Search Results (23,981)

Vascular calcification (VC) is a major complication of chronic kidney disease (CKD) that is strongly associated with cardiovascular mortality. While indoxyl sulfate (IS), a protein-bound uremic toxin, has been implicated in the progression of VC, the underlying molecular mechanisms remain unclear. We investigated the procalcific effects of IS using a two-step nephrectomy-induced CKD mouse model and cultured vascular smooth muscle cells. In vivo, progressive renal impairment was associated with elevated circulating IS levels and enhanced VC. In vitro, IS dose- and time-dependently induced calcium deposition, increased reactive oxygen species (ROS) production, and upregulated osteogenic markers, including runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), and osteocalcin (OCN), whereas N-acetyl-L-cysteine (NAC) partially attenuated IS-induced ROS accumulation and cell injury. Mechanistically, IS exposure activated extracellular signal-regulated kinase (ERK) and Wnt/β-catenin signaling while suppressing nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant responses, as reflected by reductions in the phosphorylated Nrf2 (pNrf2) to total Nrf2 and heme oxygenase-1 (HO-1) expression. Pharmacological inhibition of ERK and Wnt/β-catenin signaling attenuated IS-induced osteogenic responses. These findings indicate that IS promotes VC in association with increased oxidative stress, activation of ERK and Wnt/β-catenin signaling, and impaired Nrf2-related antioxidant defense. These integrated findings provide mechanistic insight into IS-associated VC and highlight oxidative stress-related signaling networks as potential therapeutic targets in CKD. Full article

The renin–angiotensin system (RAS) and vasopressin system (VAS) play an essential role in the regulation of multiple vital body functions. A survey of the literature provides evidence that the central and systemic RAS and VAS are activated during pregnancy and cooperate in the regulation of blood circulation and in the exchange of substrates and metabolites between the mother and fetus. The present review is focused on the engagement of the RAS and VAS in the regulation of blood circulation in healthy pregnant women and fetuses and in gestations complicated by cardiovascular, metabolic and psychogenic diseases. The presence of several components of the RAS and VAS, such as renin, angiotensin-converting enzymes (ACE1, ACE2), angiotensins [Ang II, Ang-(1–7)], angiotensin receptors (AT1R, AT2R), and AVP receptors (V1aR), in the placenta and the myometrium allows us to assume that the RAS and VAS play a prominent role in function of the maternal–placental–fetal unit. Gestation is also associated with the activation of components of the RAS and VAS in appropriate regions of the central nervous system that are involved in the regulation of blood pressure. Experimental studies suggest that the RAS and VAS participate in the autonomic control of blood circulation and in the regulation of emotional aspects of pregnancy and maternity. Abnormal functioning of the RAS and/or VAS was found in eclampsia, metabolic diseases (diabetes mellitus) and psychogenic disorders (anxiety, stress, and depression). Some of these abnormalities may have an immunological or genetic background. In eclampsia, the presence of specific agonistic angiotensin receptor autoantibodies (AT1-AA) and altered genotypes of AGT, ACE2, AT1R, and AT2R were reported. Polymorphism of the AVP promoter was also described. Inappropriate pharmacotherapy or toxic environmental pollution may disturb the regulation of the cardiovascular system of the mother and fetus by the RAS and VAS during gestation. Further studies are necessary to better recognize the mechanisms of action of the RAS and VAS in healthy and pathological pregnancies. Full article

Atrial cardiomyopathy (ACM) is defined as any complex of structural, architectural, functional, electrophysiological, and molecular changes affecting the atria that may result in clinically significant health consequences. ACM can be caused by a variety of factors, including age-related changes, valvular or vascular disease, genetic diseases, congestive heart failure, metabolic diseases, cardiovascular disease (CVD) risk factors such as arterial hypertension (AH) or obesity, obstructive sleep apnea, and other infectious or noninfectious diseases predisposing to chronic inflammation. The diagnosis of ACM relies on several modalities, including electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), computed tomography (CT), electroanatomical mapping (EAM), genetic studies, and biomarkers, which can detect and characterize structural, mechanical, and electrical atrial dysfunction. These changes often include structural atrial remodeling (fibrosis), abnormal structure of the atrial wall and its components, and contractile and electrical dysfunctions. When assessing aspects of ACM, structural changes in the atria such as left atrium (LA) size and fibrosis; LA architectural changes such as the expression of remodeling; changes in LA mechanics such as echocardiographic stress indices; changes in reservoir function and changes in contraction; biological factors determining changes in biomarkers; possible genetic predispositions and higher expression of certain genes encoding certain proteins; and arrhythmogenic factors associated with a higher risk of atrial fibrillation (AF) and stroke and a worse short- and long-term prognosis are very important. When considering the challenges of diagnosing ACM, it should be noted that without standardized diagnostics, most ACM diagnostic situations remain primarily research tools rather than practical clinical diagnostic methods. This review critically evaluates the evidence and translational gaps in the diagnosis of ACM, synthesizing the emerging role of advanced diagnostics and their clinical and prognostic implications as a key future tool for individual risk stratification. Full article

Background: Coronary artery calcium score (CACS) is a well-established marker of coronary atherosclerotic burden and cardiovascular risk. While its association with left ventricular dysfunction has been extensively investigated, the relationship between CACS and right ventricular (RV) function remains insufficiently explored. This study aimed to evaluate the association between CACS and echocardiographic RV function parameters and to explore the discriminatory ability of CACS for identifying patients meeting predefined echocardiographic thresholds of RV dysfunction in patients with suspected stable coronary artery disease (CAD). Methods: This retrospective observational study included 96 patients who underwent coronary computed tomography angiography and transthoracic echocardiography within a 3-month interval. CACS was calculated using the Agatston method. RV function was assessed using tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RV-FAC), and tissue Doppler-derived systolic velocity (S′). Correlation analyses, subgroup comparisons, multivariable linear regression, receiver operating characteristic (ROC) analyses, decision curve analysis (DCA), and calibration analyses were performed. Results: CACS demonstrated significant inverse correlations with TAPSE (r = −0.42, p < 0.001), RV-FAC (r = −0.36, p = 0.002), and S′ (r = −0.31, p = 0.006). Patients with higher CACS values exhibited progressively impaired RV systolic function. In multivariable regression analyses, higher CACS remained associated with lower TAPSE, RV-FAC, and S′ after adjustment for age, hypertension, and diabetes mellitus. Exploratory ROC analyses demonstrated moderate discriminatory performance, with AUC values ranging from 0.70 to 0.76. DCA suggested a potential net benefit across a range of threshold probabilities, while bootstrap calibration analysis demonstrated acceptable agreement between predicted and observed outcomes. Conclusions: In this retrospective single-center cohort, higher CACS values were associated with lower conventional echocardiographic measures of right ventricular systolic function. However, given the selected study population, relatively small sample size, limited clinical and instrumental characterization, potential residual confounding, and absence of external validation, these findings should be considered exploratory. The present data do not establish CACS as a clinical predictor of right ventricular dysfunction or support its use for clinical decision-making. Full article

Atherosclerosis remains the principal underlying cause of myocardial infarction, ischemic stroke and peripheral artery disease, and its progression reflects a complex interplay between lipid accumulation, endothelial dysfunction, chronic vascular inflammation and maladaptive remodeling of the arterial wall. The Notch signaling pathway, an evolutionarily conserved juxtacrine communication system, has emerged as a central regulator of every cell type implicated in atherogenesis, including endothelial cells, vascular smooth muscle cells, monocytes/macrophages and T lymphocytes. Depending on the receptor–ligand pairing, the hemodynamic context and the cellular compartment involved, Notch signaling can be either atheroprotective or atherogenic, a duality that has complicated efforts to translate mechanistic insight into therapy. This review summarizes current knowledge of the molecular architecture of the Notch pathway in the vasculature, dissects its cell type-specific and stage-specific contributions to atherosclerotic plaque initiation, progression, calcification and destabilization, and critically appraises pharmacological strategies designed to modulate Notch activity, including γ-secretase inhibitors, ligand- and receptor-directed monoclonal antibodies, soluble decoy receptors, microRNA-based approaches and drug repurposing strategies such as statins. Particular attention is paid to the cardiovascular toxicities that have emerged from oncology trials of Notch pathway inhibitors, which illustrate both the pharmacological tractability and the narrow therapeutic window of this pathway. We conclude that Notch-directed therapy for atherosclerosis is mechanistically well justified but will require cell type-selective and context-selective delivery strategies to be clinically viable. Full article

Background: Atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD), ischemic stroke (IS), and peripheral artery disease (PAD), represents a growing global health burden. Integrins have emerged as potential biomarkers and therapeutic targets. This study aimed to explore the role of integrins as biomarkers for ASCVD and to identify potential drug targets. Methods: A total of 33,210 UK Biobank participants were included. Cox proportional hazards models were used to assess associations between circulating integrin levels and ASCVD and its subtypes. Mendelian randomization and colocalization analyses were performed to investigate potential causal relationships and shared genetic variants underlying integrin levels and disease risk. Results: During a median follow-up of 14.04 years, 2468 participants developed ASCVD. In subtype-specific analyses, 1541 CHD events, 1050 IS events, and 590 PAD events were identified. In observational analyses, ITGA11, ITGA2, ITGAM, ITGAV, ITGB1 and ITGB2 were associated with lower ASCVD risk, whereas ITGA5 and ITGBL1 were associated with higher risk. For ASCVD mortality, ITGA11, ITGAM, ITGAV, and ITGB2 showed protective associations, while ITGAX and ITGB6 were linked to increased risk. Sex-stratified analyses revealed distinct patterns, including male-specific risk associations for ITGAX and ITGBL1 and a female-specific protective association for ITGB2. Mendelian randomization supported causal associations for five integrins, with ITGA11 showing consistency with observational findings. Colocalization analysis suggested shared causal variants between ITGAV and both CHD and IS. Conclusions: This study provides both observational and genetic evidence for the critical role of integrins in ASCVD, implicating their potential for assessing disease risk and serving as candidate therapeutic targets. Full article

Fracture healing depends on coordinated osteogenesis and restoration of the vascular microenvironment. Endothelial cells support skeletal repair through angiogenesis, tissue perfusion and angiocrine signaling that regulates osteoprogenitor recruitment and differentiation. This narrative review examines endothelial dysfunction (ED) as a potential systemic contributor to impaired fracture healing by integrating evidence from vascular biology, experimental models and clinical studies. ED is characterized by reduced nitric oxide (NO) bioavailability, oxidative stress, inflammation and impaired vascular repair. These changes may disrupt angiogenic–osteogenic coupling through altered hypoxia-inducible factor 1-alpha subunit (HIF-1α)/vascular endothelial growth factor (VEGF) signaling, endothelial Notch activity, platelet-derived growth factor (PDGF)-mediated vascular remodeling and endothelial progenitor cell (EPC) mobilization. Conditions associated with endothelial dysfunction, including diabetes, aging, chronic kidney disease (CKD), smoking, obesity and chronic inflammatory disease, are also linked to delayed union, nonunion and poorer orthopedic outcomes. Cardiovascular disease and perioperative cardiovascular instability may further impair perfusion and physiological reserve during repair. However, the available evidence is predominantly experimental or observational, and direct causal evidence in fracture patients remains limited. Prospective studies combining standardized endothelial assessments with fracture-healing outcomes are needed to clarify clinical relevance and identify potential therapeutic targets. Full article

Insulin resistance (IR) represents one of the most pressing problems in contemporary public health. Its estimated global prevalence ranges from approximately 15.5% to over 61%, depending on the population studied, the diagnostic criteria applied, and the method used for its assessment. Despite the scale of the problem, IR remains underrecognized and lacks formal definition as a distinct disease entity, even as a growing number of clinicians and researchers worldwide describe it as such. Its asymptomatic or mildly symptomatic course allows it to remain undetected for years, during which it makes a significant contribution to the development of type 2 diabetes, cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and has been increasingly linked to cellular senescence, certain cancers, neuropsychiatric disorders, and other metabolic conditions. The aim of this review was to summarize current knowledge on the pathophysiology, diagnosis, and clinical implications of insulin resistance, to discuss current challenges in its diagnosis, and to evaluate whether available scientific evidence supports its recognition as a distinct disease entity. This narrative review is based on clinical, epidemiological, and mechanistic data retrieved from PubMed and Google Scholar. Meta-analyses, systematic reviews, clinical and observational studies, clinical guidelines, and expert position statements were analyzed. Animal studies were excluded to maintain a focus on human public health implications. The diagnostic gold standard—the hyperinsulinemic-euglycemic clamp—was discussed, along with surrogate methods used in clinical practice (HOMA-IR, OGTT with insulin measurements, the TyG index, and the TG/HDL-C ratio). Factors potentially contributing to the pathogenesis of IR were examined, including hyperinsulinemia (HI), high-carbohydrate diets, inflammation, stress, and sleep disturbances, as well as conditions in which IR occurs physiologically. The findings indicate that current evidence supports the need for a clearer clinical and diagnostic framework for insulin resistance and suggest that its recognition as a distinct disease entity could facilitate earlier diagnosis, improve the standardization of clinical management, and enable earlier metabolic intervention. Given the steadily rising prevalence of metabolic disease, systemic efforts directed at the early identification and treatment of IR may be a key component of strategies aimed at reducing the population-level burden of metabolic disease and its negative consequences. Full article

Aortitis—inflammation of the aortic wall—presents at the interface of vasculitis, infection, structural aortic disease, and cardiovascular risk. It may occur in giant cell arteritis (GCA), Takayasu arteritis, immunoglobulin G4 (IgG4)-related disease, drug-induced injury, infection, or as an isolated finding after aortic surgery. Modern imaging detects aortic inflammation more frequently, but the main challenge is classification rather than detection: determining whether disease is infectious or immune-mediated, active or dominated by fixed structural damage, systemic or isolated, and whether the dominant threat is aneurysm, dissection, undertreated infection, or avoidable immunosuppression. This review considers aortitis as a high-risk vascular syndrome requiring aetiology-first classification rather than descriptive labelling. Before escalating immunosuppression, infection must be actively excluded and inflammatory activity distinguished from fixed vascular damage. Treatment should be individualised according to phenotype, age, vascular territory, comorbidity, and toxicity risk, with surveillance continuing even after symptoms and inflammatory markers improve. Optimal care depends on multidisciplinary assessment integrating rheumatology, infectious diseases, vascular surgery, radiology, and cardiology expertise. Progress will require standardised imaging definitions, registries linking inflammatory control with structural vascular outcomes, and validation of artificial intelligence (AI) tools before clinical adoption. Full article

Background: Single-access transfemoral transcatheter aortic valve implantation (TAVI) reduces the need for multiple vascular access and therefore, the related risk of related complications. However, the impact of patient age on its clinical outcomes remains uncertain. Methods: This is a secondary analysis of previously reported propensity score matched study comparing clinical outcomes of single- versus dual-access transfemoral TAVI using SAPIEN-3-Ultra. We examined the relation between patient age, access strategy and outcomes—specifically, 30-day safety endpoint according to the Valve Academic Research Consortium 3 (VARC-3) and major adverse cardiovascular events (MACE), defined as death, permanent pacemaker, neurological or vascular complications—using logistic regression interaction analyses, and restricted cubic spline modelling. Results: A total of 204 patients (propensity score-matched cohort) were included in the study. The elderly group were more likely to have hypertension, peripheral vascular disease or stroke. The use of single access was comparable. The elderly cohort demonstrated a tendency toward longer fluoroscopy and procedural times compared with the non-elderly group. This pattern likely reflects the greater technical complexity and heightened procedural caution often associated with older patients, including more challenging vascular anatomy and the need for careful device handling. Although not statistically significant, these findings remain clinically meaningful and are consistent with the notion that procedures in elderly patients frequently require more meticulous planning and execution. There was a significant interaction between access strategy and age in reducing MACE, but not in VARC-3 safety outcomes. Single access was associated with a significant reduction in MACE (5.4% vs. 26.7%, p = 0.015) with comparable technical and safety outcomes when compared with elderly patients who underwent dual-access TAVI. Conclusions: Single-access TAVI was linked to favourable early outcomes, maintained procedural success, and suggested a possible age-dependent pattern in the occurrence of MACE. Our findings support the need for randomised studies to demonstrate superiority of single- versus dual-access TAVI, particularly in the elderly population. Full article

Background: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is associated with increased cardiovascular (CV) morbidity and mortality. Galectin-3 is a marker of fibrosis and adverse CV outcomes in chronic kidney disease (CKD), while mid-regional pro-atrial natriuretic peptide (MR-proANP) and heart-type fatty acid-binding protein (H-FABP) reflect myocardial wall stress and subclinical myocardial injury. Data on the combined behavior of these biomarkers in IgAN are limited. We investigated their association with renal function and cardiovascular parameters in IgAN. Methods: In this cross-sectional study, 90 patients with biopsy-proven IgAN were examined, but 76 patients’ data were evaluated. Serum galectin-3, MR-proANP, and H-FABP concentrations were measured by ELISA. Renal function was assessed using estimated glomerular filtration rate (eGFR, CKD-EPI). All patients underwent transthoracic echocardiography and arterial stiffness assessment, including pulse wave velocity of the aorta (PWVao) and central systolic blood pressure (SBPao). Results: Patients with reduced renal function (eGFR <60 mL/min/1.73 m²) had significantly higher galectin-3 (p = 0.011), MR-proANP (p < 0.001), and H-FABP (p < 0.001) concentrations. Biomarker levels increased progressively with declining eGFR. Galectin-3 concentrations were higher in patients with increased left ventricular mass index (p = 0.015). All three biomarkers were elevated in patients with higher central aortic systolic pressure. MR-proANP and H-FABP increased with worsening albuminuria, whereas galectin-3 did not. In multivariate analyses, eGFR was the only independent predictor of all three biomarkers. Conclusions: In IgAN, galectin-3, MR-proANP, and H-FABP concentrations are closely linked to renal function and markers of cardiovascular remodeling. These findings suggest that galectin-3, MR-proANP, and H-FABP provide complementary information regarding the complex interaction between renal dysfunction and cardiovascular remodeling in IgA nephropathy. Prospective multicenter studies are warranted to determine their incremental prognostic value and potential clinical utility for cardiovascular risk stratification. Full article

Compartment-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes provide a powerful resource to study cellular and molecular underpinnings of congenital heart disease (CHD) and acquired cardiovascular disease (CVD). Human heart development requires coordinated and complex regulation of key signaling pathways including Notch, BMP, Wnt, Nodal, and Shh during each step of heart morphogenesis. Compartment-specific cardiac cells for modeling the various structures in the heart can be generated by fine tuning these signaling pathways in a sequential manner thereby mimicking spatiotemporal regulation during embryonic heart morphogenesis. In this review, we provide a brief overview of key signaling pathways that are responsible for forming the distinct structures of the heart originating from the first heart field (FHF) and second heart field (SHF). We then summarize recent differentiation protocols that leverage key heart-development related signaling molecules to generate compartment-specific cardiomyocytes and organoids for disease modeling and therapeutic development in cardiovascular disease. Full article

Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants associated with higher serum lipids, although primarily in cross-sectional studies, limiting causal inference. We aim to determine whether there is a causal relationship between PFAS and serum lipid levels by emulating a target trial of a hypothetical PFAS-reduction intervention using observational data. The target trial would enroll adults aged ≥20 years without prior cardiovascular, kidney, or liver disease, diabetes, or use of related medications. Participants would be randomly assigned to either PFAS-reduction counseling or no counseling, with adherence evaluated after 10 years, and then followed up after 10 years to assess effects on serum lipids. To emulate the target trial, we will use data from the Copenhagen City Heart Study on three successive clinical visits: baseline, follow-up, and outcome assessment visit, 10 years apart. Eligible participants meet the target trial criteria, have available blood samples for PFAS quantification at follow-up, and information on serum lipids at the outcome assessment. Intervention strategies will be evaluated based on observed reductions in PFAS concentrations between baseline and follow-up visit. Serum lipids are assessed at the outcome assessment visit. The emulation assumes exchangeability by adjusting for baseline and time-varying confounders using G-computation. This protocol explores applying the target trial emulation framework to improve causal inference in environmental epidemiology. Full article

Background and Objectives: Soluble suppression of tumorigenicity-2 (sST2) is a biomarker associated with myocardial stress, inflammation, and fibrosis. Although elevated sST2 levels have demonstrated prognostic significance in heart failure and acute coronary syndromes, their clinical relevance in patients undergoing percutaneous coronary intervention (PCI) remains incompletely defined. This study aimed to evaluate the association between baseline serum sST2 levels and long-term clinical outcomes in an unselected real-world cohort of patients undergoing PCI. Materials and Methods: A total of 758 consecutive patients with coronary artery disease who underwent PCI between September 2015 and November 2017 were enrolled. Baseline serum sST2 levels were measured before PCI, and patients were stratified according to the median value (28.3 ng/mL). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs), defined as a composite of cardiac death, nonfatal myocardial infarction, and nonfatal stroke. Multivariable Cox proportional hazards models and receiver operating characteristic analyses were performed to assess the association of sST2 with clinical outcomes and its discriminatory ability. Results: During a median follow-up of 28.3 months, MACCEs occurred in 19 patients (2.5%). Patients with higher sST2 levels had significantly higher rates of MACCEs (4.2% vs. 0.8%, p = 0.005) and all-cause mortality (11.9% vs. 2.6%, p < 0.001) than those with lower sST2 levels. Although the association between elevated sST2 and MACCE was attenuated after multivariable adjustment (adjusted hazard ratio, 3.28; 95% confidence interval, 0.91–11.83; p = 0.070), receiver operating characteristic analysis demonstrated moderate predictive performance for MACCE (AUC, 0.723) and all-cause mortality (AUC, 0.763). The optimal cutoff value for predicting MACCE was 52.2 ng/mL. Conclusions: Elevated baseline serum sST2 levels were associated with adverse long-term clinical outcomes in an unselected, real-world cohort of patients undergoing PCI. Further studies are warranted to clarify its prognostic role in this population. Full article

Background and Clinical Significance: Renal disease is the leading cause of secondary hypertension in children and adolescents. Among younger patients presenting with severe hypertension, renovascular and renal parenchymal disorders should be considered promptly; Case presentation: We describe the case of a 16-year-old male who presented with severe fatigue and was found to have resistant arterial hypertension (180/120 mmHg). His medical history was notable for blunt epigastric trauma sustained during football training approximately 6 months before presentation. Magnetic resonance imaging of the kidneys and retroperitoneum demonstrated a large right-sided perinephric hematoma compressing the kidney. Plasma renin activity and aldosterone levels were markedly elevated, establishing the diagnosis of Page kidney. Percutaneous drainage was performed by placement of a drainage catheter into the perinephric collection, resulting in evacuation of a substantial volume of liquefied hematoma. Following the procedure, arterial blood pressure gradually normalized, accompanied by resolution of the hormonal abnormalities; Conclusions: Page kidney is a rare but important cause of secondary hypertension resulting from activation of the renin-angiotensin-aldosterone system due to external renal compression and impaired intrarenal perfusion. Although its clinical presentation may be insidious, delayed recognition can lead to severe cardiovascular and renal complications. Management includes percutaneous drainage or surgical decortication of the affected kidney, together with antihypertensive treatment targeting the renin-angiotensin-aldosterone system. Early diagnosis and treatment are essential to optimize clinical outcomes and preserve renal function. Full article