LRRC8 complex, functionally encoding the endothelial volume regulatory anion channel and regulating vascular function. This study aims to identify the molecular identity of the endothelial LRRC8 complex and its function in vascular reactivity and blood pressure control.

Methods: We generated germline epitope-tagged Lrrc8a-3xFlag knock-in mice and endothelium-specific Lrrc8a-3xFlag overexpression mice to permit LRRC8A and LRRC8C immunoprecipitation and define LRRC8 subunit interactions. We combined in vivo and in vitro loss-of-function models, electrophysiology, immunoblotting, and pressure myography of third-order mesenteric arteries to examine the contributions of individual LRRC8A/B/C subunits to vascular function and underlying signaling pathways. The contributions of LRRC8C to blood pressure control in vivo were further assessed using the angiotensin-induced hypertension model in Lrrc8c knockout mice.

Results: Although all LRRC8A-E subunits are expressed in endothelium, co-immunoprecipitation revealed enrichment of LRRC8A/B/C, suggesting the existence of an endothelial LRRC8A/B/C heteromer. Lrrc8a/b/c depletion studies showed codependent expression of LRRC8A/B/C, but not LRRC8D. Only LRRC8A and LRRC8C deficiency impaired AKT and endothelial NO synthase phosphorylation, increased myogenic tone (2.2- and 1.9-fold increase, respectively), and reduced endothelial NO synthase-dependent vasodilation (45% and 61% reduction, respectively). Global Lrrc8c knockout mice phenocopied Lrrc8a knockouts and exhibited exacerbated angiotensin-induced hypertension, as evidenced by 15% increase in mean arterial pressure.

Conclusions: LRRC8A/B/C form the endothelial LRRC8 heteromeric complex. LRRC8C is nonredundant in supporting endothelial AKT-endothelial NO synthase signaling, vascular relaxation, and resistance to hypertension.

Background: Sepsis is a life-threatening condition and a major cause of mortality in intensive care units worldwide, a clear unmet medical need. CNP (C-type natriuretic peptide) regulates inflammation and cardiovascular homeostasis, but its involvement in sepsis pathogenesis is not fully elucidated. This study investigated the intrinsic role of CNP, and therapeutic potential of the peptide, in offsetting the pathogenesis of sepsis.

Methods: Plasma concentrations of CNP, and its N-terminal cleavage product NT-proCNP (N-terminal pro-CNP), were measured in sepsis patients. Cardiac function, vascular hemodynamics, endothelial integrity, and biomarkers of inflammation were analyzed in wild-type, endothelium-restricted (ecCNP^-/-), or cardiomyocyte-restricted (cmCNP^-/-) CNP knockout animals, or global NPR (natriuretic peptide receptor)-C^-/- deficient mice, in etiologically distinct models of sepsis. CNP (0.2 mg/kg per d) was infused to rescue any adverse phenotype and probe therapeutic potential.

Results: Circulating (NT-proCNP) increased in sepsis patients and was associated with reduced disease severity. ecCNP^-/- mice exhibited an aggravated phenotype compared with wild-type mice in experimental sepsis, exemplified by impaired microcirculatory flow, edema, and increased expression of inflammatory biomarkers. In addition, cmCNP^-/- animals showed overt cardiac dysfunction following lipopolysaccharide treatment. This worsened phenotype was mirrored in NPR-C^-/- mice, implying that this cognate NPR subtype underpins the salutary actions of endogenous CNP. Pharmacological CNP administration improved microvascular perfusion, cardiac output, and inflammation in wild-type and ecCNP^-/-, but not NPR-C^-/-, mice.

Conclusions: Endogenous CNP plays a protective role in sepsis by preserving microvascular perfusion, reducing inflammation, maintaining endothelial integrity, and sustaining cardiac function via NPR-C. Pharmacologically targeting CNP signaling warrants further evaluation as a potential therapeutic opportunity in sepsis.

Background: The placenta is known to be critical in the cause of preeclampsia. However, there is a subset of preeclampsia cases without identifiable placental pathology. We evaluated which clinical preeclampsia classification system best distinguishes preeclampsia with placental pathology from preeclampsia without placental pathology.

Methods: We evaluated 5 placental pathological features in 197 placentas from patients with preeclampsia grouped by 3 clinical preeclampsia subclasses: (1) preeclampsia with calculated infant birthweight <10th percentile for gestational age (small for gestational age [SGA] preeclampsia) versus preeclampsia with birthweight ≥10th percentile for gestational age (not SGA preeclampsia); (2) preeclampsia with delivery before 34 weeks of gestation (early delivery preeclampsia) versus preeclampsia with delivery at or after 34 weeks of gestation (late delivery preeclampsia); and (3) preeclampsia with severe features versus preeclampsia without severe features. Clinical, histological and molecular findings in patients with preeclampsia were compared with normotensive patients, with and without SGA infants (N=1078 total).

Results: The SGA versus not small for gestational age preeclampsia classification system performed best (likelihood ratios [95% CI] for ≥3 of 5 placental pathological findings: 15.7 [6.5-38.1] in SGA preeclampsia versus not small for gestational age preeclampsia; 6.8 [4.3-10.8] in early delivery preeclampsia versus late delivery preeclampsia; and 5.2 [1.95-14.1] in preeclampsia with severe features versus preeclampsia without severe features; all P<0.0001). SGA preeclampsia and SGA normotensive placentas were abnormal and shared alterations in hypoxia, TNFα, glycolysis, unfolded protein response, estrogen response, UV response, p53, TGFβ, and mTORC1 signaling pathways.

Conclusions: Classifying preeclampsia based on birthweight percentile for gestational age is the most useful system for consistently identifying preeclampsia associated with placental pathology.

Background: Altered gut microbiota composition has been implicated in the development of hypertension. Evidence suggests bacterial products and metabolites can enter circulation, act on peripheral tissues, and modulate blood pressure (BP). We identified extracellular vesicles (EVs) of bacterial origin (bacterial extracellular vesicles [bEVs]) in the circulation of spontaneously hypertensive stroke-prone rats (SHRSP). We hypothesized that bEVs mediate communication between microbiota and the host, and that bEVs from SHRSP microbiota contain unique cargo that promotes hypertension.

Methods: EVs were isolated from plasma and cecal content of SHRSP and Wistar-Kyoto (WKY) rats. Multiomics analysis, including 16S rRNA sequencing, small RNA sequencing, lipidomics, and proteomics were performed to assess the cargo of bEVs. BEVs from WKY and SHRSP were transplanted by oral gavage to WKY and SHRSP recipients, and the effects on BP and sympathetic activity were monitored. The potential role of bEVs on BP was also evaluated in Dahl S and obstructive sleep apnea models of hypertension.

Results: Significant differences were observed in WKY and SHRSP bEV cargo, including small RNAs, proteins, and PAMPs (pathogen-associated molecular patterns). Transplantation of SHRSP bEVs to WKY rats increased renal sympathetic nerve activity and elevated BP. Moreover, we showed that bEVs influence BP regulation in Dahl S and obstructive sleep apnea-induced hypertension.

Conclusions: Our findings position bEVs as critical mediators of microbiota-host communication in BP regulation and demonstrate that bEVs from the altered SHRSP microbiota promote hypertension. Our findings shed new light on the role of bEVs in hypertension pathogenesis and offer new perspectives for diagnostics and therapeutic interventions.

Background: Endothelial dysfunction is a key feature of pulmonary arterial hypertension (PAH). Previously, we demonstrated decreased Wnt7a transcript levels, causing reduced angiogenesis in PAH. Wnt7a expression correlates with tip formation via ROR2 (receptor tyrosine kinase-like orphan receptor 2), a tyrosine kinase receptor. We hypothesized that ROR2 activation in pulmonary microvascular endothelial cells (PMVECs) promotes angiogenesis, particularly endothelial barrier establishment, and its loss causes PAH.

Methods: Endothelial-specific ROR2 knockout (ROR2 ECKO) and wild-type mice were studied under normoxia and chronic hypoxia using echocardiography, hemodynamics, and lung morphometry. PMVECs from healthy and PAH lungs were transfected with ROR2 siRNA/constructs for functional and molecular studies. Focal adhesion activation and force generation were assessed via Förster resonance energy transfer-based methods. Bulk and single-cell transcriptomic analyses were performed on siROR2 (ROR2 siRNA) PMVECs and ROR2 ECKO lungs.

Results: ROR2 ECKO mice exacerbated pulmonary hypertension and vascular remodeling in hypoxia. Single-cell RNA-sequencing of lung endothelial cells revealed dysregulated barrier formation and angiogenesis. Evans blue dye extravasation confirmed reduced endothelial barrier integrity in ROR2 ECKO mice. ROR2-deficient PAH PMVECs displayed increased adhesion, permeability, and focal adhesion numbers, with reduced VE-cadherin at cell junctions. Confocal imaging and foster resonance energy transfer revealed ROR2 localization in focal adhesions, interacting with ITGB1 (integrin β1) which remained in an active, adhesion-promoting state in ROR2-deficient cells. Restoring ROR2 in PAH PMVECs normalized adhesion, barrier function, and focal adhesion abundance. Transcriptomic analysis revealed Rab12 mediated ROR2-ITGB1 crosstalk, whose knockdown mimicked ROR2 deficiency in PMVECs.

Conclusions: ROR2 regulates pulmonary angiogenesis by maintaining endothelial barrier integrity and facilitating integrin recycling. ROR2 restoration could be a potential therapeutic approach for PAH.

Background: Understanding the association between improving medication adherence, intensifying antihypertensive medications, or both on blood pressure (BP) control can guide clinical care and quality improvement.

Methods: Retrospective cohort study of primary care patients with hypertension and 2 uncontrolled BP readings in 2021. Using prescription fills, we classified patients as high (≥80%) versus low (<80%) adherence in the 6 months before and after their second uncontrolled reading (aka index visit). We defined intensification as a prescription for a higher dose or a new medication class at that visit. The outcome was BP control (<130/80 mm Hg) between 30 and 270 days afterward. We identified factors associated with intensification at the index visit. For patients with low adherence before the index visit, we used multilevel logistic regression to measure the association between intensification, postvisit adherence, and subsequent BP control.

Results: Of 27 699 patients with uncontrolled BP, 24% had low adherence before the index visit. Patients with high adherence and prior intensification had the highest adjusted probability of intensification (28% [95% CI, 27%-29%]). Among patients with low previsit adherence, 19% received intensification and 46% transitioned to high adherence. Without intensification or improved adherence, the adjusted probability of control was 23%. Neither intensification alone (24%) nor improved adherence alone (25%) significantly increased the adjusted probability of control. Patients who both received intensification and improved adherence had the highest adjusted probability of control (31%; P<0.01 versus no action).

Conclusions: Physicians should simultaneously intensify treatment and encourage adherence. Health systems should encourage intensification regardless of adherence status.

Background: Epidemiological evidence suggests higher rates of heart failure in adults born at an extremely low birth weight (ELBW). Reports on the echocardiographic phenotype in this population are inconsistent and do not consider the effect of modifiable contributors such as blood pressure.

Methods: This study reports on the echocardiographic findings of the PREMATurity as predictor of children's Cardiovascular-renal Health (PREMATCH) study, a prospective case-control study evaluating renal and cardiovascular outcomes in children with ELBW in comparison to term-born controls. Left ventricular (LV) mass was the primary outcome. Data were analyzed with multivariable-adjusted regression models considering anthropometric variables and systolic blood pressure as covariates.

Results: Eighty cases (median age, 10.8 years) and 72 controls (median age, 11.4 years) were included. Multivariable-adjusted analyses revealed that the adjusted difference in LV mass in cases versus controls was -8.49 g (CI, -13.78 to -3.20; P=0.002). Sex, height, weight, and body fat percentage were significant covariates. There was a positive interaction between ELBW status and systolic blood pressure (P_interaction=0.039). There was a -6.47 g (CI, -11.7 to 1.28; P=0.016) difference in LV mass between normotensive cases and controls, while the difference disappeared between subjects with increased blood pressure or hypertension.

Conclusions: ELBW children exhibit lower LV mass during childhood in comparison with term-born controls. However, elevations in systolic blood pressure are associated with a steeper increase in LV mass in cases than in controls. Our findings question whether cutoffs for the general population are adequate to evaluate and manage hypertension and LV hypertrophy in children with ELBW.