Hypertension最新文献

Background: Cardiovascular disease (CVD) risk differs across Asian subgroups, possibly due to differences in hypertension burden. We characterized lifetime blood pressure (BP) trajectories for East and South Asian individuals and compared their associations with CVD risk.

Methods: Among 148 872 UK Biobank participants with primary care utilization data, life course BP trajectories were fitted as a function of age by sex according to self-identified ethnicity. We determined associations of time-averaged young adulthood (18-39 years), middle age (40-64 years), and later life (≥65 years) systolic BP (SBP) and diastolic BP with incident atherosclerotic CVD risk.

Results: The predicted SBP/diastolic BP (95% CI) at age 30 years was 108 (103-114)/68 (65-71) mm Hg for East Asian and 114 (110-118)/72 (71-73) mm Hg for South Asian individuals. By age 40, South Asian individuals were projected to reach an SBP of 130.0 mm Hg, whereas East Asian individuals reached the equivalent SBP by age 49 years. Among South Asian individuals, each SD increase in young adulthood SBP was associated with a higher atherosclerotic CVD risk with an odds ratio (95% CI) of 1.41 (1.12-1.75), but not among East Asians (P_interaction=0.01). Midlife SBP was associated with peripheral artery disease among South Asian individuals (odds ratio, 2.08 [95% CI, 1.51-2.88]) and with ischemic stroke among East Asian individuals (odds ratio, 3.84 [95% CI, 1.08-5.07]). Later-life SBP was associated with myocardial infarction risk by 1.52 (1.15-1.92)-fold among South Asians and ischemic stroke by 2.50 (1.06-3.80)-fold among East Asian individuals.

Conclusions: East and South Asian individuals exhibit distinct BP trajectories that age-differentially associate with incident CVD. Disaggregating Asian subgroups may inform tailored hypertension screening and management.

Background: Primary aldosteronism is the most common form of secondary hypertension. The most frequent genetic cause of aldosterone-producing adenomas is somatic mutations in the potassium channel KCNJ5. They affect the ion selectivity of the channel, with sodium influx leading to cell membrane depolarization and activation of calcium signaling, the major trigger for aldosterone biosynthesis.

Methods: To investigate how KCNJ5 mutations lead to the development of aldosterone-producing adenomas, we established an adrenocortical cell model in which sodium entry into the cells can be modulated on demand using chemogenetic tools (H295R-S2 α7-5HT3-R [α7-5HT3 receptor] cells). We investigated their functional and molecular characteristics with regard to aldosterone biosynthesis and cell proliferation.

Results: A clonal cell line with stable expression of the chimeric α7-5HT3-R in H295R-S2 cells was obtained. Increased sodium entry through α7-5HT3-R upon stimulation with uPSEM-817 led to cell membrane depolarization, opening of voltage-gated Ca²⁺ channels, and increased intracellular Ca²⁺ concentrations, resulting in the stimulation of CYP11B2 expression and increased aldosterone biosynthesis. Increased intracellular sodium influx did not increase proliferation but rather induced apoptosis. RNA sequencing and steroidome analyses revealed unique profiles associated with Na⁺ entry, with only partial overlap with Ang II (angiotensin II) or potassium-induced changes.

Conclusions: H295R-S2 α7-5HT3-R cells are a new model reproducing the major features of cells harboring KCNJ5 mutations. Increased expression of CYP11B2 and stimulation of the mineralocorticoid biosynthesis pathway are associated with a decrease of cell proliferation and an increase of apoptosis, indicating that additional events may be required for the development of aldosterone-producing adenomas.

Background: Excessive hypercholesterolemia in pregnancy increases the risk of preeclampsia, though the mechanisms remain unclear. We recently showed that uterine artery function is impaired in hypercholesterolemia-preeclampsia via activation of the TLR4 (toll-like receptor 4)/PGHS1 (prostaglandin H synthase 1) pathway. Low-dose aspirin lowers preeclampsia risk in high-risk pregnancies by inhibiting PGHS1, but its effects in hypercholesterolemia-preeclampsia pregnancies are not known. Moreover, oxidized low-density lipoprotein levels rise in hypercholesterolemia-preeclampsia, potentially activating TLR4 and LOX-1 (lectin-like oxLDL receptor-1; scavenger receptor linked to vascular dysfunction in preeclampsia). However, whether this occurs in hypercholesterolemia-preeclampsia is not known.

Methods: Sprague Dawley rats received a control or high-cholesterol diet (to induce hypercholesterolemia-preeclampsia) from gestational day 6 to 20, with placebo or low-dose aspirin (1.5 mg/daily) given from gestational day 10 to 20. On gestational day 20, pregnancy outcomes and uterine artery function were assessed.

Results: Uterine artery blood flow velocity and placental weights were higher in hypercholesterolemia-preeclampsia placebo-treated dams versus controls, but these were reduced by low-dose aspirin. Endothelium-dependent vasodilation was impaired in the uterine arteries of the hypercholesterolemia-preeclampsia placebo group versus controls and was corrected by low-dose aspirin. Ex vivo inhibition of TLR4, PGHS1, or LOX-1 also normalized endothelium-dependent vasodilation in the hypercholesterolemia-preeclampsia placebo-treated dams. Exposure to oxidized low-density lipoprotein in the bath (modeling a secondary hit) further impaired endothelium-dependent vasodilation in the uterine arteries of the hypercholesterolemia-preeclampsia placebo group, partially via TLR4 and LOX-1, which was prevented by low-dose aspirin.

Conclusions: Low-dose aspirin improved uterine artery endothelial function in hypercholesterolemia-preeclampsia pregnancies; likely by suppressing the TLR4/LOX-1/PGHS1 pathway.

Background: Maternal hypertensive disorders during pregnancy are a worldwide health problem, particularly in the countries/regions with low sociodemographic levels. This study aimed to reveal and predict the hypertensive disorders during pregnancy-related epidemiological trends.

Methods: Using data from the Global Burden of Disease 2019 study, we constructed an age-period-cohort model to assess the net drift (annual percentage changes), associated age, period, and cohort effects across global and different sociodemographic index (SDI) regions. Moreover, we analyzed attributable risk factors and future trends based on the autoregressive integrated moving average model.

Results: The numbers of hypertensive disorders during pregnancy worldwide increased by 10.9% (95% uncertainty interval, 6.1-15.3) from 1990 to 2019 and only increased in the low-SDI countries. The age-standardized incidence rate declined by 23.6% (20.6, 26.9), with a global net drift of -0.8%, whereas some higher-SDI countries showed a positive net drift. After controlling for period and cohort factors, the highest incidence was observed in the 20- to 29-year age group. The period and cohort effects showed decreasing trends, whereas unfavorable period effects occurred after 2010 in high-SDI and middle-high-SDI countries. High-income North America and western sub-Saharan Africa have shown increased numbers of disability-adjusted life years due to malnutrition. The autoregressive integrated moving average model revealed downward trends in the global incidence and age-standardized incidence rate by 2030.

Conclusions: Our study highlights significant regional and national variations and age differences in the burden of hypertensive disorders during pregnancy associated with SDI stratification, which will facilitate the targeting of cost-effective health policy planning, resource allocation, and women's health management by policymakers.

Background: The mediating role of inflammatory biomarkers in the causal relationship between body composition and hypertension remains unclear and requires further investigation.

Methods: This study used a combination of retrospective observational analysis and Mendelian randomization approaches. Observational data were derived from 4717 Chinese children and adolescents aged 6 to 18 years who underwent dual-energy X-ray absorptiometry to assess body composition. Mendelian randomization analyses utilized summary statistics from large-scale data sets, including UK Biobank, deCODE2021, International Consortium of Blood Pressure, FinnGen, and other consortia. The inflammatory biomarkers included leptin, insulin, adiponectin, osteocalcin, FGF23 (fibroblast growth factor 23), and PTH (parathyroid hormone).

Results: The observational analysis revealed that increased fat mass positively influenced diastolic blood pressure through osteocalcin, while fat-free mass had an inverse effect. Insulin mediated the association between fat mass and systolic blood pressure, diastolic blood pressure, and hypertension, with additional indirect effects observed for PTH (all P<0.05). The Mendelian randomization analyses demonstrated a causal relationship between childhood body mass index and hypertension mediated by insulin (indirect effect: odds ratio, 0.87 [95% CI, 0.78-0.97]) and adiponectin (odds ratio, 1.13 [95% CI, 1.04-1.23]). Adiponectin mediated the effects of fat-free mass (odds ratio, 0.81 [95% CI, 0.71-0.93]) and fat mass (odds ratio, 1.30 [95% CI, 1.11-1.51]) on hypertension. Leptin, adiponectin, and insulin also mediated the causal effects of body composition on systolic blood pressure, diastolic blood pressure, and hypertension.

Conclusions: These findings indicate that body composition influences blood pressure through distinct inflammatory biomarkers. Targeting inflammatory biomarkers may provide tailored strategies for managing body composition and hypertension.

Genome-wide association studies have identified >3500 associated single nucleotide polymorphisms and over 1000 independent loci associated with hypertension. These individually have small effect sizes, and few associated loci have been experimentally tested for causal roles in hypertension using animal models or in humans. Thus, methods to prioritize and maximize the relevance of identified single nucleotide polymorphisms and associated loci are critical to determine their importance in hypertension. We propose several approaches to aid in these efforts, including: (1) integration of genome-wide association study data with multiomic data sets, including proteomics, transcriptomics, and epigenomics, (2) utilizing linked clinical and genetic data sets to determine genetic contributions to hypertension subphenotypes with distinct drivers, and (3) performing whole exome/genome sequencing on cohorts of individuals with severe hypertension to enrich for rare variants with larger effect sizes. Rather than creating longer lists of hypertension-associated single nucleotide polymorphisms, these approaches are needed to identify key mediators of hypertension pathophysiology.

Background: Psychosocial stress is a cardiovascular risk factor; however, little is known about whether prenatal psychosocial stressors influence postpartum cardiovascular health. We aimed to examine the associations of multiple measures of prenatal psychosocial stress on maternal blood pressure (BP) in the first 4 years after birth.

Methods: Among 225 MADRES cohort (Maternal and Developmental Risks From Environmental and Social Stressors) participants, we examined associations of average prenatal Perceived Stress Scale (PSS), Center for Epidemiological Studies Depression (CES-D) scores, and second-trimester neighborhood social cohesion scores on systolic and diastolic BP collected at annual postpartum study visits (1-4 years) using linear mixed-effects models, adjusted for covariates.

Results: Higher prenatal PSS and CES-D scores were associated with greater diastolic BP at 1 year postpartum (0.24 [95% CI, 0.01-0.46] and 0.24 [95% CI, 0.08-0.40] mm Hg per 1-unit higher PSS and CES-D, respectively) and greater systolic BP (0.25 [95% CI, 0.02-0.48] mm Hg per 1-unit higher CES-D). Overall associations of PSS and CES-D with BP were attenuated over the 4-year postpartum period (P<0.05). Stratified analyses suggested larger associations of PSS and CES-D among US-born participants and participants with normotensive pregnancies. While neighborhood social cohesion was not associated with postpartum BP overall, higher neighborhood social cohesion scores were associated with lower BP at 1 year postpartum among participants with normotensive pregnancies and lower systolic BP among foreign-born Hispanic participants.

Conclusions: Higher prenatal perceived stress and depressive symptoms were associated with greater 1-year postpartum BP, whereas neighborhood cohesion was associated with lower 1-year postpartum BP. These results suggest prenatal psychosocial factors may impact cardiovascular health within the first year after birth.

Background: Cardiac hypertrophy constitutes the primary pathological basis for heart failure and exerts a considerable influence on morbidity and mortality. Deubiquitinating enzymes are crucial regulators of protein degradation and play a pivotal role in cardiac pathophysiology. This study aimed to clarify the involvement of a deubiquitinating enzyme, MYSM1 (Myb-like, SWIRM, and MPN domains 1), in cardiac hypertrophy and to explore the underlying mechanism.

Methods: Cardiac hypertrophy was developed by angiotensin II or transverse aortic constriction surgery. Cardiomyocyte-specific knockdown of MYSM1 was accomplished using the adeno-associated virus serotype 9-cTNT-Mysm1-shRNA. Co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis was utilized to identify potential substrates of MYSM1.

Results: First, we discovered that the expression of MYSM1 increases during cardiac hypertrophy. MYSM1 knockdown mitigated cardiac dysfunction and hypertrophy after angiotensin II administration. Cardiomyocyte-specific knockdown of MYSM1 with adeno-associated virus serotype 9 alleviated myocardial dysfunction and hypertrophy caused by transverse aortic constriction surgery. Through co-immunoprecipitation and LC-MS, poly (ADP-ribose) polymerase 1 (PARP1) was identified as a potential substrate protein of MYSM1. PARP1 initiates a novel form of programmed cell death termed parthanatos, which is characterized by excessive PARylation, nuclear translocation of AIF, and depletion of nicotinamide adenine dinucleotide. MYSM1 deubiquitinates and stabilizes PARP1 in an MPN domain-dependent manner. In addition, MYSM1 mediates cardiac hypertrophy through PARP1-dependent cardiomyocyte parthanatos.

Conclusions: This study identified the role of the MYSM1-PARP1 axis in mediating cardiac hypertrophy and suggested that MYSM1 is a promising pharmacological target for the treatment of cardiac hypertrophy.

Background: The pathophysiology of familial thoracic aortic aneurysm and dissection (TAAD) is linked to genetic variants that affect aortic components. Although hypertension is a risk factor for TAAD, the precise genetic link remains unclear.

Methods: A family with autosomal dominant TAAD complicated by hypertension was studied to identify candidate mutations. The effect of the identified mutation on TAAD development was investigated using a CRISPR-Cas9-generated knock-in mouse model to elucidate the mechanism underlying hypertension-induced TAAD.

Results: The KCNJ5 p.R242Q mutation was identified in the family and met the criteria for cosegregation, rarity, and conservation. Utilizing our mouse model, we observed that a significant proportion of heterozygous mice with the mutation displayed dilated thoracic aortas. The mutation's allele dose was positively correlated with TAAD incidence following β-aminopropionitrile monofumarate treatment. Pathological changes in the thoracic aorta, including collagen deposition and dilation, elevated transforming growth factor-β activity, and extracellular matrix remodeling, were associated with hypertension. Furthermore, the mutation was found to induce lifelong isolated systolic hypertension, attributable to autonomous epinephrine secretion from the adrenal medulla. Unlike wild-type, mutated KCNJ5 was highly expressed in the adrenal medulla instead of the adrenal cortex. Treatment with the adrenergic β-receptor blocker propranolol reduced systolic hypertension and mitigated TAAD in the heterozygous mice.

Conclusions: Familial TAAD may stem from KCNJ5 dysfunction in the G-protein-coupling domain, causing isolated systolic hypertension via increased epinephrine secretion and disruption of thoracic aortic homeostasis. These findings establish a genetic link between systolic hypertension and TAAD.

Background: Severe preeclampsia (sPE) is a serious condition posing risks to both maternal and fetal health. Based on mass spectrometry analysis, we identified a key protein, PSME3 (proteasome activator subunit 3), an 11S proteasome activator, whose protein level was significantly downregulated in sPE placentas and whose function in sPE remains unknown.

Methods: PSME3 protein levels in human placental tissue were detected using Western blot, and PSME3 concentration in serum was detected by ELISA assay. The human preeclampsia-like phenotypes of Psme3^-/- pregnant mice were examined. Trophoblast cell apoptosis was detected by flow cytometry. Pregnant mice were treated with 9.5% O₂ to construct a preeclampsia mouse model for detecting placental Psme3 expression. The regulation of PSME3 expression by hypoxia was detected in trophoblast cell lines treated with 21% O₂ or 1% O₂.

Results: PSME3 protein levels were significantly downregulated in sPE placentas and serum. Pregnant mice with Psme3^-/- embryos and placentas spontaneously presented human preeclampsia-like symptoms, including hypertension and proteinuria, increased serum soluble fms-like tyrosine kinase 1 concentration, fetal growth restriction, and increased cellular apoptosis. Mechanically, PSME3 knockdown promoted the apoptosis of trophoblast cells by repressing the degradation of UBE2V2 (ubiquitin conjugating enzyme E2 V2). Moreover, the placentas of hypoxia-induced preeclampsia mice presented significantly reduced Psme3 protein levels and elevated Ube2v2 protein levels. Hypoxia-inducible factor-1α functioned as a transcriptional repressor of PSME3.

Conclusions: In sPE placentas, hypoxia of the placenta may lead to the transcriptional inhibition of PSME3. PSME3 deficiency promotes the accumulation of UBE2V2, thereby inducing trophoblast cell apoptosis. Our study provides a new perspective for elucidating the pathogenesis of sPE.