Search Results (1,240)

Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure in which the ejection fraction remains within the normal range (≥50%); however, patients still experience typical symptoms of heart failure. One of the most common manifestations in this population is exercise intolerance, which in some cases may be the only presenting symptom. Exercise intolerance refers to a reduced capacity to perform physical activity. Several processes, including impaired cGMP–PKG signaling, increased collagen deposition, endothelial dysfunction, increased arterial stiffness, pulmonary hypertension, and vascular remodeling, contribute to the pathophysiology of HFpEF. The disruption of these fundamental physiological processes significantly impairs exercise capacity, leading to attenuated increases in heart rate, stroke volume, and/or contractility, along with abnormal ventricular–vascular coupling during exertion. When EI is suspected, a spectrum of diagnostic modalities—from simple, low-cost tools such as the 6 min walk test to advanced imaging—can be used to evaluate its presence and its association with HFpEF. When EI in HFpEF is diagnosed, management should focus on addressing this limitation to improve quality of life and reduce morbidity and mortality. Exercise training and pharmacological therapies, such as SGLT2 inhibitors, may be beneficial in this population. In conclusion, EI is a common manifestation of HFpEF that significantly impacts patients’ quality of life. Understanding its underlying mechanisms and addressing it appropriately are essential to improving patient outcomes. Full article

Background: Pericardial effusion is a common finding on pre-procedural computed tomography (CT) in patients undergoing transcatheter aortic valve implantation (TAVI). However, its clinical significance remains uncertain. Using artificial intelligence (AI)-based image analysis, we sought to determine whether pericardial effusion represents an incidental imaging finding, a marker of hemodynamic burden, or a prognostically relevant phenotype. Methods: This retrospective single-center study included 470 consecutive patients undergoing TAVI for severe aortic stenosis. Pericardial effusion volume was quantified using an AI-based CT segmentation workflow and categorized as no effusion (0 mL), trace effusion (>0–<5 mL), small effusion (5–<30 mL), or larger effusion (≥30 mL). Associations with baseline clinical and echocardiographic characteristics were assessed. Long-term mortality was evaluated using Kaplan–Meier analysis, Cox regression models, and restricted cubic spline analyses. Results: Detectable pericardial effusion was present in 276 patients (58.7%), although larger effusions were uncommon (5.1%). Increasing pericardial effusion volume was associated with a higher prevalence of atrial fibrillation (p = 0.001), higher systolic pulmonary artery pressure (p = 0.004), and lower TAPSE/sPAP ratios (p = 0.007). In contrast, left ventricular ejection fraction and transvalvular gradients did not differ across effusion categories. During long-term follow-up, no significant differences in mortality were observed between pericardial effusion groups (log-rank p = 0.46). Pericardial effusion volume was not associated with mortality when analyzed as a continuous variable (HR 1.00, 95% CI 0.996–1.01; p = 0.842), after logarithmic transformation (adjusted HR 0.91, 95% CI 0.76–1.08; p = 0.293), or in restricted cubic spline analyses. Conclusions: AI-derived pericardial effusion volume identifies a hemodynamic phenotype characterized by atrial fibrillation, pulmonary hypertension, and impaired right ventricular–pulmonary arterial coupling. Despite these associations, pericardial effusion volume does not independently predict long-term mortality after TAVI, suggesting that it reflects cardiovascular congestion and remodeling rather than a prognostically relevant phenotype. Full article

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by progressively increased pulmonary vascular resistance and right heart failure. Its pathogenesis involves multiple factors, including genetic predisposition, inflammation, oxidative stress, and imbalances between cell proliferation and apoptosis. Recent studies indicate that autophagy has a context-dependent dual role in PAH. Flux-competent autophagy may be protective by clearing damaged mitochondria, limiting excessive inflammation, and maintaining metabolic homeostasis, whereas excessive autophagy initiation or impaired autophagosome-lysosome degradation may promote metabolic dysfunction, inflammatory signaling, abnormal vascular cell phenotypes, and pulmonary vascular remodeling. This focused narrative review summarizes the molecular mechanisms and key signaling pathways linking autophagy to PAH, with emphasis on PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) energy-sensing axis. It also evaluates potential therapeutic strategies targeting key nodes of autophagy, such as AMPK activators and mTOR inhibitors, along with their clinical research progress. Finally, this review provides an outlook on future research directions, emphasizing the need to further elucidate the dynamic regulatory mechanisms and cell-type specificity of autophagy in order to advance the clinical translation of autophagy-targeted precision therapies for PAH. Full article

Background: Hypertension and diabetes commonly coexist in patients with chronic obstructive pulmonary disease (COPD), but their associations with arterial blood gas parameters remain insufficiently characterized, particularly after accounting for measured differences in baseline characteristics. This study aimed to examine the associations between coexisting hypertension and diabetes and selected arterial blood gas parameters in older patients with COPD. Propensity score matching (PSM) was used to improve the comparability of the study groups and reduce confounding from measured baseline covariates. Patients and Methods: A retrospective cross-sectional study was conducted involving 1030 patients. The comorbidity group comprised COPD patients with both hypertension and diabetes (n = 340), while the COPD-only group refers to COPD patients without hypertension or diabetes (n = 690). Propensity score matching (PSM) was estimated using a regression model with covariates including age, sex, marital status, BMI, temperature, and pulse. Balance was assessed using standardized mean difference (SMD), and linear regression models were adopted to evaluate the association between coexisting hypertension and diabetes and each blood gas indicator (PCO₂, PO₂, SaO₂). Results: We performed 1:1 nearest-neighbor matching and successfully generated 340 matched pairs, forming a total matched cohort of 680 patients; all unmatched participants from the original 1030 subjects were excluded from subsequent outcome comparisons. Covariate balance was optimized for most baseline indicators after PSM, although mild residual imbalance remained in age and BMI after matching. The comorbidity group demonstrated a statistically significant reduction in PCO₂ (B: −2.54, 95% CI: −4.52 to −0.56) compared to the COPD-only group, while no significant differences were observed in PO₂ (B: −2.48, 95% CI: −7.6 to 2.64) or SaO₂ (B: −1.16, 95% CI: −2.67 to 0.35). In addition, a sensitivity analysis adjusting for age and BMI was conducted to evaluate the robustness of the findings. Conclusions: After propensity score matching, coexisting hypertension and diabetes were associated with lower PCO₂ levels in elderly COPD patients, while no significant associations were found for PO₂ or SaO₂. Full article

Mucuna pruriens (Linn.) DC. var. pruriens is used as a traditional medication to enhance male sexual function, yet integrated evidence linking vascular-cell mechanisms to in vivo efficacy and safety of a standardized extract remains limited. This study evaluated the ethanolic seed extract of M. pruriens var. pruriens (MPSE) on erectile function-related mechanisms, addressing the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP)–phosphodiesterase type 5 (PDE5) pathway in vitro, together with mounting frequency, anxiety-like behavior, locomotor activity, and cardiovascular safety in vivo. Soxhlet extraction with 80% ethanol yielded a dark brown, syrupy extract (12.28% w/w), which was standardized by high-performance thin-layer chromatography to contain 278 mg/g extract (27.8% w/w) of L-DOPA (Rf 0.38). Mechanistic effects were assessed in human umbilical vein endothelial cells (HUVECs), pulmonary artery smooth muscle cells (PASMCs), and a PDE5A1 enzyme assay. Male Wistar rats received MPSE (50, 100, and 200 mg/kg) orally for 15 days, with hemodynamic assessment in normotensive and Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. MPSE significantly increased eNOS expression and NO production in HUVECs, elevated intracellular cGMP in PASMCs, and directly inhibited PDE5A1 enzymatic activity. Repeated administration significantly increased mounting frequency relative to baseline without altering serum testosterone levels, anxiety-like behavior, locomotor activity, mean arterial pressure, or heart rate. These findings indicate that MPSE modulates erectile function-related mechanisms, primarily through peripheral vascular effects on the NO–cGMP–PDE5 pathway, and suggest a favorable safety profile. Erectile function itself was not directly assessed and warrants confirmation in models of erectile response. MPSE nevertheless represents a promising plant-derived candidate for erectile dysfunction. Full article

Defined natural products are often framed as intrinsically safer multi-target alternatives to selective drugs, but this assumption is not pharmacologically justified. This critical review evaluates product-specific adjunctive evidence in respiratory allergy, inflammatory bowel disease, type 2 diabetes, depression, and insomnia. MEDLINE/PubMed records published from 2020 to 23 June 2026 were prioritized, while earlier pivotal randomized trials and quantitative safety studies were retained. Evidence was gated by product identity, human exposure, exposure-compatible target engagement, incremental efficacy, and safety boundaries. Nigella sativa oil improved Asthma Control Test scores by 1.5 points over placebo after 4 weeks, although the clinical importance is uncertain and FEV1 was not significantly improved. Curcumin plus mesalamine induced remission in mild-to-moderate ulcerative colitis (53.8% versus 0%), whereas indigo naturalis produced strong response rates but is constrained by pulmonary arterial hypertension. Berberine improves glycemic surrogates but lacks cardiovascular or renal outcome evidence and shows commercial potency variability. Saffron has a short-term antidepressant signal, while St John’s wort combines extract-dependent efficacy with CYP3A4/P-glycoprotein induction. Overall, selected defined natural products may merit narrow adjunctive roles, but undefined mixtures should not be treated as mechanistically established interventions without batch-level characterization, human pharmacokinetics, objective endpoints, and prospective interaction surveillance. Full article

Background: Non-group 1 pulmonary hypertension, also known as secondary pulmonary hypertension (SPH), is predominantly observed among females. However, there is a significant lack of data concerning factors associated with hospitalization among patients diagnosed with SPH. This study aims to provide clinicians with vital insights for the identification of high-risk groups and for the more effective management of contributory risk factors within the female population affected by SPH. Methods: Using the 2019 National Inpatient Sample, we identified female admissions with SPH (n = 648,190), accounting for 3.8% of the total 17,236,228 female admissions. An Artificial Neural Network (ANN) analysis was conducted to evaluate predictive factors. We randomly allocated 3,319,543 patients into training and testing datasets at a ratio of 70:30, comprising 2,323,696 (70%) for training and 995,847 (30%) for testing, to calibrate and validate the performance of the ANN algorithm. Model performance was assessed by comparing misclassification rates between training and testing sets and by the area under the receiver operating characteristic curve (AUC); only internal validation was performed. Results: Females hospitalized with SPH were generally of older age, with a median of 75 years compared to 58 years, and more frequently identified as White (67.7% versus 65.5%) or Black (20.5% versus 15.5%) relative to those without SPH. They also demonstrated a higher prevalence of most atherosclerotic cardiovascular disease (ASCVD) risk factors or their equivalents, including complicated hypertension (50.6% versus 17.8%), diabetes with chronic complications (30.6% versus 13.7%), and hyperlipidemia (50.8% versus 29.2%), as well as other comorbidities such as COPD (43.4% versus 20.2%) and CKD (43.3% versus 14.0%), and exhibited increased all-cause mortality (4.5% versus 1.8%) (p < 0.001). Our ANN model achieved an AUC of 0.823, indicating good predictive capability. The rates of incorrect predictions were comparable in both the testing and training cohorts, at 3.8% each. The factors most strongly associated with a coded SPH diagnosis included age at admission, complicated hypertension, chronic kidney disease, chronic obstructive pulmonary disease, uncomplicated hypertension, prior VTE, race, arthropathies, and AIDS. Conclusions: Our ANN model identified demographic and comorbidity factors associated with a coded SPH diagnosis among hospitalized females, with good discrimination (AUC = 0.823). Because the model classifies the presence of an existing diagnosis rather than predicting future hospitalization, and was validated only internally, external and prospective validation is required before clinical application. Once validated, these factors could support individualized, sex-specific risk stratification for high-risk female populations, consistent with the goals of personalized medicine. Full article

Pulmonary Hypertension (PH) in patients with Interstitial Lung Disease (ILD) is a critical, yet underrecognized, complication that affects patients’ quality of life and increases mortality. Emerging evidence further suggests that PH-ILD is not merely a consequence of hypoxia and parenchymal fibrosis, as the severity of pulmonary vascular disease often correlates poorly with the extent of fibrotic lung involvement, indicating more complex underlying pathophysiological mechanisms. Diagnosis requires a high index of suspicion when symptoms appear “disproportionate” to the degree of parenchymal lung disease. Key indicators include diffusing capacity for carbon monoxide (DLCO) < 45%, a forced vital capacity to diffusing capacity for carbon monoxide ratio (FVC/DLCO) > 1.6, and radiological findings of increased pulmonary artery diameter. While echocardiography and circulating biomarkers serve as useful screening tools, right heart catheterization remains the gold standard for definitive diagnosis. Early identification is essential for risk stratification, lung transplant evaluation, and determining eligibility for targeted pharmacological interventions, as this group of patients remains one of the most therapeutically challenging forms of pulmonary vascular disease. Ongoing research and advances in diagnostic tools are increasingly focused on refining phenotypic classification, identifying valuable biomarkers, and elucidating molecular drivers that may enable personalized treatment strategies in this heterogeneous patient group. Full article

Background: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), termed COPD-associated pulmonary hypertension (COPD-PH), and is associated with worse clinical outcomes. The efficacy and safety of pulmonary vasodilators in COPD-PH remain uncertain. Methods: We performed a systematic review and meta-analysis of randomized studies evaluating pulmonary vasodilators in adults with COPD-PH. Fifteen studies were identified, with 11 contributing to quantitative analyses. Outcomes included six-minute walk distance (6MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), partial pressure of arterial oxygen (PaO₂), and systolic pulmonary arterial pressure (sPAP). Results: Pulmonary vasodilators significantly reduced mPAP (MD −3.88 mmHg, 95% CI −7.23 to −0.53) and PVR (SMD −0.90, 95% CI −1.70 to −0.10). However, no significant improvements were observed in 6MWD or PaO₂. An exploratory composite hemodynamic score supported an overall hemodynamic benefit. Subgroup analyses suggested a more favorable profile for nitric oxide donors, whereas endothelin receptor antagonists were associated with worsened oxygenation. Conclusions: Pulmonary vasodilators improve pulmonary hemodynamics in COPD-PH but do not consistently improve exercise capacity or oxygenation. Current evidence does not support routine use outside specialized centers or clinical trials, and treatment effects appear to vary by drug class. Full article

Exercise-induced pulmonary hypertension (EIPH) represents an abnormal pulmonary vascular response to increased blood flow during exercise, best characterized by a disproportionate rise in pulmonary arterial pressure relative to cardiac output. The shift from fixed pressure thresholds to flow-adjusted metrics, particularly the mPAP–cardiac output slope, reflects a more physiologically sound approach and is now incorporated in the 2022 guidelines of the European Society of Cardiology/European Respiratory Society as well as the World Symposium on PH. EIPH is a hemodynamic phenotype, not a standalone disease. Accumulating evidence demonstrates that EIPH has important diagnostic and prognostic implications. It is associated with reduced exercise capacity, increased risk of adverse cardiovascular outcomes, and reduced survival, even in patients with normal resting hemodynamics. Exercise hemodynamic abnormalities may also identify early or latent pulmonary vascular disease and early left heart dysfunction, particularly in at-risk populations such as systemic sclerosis, HFpEF, and genetic predisposition. In this review, we provide the current definition of EIPH as well as an overview of the prognostic implications and management of exercise-induced PH in cardiac and pulmonary diseases. Full article

Panvascular diseases, characterized by systemic vascular dysfunction across multiple organ systems, represent a complex interplay of genetic susceptibility and environmental triggers. Ring Finger Protein 213 (RNF213), initially identified as the principal susceptibility gene for moyamoya disease (MMD), has emerged as a central regulator of panvascular pathophysiology. This review synthesizes current evidence elucidating RNF213′s multifaceted roles in vascular homeostasis, spanning its functions as an E3 ubiquitin ligase, mechanosensor, and immune modulator. The “second-hit” hypothesis posits that RNF213 mutations establish a genetic predisposition, while secondary insults—such as infection, hypoxia, or hemodynamic stress—precipitate pathological manifestations. Mechanistically, RNF213 orchestrates critical processes including endothelial integrity, angiogenesis, and inflammatory responses through pathways such as HIF-1α/VEGF, NF-κB, and Wnt signaling. Its dysfunction disrupts vascular remodeling, promotes aberrant smooth muscle proliferation, and exacerbates hypoxia-inflammation cycles, contributing to diverse pathologies ranging from intracranial aneurysms and arterial dissections to pulmonary hypertension and coronary artery disease. Emerging insights into RNF213′s interactions with gut microbiota, lipid metabolism, and epigenetic regulators further underscore its systemic influence. Despite advancements, unresolved questions persist regarding the context-dependent duality of RNF213 variants and organ-specific regulatory mechanisms. This review highlights the imperative for integrated approaches combining genetic, molecular, and environmental perspectives to unravel RNF213′s panvascular roles. We also outline unresolved questions regarding context-dependent effects of RNF213 variants and organ-specific regulatory mechanisms, and discuss potential avenues for future research integrating genetic, molecular, and environmental perspectives to advance understanding of RNF213′s panvascular roles. Full article

First-generation H₂S donors fail in pulmonary arterial hypertension (PAH) not due to lack of efficacy, but because they release H₂S indiscriminately. This review articulates a conceptual framework for advancing H₂S donor therapy along three complementary directions. Donor 2.0 for precision delivery: Donors remain inert in normal tissues, but release H₂S upon sensing PAH microenvironment signals [reactive oxygen species (ROS), hypoxia, esterases, matrix metalloproteinases (MMPs)], combined with lesion-selective enrichment and organelle targeting. Donor–endogenous synergy: Move from chronic exogenous supplementation to restoring the patient’s own H₂S synthesis via epigenetic derepression of CSE, oxidative reactivation of CBS, and substrate support for 3-MST. Systemic sensitization: Redefine H₂S donors as combination enhancers that reverse acquired insensitivity to ERAs, PDE5i, and prostacyclin analogues through protein S-sulfhydration. These three mutually reinforcing dimensions transform H₂S donors from passive releasers into programmable, context-sensitive therapeutic platforms, addressing the fundamental limitations of current PAH therapies. Full article

Post-infarction left ventricular aneurysm is an uncommon but severe mechanical complication of transmural myocardial infarction, particularly in patients with delayed presentation or incomplete myocardial salvage. It may lead to profound distortion of left ventricular geometry, adverse remodelling, intraventricular thrombosis, mitral regurgitation, pulmonary hypertension, and advanced heart failure. We report the case of a 65-year-old male patient referred two months after a late-presenting anterior ST-segment elevation myocardial infarction caused by proximal occlusion of the left anterior descending coronary artery. At admission, the patient presented with severe decompensated heart failure, low-output status, multiorgan dysfunction, and a left ventricular ejection fraction of 12%. Transthoracic echocardiography and cardiac magnetic resonance imaging demonstrated a giant apical left ventricular aneurysm involving approximately 75% of the ventricular cavity, partial intraluminal thrombosis, extensive transmural scarring in the left anterior descending territory, and imaging features suggestive of a chronic contained free-wall rupture/pseudoaneurysmal component. Following multidisciplinary evaluation, the patient underwent surgical ventricular reconstruction using an endoventricular circular restoration technique guided by an intraventricular balloon sizer, combined with left internal thoracic artery bypass grafting to the left anterior descending artery. The early postoperative course required temporary inotropic, vasopressor, inhaled nitric oxide, and intra-aortic balloon pump support, followed by progressive haemodynamic recovery. The patient was discharged on postoperative day seven with functional improvement to NYHA class II. At six-month follow-up, he remained clinically stable without overt signs of heart failure, and echocardiography showed preserved ventricular geometry and improvement of left ventricular ejection fraction to 45%. This case highlights the potential role of carefully planned, balloon-guided surgical ventricular reconstruction in selected patients with giant post-infarction left ventricular aneurysms and end-stage heart failure when residual viable myocardium is present. Full article

Objective: This study investigated the modifying effect of time to admission (TTA) on the relationship between admission to operation time (ATO) and outcomes in elderly patients with hip fractures. Methods: This retrospective cohort study included elderly patients with hip fractures treated at the trauma center. We collected data on patient characteristics, comorbidities, TTA, ATO, and all-cause mortality. Statistical analyses were conducted using R and EmpowerStats software. Results: Two thousand three hundred and sixty patients were included, with a median follow-up duration of 39.00 (29.05–50.79) months. Patients were stratified into four groups by ATO: ATO ≤ 2 d; 2 < ATO ≤ 4 d; 4 < ATO ≤ 6 d; and ATO > 6 d. The median TTA for each ATO group was as follows: 24 (4–168), 8 (4–48), 10.5 (4–48), and 10 (4–48) h, respectively. During follow-up, 733 patients (31.07%) died. Interaction analyses further stratified patients by TTA: ≤24 h vs. >24 h. The results demonstrated that TTA exerted a significant modifying effect on the ATO–mortality association. In the TTA ≤ 24 h group, each 1 d ATO delay was associated with a 5% increased risk of mortality (HR = 1.05; 95% CI: 1.01–1.09, p = 0.0095). In contrast, ATO delay was not associated with higher mortality in the TTA > 24 h group (HR = 0.98; 95% CI: 0.93–1.02, p = 0.3050). Notably, the TTA–ATO–mortality interaction remained statistically significant across several high-risk subgroups: females, those with femoral neck fractures, age-adjusted Charlson comorbidity index ≤ 4, hypertension, coronary artery disease, arrhythmia, and absence of chronic obstructive pulmonary disease. Conclusions: TTA is an important effect modifier of the association between ATO and mortality among elderly patients with hip fractures. Full article

Pulmonary hypertension (PH) is a progressive disease that severely compromises right ventricular function, characterized by two major pathological features: pulmonary arterial constriction and pulmonary arterial remodeling. Bellidifolin (BEL), a natural ketone compound, exhibits potent anti-inflammatory and antioxidant effects; however, its role in PH remains unexplored. This study evaluated the impact of BEL on the two pathological processes: pulmonary arterial constriction and pulmonary arterial remodeling. First, the effects of BEL on pulmonary arterial constriction were evaluated using wire myography. The study revealed that BEL (6–96 μmol/L) inhibited the contraction response of intact endothelial and denuded pulmonary arterial rings precontracted with norepinephrine (1 μmol/L) in a concentration-dependent manner. BEL (90 μmol/L) suppressed pulmonary constriction induced by intracellular calcium release and extracellular calcium influx. In cellular experiments, BEL inhibited the proliferation, migration, and phenotypic transformation of pulmonary arterial smooth muscle cells (PASMCs) induced by 10 μmol/L CoCl₂ (72 h), as evidenced by upregulation of the contractile phenotype markers α-SMA and SM22α and downregulation of the synthetic phenotype markers OPN, vimentin, and PCNA. Multi-omics analysis identified Aldh1A1, Mgp, Col4a6, and Igfbp5 as significantly enriched candidates. Among these candidates, Cellular Thermal Shift Assay demonstrated that BEL enhanced the thermal stability of Igfbp5 in PASMCs, suggesting that Igfbp5 may be a potential direct target of BEL. Moreover, KEGG pathway analysis revealed significant enrichment of the PI3K-AKT-mTOR pathway, which is known to be involved in cell proliferation and is regulated by Igfbp5. BEL may inhibit the PI3K-AKT-mTOR pathway by suppressing Igfbp5. The results indicate that BEL may regulate Igfbp5 to inhibit the PI3K-AKT-mTOR pathway, thereby exerting anti-proliferative and inhibitory effects on migration and phenotypic transformation. Full article