Patients with coexisting type 2 diabetes mellitus (T2DM) and hypertension (HTN) face a synergistically elevated risk of major adverse cardiovascular events (MACE). Evidence for prediction models developed specifically in established T2DM-HTN comorbidity population remains limited. To methodologically explore and preliminarily evaluate an interpretable machine learning framework for 1-year MACE prediction in hospitalized patients with coexisting T2DM and HTN using routine clinical data. This retrospective study included 1,054 hospitalized patients with T2DM and HTN, of whom 249 (23.6%) experienced MACE during 1-year follow-up. The dataset was randomly divided into training (60%), validation (20%), and independent test (20%) cohorts using stratified sampling. LASSO regression was applied for feature selection from 69 clinical variables. Four algorithms, including logistic regression, random forest, support vector machine, and XGBoost, were developed and compared. Model performance was assessed using discrimination, calibration, and clinical utility metrics. SHapley Additive exPlanations (SHAP) were used to interpret the final model. LASSO identified six stable predictors: HbA1c, age, hypertension duration, cystatin C (CysC), T2DM duration, and carotid intima-media thickness (CIMT). Sex was additionally incorporated based on clinical relevance. Multivariable logistic regression showed that HbA1c, age, hypertension duration, T2DM duration, CysC, and CIMT were associated with 1-year MACE risk, whereas sex was not statistically significant. Logistic regression showed the best relative balance between discrimination, calibration, and simplicity on the validation set, although learning curves indicated limited incremental improvement with increasing training sample size. After isotonic regression recalibration, the final logistic regression model achieved an ROC-AUC of 0.828, a PR-AUC of 0.656, and a Brier score of 0.116 on the independent test set. Decision curve analysis indicated potential clinical net benefit. SHAP linked model predictions to glycemic burden, aging, cumulative disease exposure, renal-related risk, and subclinical atherosclerosis. An interpretable logistic regression model based on seven routine clinical variables showed relatively good internal performance for predicting 1-year composite MACE risk in hospitalized patients with coexisting T2DM and HTN. CysC provided additional prognostic information beyond its conventional role as a renal filtration marker, although this association should be interpreted as prognostic rather than causal. External validation is required before the model can be considered for clinical decision support.
In the UK, the majority (90%) of hypertension is managed in primary care. Yet, for the 10% who require secondary-care input, there is no specialist register for doctors who manage hypertension. There is a mismatch across the nations with regards to access to secondary care for management of complex hypertension cases. Heterogeneity exists in terms of local specialist services, referral pathways, and specialties overseeing care. We polled across primary care in the UK to assess accessibility to a local specialist hypertension clinic, the clinical reasons for referral and the specialty referred to. Cardiology was by far and away the leading specialty for referrals. Yet the vast majority of cardiology trainees in the UK are receiving minimal, if any, specialist training in hypertension. A cardiology registrar is likely to spend substantially more days on-call for general medicine than the amount of specialist clinics they can attend in hypertension. We are facing a major deficit in the specialist management of hypertension if the trainees of today are not ready to provide the required expertise and oversight for the complex cases of tomorrow.
This study systematically evaluates the association between trace metal exposure and hypertension risk, explores dose-response patterns, and investigates underlying molecular mechanisms. A systematic review was conducted according to PRISMA guidelines, including 39 high-quality observational studies retrieved from PubMed, Web of Science, Embase, and the Cochrane Library. Meta-analysis results showed a significant positive association between blood lead exposure and hypertension (OR = 1.16, 95% CI: 1.02-1.31) as well as gestational hypertension (OR = 1.56, 95% CI: 1.21-2.02). Conversely, blood manganese demonstrated a potential protective effect, showing a monotonically declining linear trend with hypertension risk and a significantly reduced risk of gestational hypertension (OR = 0.40, 95% CI: 0.25-0.65). Dose-response analysis based on restricted cubic splines revealed nonlinear patterns: blood cadmium exhibited a U-shaped dose-response relationship (P non-linear = 0.005) with risk rising markedly above 3.5 µg/L, and dietary zinc showed a J-shaped curve (P non-linear = 0.004) peaking around 22 mg/day. Urinary biomarkers (cadmium, lead, arsenic, zinc, vanadium, and cobalt) generally showed stronger associations with hypertension than blood biomarkers. However, for several metals - including vanadium, cobalt, chromium, and nickel - the available evidence was limited to one to three studies, and the corresponding risk estimates should therefore be interpreted with caution and require confirmation in future larger-scale studies. Bioinformatics analysis highlighted that trace metal exposure may promote hypertension through mechanisms such as oxidative stress, inflammatory responses (e.g., TNF signaling), and disruption of the AGE-RAGE pathway. The findings suggest that lead exhibits threshold-free linear toxicity, while manganese may have a protective effect. Pregnant women were identified as a particularly sensitive population to environmental metal exposure. This study provides epidemiological evidence and explores molecular mechanisms, supporting preventive strategies for environmentally induced hypertension. The image summary is shown in the Graphical Abstract.
Obstructive sleep apnea (OSA) is common in children and has been linked to cardiovascular dysregulation, including elevated blood pressure (BP). This study examined whether OSA severity is independently associated with morning hypertension in a pediatric clinical cohort, and whether associations vary by developmental stage and sex. We retrospectively analyzed 806 children aged 1 to 18 years (55.2% Male) who underwent overnight polysomnography (PSG) and had BP recorded before and after the PSG at the University of Louisville and Norton Pediatric Sleep Center. OSA was categorized based on the total apnea hypopnea index (AHI) and severity was categorized based on the obstructive apnea hypopnea index (OAHI) the cohort was stratified as: normal/snoring (OAHI < 1 event/hr, n = 318), mild OSA (OAHI 1-4.9 events/hr, n = 205), moderate OSA (OAHI 5-9.9 events/hr, n = 103), and severe OSA (OAHI ≥ 10 events/hr, n = 180). Evening and morning blood pressures were recorded and classified per American Academy of Pediatrics guidelines. ANOVA/ANCOVA, linear regression, and multivariable logistic regression examined associations between the total AHI and blood pressure, with adjustment for age, sex, body mass index (BMI) z-score, and comorbidities. Morning systolic blood pressure (SBP) rose from 108 ± 13 mmHg in non-OSA children to 118 ± 15 mmHg in severe OSA. Severe OSA more than doubled the odds of morning hypertension across all adjusted models (OR 2.35; 95% CI 1.57-3.52, p < 0.001). Each 1-unit increase in AHI was associated with a 0.137 mmHg rise in morning SBP after adjustment (p < 0.001). Moderate OSA's association was attenuated after BMI adjustment, while BMI z-score itself was an independent predictor of BP grade (OR 1.52; 95% CI 1.27-1.82; p < 0.001). Participants were categorized by developmental age. Subgroup analyses found the strongest association between AHI and systolic blood pressure in preschool children, while the link with diastolic blood pressure appeared only in older groups. Sex-stratified analyses showed similar AHI-blood pressure associations in both males and females, with no significant interaction. Severe OSA independently increased the risk of morning hypertension in children, regardless of obesity status, sex, or developmental stage. Routine BP monitoring is warranted across the full OSA severity spectrum.
This study aimed to evaluate whether the magnesium depletion score (MDS), an indicator of magnesium deficiency, is associated with the development of complex regional pain syndrome type 1 (CRPS-1) in patients with traumatic extremity injuries. Between November 2024 and May 2025, a total of 117 patients who suffered from traumatic extremity injuries were included. Demographic and clinical data of the patients were collected and recorded, and the MDS was calculated. Age, sex, body mass index (BMI), smoking status, alcohol consumption, diabetes, hypertension, duration of immobilization, MDS, and injury-related characteristics were evaluated as potential risk factors for CRPS-1 development. Of the patients, 40 were male and 77 were female with a mean age of 51.9 ± 15.01 (range, 20 to 91 years). In a total of 42.7% of patients with traumatic extremity injuries, CRPS-1 developed. The female-to-male ratio was higher among patients with CRPS-1 than among those without. The MDS, hypertension, diabetes, smoking, and alcohol consumption were not found to be independent risk factors. However, prolonged immobilization (more than one month) was found to be an independent risk factor for the development of CRPS-1. Our study results suggest that the MDS score is not a risk factor for developing CRPS-1, but immobilization for more than one month significantly increases the risk. Taken together, these findings indicate that the duration of immobilization following injury may be a more decisive factor in the development of CRPS-1 than demographic and clinical characteristics.
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In view of the substantially increased risk of adverse outcomes, this study aims to determine the concurrent prevalence of hypertension and diabetes, quantify the synergy factor, and assess its age trend in a segment of the Indian population. Electronic health records of more than 56000 persons undergoing health check-up in a group of hospitals were analysed for age-trend and sex differences for hypertension in cases with diabetes and diabetes in cases with hypertension, in addition to the concurrent prevalence. The synergy factor between the two diseases was determined as the occurrence in excess of their joint occurrence by chance. The overall concurrent prevalence was around 5% - nearly twice of that expected by chance if they were independent diseases - thus measuring their synergy. This synergy started to rise rapidly at age around 40 years in either sex, continued to rise until around to 58 years, and then slowed down to plateau at nearly 17% at around 70 years. Hypertension in cases with diabetes was about 4 times as common as in those without diabetes, and diabetes in hypertensive cases was about 2½ times as common as in those without hypertension. The findings quantify the inter-dependence of hypertension and diabetes in a segment of the Indian population and underscore the need for integrated screening strategies, especially around the age of 40 years, to mitigate the dual burden.
While portal hypertension (PH) typically resolves after liver transplantation (LT), persistence of PH may affect post-transplant outcomes. We assessed the evolution of PH after LT and its impact on adverse outcomes. We recorded clinical, laboratory, and imaging parameters of LT recipients between 2016 and 2022 in Vienna and Zagreb. Persistent features of CSPH were defined as the presence of portosystemic collaterals, platelet count (PLT) ≤ 110 G/L, and/or splenomegaly (≥ 13 cm). PH-related clinical events were defined as variceal bleeding, ascites requiring intervention, hepatic hydrothorax, portal vein thrombosis, or liver-related death within 12 months post-LT. Post-LT outcomes were analyzed using landmark Cox regression for 3 months post-LT. Of 645 LT recipients (76% male, median age 59 years) listed with a median MELD of 15 points and PLT of 99 G/L, features of CSPH were present in 537 (83.3%) at baseline. At year 1 after LT, MELD improved to 9 (IQR 7-12), PLT increased to 160 G/L (IQR 120-207), and features of CSPH persisted in 251/453 classifiable patients (55.4%). PH events occurred in 75 (11.6%) and 84 (13%) deaths. In a landmark analysis from 3 months post-LT (n = 521, 29 deaths), persistent thrombocytopenia (< 110 G/L) at M3 independently predicted mortality (aHR 2.31, 95% CI 1.01-5.30, p = 0.048) after adjustment for MELD, age, CRP, and pre-LT TIPS. While PH improves after LT, features of CSPH persisted in 55% of classifiable patients and PH-related clinical events occurred in 11.6% within the first year after LT. Persistent thrombocytopenia (< 110 G/L) at 3 months post-LT independently predicted post-LT mortality (aHR 2.31, 95% CI 1.01-5.30, p = 0.048).
Elevated nighttime blood pressure (BP), nocturnal non-dipping, and exaggerated morning BP surge (MBPS) are established risk factors for cardiovascular events. These diurnal BP variability patterns can be assessed by ambulatory BP monitoring (ABPM) but not by conventional home BP monitors. We aimed to examine whether home BP data are associated with these BP variability patterns. Treated hypertensive participants in the HI-JAMP study underwent 24-hour ABPM followed by home BP monitoring (HBPM). Home BP was measured twice each morning and evening for 5 days using a multisensor device that also recorded room temperature. A total of 2,248 participants with complete ABPM and HBPM data were analyzed. Among 2,248 participants, ABPM-defined nocturnal hypertension was present in 679 (30.2%), exaggerated MBPS in 171 (7.7%), and nocturnal non-dipping in 969 (43.1%). Of these, 39 participants (1.8%) had both nocturnal hypertension and exaggerated MBPS. Nocturnal hypertension, exaggerated MBPS, and non-dipping were each associated with elevated morning home systolic BP (SBP) of ≥ 135 mmHg measured by HBPM (odds ratios: 3.76, 2.00, and 1.33, respectively). Nocturnal hypertension (odds ratio: 1.84) and non-dipping (odds ratio: 1.69) were associated with higher room temperature, whereas exaggerated MBPS (odds ratio: 1.86) was associated with lower room temperature, independent of elevated morning home SBP. Individuals with high morning home BP were more likely to show abnormal diurnal BP variability. Incorporating room temperature into home BP assessments may provide additional context when interpreting home BP measurements. University Hospital Medical Information Network Clinical Trials Registry, UMIN000029151 (HI-JAMP study).
Balloon pulmonary angioplasty (BPA) improves haemodynamics and outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is frequently initiated before BPA to reduce procedural risks. However, evidence supporting continuation after successful BPA is lacking and current guidelines provide no criteria for treatment discontinuation. Consequently, many patients remain on long-term riociguat despite uncertain benefit, potential adverse effects and high costs. STOP-RIO is a multicentre, open-label, randomised, non-inferiority (NI) trial conducted in the two Dutch CTEPH expert centres. Seventy-four adult CTEPH patients treated with riociguat monotherapy with a mean pulmonary artery pressure (mPAP) <30 mmHg post-BPA will be randomised (1:1) to stop or continue the medication. The primary endpoint is the between-group difference in baseline-adjusted mPAP at rest measured by right heart catheterisation at 16 weeks. NI will be tested for the primary endpoint and for the two secondary endpoints highest in hierarchy N-terminal pro-B-type natriuretic peptide and 6-min walk distance. Additional secondary endpoints include haemodynamic parameters, safety outcomes, patient-reported outcomes and healthcare use. The primary analysis will be performed in a per-protocol population with secondary intention-to-treat and exploratory analyses. A prospective health economic evaluation will be conducted from a societal perspective. The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and has received ethical approval. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publication and shared with patient organisations and scientific congress. EU Clinical Trials Register: 2024-5 19 225-38-00.
Hypertension is a leading risk factor for cardiovascular disease, promoting atherosclerosis through interrelated mechanisms of mechanical stress and vascular inflammation. The adventitia and perivascular adipose tissue have emerged as critical sites of immune cell accumulation and cytokine production in hypertension. This review examines the cellular and molecular mechanisms linking adventitial inflammation to vascular stiffening and end-organ damage. Hypertension induces accumulation of effector memory T cells in the adventitia and perivascular fat, driven by chemokines including RANTES/CCL5. Immune cell derived cytokines including IL-17A and IFN-γ promote endothelial dysfunction, vascular superoxide production, and adventitial collagen deposition via p38 MAP kinase activation. Chronic vascular oxidative stress generates isolevuglandin (IsoLG)-protein adducts that act as neoantigens, activating dendritic cells and T cells to drive aortic stiffening that precedes frank hypertension. Stiffened arteries impair Windkessel function and activate microvascular endothelial signaling to adjacent immune cells, further promoting an injurious response in the kidney, brain and vessels. Adventitial and perivascular inflammation are thus not merely consequences of elevated blood pressure but active drivers of vascular disease and end-organ damage through feed-forward immune mechanisms. Targeting these pathways represents a promising therapeutic strategy in hypertension-associated vascular disease.
Pulmonary hypertension (PH) in preterm infants is a complex and heterogeneous condition that significantly contributes to hypoxic respiratory failure (HRF), bronchopulmonary dysplasia (BPD), and mortality. Unlike term infants, PH in preterm neonates arises from multiple overlapping pathophysiological mechanisms and distinct hemodynamic phenotypes. These diverse phenotypes complicate diagnosis and limit the effectiveness of uniform treatment approaches. Despite increasing recognition of this heterogeneity, current literature and clinical guidelines provide limited clarity on the optimal diagnosis and management of HRF with PH in preterm infants. In particular, the role of inhaled nitric oxide (iNO) remains highly controversial in this population. Although advances in targeted neonatal echocardiography and functional hemodynamic assessment have enhanced our ability to characterize cardiovascular physiology at the bedside, the integration of these tools into standardized management strategies remains inconsistent. As a result, clinical decision-making in preterm infants with PH is often variable and not clearly guided by evidence-based frameworks. This narrative review provides a comprehensive, physiology-based overview of the diagnosis and management strategies for acute PH and HRF in preterm infants, with a focus on the controversies surrounding iNO use and the role of inotropic and vasoactive agents in optimizing hemodynamics. While iNO may improve oxygenation in selected cases, randomized trials have not demonstrated reductions in mortality or BPD in preterm infants, and concerns persist regarding an increased risk of severe intraventricular hemorrhage. Accordingly, management should be guided by the underlying physiological phenotype, integrating clinical assessment, serial functional echocardiographic evaluations, and targeted therapeutic strategies to optimize outcomes in this vulnerable population.
Endothelial dysfunction is an early and pivotal event in the development of cardiovascular disease and a key mechanism linked to atherosclerotic plaque formation. Endocan and endoglin are emerging cardiometabolic markers and novel endothelial mediators that promote vascular smooth muscle cell proliferation and migration, contributing to intima-media thickening. We aimed to assess endocan and soluble endoglin levels in young adults in the United Arab Emirates (UAE) and the associations among hyperglycemia, dyslipidemia, and endothelial dysfunction. In this cross-sectional case-control study at UAE University, 182 young adults aged 18-22 years were classified as normal body weight (BW) (n = 61) or excess BW (n = 121) based on their body mass index. Anthropometry, systolic and diastolic blood pressures (SBP and DBP), inflammatory markers, the lipid profile, HbA1c, and plasma endocan and endoglin were measured. Multivariable linear regression analysis was performed to determine the associations between endoglin and log-transformed endocan and BW status and cardiometabolic variables, adjusting for age, sex, and family history of type 2 diabetes mellitus and hypertension. Of the 182 participants, 88 (48%) were women, 121 (67%) had excess BW, and the mean (standard deviation) age was 19.96 years (1.79). Compared with the normal body weight group, the excess body weight group had significantly higher SBP, DBP, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α, interleukin-6, apolipoprotein B (Apo-B), and log-transformed endocan (all p ≤ 0.041), along with significantly lower high-density lipoprotein-cholesterol (p = 0.021) and apolipoprotein A (Apo-A) (p = 0.041) levels. In the adjusted models, endoglin was positively associated with excess BW, DBP, TC, and LDL-C, whereas log-transformed endocan was positively associated with excess BW, SBP, DBP, TC, LDL-C, Apo-B, and hs-CRP. Among these young adults, elevated endocan and endoglin levels correlated with excess body weight and adverse metabolic profiles. Prospective studies are needed to determine whether these biomarkers predict future cardiometabolic or vascular outcomes.
Heart failure (HF) and cancer are leading causes of global morbidity and mortality that share a significant bidirectional relationship. Epidemiologic studies reveal that cancer patients and survivors face a substantially elevated risk of HF, largely driven by cardiotoxic systemic therapies including chemotherapy, targeted therapy, immunotherapy and radiation therapy. Conversely, individuals with HF have a markedly increased incidence of cancer. This interconnection is underpinned by age and shared modifiable risk factors, including smoking, hypertension, diabetes and obesity, as well as common pathophysiological mechanisms such as chronic inflammation, neurohormonal activation, oxidative stress and dysregulated angiogenesis. Clonal haematopoiesis of indeterminate potential has emerged as a novel biological link, promoting both maladaptive cardiac remodelling and tumourigenesis. Clinically, the coexistence of HF and cancer creates complex management challenges, as each condition worsens the prognosis of the other and limits therapeutic options. In addition to providing a broad overview of the topic, this review incorporates three aspects that are underexplored in existing cardio-oncology literature-management of advanced metastatic cancer in patients with HF, use of advanced HF therapies in patients with cancer and disparities in cardio-oncology care and clinical trial representation. Effective management of patients with HF and cancer requires a multidisciplinary cardio-oncology approach that incorporates rigorous risk stratification, early detection using serial cardiac biomarkers and imaging and personalised management tailored to cancer treatment. Irrespective, cancer patients with HF have a poor prognosis. It is necessary to balance oncological efficacy with cardiovascular safety while providing a clear definition of the goals of care. Early integration of palliative and rehabilitative care can significantly improve patient quality of life and outcomes. Nevertheless, effective novel treatment strategies have significantly improved the overall survivorship for patients with cancer and/or HF.
Atrial fibrillation (AF) is the most prevalent sustained arrhythmia and is associated with significant morbidity and mortality. Data on AF in hospitalized patients in the Middle East are limited. We analyzed 536 hospitalized patients with nonvalvular AF from the Jordan atrial fibrillation (JoFib) registry. A prospective multicenter study of 2020 patients enrolled between May 2019 and December 2020. Patients were stratified into new-onset atrial fibrillation (NOAF) and previously diagnosed AF, and their clinical characteristics and in-hospital outcomes were compared. The cohort had a mean age of 70.2 ± 14.1 years, and 48.7% were male. The most common comorbidities were hypertension (77.6%), diabetes (52.1%), and heart failure (31.3%). NOAF patients were significantly younger and more likely to be smokers, whereas those with prior AF had more comorbidities and larger left atrial size. Overall, in-hospital mortality was 6.7% but was significantly higher in NOAF patients. Hospitalized patients with NOAF are younger, more often smokers, and face higher in-hospital mortality compared with chronic AF, underscoring the need for early recognition and risk factor modification to prevent hospitalization. ClinicalTrials.gov Identifier: NCT03917992.
To consolidate evidence on the clinical profile of segmental arterial mediolysis (SAM), and to identify independent predictors of unfavourable outcomes and mortality. PubMed/MEDLINE was systematically searched for SAM reports with patient-level data. Data analysis used chi-square/Fisher's exact, Mann-Whitney, Kruskal-Wallis tests, and multivariable logistic regression, with sensitivity analyses across three subgroups. 230 confirmed cases of SAM were included (mean age 54.5 years; 65% male). Hypertension was the most common comorbidity (21.7%). Most patients (84%) presented acutely, typically with abdominal pain (49%) or hemorrhage (19.6%). Multifocal involvement frequently involved the superior mesenteric (40%), hepatic (40%), and celiac arteries (36.5%). Imaging was dominated by aneurysms (69-100%) and dissections (0-65%). Elevated ESR/CRP was associated with organ ischemia (OR 3.36, 95% CI 1.65-6.86, p=0.002). Management was guided by clinical stability and lesion morphology, with medical therapy and transarterial embolization being the most common. Overall, 81.3% achieved favorable outcomes; 18.7% had progression or death. Overall mortality was 9.1%. Neurological territory involvement (OR 7.25, 95% CI 2.61-20.14, p<0.001) and organ ischemia on imaging (OR 2.56, 95% CI 1.07-6.10, p=0.034) were independent predictors of unfavorable outcome. Neurological involvement (OR 5.73, 95% CI 1.71-19.15, p=0.005) and female sex (OR 3.88, 95% CI 1.38-10.88, p=0.010) were independent predictors of mortality. Findings were robust on sensitivity analyses. SAM typically presents with multifocal mesenteric/hepatic aneurysms or dissections and favorable outcomes with conservative or endovascular management. Neurological involvement and organ ischemia predict worse outcomes, supporting risk-stratified management and surveillance.
Multiple endocrine neoplasia type 1 (MEN1) is a complex endocrine tumour syndrome. Broader understanding of its diverse clinical manifestations has transformed its surveillance and management. The protracted nature of MEN1 significantly impacts quality of life, requiring careful observation, symptom control and tailored treatment decisions with coordinated, multidisciplinary team (MDT) care. This case report follows the clinical journey of a patient with MEN1 and illustrates how management can be challenging when faced with overlapping chronic conditions. In this instance, the patient's course was further complicated by chronic thromboembolic pulmonary hypertension (CTEPH), posing additional diagnostic and therapeutic considerations. The case underscores the importance of vigilant follow-up of patients, not only due to high disease penetrance and risk of recurrence, but to avoid diagnostic overshadowing of other significant co-morbidities. With a focus on long-term outcomes and balancing invasive interventions, this case report truly demonstrates the strengths of the MDT approach in healthcare.
Gene-environment interplay contributes to the heterogeneous etiology of Alzheimer's disease (AD). Hypertension (HTN) is a major modifiable vascular risk factor, but whether its association with AD differs across APOE genotypes remains unclear. We examined the interaction between HTN and APOE genotypes in relation to incident AD and explored plasma proteomic correlates as potential biological clues. Longitudinal data from 318,923 UK Biobank participants without dementia were analyzed; participants had a mean age of 56.24 years, an APOE ε4 frequency of 28.29%, and a median follow-up period of 13 years. Cox proportional hazards models with competing-risk adjustment for death were used to assess additive and multiplicative interactions between HTN and APOE genotypes. Plasma proteomic data from 34,141 participants, covering 2790 proteins, were further analyzed using mediation and bioinformatics approaches. HTN showed a significant multiplicative interaction with APOE ε4 status for incident AD (p < .001). The association between HTN and AD risk was strongest among APOE ε2 carriers, followed by ε33 carriers and ε4 carriers, with hazard ratios of 1.570, 1.213, and 1.129, respectively. Among APOE ε2 carriers, prosaposin and ganglioside GM2 activator significantly mediated the HTN-AD association, with mediation proportions of 10.46% and 3.37%, respectively. These proteins were enriched in sphingolipid metabolism and lysosomal function. The association between HTN and incident AD varies across APOE genotype strata, with the strongest relative association observed among APOE ε2 carriers. These findings suggest genotype-dependent heterogeneity in vascular contributions to AD risk. Proteomic results should be interpreted as exploratory biological clues and require further validation. The association between hypertension and incident Alzheimer’s disease differed across APOE genotype strata, with the strongest relative association observed among APOE ε2 carriers. Multiplicative, but not additive, interaction supports cautious interpretation of clinical implications and does not establish absolute risk scale synergy. Exploratory plasma proteomic analyses identified PSAP-, GM2A-, and BRK1-related signals involving sphingolipid, lysosomal, and WAVE-complex biology.
Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous syndrome characterized by impaired ventricular relaxation, systemic inflammation, and multisystem cardiovascular dysfunction. Despite growing recognition of HFpEF as a major global health burden, effective targeted therapies remain limited due to an incomplete understanding of its phenotypic diversity. Increasing evidence suggests that left atrial (LA) myopathy represents a central mechanistic and phenotypic axis in HFpEF rather than merely a secondary consequence of elevated left ventricular filling pressures. LA myopathy encompasses structural remodeling, fibrosis, impaired compliance, and electrical dysfunction that collectively disrupt reservoir, conduit, and booster pump function. These abnormalities contribute to elevated filling pressures, pulmonary venous congestion, pulmonary vascular remodeling, and impaired exercise hemodynamics. Emerging data demonstrate strong associations between impaired LA strain, reduced compliance, pulmonary hypertension, atrial fibrillation, and adverse clinical outcomes in HFpEF. Importantly, LA dysfunction may identify a distinct HFpEF phenotype characterized by disproportionate pulmonary vascular disease and severe exercise intolerance. Advances in multimodality imaging, including speckle-tracking echocardiography and cardiac magnetic resonance imaging, have improved the ability to characterize atrial structure and function and may enable earlier recognition of atrial disease. Therapeutic strategies targeting neurohormonal activation, fibrosis, pulmonary vascular coupling, rhythm control, and interatrial pressure modulation are increasingly being explored as potential approaches to modify this phenotype. This narrative review examines the mechanistic basis of LA myopathy in HFpEF, its relationship with pulmonary hypertension and exercise intolerance, contemporary diagnostic approaches, prognostic significance, and emerging therapeutic implications. Reframing LA myopathy as a central phenotypic axis may facilitate phenotype-directed management and improve therapeutic precision in HFpEF.
Gestational hypertension (GH) remains a major cause of maternal and fetal morbidity. miR-498 has been implicated in vascular dysfunction, yet its role and mechanism in GH remain unclear. Clinical serum samples from 106 GH patients and 82 healthy pregnant controls were collected to detect circulating miR-498 expression and analyze its correlation with clinical parameters. The dual-luciferase reporter assay was applied to confirm the direct binding between miR-498 and PTEN. All in vitro functional experiments, including CCK-8 proliferation assay, Transwell migration and invasion assays, were conducted exclusively in HUVECs. Hsa-miR-498-5p (miR-498) was significantly downregulated in serum of GH patients and presented favorable diagnostic performance. Circulating miR-498 levels were negatively correlated with systolic blood pressure and neonatal birth weight, while positively correlated with gestational age. Mechanistically, miR-498 directly targeted PTEN. miR-498 overexpression enhanced the proliferative, migratory and invasive capacities of HUVECs, and ectopic PTEN overexpression could reverse these cellular phenotypes. Downregulated miR-498 aggravates endothelial dysfunction and facilitates GH progression via inhibiting PTEN/AKT signaling. This study identifies circulating miR-498 as a promising non-invasive diagnostic biomarker and reveals a vascular-specific regulatory axis for GH.