Vascular Disease Research Articles

Alleviation of Angiotensin II-Induced Vascular Endothelial Cell Injury through Long Non-coding RNA TUG1 Inhibition.

Hypertension damages endothelial cells, causing vascular remodelling. It is caused by Ang II-induced endothelial cell (EC) destruction. The long noncoding RNA (lncRNAs) are emerging regulators of endothelium homeostasis. Injured endothelium expresses lncRNA taurine-upregulated gene 1 (TUG1), which may mediate endothelial cell damage, proliferation, apoptosis, and autophagy and contribute to cardiovascular disease. However, uncertainty surrounds the function of lncRNA TUG1, on arterial endothelium cell damage. This research aimed to investigate the role and mechanism of lncRNA TUG1 in vascular endothelial cell injury. A microarray analysis of lncRNA human gene expression was used to identify differentially expressed lncRNAs in human umbilical vein endothelial cell (HUVEC) cultures. The viability, apoptosis, and migration of Ang II-treated HUVECs were then evaluated. In order to investigate the role of lncRNA TUG1 in hypertension, qRT-PCR, western blotting, and RNA-FISH were used to examine the expression of TUG1 in SHR mice. Ang II-activated HUVECs and SHR rats' abdominal aortas highly express the lncRNA TUG1. LncRNA TUG1 knockdown in HUVECs could increase cell viability, reduce apoptosis, and produce inflammatory factors. In SHR rat abdominal aortas, lncRNA TUG1 knockdown promoted proliferation and inhibited apoptosis. HE spotting showed that lncRNA TUG1 knockdown improved SHR rats' abdominal aorta shape. lncRNA TUG1 knockdown promotes miR-9- 5p, which inhibits CXCR4 following transcription. The lncRNA TUG1/miR-9-5p/CXCR4 axis and vascular cell injury were also examined. MiR-9-5p silencing or CXCR4 overexpression lowered cell survival, apoptosis, and lncRNA TUG1-induced IL-6 and NO expression. lncRNA TUG1 suppression could reduce Ang II-induced endothelial cell damage by regulating and targeting miR-9-5p to limit CXCR4 expression and open new vascular disease research pathways.

Prospective evaluation of patients with non-cirrhotic portal hypertension: A single centre study.

Non-cirrhotic portal hypertension (NCPH) is a spectrum of liver diseases, including porto-sinusoidal vascular disorder, with portal hypertension (PH) in the absence of cirrhosis. The natural history and diagnostic approach to NCPH are not well understood. We aimed to evaluate disease progression and outcomes in NCPH. Patients with or at risk for NCPH were enrolled in a single centre prospective study; two groups were formed based on the presence of specific features of PH, such as varices, collaterals, portal hypertensive gastropathy or portal hypertensive bleeding. All participants underwent a baseline liver biopsy. Liver stiffness measurement (LSM), and imaging were repeated every 6-12 months. Fifteen patients without specific features of PH (Group I), and 35 patients with specific features (Group II) were enrolled. The median follow-up time was 50 months. Group II had higher hepatic venous pressure gradients, non-invasive measures of PH and a lower platelet count (PLT) when compared to Group I. Rates of survival and decompensation were similar in both groups. Patients with PLT ≤100 K/mcL had lower survival compared to those with PLT >100 K/mcL. Patients with LSM ≥10 kPa had lower survival and survival without decompensation when compared to patients with LSM <10 kPa. Patients irrespective of specific features of PH had similar survival or survival without decompensation. Patients without specific features are at risk for disease progression and should be monitored closely. Thrombocytopenia and increased LSM are associated with severe forms of liver disease, which are strongly associated with outcomes.

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells.

Induced pluripotent stem cell (iPSC) derived endothelial cells (iECs) have emerged as a promising tool for studying vascular biology and providing a platform for modelling various vascular diseases, including those with genetic origins. Currently, primary ECs are the main source for disease modelling in this field. However, they are difficult to edit and have a limited lifespan. To study the effects of targeted mutations on an endogenous level, we generated and characterized an iPSC derived model for venous malformations (VMs). CRISPR-Cas9 technology was used to generate a novel human iPSC line with an amino acid substitution L914F in the TIE2 receptor, known to cause VMs. This enabled us to study the differential effects of VM causative mutations in iECs in multiple in vitro models and assess their ability to form vessels in vivo. The analysis of TIE2 expression levels in TIE2L914F iECs showed a significantly lower expression of TIE2 on mRNA and protein level, which has not been observed before due to a lack of models with endogenous edited TIE2L914F and sparse patient data. Interestingly, the TIE2 pathway was still significantly upregulated and TIE2 showed high levels of phosphorylation. TIE2L914F iECs exhibited dysregulated angiogenesis markers and upregulated migration capability, while proliferation was not affected. Under shear stress TIE2L914F iECs showed reduced alignment in the flow direction and a larger cell area than TIE2WT iECs. In summary, we developed a novel TIE2L914F iPSC-derived iEC model and characterized it in multiple in vitro models. The model can be used in future work for drug screening for novel treatments for VMs.

Insights into the biocontrol and plant growth promotion functions of Bacillus altitudinis strain KRS010 against Verticillium dahliae

BackgroundVerticillium wilt, caused by the fungus Verticillium dahliae, is a soil-borne vascular fungal disease, which has caused great losses to cotton yield and quality worldwide. The strain KRS010 was isolated from the seed of Verticillium wilt-resistant Gossypium hirsutum cultivar “Zhongzhimian No. 2.”ResultsThe strain KRS010 has a broad-spectrum antifungal activity to various pathogenic fungi as Verticillium dahliae, Botrytis cinerea, Fusarium spp., Colletotrichum spp., and Magnaporthe oryzae, of which the inhibition rate of V. dahliae mycelial growth was 73.97% and 84.39% respectively through confrontation test and volatile organic compounds (VOCs) treatments. The strain was identified as Bacillus altitudinis by phylogenetic analysis based on complete genome sequences, and the strain physio-biochemical characteristics were detected, including growth-promoting ability and active enzymes. Moreover, the control efficiency of KRS010 against Verticillium wilt of cotton was 93.59%. After treatment with KRS010 culture, the biomass of V. dahliae was reduced. The biomass of V. dahliae in the control group (Vd991 alone) was 30.76-folds higher than that in the treatment group (KRS010+Vd991). From a molecular biological aspect, KRS010 could trigger plant immunity by inducing systemic resistance (ISR) activated by salicylic acid (SA) and jasmonic acid (JA) signaling pathways. Its extracellular metabolites and VOCs inhibited the melanin biosynthesis of V. dahliae. In addition, KRS010 had been characterized as the ability to promote plant growth.ConclusionsThis study indicated that B. altitudinis KRS010 is a beneficial microbe with a potential for controlling Verticillium wilt of cotton, as well as promoting plant growth.

Documentary analysis of national and international guidance for community clinicians referring patients with suspected chronic limb-threatening ischaemia

BackgroundDelayed referral of patients with chronic limb-threatening ischaemia (CLTI) from the community to vascular services may increase risk of amputation due to delayed revascularisation. Lack of appropriate guidance for clinicians...

SEX DIFFERENCES IN THE CORONARY SYSTEM OF THE HUMAN HEART

The aim of this study is to investigate sex differences in the coronary system of the heart, considering all relevant consequence, and to compile and analyze the gathered data. Materials and Methods. The authors independently conducted a literature search and selection process using the PubMed database for the review, followed by the generalization of the obtained data. Results. Women exhibit a higher propensity than men for certain cardiovascular diseases, including persistent angina, non-obstructive coronary heart disease, coronary microvascular dysfunction, spontaneous coronary artery dissection, stress cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF). In comparison to men, women typically present with elevated rates of underlying comorbidities, encompassing not only advanced age but also hypertension, diabetes mellitus, obesity, chronic renal failure, peripheral vascular disease, HFpEF, and inflammatory conditions like rheumatoid arthritis. Many of these conditions are linked to diffuse atherosclerosis and microvascular ischemia, with notable parallels between non-obstructive coronary heart disease and coronary microvascular dysfunction. Special attention is paid to patients sharing an increased risk of coronary heart disease events, which is consistent between women and men, except for those with severe coronary flow reserve (CFR) impairment, where women demonstrate an even higher risk. In particular, in cases where CFR impairment is not attributable to obstructive coronary heart disease (precluding revascularization to mitigate cardiovascular risk), there may be justification for a novel therapeutic approach for systemic coronary heart disease management. Cases of severe coronary microvascular dysfunction, often concurrent with non-obstructive coronary heart disease, may indicate a shared mechanism influencing coronary heart disease risk in both genders. This mechanism might involve inflammation, endothelial dysfunction, and heightened cardiomyocyte oxygen demand, culminating in microvascular ischemia, myocardial injury, and compromised cardiac function. Conclusions. Enhanced comprehension of the interplay between coronary vasomotor dysfunction and the concomitance of coronary heart disease with other conditions, such as insulin resistance and heart failure, could foster the advancement of novel systemic treatments aimed at leveraging “complete revascularization” more effectively.

From Atherosclerosis to Spontaneous Coronary Artery Dissection: Defining a Clinical and Genetic Risk Spectrum for Myocardial Infarction.

Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease. Recent studies have revealed several associated variants with varying effect sizes for SCAD, giving rise to a complex genetic architecture. Associated genes highlight an important role for arterial cells and their extracellular matrix in the pathogenesis of SCAD, as well as notable genetic overlap between SCAD and other systemic arteriopathies such as fibromuscular dysplasia and vascular connective tissue diseases. Further investigation of individual variants (including in the associated gene PHACTR1) along with polygenic score analysis have demonstrated an inverse genetic relationship between SCAD and atherosclerosis as distinct causes of AMI. SCAD represents an increasingly recognized cause of AMI with opposing clinical and genetic risk factors from that of AMI due to atherosclerosis, and it is often associated with complex underlying genetic conditions. Genetic study of SCAD on a larger scale and with more diverse cohorts will not only further our evolving understanding of a newly defined genetic spectrum for AMI, but it will also inform the clinical utility of integrating genetic testing in AMI prevention and management moving forward.

The association between triglyceride-glucose index and related parameters and risk of cardiovascular disease in American adults under different glucose metabolic states

BackgroundCardiovascular disease (CVD) encompasses an array of cardiac and vascular disorders, posing a significant threat to global health. It remains unclear whether there exists an association between triglyceride-glucose index (TyG) and its derived indices and the incidence of cardiovascular disease, and in particular, the strength of the association in populations with different glucose metabolisms is not known.MethodsData extracted from the National Health and Nutrition Examination Survey (NHANES) covering the period from 1999 to 2020, involving a cohort of 14,545 participants, were leveraged for the analysis. Statistical assessments were executed utilizing R software, employing multivariable logistic regression models to scrutinize the correlation between TyG and its associated parameters with the incidence of cardiovascular disease across diverse glucose metabolism categories. Interaction analyses and restricted cubic splines were applied to evaluate potential heterogeneity in associations and investigate the link between TyG and its derivatives with the occurrence of cardiovascular disease. Furthermore, receiver operating characteristic curves were constructed to evaluate the extent of variability in the predictive performance of TyG and its derived parameters for cardiovascular disease across distinct glucose metabolic statuses.ResultsThis study found that TyG and its related parameters were differentially associated with the occurrence of cardiovascular disease in different glucose metabolic states. Curvilinear correlations were found between TyG in the IFG population and TyG-WC, TyG-BMI, and TyG-WHtR in the impaired glucose tolerance (IGT) population with the occurrence of cardiovascular disease. In addition, the introduction of TyG and its derived parameters into the classical Framingham cardiovascular risk model improved the predictive performance in different glucose metabolism populations. Among them, the introduction of TyG-WHtR in the normal glucose tolerance (NGT), impaired fasting glucose (IFG), IFG & IGT and diabetes groups and TyG in the IGT group maximized the predictive power.ConclusionsThe findings provide new insights into the relationship between the TyG index and its derived parameters in different glucose metabolic states and the risk of cardiovascular disease, offering important reference value for future clinical practice and research. The study highlights the potential for improved risk stratification and prevention strategies based on TyG and its derived parameters.

Effective diameter of the abdominal aorta in children.

Measure out of the standard interval in the aorta diameter is a clue for aortic aneurysm or hypoplasia. Pediatric studies focusing specifically on the normal diameter of the abdominal aorta (AA) were limited in the literature. Therefore, the main goal of this work was to determine changes in the effective diameter of AA in healthy children aged 1-18years for diagnosis of vascular diseases. This retrospective work focused on abdominopelvic computed tomography views of 180 children (sex: 90 males / 90 females, average age: 9.50 ± 5.20years) without any abdominopelvic disease to measure diameters of AA, common iliac artery (CIA), external iliac artery (EIA), and first lumbar vertebra (L1). Vessel and vertebra diameters increased in pediatric subjects between 1 and 18years (p < 0.001). Considering pediatric age periods, vessel diameters increased steadily, but L1 diameter showed an irregular growth pattern between age periods. All parameters were greater in males than females (p < 0.05), except from effective diameters of AA over the coeliac trunk (p = 0.084) and over the renal artery (p = 0.051). The ratios of diameters of vessels to L1 increased depending on ages between 1 and 18years. Considering pediatric age periods, the ratios increased from infancy period to postpubescent period in irregular pattern; however, the ratios for right and left CIA, and AA over the aortic bifurcation did not alter after late childhood period. All ratios for males were similar to females (p > 0.05). Our age-specific ratios may be beneficial for surgeons and radiologists for the diagnosis of vascular disorders such as aortic aneurysm.

Pediatric three-dimensional quantitative cardiovascular computed tomography.

High-resolution, isotropic, 3-dimensional (D) data from pediatric cardiovascular computed tomography (CT) offer great potential for the accurate quantitative evaluation of pediatric cardiovascular and pulmonary vascular diseases. Recent pilot studies using pediatric 3-D cardiovascular CT have shown promising results in assessing cardiac function in conditions such as tetralogy of Fallot, cardiac defects with a hypoplastic ventricle, Ebstein anomaly, and in quantifying myocardial mass. In addition, the quantitative assessment of pulmonary vascularity is useful for evaluating differential right-to-left pulmonary vascular volume ratio, the effectiveness of pulmonary angioplasty, and predicting pulmonary hypertension. These initial experiences could broaden the role of pediatric cardiovascular CT in clinical practice. Furthermore, the current barriers to its widespread use, pertinent solutions to these problems, and new applications are discussed. In this review, the 3-D quantitative evaluations of cardiac function and pulmonary vascularity using high-resolution pediatric cardiovascular CT data are illustrated.

Management of Pulmonary Vascular Disease Associated with Congenital Left to Right Shunts: A Single Center Experience.

To describe the course and outcomes of children under 18 with left-to-right (LR) shunts and pulmonary arterial hypertension (PAH) undergoing one of two management approaches: PAH treatment prior to LR shunt repair (Treat First) and LR shunt repair first, with or without subsequent PAH treatment (Repair First). Retrospective single center study, conducted from September 2015 to September 2021, of children LR shunts and PAH (defined as indexed pulmonary vascular resistance (PVRi) ≥ 4WU*m2) but without Eisenmenger physiology. Patient characteristics, longitudinal hemodynamics data, PAH management, LR shunt repair, and outcomes were reviewed. Of 768 patients evaluated for LR shunt closure, 51 (6.8%) had LR shunt associated PAH [median age 1.1 (0.37,5) years, median PVRi 6 (5.2,8.7) WU*m2]. Of the "Treat First" group (n=33, 65%), 27 (82%) underwent LR shunt closure and 6 (18%) did not respond to PAH therapy and did not undergo LR shunt closure. In the "Repair First" group (n=18, 35%), 12 (67%) received PAH therapy and 6 (33%) did not. Mortality rates were 6% in "Treat First" and 11% in "Repair First", follow-up of 3.4 and 2.5 years, respectively. After LR shunt closure, there was no significant change in PVRi over a median follow-up of 2 years after surgery (p=0.77). In children with LR shunts and associated PAH, treatment with PAH-targeted therapy before defect repair does not appear to endanger the subjects and may have some benefit. The response to PAH-targeted therapy before shunt closure persists 2-3 years post-closure, providing valuable insights into the long-term management of these patients.

French guidelines on TIPS: Indications and modalities.

Transjugular intrahepatic portosystemic shunt (TIPS) has become essential in the treatment or prevention of portal hypertension-related complications. In the early 1990s, the primary indication was refractory bleeding. It is now proposed for the treatment of ascites for the prevention of bleeding and in patients with vascular diseases of the liver. Thus, there are a growing number of patients being treated with TIPS all over the world. The broadening of indications, the involvement of multiple stakeholders, the need for an accurate selection, the positioning in relation to transplantation and the lack of standardization in pre-therapeutic assessment, in the procedure itself and in the follow-up have led the board of the French Association for the Study of the Liver to establish recommendations.

Nanozymes for the Therapeutic Treatment of Diabetic Foot Ulcers.

Diabetic foot ulcers (DFU) are chronic, refractory wounds caused by diabetic neuropathy, vascular disease, and bacterial infection, and have become one of the most serious and persistent complications of diabetes mellitus because of their high incidence and difficulty in healing. Its malignancy results from a complex microenvironment that includes a series of unfriendly physiological states secondary to hyperglycemia, such as recurrent infections, excessive oxidative stress, persistent inflammation, and ischemia and hypoxia. However, current common clinical treatments, such as antibiotic therapy, insulin therapy, surgical debridement, and conventional wound dressings all have drawbacks, and suboptimal outcomes exacerbate the financial and physical burdens of diabetic patients. Therefore, development of new, effective and affordable treatments for DFU represents a top priority to improve the quality of life of diabetic patients. In recent years, nanozymes-based diabetic wound therapy systems have been attracting extensive interest by integrating the unique advantages of nanomaterials and natural enzymes. Compared with natural enzymes, nanozymes possess more stable catalytic activity, lower production cost and greater maneuverability. Remarkably, many nanozymes possess multienzyme activities that can cascade multiple enzyme-catalyzed reactions simultaneously throughout the recovery process of DFU. Additionally, their favorable photothermal-acoustic properties can be exploited for further enhancement of the therapeutic effects. In this review we first describe the characteristic pathological microenvironment of DFU, then discuss the therapeutic mechanisms and applications of nanozymes in DFU healing, and finally, highlight the challenges and perspectives of nanozyme development for DFU treatment.

CCT‘S CRYSTAL BALL: PREDICTING CARDIOVASCULAR RISK IN AORTIC VALVE STENOSIS PATIENTS UNDERGOING VALVE REPLACEMENT

Abstract Background and Aims Currently, computed tomography cardiac imaging (CTCI) plays a fundamental role in the pre–procedural planning of degenerative–calcific aortic valve stenosis(AS) correction. However, its prognostic role in assessing mortality and major adverse cardiovascular events (MACE) has not been extensively explored. CTCI allows for the evaluation of coronary artery calcification(CAC), mitral annular calcifications (MAC), aortic valve calcifications (CVA), and thoracic aorta calcifications (CAT). The aim of our study was to assess whether the presence and extent of CAC, MAC, CVA, and CAT could influence non–cardiovascular mortality (NCM), cardiovascular mortality (CM), and MACE in patients undergoing valve replacement(VR). Materials and Methods We collected retrospectivelly clinical and instrumental data and reviewed CTCI using a semi–quantitative approach. CACs were classified according to the visual 2022 Coronary Artery Disease–Reporting and Data System. MACs were defined following the Guerrero et al. study, CVAs according to the Win Registry and CATs were assessed in the ascending aorta, aortic arch, and descending aorta according to the Vos classification. Results 244 patients(59% male, mean age 80.1±6.6 years), with 91% undergoing transfemoral VR, were enrolled(2016–2018). CM was significantly higher in patients with hypertension,cerebro/peripheral vascular disease, stage IV–V renal insufficiency and history of atrial fibrillation (p=0.012,p&amp;lt;0.001,p=0.005, p=0.034 and p=0.024, respectively). CM was also more pronounced in patients with STS SCORE≥6.7±5.2 and EuroSCOREII≥ 5.5±5.8(p=0.016 and p=0.037). Extensive CAC(p=0.019), a MAC score&amp;gt;7(p=0.051), moderate and severe AVC (p=0.029 and p=0.053) and TAC&amp;gt;270° in aortic arch(p=0.019) were linked to CM. In multivariate analysis, a high MAC score and the presence of moderate AVC persisted as risk factors for CM. The presence of a MAC score &amp;gt;7(p=0.006) and the extension of descending TAC &amp;gt;1.5 mm (p=0.034) were associated with an increased risk of NCM.The presence of extensive TAC (≥270°) measured in the aortic arch and descending aorta were associated with MACE (p=0.034 and p=0.0504 respectively). Conclusions CTCI emerges as a crucial tool for evaluating prognostic risk in patients undergoing VR for AS. This type of evaluation can assist clinicians in pre–procedural planning and patient management, allowing for better identification of high–risk patients and optimization of therapeutic strategies

De Novo Elastin Assembly Alleviates Development of Supravalvular Aortic Stenosis.

A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of ELN, is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin. We use SVAS here as a model of vascular proliferative disease using both human induced pluripotent stem cell-derived vascular smooth muscle cells and developmental Eln± mouse models to establish de novo elastin assembly as a new therapeutic intervention. We demonstrate mitigation of vascular proliferative abnormalities following de novo extracellular elastin assembly through the addition of the polyphenol epigallocatechin gallate to SVAS human induced pluripotent stem cell-derived vascular smooth muscle cells and in utero to Eln± mice. We demonstrate de novo elastin deposition normalizes SVAS human induced pluripotent stem cell-derived vascular smooth muscle cell hyperproliferation and rescues hypertension and aortic mechanics in Eln± mice, providing critical preclinical findings for the future application of epigallocatechin gallate treatment in humans.

Potential mediating role of iron biomarkers in the association of sex with glucose, insulin, and type 2 diabetes

Abstract Context Sex-specific prevalence and incidence of type 2 diabetes (T2D) have been reported, but the underlying mechanisms are uncertain. Objective In this study, we aimed to investigate whether iron biomarkers mediate the association between biological sex and glucose metabolism and the incidence of T2D. Methods We used data from the general population enrolled in the prospective Prevention of REnal and Vascular ENd-stage Disease study in Groningen, Netherlands. We measured ferritin, transferrin saturation (TSAT), hepcidin, soluble transferrin receptor (sTfR), fasting plasma glucose (FPG), fasting plasma insulin (FPI) levels, and incidence of T2D. We used multivariable regression and mediation analyses to investigate our hypothesis. All iron biomarkers, FPG, and FPI were log-transformed. Results The mean (SD) age of the 5,312 (51.3% female) individuals was 52.2 (11.6) years. Compared with males, females had lower FPG (β= -0.01; 95%CI = -0.02, -0.01) and FPI (β= -0.03; 95%CI = -0.05, -0.02) levels. Ferritin, hepcidin, and sTfR showed potential mediating effects on the association between sex and FPG, 21%, 5%, and 7.1%, respectively. Furthermore, these variables mediated 48.6%, 5.7%, and 3.1% of the association between sex and FPI, respectively. Alternatively, TSAT had a suppressive mediating role in the association of sex with FPG and FPI. The incidence of T2D was lower in females than in males (HR = 0.58; 95%CI = 0.44, 0.77), with 19.2% of this difference being mediated by ferritin. Conclusion Iron biomarkers may partially mediate the association between sex and glucose homeostasis. Future studies addressing the causality of our findings are needed.

FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is essential for the development of new organ systems, but transcriptional control of angiogenesis remains incompletely understood. Here we show that FOXC1 is essential for retinal angiogenesis. Endothelial cell (EC)-specific loss of Foxc1 impairs retinal vascular growth and expression of Slc3a2 and Slc7a5, which encode the heterodimeric CD98 (LAT1/4F2hc) amino acid transporter and regulate the intracellular transport of essential amino acids and activation of the mammalian target of rapamycin (mTOR). EC-Foxc1 deficiency diminishes mTOR activity, while administration of the mTOR agonist MHY-1485 rescues perturbed retinal angiogenesis. EC-Foxc1 expression is required for retinal revascularization and resolution of neovascular tufts in a model of oxygen-induced retinopathy. Foxc1 is also indispensable for pericytes, a critical component of the blood-retina barrier during retinal angiogenesis. Our findings establish FOXC1 as a crucial regulator of retinal vessels and identify therapeutic targets for treating retinal vascular disease.

Implications of trial eligibility in patients with heart failure with mildly reduced or preserved ejection fraction.

Clinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings. Patients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON-HF, EMPEROR-Preserved, DELIVER, FINE-ARTS, and SPIRRIT-HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial-eligible and trial-ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75years, P<0.001) with higher rates of coronary artery disease (66% vs. 59%, P<0.001) and peripheral vascular disease (40% vs. 33%, P<0.001), but less mitral regurgitation, lower E/e' ratio, and smaller left atrial sizes. Both eligible and ineligible patients demonstrated high rates of structural heart disease consistent with HFpEF [elevated left atrial size or left ventricular (LV) hypertrophy/increased LV mass], although this was slightly higher among eligible patients (95% vs. 92%, P=0.001). The two cohorts demonstrated similar LV global longitudinal strain along with a similar prevalence of atrial fibrillation/flutter, hypertension, and obesity. Ineligible patients had similar all-cause mortality (33% vs. 33% at 3years) to those eligible but lower rates of heart failure hospitalization (20% vs. 28% at 3years, P<0.001). Among patients with HFmrEF/HFpEF from a large health system, approximately one in seven were eligible for major trials based on key criteria applied through a clinical computable phenotype. These findings highlight the large proportion of patients with HFmrEF/HFpEF ineligible for contemporary trials for whom the generalizability of trial findings may be questioned and further investigation would be beneficial.

WEARABLE CARDIOVERTER DEFIBRILLATOR IN PATIENT WITH TRANSIENT RISK OF SUDDEN CARDIAC DEATH : SINGLE CENTRE EXPERIENCE

Abstract Background Cardiovascular disease is still the first cause of death, with sudden cardiac death ( SCD) as a first presentation in 25% of cases, related to coronary artery disease. Implantable cardioverter defibrillator (ICD) demontrated a reduction of SCD in high risk patients with good functional status. However the risk of SCD should be transient, so the use of a wearable cardioverter defibrillator (WCD) is considered in current guidelines and in clinical practice. The purpose of this study was to investigate the safety and the adherence to WCD in a real world population; moreover we reviewed the rate of ICD implantation after WCD use. Methods We considered consecutively 96 patients discharged from Piacenza cardiology department for potentially transient high risk of SCD, weared a WCD from August 2017 to June 2023. The patients were discharged in high risk mode of SCD with WCD protection and followed through remote monitoring or outpatient.A clinical and echocardiographic evalutation was performed at baseline and repeated at the end of the WCD use period. Results Out of 95 patients , with average age 66,0 ±11,1 years old and baseline average left ventricular ejection fraction (LVEF) 28,6±7,5, 81,2% were males, 72,9% suffered from arterial hypertension, 26% diabetes mellitus, 13,5% peripheral vascular disease, 14,6% chronic renal failure, 4,1% previous stroke.66% of these patients weared WCD for severe systolic disfunction in ischemic cardiac disease after recent myocardial infarction, after percutaneous coronary intervention or coronary artery bypass graft, 4% after removal of an infected ICD, 6% whilst awaiting completion of diagnostic tests (chanalopathies/right arrhythmogenic ventricular cardiomyopathy), 24% newly diagnosed cardiomyopathy. The average wearing time of WCD was 22,7±3,1 hours daily. We received these events: 1 sustained ventricular tachicardia, 2 non sustained ventricular tachicardia, 5 atrial fibrillation with 3 T wave oversensing. One patient recedived inappropriate shock. One death was detected due to severe heart failure. After 56,0±37,8 days of average wearing time 52% of patients were scheduled for ICD implantation. Conclusions In our experience we may consider that WCD use is effective, safe and with a good adherence in all patients. The WCD allows saving resources preventing inapprpriate ICD implantation in patient with transient SCD risk.

A NEGLECTED RARE DISORDER: IGG4 RELATED DISEASE

Abstract IgG4–related disease (IgG4–RD) is an autoimmune disorder characterized by infiltration of plasma cells with IgG4. Almost any organ could be affected. Common presentations include lung manifestation, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. Cardiovascular involvement is less frequent. Corticosteroids are first line therapy, with or without anti–rheumatic drugs. Long–term prognosis of IgG4–RLD remains unknown. We present the case of a 65–years old woman, with a previuos diagnosis of IgG4–RD with mediastinal involvement. In the meantime she was recovered for pyelonephritis with high fever and positive blood coltures (S. hominis). We were called to perform a transthoracic echocardiogram to rule out infective endocarditis. The exam showed normal size of cardiac chambers, normal biventricular systolic function, absence of relevant valvular disease. In apical view we noticed a hyperechogenic ovalar imagine in the right atrium, not visible in all the projections. A first differential diagnosis included a mass with site of implantation at the top of the right atrium or something external but contiguous to heart structures. To clear this doubt the patient performed a thoracic CT with stunning results. The CT highlighted parietal encasement of chardiac structures and, particularly, of the superior vena cava at the confluence in right atrium, explaining the image we saw with transthoracic echo. The exam also showed encasement of ascending aorta, aortic arch and descending aorta with maximum thickness of 18 mm. CT also reported encasement of right pulmonary arthery. The CT highlighted a progression of the disease with indication to more aggressive therapy. In fact IgG4–RD of the cardiovascular system results in serious complications that need to be recognized and treated. Aortic involvement in IgG4–RD is extremely rare and tipically affects the infrarenal abdominal aorta. Cardiovascular IgG4–RD could also lead to aortitis, medium–vessel arteritis, pulmonary vascular disease, phlebitis, valvulopathy, pericarditis and myocardial disease. These forms of Igg4–RD are often underdiagnosed as clinical presentations is similar to cardiovascular disease due to more common aetiologies. Regarding our case the patient began methotrexate based on the results of the CT. This was a really interesting case for our working group to deepen this little–known disease. “The eyes see only what the mind is prepared to comprehend”.