Hypertension最新文献

Background: Aldosterone-producing adenomas (APAs) are a common cause of primary aldosteronism that can lead to cardiovascular complications if left untreated. Machine learning-based bioinformatics approaches have emerged as powerful tools for identifying potential disease markers, gaining widespread recognition in biomedical research. We aimed to use machine learning to discover novel biomarkers of APAs to identify new pathophysiological mechanisms.

Methods: We applied 2 machine learning algorithms to published RNA sequencing data to identify APA feature genes. Validation was performed using APA tissue samples, spatial transcriptomics, pig adrenal glands, and in vitro assays in a human adrenocortical cell line.

Results: Machine learning identified ATP2A3 as a key feature gene in APA, and its upregulation in APAs compared with the adjacent cortex was confirmed by spatial transcriptomics. In human adrenocortical cells, angiotensin II treatment increased ATP2A3 gene expression 9.15-fold. Silencing ATP2A3 decreased basal CYP11B2 expression and aldosterone secretion by 3.51-fold and 1.46-fold, respectively, and by 1.77-fold and 1.94-fold under angiotensin II stimulation. Dietary sodium restriction in pigs significantly increased ATP2A3 mRNA and protein levels. Spatial transcriptomics showed that APA cells exhibited higher ATP2A3 gene expression compared with all other adrenal cell types. The suppressive effect of ATP2A3 silencing on CYP11B2 expression was further enhanced by Ca²⁺ inhibitors.

Conclusions: The ATP2A3 gene is highly expressed in APA and is a key regulator of CYP11B2 expression and aldosterone production.

Background: Circulating proteins in blood are involved in various physiological processes, but their contributions to blood pressure regulation remain partially understood. In traditional observational studies, identifying circulating proteins causally associated with blood pressure is challenging because of potentially unmeasured confounding and possible reverse causality.

Methods: Two-sample Mendelian randomization analyses were conducted to estimate the causal effects of 2270 circulating proteins (data sourced from 8 genome-wide association studies) on diastolic blood pressure, systolic blood pressure, and pulse pressure. Colocalization analyses were then used to investigate whether the circulating proteins and blood pressure traits shared causal genetic variants. To further verify the findings, we subsequently performed Steiger filtering analyses, annotation of protein-altering variants, assessment of overlap between protein quantitative trait loci and expression quantitative trait loci, protein-protein interaction and functional enrichment analyses, and drug target evaluation. To provide more potential biomarkers, we further evaluated the epidemiological associations of 2923 circulating proteins with blood pressure and hypertension by cross-sectional and longitudinal analyses using individual data in the UK Biobank.

Results: Mendelian randomization and colocalization analyses identified 121 circulating proteins with putative causal effects on at least 1 blood pressure trait. Many of the identified proteins are enriched in the pathways relevant to blood pressure regulation, and a majority of these proteins are either known drug targets or druggable candidates.

Conclusions: This study has uncovered numerous circulating proteins potentially causally associated with blood pressure, providing insights into the regulatory mechanisms of blood pressure and potential therapeutic targets to facilitate blood pressure management.

Background: Preeclampsia is a pregnancy-specific disorder with unclear pathogenesis. Irisin, a recently identified exercise-induced factor, significantly influences lipid metabolism and cardiovascular function. Nonetheless, its role in trophoblast development during human placentation and the related intracellular signaling pathways remain poorly understood.

Methods: We assessed peripheral blood irisin expression in early pregnancy among patients with preeclampsia and its correlation with key clinical indicators. In trophoblast cell lines and mice, we used exogenous irisin and viral knockdown to investigate functional changes. Phosphorylation-specific antibody arrays and dual-luciferase reporter assays were used to explore downstream molecular mechanisms, which were subsequently validated in trophoblast cell lines and relevant gene knockout mice.

Results: In early pregnancy, patients with preeclampsia exhibit decreased peripheral blood irisin levels, occurring earlier than traditional predictive markers, such as PLGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1). Furthermore, irisin concentration is positively correlated with proteinuria and abnormal blood pressure during pregnancy. Exogenous irisin significantly enhanced trophoblast cell migration, invasion, and proliferation while inhibiting apoptosis. It also increased STAT (signal transducers and activators of transcription) 4 phosphorylation and its binding to the GLUT (glucose transporter)-3 promoter, resulting in elevated GLUT-3 expression and glucose uptake in trophoblast cells. In vivo, increased peripheral irisin promoted embryo implantation, vascular remodeling, and enhanced glucose uptake, whereas reduced irisin resulted in a preeclampsia-like phenotype characterized by elevated blood pressure, proteinuria, renal-placental dysfunction, adipose accumulation, and restricted fetal growth.

Conclusions: Peripheral irisin improves preeclampsia by promoting embryo implantation and vascular remodeling through the activation of the STAT4/GLUT-3 pathway. Reduced peripheral irisin may contribute to preeclampsia-like pathologies. This study supports the advocacy for appropriate exercise during early pregnancy and provides new insights for preeclampsia prevention.

Background: Whether maternal hypertension contributes to the enhanced susceptibility to vascular remodeling in adult offspring through epigenetic mechanisms remains unclear. We aimed to address this gap in the literature using a transgenerational mouse model.

Methods: Gestational hypertension was induced in pregnant mice using chronic angiotensin II infusion. Blood pressure was monitored using the tail-cuff method. Two months post-delivery, an N⁶-methyladenosine epitranscriptomic microarray analysis was performed on the carotid arteries of second-generation mice. A unilateral carotid artery injury model was used to study the postinjury vascular response in vivo. Furthermore, carotid ultrasonography, immunohistochemistry, and molecular biological parameters were assessed in adult offspring.

Results: Exposure to maternal hypertension decreased the birth weight of live pups and increased the fetal death rate. Compared with normal offspring, adult offspring with hypertension had wire-induced injury that led to greater vascular remodeling, which was associated with aggravated inflammation imbalance, fibrosis, and oxidative stress. In addition, aberrant N⁶-methyladenosine methylation, increased N⁶-methyladenosine levels, and increased METTL3 (methyltransferase-like 3) expression were detected in the vessels of offspring with hypertension. Maternal METTL3 deficiency increased the birth weight of live pups with hypertension, improved vascular dysfunction, and alleviated vascular inflammation in adult offspring with hypertension after injury.

Conclusions: Maternal hypertension can induce transgenerational transmission of enhanced susceptibility to vascular remodeling, and the possible underlying mechanism is associated with altered METTL3-mediated N⁶-methyladenosine methylation. Therefore, this study reveals the role of epigenetic effects across generations and provides new insights into vascular remodeling causes.

Background: Orthostatic hypertension is an emerging risk factor for adverse events. Recent consensus statements combine an increase in blood pressure upon standing with standing hypertension, but whether these 2 components have similar risk associations with cardiovascular disease (CVD) is unknown.

Methods: The ARIC study (Atherosclerosis Risk in Communities) measured supine and standing blood pressure during visit 1 (1987-1989). We defined systolic orthostatic increase (a rise in systolic blood pressure [SBP] ≥20 mm Hg, standing minus supine blood pressure) and elevated standing SBP (standing SBP ≥140 mm Hg) to examine the new consensus statement definition (rise in SBP ≥20 mm Hg and standing SBP ≥140 mm Hg). We used Cox regression to examine associations with incident coronary heart disease, heart failure, stroke, fatal coronary heart disease, and all-cause mortality.

Results: Of 11 369 participants (56% female; 25% Black adults; mean age, 54 years) without CVD at baseline, 1.8% had systolic orthostatic increases, 20.1% had standing SBP ≥140 mm Hg, and 1.3% had systolic orthostatic increases with standing SBP ≥140 mm Hg. During up to 30 years of follow-up, orthostatic increases were not significantly associated with any of the adverse outcomes of interest, while standing SBP ≥140 mm Hg was significantly associated with all end points. In joint models comparing systolic orthostatic increases and standing SBP ≥140 mm Hg, standing SBP ≥140 mm Hg was significantly associated with a higher risk of CVD, and associations differed significantly from systolic orthostatic increases.

Conclusions: Unlike systolic orthostatic increases, standing SBP ≥140 mm Hg was strongly associated with CVD outcomes and death. These differences in CVD risk raise important concerns about combining systolic orthostatic increases and standing SBP ≥140 mm Hg in a consensus definition for orthostatic hypertension.

Background: Hypertension is a major global health issue. Aldosterone synthase inhibitors (ASIs) have emerged as a promising therapeutic strategy for blood pressure control.

Methods: A thorough search of the MEDLINE and Embase databases up to March 30, 2024, identified randomized trials comparing ASIs with a placebo for hypertension treatment. Data extraction was done independently by 2 authors. Both random-effects (REML) and fixed-effects meta-analyses were conducted to account for diversity and study size, respectively. Risk ratios for binary outcomes and mean differences for continuous outcomes were calculated.

Results: Seven randomized controlled trials involving 1440 patients (mean age, 60 years; 39% women) were included. The analysis showed that ASIs reduced office systolic blood pressure by 6.3 mm Hg ([95% CI, -8.8 to -3.8]; P<0.0001) and diastolic blood pressure by 2.2 mm Hg ([95% CI, -4.2 to -0.2]; P=0.03). The risk ratio for adverse events was 1.1 ([95% CI, 0.9-1.2]; P=0.3), with a similar trend for serious adverse events (risk ratio, 1.0 [95% CI, 0.5-2.3]; P=0.95). No treatment-related deaths occurred. However, the risk of hyperkalemia was higher with ASIs (risk ratio, 2.5 [95% CI, [1.2-5.4]; P<0.02).

Conclusions: ASIs effectively reduce systolic and diastolic blood pressure in hypertensive patients and have a tolerable safety profile. The increased risk of hyperkalemia requires careful monitoring. These findings suggest ASIs are a potential treatment option for hypertension, pending further research in larger studies.

Background: Hypertension is a major cardiovascular risk factor, yet traditional care often results in suboptimal blood pressure (BP) control at the population level. We implemented a remote hypertension management program that monitored home BP and titrated medications per algorithm. This study assessed the program's long-term effects by examining participants' office BP up to 42 months post-enrollment.

Methods: Participants of the remote hypertension program were categorized into 4 groups: (1) enrolled-maintenance (achieved goal home BP of ≤130/80 mm Hg), (2) enrolled-early exit (left before achieving goal BP), (3) education-only (lifestyle modifications and medications compliance), and (4) white coat hypertension group (high office BP but normal home BP). Office BP readings of participants were collected up to 42 months post-enrollment. A linear mixed-effects regression model estimated mean BP levels and studied factors associated with above-goal systolic BP in the maintenance group.

Results: Office BP readings from 3601 participants (mean age, 61±11 years; 57% female; 60% white; 52% atherosclerotic cardiovascular disease) were extracted from electronic health records and analyzed. All groups sustained office BP below their qualifying values (P<0.001) over 42 months. In the maintenance group, 89.7% of participants maintained systolic BP at goal, compared with 63.5% in the early exit group, 69.4% in the education-only group, and 90.7% in the white coat hypertension group. Age >50 years was associated with above-goal systolic BP in the maintenance group.

Conclusions: Participants who achieved BP control through the remote hypertension program maintained goal systolic BP in 90% of cases up to 42 months post-enrollment. These findings highlight the long-term benefits of remote, intensive management programs for effective hypertension control.

Background: Transcatheter renal denervation (RDN) remains inconsistent despite developments in ablation technologies, due to the lack of an intraprocedural physiological end point.

Objective: To identify whether aorticorenal ganglion (ARG) guided RDN using microwave (MW) catheter leads to more consistent denervation outcomes compared with empirical MW ablation.

Methods: Pigs underwent sham procedure (n=8) or bilateral RDN using an in-house built open-irrigated MW catheter. Before denervation, ipsilateral ARG pacing was performed leading to renal artery vasoconstriction. MW ablation group (MW-group; n=7) received 1 ablation (100-120 W for 360 seconds) in the mid-main renal artery based on artery caliber. ARG-guided-MW ablation group (ARG-MW-group; n=7) was permitted an additional ablation more distally or at higher power until a vasoconstrictive response was abolished. Animals were euthanized at 4 to 5 weeks post-procedure.

Results: ARG pacing caused an ipsilateral reduction in renal artery caliber from 4.67 to 4 mm; P=0.0006 in MW-group and 4.8 to 3.9 mm; P=0.001 in ARG-MW-group. Repeat ARG pacing at euthanasia led to a reduction in renal artery caliber in MW-group from 5.1 to 4.8 mm; P=0.006, but not in ARG-MW-group from 4.88 to 4.55 mm; P=0.08. There were no differences in ablation injury volumes between the groups. Compared with undenervated sham controls, ARG-MW-RDN versus MW-RDN caused median reductions in viable nerve area (antityrosine hydroxylase staining) at 4 to 5 weeks by 92.6% (interquartile range, 0.94-19.59%; P<0.0001) versus 55.02% (interquartile range, 15.87-75.11%; P=0.006) and median renal cortical norepinephrine content by 68.06% (interquartile range, 27.16-38.39%; P<0.0001) versus 25.25% (interquartile range, 56.97-157.7%; P=NS).

Conclusions: ARG pacing serves as a physiological procedural end point to guide MW denervation to improve denervation outcomes.

The term early life stress encompasses traumatic events occurring before the age of 18 years, such as physical abuse, verbal abuse, household dysfunctions, sexual abuse, childhood neglect, child maltreatment, and adverse childhood experiences. Adverse psychological experiences in early life are linked to enduring effects on mental and physical health in adulthood. In this review, we first describe the effects and potential mechanisms of early life stress on the components of the vasculature. Next, we dive into the impact of early life stress on the vasculature across the lifespan through alterations of the epigenetic landscape. Finally, we consolidate the critical gaps in knowledge for focusing future research including the potential for resilience in combatting the impact of early life stress on vascular health.