Vascular Function Research Articles (Page 1)

We aimed to investigate the effects of Xuebijing (XBJ) combined with levosimendan on the immune function and coagulation function in patients with sepsis complicated by myocardial injury. This double-blind, randomized controlled trial involved 88 sepsis patients with myocardial injury, split into control (n = 44, levosimendan plus conventional therapy) and combination (n = 44, control group's treatment plus XBJ injection) groups. Primary outcomes: coagulation parameters [prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count (PLT), fibrinogen (Fib), and D-dimer (D-D)], immune function indicators (peripheral blood T lymphocyte subsets: CD4+, CD8+, and the CD4+/CD8+ ratio). Secondary outcomes: inflammatory markers [procalcitonin (PCT), C-reactive protein (CRP), and tumor necrosis factor (TNF-α)], vascular endothelial function markers [endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), and soluble thrombomodulin (sTM)], myocardial function biomarkers [cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and B-type brain natriuretic peptide (BNP)], and hemodynamic parameter [heart rate (HR), mean arterial pressure (MAP), and central venous pressure (CVP)]. Post-treatment, serum levels of PCT, CRP, TNF-α, ET-1, vWF, sTM, PT, APTT, D-D, CD8+, cTnI, CK-MB, BNP, and HR were lower in both groups, with further reductions in the combination group. Levels of NO, VEGF, PLT, Fib, CD4+, CD4+/CD8+ ratio, MAP and CVP were higher in the combination group than in the control group (all P < 0.05). The combination of XBJ and levosimendan improves coagulation function, regulates immune function, enhances vascular endothelial function and hemodynamics, reduces inflammation, and alleviates myocardial injury.

Anthracyclines, which are key to many chemotherapeutic protocols, have been associated with increased vascular stiffness, a major factor associated with cardiovascular morbidity and mortality. There is no evidence-based intervention to prevent anthracycline-associated vascular dysfunction. To investigate whether atorvastatin pretreatment is associated with attenuation of the anthracycline-induced increase in aortic stiffness. This study is a secondary analysis of a double-blind, randomized clinical trial (Statins to Prevent the Cardiotoxicity From Anthracyclines [STOP-CA]). Enrollment occurred between January 25, 2017, and September 10, 2021, with the last follow-up on October 10, 2022. Primary analyses were reported on August 8, 2023. STOP-CA was a multicenter trial across 9 academic centers in the US and Canada. Participants were patients with newly diagnosed lymphoma scheduled to undergo anthracycline-based chemotherapy with no clinical indication for a statin. Atorvastatin (40 mg, once daily) or placebo for 12 months. This subanalysis of the STOP-CA trial includes post hoc end points with cardiac magnetic resonance imaging-derived aortic arch pulse wave velocity (PWV) and aortic distensibility (AD). An intention-to-treat approach was applied. The proportions of participants with a 1 SD or more increase in PWV and a 1 SD or more decrease in ascending aortic distensibility (AAD) were calculated in each group over 12 months. An increase in PWV of 0.15 m per second or more, a previously defined annual rate in individuals of similar age, was also assessed as a secondary end point. Of the 300 participants (150 randomized to atorvastatin and 150 randomized to placebo), 152 (mean [SD] age, 51 [17] years; 72 female [47%]; 82 treated with atorvastatin) had paired PWV data, and 168 had paired AD data. The PWV values remained similar in the atorvastatin group (mean [SD], 6.5 [1.9] vs 6.5 [2.0] m per second) but increased in the placebo group (5.7 [1.8] vs 6.8 [2.0] m per second) over 12 months. A 1 SD or more increase (0.8 m per second) in PWV was observed among 4 of 82 patients (5%) with atorvastatin and 35 of 70 patients (50%) with placebo (odds ratio, 0.05; 95% CI, 0.02 to 0.16; P < .001) at 12 months. A 1 SD or more decrease (1.8 × 10-3 mm Hg-1) in AAD was observed among 6 of 88 patients (7%) with atorvastatin and in 14 of 80 patients (18%) with placebo. A 1 SD or more increase in PWV was associated with a mean left ventricular ejection fraction decline of 2.70% (95% CI, -4.65% to -0.81%; P = .006). Pretreatment with atorvastatin was associated with preservation of vascular function among patients with lymphoma undergoing anthracycline-based chemotherapy. ClinicalTrials.gov Identifier: NCT02943590.

Coronary artery disease (CAD) is a major cause of health problems and deaths worldwide. Endothelial function is an independent predictor of CAD. Chinese herbal medicine has been proven to effectively improve the clinical symptoms and prognosis of patients with CAD. The purpose of this study was to evaluate the efficacy and safety of Chaihu Guizhi granules in patients with stable angina pectoris (SAP), explore the possible mechanism through which Chaihu Guizhi formula (CHGZ) improves vascular endothelial function, and provide evidence-based medical support for the rational clinical use of CHGZ. In this randomized, double-blind, placebo-controlled study, 90 patients were randomly assigned to the control group or the CHGZ group. The patients in the CHGZ group received conventional Western medicine and CHGZ granules for 4 weeks, while the patients in the placebo group received conventional Western medicine and placebo. The efficacy for angina pectoris, nitroglycerin discontinuation rate, traditional Chinese medicine (TCM) syndrome score, seattle angina questionnaire (SAQ) score, cardiac markers, vascular endothelial function and safety indicators were evaluated before and after the intervention. At the end of this study, compared with those in the control group, the curative effect on angina pectoris; the total nitroglycerin discontinuation rate; the total TCM syndrome score; and the scores of several dimensions of the SAQ, B-type natriuretic peptide precursor (NT-proBNP), asymmetric dimethylarginine, endothelial nitric oxide synthase, nitric oxide (NO) and endothelin 1 in CHGZ group were significantly greater (P < .05 or P < .01). CHGZ may be a beneficial adjuvant treatment for SAP patients. CHGZ can effectively improve clinical symptoms, quality of life, and vascular endothelial function and is safe. The detailed mechanism through which CHGZ affects vascular endothelial function should be further studied in the future.

Proteins linked to heritable coronary heart disease (CHD) could uncover new pathophysiological mechanisms of atherosclerosis. We report on the protein profile associated with a family history of early-onset CHD and whether the relation between proteins and coronary atherosclerotic burden differs according to family history status, as well as inferences from Mendelian randomization. Data on coronary atherosclerotic burden from computed tomography angiography and Olink proteomics were retrieved for 4521 subjects, free of known CHD, from the SCAPIS (Swedish Cardiopulmonary Bioimage Study). Records of myocardial infarction and coronary revascularization therapies in any parent or sibling of subjects were retrieved from national registers. Linear associations between family history and proteins were adjusted for age, sex, and study site. Statistical interactions between proteins and family history for the association between proteins and the coronary atherosclerotic burden were also studied. Mendelian randomization for causal associations between proteins and CHD was performed with GWAS summary data from UKB-PPP (UK Biobank Pharma Proteomics Project), CARDIoGRAMplusC4D, and FinnGen. Of 4251 subjects, family history of early-onset CHD was present in 9.5%. Thirty-eight proteins, with biological features of inflammation, lipid metabolism, and vascular function, were associated with family history using a false discovery rate of 0.05. The strongest associations were observed for follistatin and cathepsin D, neither of which was attenuated by adjusting for cardiovascular risk factors. Eighteen proteins were statistical interactors with family history in the association between each protein and the coronary atherosclerotic burden, most notably the LDL (low-density lipoprotein) receptor, transferrin receptor protein 1, and PECAM1 (platelet endothelial cell adhesion molecule 1). In 2-sample Mendelian randomization, a novel association was found for follistatin and myocardial infarction, and previous associations for PCSK9 (proprotein convertase subtilisin/kexin type 9) and PECAM1 were repeated. These findings highlight new potential mechanisms for heritable and general atherosclerosis.

In people with obstructive sleep apnea (OSA), adverse cardiovascular events, such as myocardial infarction, occur more commonly in the middle of the night than at other times of the day. These events could occur as a result of the nighttime physiological changes in OSA, but the endogenous circadian system has been implicated in increased cardiovascular risk in OSA. Vascular endothelial function is a marker of prospective cardiovascular risk and is impaired in OSA. We hypothesized that the nighttime risk in OSA could be due to a circadian system-driven nighttime impairment in vascular endothelial function. Twelve adults (healthy except for untreated moderate to severe OSA, 8 men and 4 women, 51± SD 7 years; apnea/hypopnea index, 29±19 hours of sleep) completed a 5-day circadian protocol consisting of 10 recurring 5-hour 20-minute periods (2 hours 40 minutes each of wake periods and sleep opportunities) to separate the circadian system's effects from those of behaviors such as exercise, meal intake, and sleep. We measured flow-mediated dilation of the brachial artery during each wake period in each participant. We discovered a significant circadian rhythm in flow-mediated dilation (P=0.019), and flow-mediated dilation normalized to shear rate (P=0.037) with a trough at the circadian phase corresponding to ≈3:00 am with a peak-to-trough change of 2.5 percentage points, or 82%. There was no significant circadian rhythm in the baseline diameter (P=0.39). These data suggest that the circadian system impairs vascular endothelial function during the biological night, potentially increasing vascular vulnerability in people with untreated OSA. URL: https://clinicaltrials.gov/; Unique Identifier: NCT02202811.

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves' disease (GD). Despite its clinical significance, the pathogenic mechanisms and reliable diagnostic biomarkers for TED remain incompletely defined. Tear fluid offers a noninvasive window into disease-related molecular changes. Tear samples were collected using Schirmer strips from 20 patients with TED, 20 patients with GD without ocular involvement, and 14 healthy controls (HCs). Proteomic profiling was performed using a novel pressure cycling technology-pulse data-independent acquisition mass spectrometry (PCT-PulseDIA-MS) workflow. A total of 5966 tear proteins were quantified. Differentially expressed proteins (DEPs) were identified through pairwise group comparisons. Patients with TED showed the most extensive tear proteomic alterations among the studied groups. One hundred seventy-four DEPs were associated with ophthalmopathy, 14 with autoimmunity, and 13 with hyperthyroidism. The ophthalmopathy-related DEPs were enriched in immune regulation, lipid metabolism, vascular function, and extracellular matrix remodeling. Several key DEPs showed significant correlations with clinical, laboratory, and imaging variables. A three-protein panel comprising calcium-activated nucleotidase 1 (CANT1), insulin-like growth factor-binding protein 7 (IGFBP7), and caspase 14 (CASP14) achieved excellent diagnostic performance in distinguishing TED from GD, with an area under the curve (AUC) of 0.971. Tear proteomics reveals distinct molecular signatures shaped by the combined influences of ophthalmopathy, autoimmunity, and hyperthyroidism throughout the pathogenesis of TED, underscoring the potential of tear proteins as early, noninvasive biomarkers for disease diagnosis.

NOTCH3, a key regulator of vascular smooth muscle cell function within the Notch signaling pathway, is essential for maintaining small artery integrity, especially in cerebral microvasculature. Pathogenic heterozygous missense variants in NOTCH3 cause CADASIL, an autosomal dominant small-vessel disease marked by extracellular domain aggregation, granular osmiophilic material deposition, and vascular smooth muscle cell dysfunction, leading to early-onset ischemic strokes, migraine with aura, and progressive cognitive decline. We report a 12-year-old Moroccan girl, born to first-degree consanguineous parents, presenting with global developmental delay, spastic tetraparesis, epilepsy, and bilateral periventricular white matter abnormalities. Whole-exome sequencing identified a novel homozygous frameshift variant in NOTCH3 (NM_000435.3:c.2985_2991del; NP_000426.2:p.(Gln996ArgfsTer274)), confirmed by Sanger sequencing, with heterozygous carrier parents. Emerging evidence shows that biallelic loss-of-function variants, unlike the gain-of-function variants underlying CADASIL, define a distinct autosomal recessive leukodystrophy characterized by early-onset pyramidal signs, epilepsy, and white matter abnormalities, thereby expanding the phenotypic and molecular spectrum of NOTCH3-related disorders. This work highlights the functional divergence between dominant and recessive NOTCH3 variants and supports the inclusion of NOTCH3 in gene panels for early-onset leukodystrophies, especially in consanguineous populations.

Background: Vitamin D deficiency has been increasingly implicated in the pathogenesis of hypertension through its regulatory effects on the renin–angiotensin system and vascular endothelial function. Objectives: This study aimed to evaluate the impact of high-dose vitamin D supplementation on blood pressure control in hypertensive individuals with concurrent vitamin D deficiency. Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted at Holy Family Medical College and Hospital, Dhaka, from January 2022 to January 2023. A total of 48 adult hypertensive patients with vitamin D deficiency (serum 25(OH)D &lt;30 ng/ml) were enrolled and randomly assigned to either the Vitamin D Group (VDG, n=24) or Placebo Group (PG, n=24). The VDG received 50,000 IU of oral cholecalciferol weekly for 8 weeks, while the PG received a matching placebo. Baseline and post-intervention measurements included systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP), along with serum 25(OH)D, parathormone, calcium, and electrolytes. Results: After 8 weeks, VDG showed significant reductions in SBP (−7.2 mmHg), DBP (−3.6 mmHg), and MAP (−4.8 mmHg) compared to negligible changes in the PG. Serum 25(OH)D levels increased substantially in VDG (+33.5 ng/ml vs. +2.0 ng/ml in PG), with normalization observed in 95.8% of VDG participants. Parathormone levels decreased significantly in VDG (−21.4 pg/ml), accompanied by a modest rise in serum calcium. No adverse effects were reported, and compliance was high in both groups. Conclusion: High-dose weekly vitamin D supplementation effectively improved vitamin D status and contributed to significant reductions in blood pressure among deficient hypertensive patients. These findings support the use of vitamin D as a safe and beneficial adjunct therapy for hypertension management in vitamin D-deficient populations. J Shaheed Suhrawardy Med Coll 2024; 16(1): 52-57

Vascular ageing (VA), characterised by vascular endothelial dysfunction, is a major contributor to age-related chronic conditions. Leucine-rich repeat-containing protein 8A (LRRC8A) is vital in maintaining vascular endothelial function; however, the role of endothelial LRRC8A in VA is undefined. We aimed to investigate the role and mechanism of endothelial LRRC8A in VA. We found that LRRC8A expression was clearly downregulated in the aged murine aortas. Further integrated analysis of single-cell and bulk RNA-seq and experimental verification revealed that endothelial LRRC8A governed VA by counteracting cell cycle, cellular senescence and oxidative stress. Additionally, endothelial LRRC8A deletion exacerbated the D-galactose (D-gal)-induced VA progression. Mechanistically, endothelial LRRC8A phosphorylated AMPK at T172 and subsequently facilitated SIRT1 nuclear translocation, ultimately counteracting the p53-dependent senescence pathway and activating the FOXO3-dependent antioxidant pathway. Therapeutically, pharmacological agonists of AMPK and SIRT1 effectively rescued endothelial cell senescence and VA in the context of endothelial LRRC8A deficiency. Additionally, endothelial-targeted adeno-associated virus (AAV)-LRRC8A gene therapy can effectively delay the progression of VA in naturally ageing mice. Our findings provide the first evidence supporting endothelial LRRC8A as a novel modulator of the AMPK-SIRT1 axis and suggest that targeting LRRC8A represents a promising therapeutic strategy for VA and age-related chronic conditions.

Background: Hypertension remains a leading global risk factor for cardiovascular disease. Complementary non-pharmacological therapies that reduce blood pressure (BP) and improve vascular function are of growing interest. Hydrotherapy including warm or hot-water immersion, aquatic exercise, foot soaks, balneotherapy and local cold applications (e.g., ice massage) is widely used in clinical and traditional settings but its role in hypertension management is not yet standardized. Objective: To summarize the changes in systolic and diastolic blood pressure through available clinical evidences in hypertensive patients using hydrotherapy modalities such as warm-water immersion, cold water therapies, ice massage, steam and sauna bath. Methods: A literature search was conducted using terms like "hydrotherapy," "hypertension," and "blood pressure", "complimentary" in PubMed, Scopus, Google Scholar, and ScienceDirect to find publications published between 1985 and 2025. Excluded were research involving animals or unrelated topics, and included were peer-reviewed English-language human studies that examined how hydrotherapy affected circulatory or autonomic processes. Key findings were summarized by screening and narratively analyzing pertinent papers. Only publicly available data were used, thus ethical approval was not necessary. Conclusions: Hydrotherapy shows promise as an adjunctive strategy for managing hypertension by enhancing vascular function and autonomic balance through endothelial and thermoregulatory mechanisms. Further research is needed to standardize protocols and confirm long-term efficacy.

Background/Objectives: Endothelial dysfunction plays a central role in the development of cardiovascular diseases. β-Casomorphin-7 (BCM-7), a biologically active peptide generated during the digestion of A1 β-casein, is presumed to contribute to this process; however, its direct effects on endothelial cells have not been previously investigated. Here, we aimed to assess whether BCM-7 treatment induces endothelial cell dysfunction through inflammatory cytokines and reactive oxygen species (ROS). Methods: In our study, we analyzed the effects of BCM-7 (5 µg/mL) in combination with lipopolysaccharide (LPS, 100 ng/mL) on human umbilical vein endothelial cells (HUVECs/TERT2). The cell viability, apoptosis, necrosis, and intracellular reactive oxygen species were measured. Furthermore, proinflammatory cytokines and enzymes involved in the regulation of inflammation were assessed with quantitative real-time PCR. The gene and protein expression of enzymes that regulate inflammation and vascular function, thus maintaining endothelial homeostasis were assessed. Results: BCM-7 enhanced intracellular ROS production p ≤ 0.001, increased the expression of interleukin-6 (IL-6) and interleukin-8 (IL-8) p ≤ 0.001, and was more effective when used in combination with LPS p ≤ 0.001. It decreased the expression of cyclooxygenase-1 (COX-1) p ≤ 0.05, during 4 h of exposure, whereas it increased the expression of cyclooxygenase-2 (COX-2) p ≤ 0.001, lipoxygenase-5 (LOX-5) p ≤ 0.01, and nitric oxide synthase 3 (NOS3) p ≤ 0.001; prostaglandin D2 synthase (PTGDS) (p ≤ 0.05), expression was also increased after short treatment. Conclusions: Our results suggest that BCM-7 may contribute to the development of endothelial dysfunction, especially in the presence of LPS, by enhancing oxidative stress and inflammatory response.

Background: Coronary microvascular dysfunction is a common finding in HFpEF and contributes to diastolic dysfunction, fibrosis, and exercise intolerance. Semaglutide, a GLP-1 receptor agonist (GLP-1RA) approved for obesity and diabetes, has demonstrated promising effects in cardiometabolic HFpEF clinical trials. Accumulating evidence suggests that GLP-1RAs exert direct cardiovascular benefits via activation of heart and vascular GLP-1 receptors. Hypothesis: Weight loss-independent benefits of semaglutide in HFpEF may involve the improvement of coronary vascular remodeling and function. Methods: Female Göttingen minipigs developed HFpEF through 8 weeks of DOCA treatment and a high-fat, Western diet containing 2% sodium. Subsequently, pigs (n=5 per group) were randomized to control or low-dose semaglutide (8 nmol/kg, IM, once weekly) for 12 weeks. We performed echocardiography, invasive systemic and LV hemodynamics, coronary histopathology and vascular function testing, fibrosis, and exercise testing. Results: Low-dose semaglutide failed to induce weight loss but improved LV diastolic function, and decreased LVEDP by 62% along with a similar reduction in PCWP. Control pigs exhibited substantial pericardial and epicardial adipose tissue accumulation, particularly surrounding the coronary arteries in conjunction with perivascular fibrosis. Semaglutide treatment significantly reduced pericardial and epicardial adipose tissue and attenuated perivascular fibrosis (p &lt; 0.01). Furthermore, control pigs exhibited profound coronary artery medial thickening and increased media-to-lumen ratio, indicative of pathological coronary artery remodeling which were both significantly reduced by GLP-1 RA therapy. Semaglutide reversed coronary artery calcium deposition and fibrosis compared to control pigs. Consistent with the histological findings, ex vivo studies demonstrated that semaglutide enhanced coronary artery endothelium-dependent relaxation by 72% as compared to control vessels (p &lt; 0.05). Summary and Conclusion: Low-dose GLP-1 RA therapy reverses coronary artery pathological remodeling in severe cardiometabolic HFpEF. These improvements in coronary vascular function likely result in improved myocardial function, exercise tolerance, and quality of life in HFpEF. Additional studies are required to confirm the direct vascular effects of GLP-1 RA therapy in HFpEF patients. Our data suggest a broader role of GLP-1R agonist therapy in the treatment of cardiovascular diseases.

Introduction: Emerging evidence shows increased cardiovascular disease (CVD) risk in Black women of childbearing age (18-49 years), a critical window for CVD prevention. Racial discrimination has been linked by various physiological pathways to CVD risks. Using ecological momentary assessment (EMA), this study aimed to examine daily experiences of microaggressions and discrimination among Black women and their potential impact on vascular function. Research Questions: (1) How often do Black women experience microaggressions and discrimination in their daily lives? (2) Are daily experiences of discrimination and microaggressions associated with vascular function? Methods: Black women of childbearing age without hypertension (N=27) underwent a lab-based peripheral vascular function assessment using flow-mediated dilation (FMD) of the brachial artery. They also answered 4 daily EMA surveys at random intervals over a 10-day monitoring period on their smartphones. Surveys included questions from validated measures assessing the experience of microaggression and discrimination. Logistic regression was used to explore associations between FMD and experiences of microaggression and discrimination, accounting for age and perceived stress. Results: On average, study participants reported 14 incidents of microaggression (SD=18.7, range=0-73) and 4 discriminatory events (SD=5.0, range=0-21) over the 10-day monitoring period. More than half (54%) reported more than 5 microaggression incidents, and 64% reported at least 1 discriminatory event. Half (50%) were at a higher risk for CVD (FMD&lt;6%; M= 6.3, SD=2.7, range=1.7-12.9). Higher risk for CVD was associated with experiencing fewer microaggression incidents (≤5 vs. &gt;5 incidents; B=-1.84, p=.048) and marginally associated with experiencing no discriminatory events (0 vs. at least 1 event; B=-2.74, p=.058). Conclusions: On average, Black women of childbearing age report experiencing microaggressions daily and discriminatory events about every two days. EMA can be a feasible tool to assess these daily experiences among Black women, and these daily experiences can vary across individuals. While more frequent experiences of microaggressions and discrimination were not associated with higher CVD risks in this preliminary sample, future studies can further investigate the potential protective (e.g., coping skills, social support) and risk factors (e.g., stress, unhealthy behaviors) related to daily experiences and CVD risks.

Background: Menopause is associated with adverse changes in vascular function that significantly increase vessel stiffness and cardiovascular disease (CVD) risk. Given the rising CVD risk in both younger and older adult females, it is important to identify predictors of vascular health, including body composition and physical activity levels, in both pre- and postmenopausal women. Research Questions: What are the optimal body composition and physical activity predictors of vascular health in Asian women, and do these predictors differ by menopausal status? Methods: A total of 236 Asian women (125 premenopausal, 111 postmenopausal) were evaluated for vascular health using carotid-femoral pulse wave velocity, central augmentation index, and mean arterial pressure assessed by SphygmoCor XCEL. Body composition measures included body fat percentage, skeletal muscle mass, and visceral adipose tissue, while anthropometric measures included body mass index and waist circumference. Physical activity was self-reported using the International Physical Activity Questionnaire. Multiple linear regression analyses were used to identify optimal predictors within and across menopausal groups. Results: For both pre- and postmenopausal samples, multiple linear regression showed that visceral adipose tissue positively predicted carotid-femoral pulse wave velocity (p&lt;0.001). Skeletal muscle mass positively predicted central augmentation index (p=0.029), while body fat percentage (p=0.020) was inversely related to central augmentation index (p=0.020). There were no predictors of mean arterial pressure. In premenopausal women, visceral adipose tissue positively predicted carotid-femoral pulse wave velocity (p=0.013). Furthermore, waist circumference positively predicted central augmentation index (p=0.010), while skeletal muscle mass was inversely related to central augmentation index (p=0.033). In postmenopausal women, visceral adipose tissue was a significant predictor of both carotid-femoral pulse wave velocity (p=0.001) and mean arterial pressure (p=0.022). Physical activity was not predictive in any model. Conclusions: Visceral adipose tissue is considered the strongest predictor of vascular health in both pre- and postmenopausal Asian women. In premenopausal women only, higher waist circumference and lower skeletal muscle mass contributed to vessel stiffness and poor vascular health, highlighting the importance of early identification and preventive strategies before menopause.

Introduction/Background: Gestational diabetes mellitus (GDM) is the most common metabolic complication during pregnancy. It increases the risk for endothelial dysfunction, hypertension and cardiovascular diseases in the mother and the child in later life. Endothelin-1 (ET-1) is a potent vasoconstrictor that promotes endothelial dysfunction and contributes to cardiovascular diseases. Research Question/Hypothesis: We hypothesise that ET-1 is a key mediator of fetal endothelial dysfunction in GDM. Methods/Approach: We obtained maternal and fetal vessels from human placentas of patients with insulin-treated GDM (iGDM) (n=10), diet-treated GDM (dGDM) (n=8) and normoglycemic controls (n=30). Groups were defined by oral glucose tolerance test and clinical data of mothers and newborns. Vascular function of fetal arteries was analyzed in a Mulvany Myograph. Fetal placental arteries from patients of all groups were incubated with the selective endothelin receptor A antagonist BQ123 and the selective endothelin receptor B antagonist BQ788. The impact of ET-1 on vascular function was studied in a concentration-dependent manner. Gene expression was quantified by real-time PCR in fetal vessels of the cotyledon base and maternal spiral arteries. ET-1 peptide levels in the venous fetal placental serum were quantified with a human ET-1 ELISA. Results/Data: ET-1-mediated vasoconstriction was shown in fetal placental arteries from the chorionic base in all study groups. At higher concentrations, ET-1-mediated vasoconstriction was significantly lower in patients with iGDM compared to normoglycemic controls. No differences in mRNA expression of pre-pro ET-1 gene (EDN1), endothelin-converting enzyme 1 (ECE1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) were found between study groups. Notably, mRNA expression of EDNRB was higher compared to EDNRA expression in fetal placental vessels of all groups. Significantly increased levels of ET-1 were detected in venous fetal placental serum in dGDM patients compared to control. The ET-1-mediated vasoconstriction was blocked by BQ123 and BQ788 in GDM patients and controls. The relative contribution of EDNRB to ET-1-mediated vasoconstriction is significantly higher in GDM patients, compared to normoglycemic controls. Conclusions: In conclusion, we could demonstrate that GDM impairs ET-1-mediated vasoconstriction in fetal placental vessels. This may contribute to the endothelial dysfunction in patients with GDM.

The global rise in obesity parallels the increasing rates of hypertension and cardiovascular disease (CVD). These trends, and recent clinical and experimental data, have revealed that obesity abolishes the protection from CVD typically conferred by female sex, predisposing young, premenopausal women to vascular dysfunction and hypertension. Findings from our group demonstrated that, in females, obesity induces hypertension via activation of the leptin-aldosterone-mineralocorticoid receptor (MR) axis. However, the origin of this sex-specific mechanism remains unknown. Based on the known effects of estrogen on blood pressure (BP) and vascular function, we tested the contribution of sex hormones. Sham and ovariectomy surgeries (OVX) were conducted in obese female agouti yellow mice to preserve or deplete female sex hormones, respectively. OVX did not significantly alter blood pressure (BP) nor autonomic control of BP or adrenal aldosterone synthase (CYP11B2) expression; however, it impaired endothelial relaxation with no further alterations to vascular function. Chronic leptin receptor blockade decreased BP in both sham and OVX mice and restored endothelium-dependent relaxation, suggesting a lack of contribution of female sex hormones to the mechanism of hypertension. Stimulation of HAC15 and human primary adrenocortical cells with female and male sex steroid hormones did not alter CYP11B2 expression. Furthermore, quantification of CYP11B2 expression in discarded human adrenal glands revealed increases with obesity in women in comparison to men and no alterations with menopause in obese hypertensive women. Collectively, these findings support that female sex hormones do not regulate aldosterone production nor do they drive the sex-specific mechanism underlying obesity-associated hypertension.

Introduction: The American Heart Association’s (AHA) Life’s Simple 7 (LS7) score defines cardiovascular health (CVH) and promotes healthy lifestyle behaviors through seven key components (Circulation, PMID: 20089546). Intrinsic frequencies (IFs) derived from carotid pressure waveforms are shown to be associated with cardiovascular performance in the Framingham Heart Study (Hypertension, PMID: 33390053). Here, we study whether IFs derived from carotid pressure waveforms relate to the AHA CVH score in a large community cohort. Methods: The study population was drawn from the Original, Offspring, and Third Generation Cohorts of the Framingham Heart Study where all the required metrics were available (N=5460; mean age 48 years). Per AHA LS7, we calculated CVH scores using fasting glucose, cholesterol, blood pressure, BMI, smoking status, and physical activity (excluding diet). Carotid pressure waveforms were acquired using an arterial tonometry device. From each non-calibrated waveform, we computed IF parameters: ω 1c , IF of the coupled heart and vascular system during systole corrected by systolic period; ω 2c , IF of the decoupled vasculature during diastole corrected by cardiac period; and △ω c , the difference between the two, which is a metric for left ventricle (LV)-arterial coupling. The association between AHA CVH score, and carotid-derived IFs was evaluated using box-and-whisker plots. Box plots were used to visualize the distribution of IFs across CVH score groups, with red lines connecting the group medians to highlight trends. Statistical significance across groups was assessed using either ANOVA or Kruskal–Wallis tests. Results: All three IF parameters showed clear, systematic trends across the CVH score groups. Specifically, ω 1c declined, ω 2c increased, and △ω c exhibited a steep decreasing trend with increasing the AHA CVH score (Figs. 1–3), reflecting improved LV-arterial coupling and vascular function with better cardiovascular health. Both one-way ANOVA and Kruskal–Wallis tests confirmed statistically significant differences (p &lt; 0.0001) across the CVH score groups for all three IF parameters. Conclusion: Our results revealed that IFs of carotid pressure waveforms are associated with AHA CVH scores. The observed trends between IFs and CVH score were consistent with previous clinical and preclinical studies where higher ω 1 and △ω but lower ω 2 were associated with higher risk for incident composite cardiovascular disease events and incident heart failure.

Background: Adipose tissue-derived extracellular vesicles (adiposomes) are key mediators of intercellular communication and play a critical role in metabolic disease progression, including diabetes. These vesicles carry bioactive molecules such as microRNAs (miRNAs) that regulate inflammation, vascular function, and metabolism. Our previous work showed that adiposomes from obese diabetic individuals impair endothelial function, promote vascular remodeling, and reduce microvascular flow-induced dilation, contributing to cardiovascular disease (CVD). However, the adiposomal cargo underlying these effects remains unknown. This study examines adiposomal miRNA profiles as potential contributors to the elevated CVD risk in obese diabetic patients. Methods: Adipose tissue samples were collected from obese individuals and classified into non-diabetic (n=17), pre-diabetic (n=10), and diabetic (n=14) groups based on fasting glucose and hemoglobin A1C. Adiposomes were isolated and characterized using nanoparticle tracking analysis and electron microscopy. miRNAs were extracted, sequenced, and analyzed bioinformatically. Correlations were assessed between miRNA expression and cardiometabolic measures, including (1) body fat and lean mass (DEXA), (2) glucose and lipid profiles, (3) brachial artery flow-mediated dilation, (4) flow-induced dilation in isolated arterioles, (5) echocardiographic cardiac function, and (6) inflammatory and endothelial biomarkers (IL-6, CRP, nitric oxide). Results: Diabetic and pre-diabetic groups exhibited distinct adiposomal miRNA profiles compared to non-diabetic controls. Top differentially expressed miRNAs included miR-361, miR-21, miR-130a, miR-181a, miR-10a, miR-126, miR-30e, miR-92b, miR-125a, and miR-221. Many of these miRNAs are implicated in hypertension, atherosclerosis, and cardiac hypertrophy. miR-221, miR-361, and miR-21 were upregulated 3–4 fold in diabetic subjects and significantly correlated with HbA1C and HOMA-IR. Regression analyses revealed associations between these miRNAs and BMI, fat percentage, impaired vascular dilation, and elevated LDL. Conclusion: Dysregulated adiposomal miRNA cargo may contribute to cardiometabolic dysfunction in obesity-associated diabetes. These findings highlight adiposomal miRNAs as potential mechanistic links and biomarkers for diabetes-related cardiovascular risk. Ongoing studies are investigating the downstream pathways regulated by these miRNAs.

Introduction: Psychosocial stressors in early pregnancy are associated with a higher risk of adverse pregnancy outcomes (APOs), including hypertensive disorders of pregnancy (HDP), gestational diabetes, and preterm birth. However, the biological pathways underlying these associations are not well delineated. This study aims to investigate proteomic markers that may underlie the association between early pregnancy psychosocial stress and APOs. Methods: Data were from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, a prospective study conducted from 2010-13. Participants were selected using a case-control design (508 HDP cases and 1081 controls). An aptamer-based assay was used to quantify 6,894 proteins in blood serum collected at the first-trimester study visit. Psychosocial stress during the month preceding the same visit was defined as a score greater than 13 on the 10-item Perceived Stress Scale. We used linear regression, adjusted for age and gestational age, to estimate the associations between stress and proteomic analytes. We then used logistic regression models to estimate the associations of these analytes with APOs. To identify potential biological pathways, we constructed a knowledge graph integrating Human Phenotype Ontology terms and STRING protein-protein interactions. Results: Among 1,589 pregnant participants, the mean (SD) age was 27 (6) years and 42% reported psychosocial stress. Heparan sulfate 6-O-sulfotransferase 3 (HS6ST3) was significantly associated with both stress and APOs after FDR correction. Higher psychosocial stress was associated with lower expression of HS6ST3 (-0.27 [95% CI -0.32, -0.22]). Also, a lower expression in HS6ST3 was associated with higher risk of HDP (aOR 0.72 [0.61, 0.85]), gestational diabetes (aOR 0.59 [0.48, 0.71]), and preterm birth (aOR 0.75 [0.61, 0.92]). Proteomic values were expressed in SD units of log2-transformed SomaScan measurements. A knowledge graph was created, which identified close connections between anxiety (phenotype term closest to stress), APOs, and HS6ST3 with shared biological pathways, including GPC* gene clusters, SHH, LYN, and PTCH1 ( Figure ). Conclusions: Early pregnancy psychosocial stress was significantly associated with lower HS6ST3 expression and increased risk of APOs. Genes known to interact with HS6ST3, which are involved in neuroimmune signaling, placental development, and vascular function, may represent plausible pathways linking psychosocial stress to APOs.

Background: Hypertension is a leading risk factor for cardiovascular disease and is highly prevalent in Asian populations. However, most genome-wide association studies (GWASs) and transcriptome-wide association studies (TWASs) have primarily focused on individuals of European ancestry, limiting generalizability to other ethnic groups. Hypothesis: We hypothesized that integrating GWAS, TWAS, and expression quantitative trait locus (eQTL) analyses in a large Taiwanese cohort would uncover novel hypertension-associated genetic loci and gene expression profiles relevant to Asian populations. Methods: We performed the first combined GWAS, TWAS, and eQTL analysis of hypertension using data from the Taiwan Biobank, including 10,739 hypertensive patients and 49,668 normotensive controls, with 4,512,191 genome-wide single nucleotide polymorphisms (SNPs). GWAS identified susceptibility loci, TWAS assessed gene-level associations, and eQTL analysis linked significant variants to gene expression changes in whole blood. Results: We identified 14 genetic loci significantly associated with hypertension, including one novel locus at 5p13.1. eQTL analysis revealed that this locus was significantly associated with DAB2 expression in whole blood. TWAS identified 55 hypertension-associated genes, 20 (36%) of which overlapped with GWAS loci. Notably, several genes outside of GWAS-identified loci—such as FBXL15 , KCNIP2 , and CRIP3 —were highly significant in TWAS and are implicated in vascular function and blood pressure regulation. Conclusions: This integrative genomic and transcriptomic study highlights novel genetic contributors to hypertension in an East Asian population. The findings improve our understanding of hypertension biology and may inform future precision medicine approaches for risk prediction and therapeutic development in diverse populations.