Vascular Mortality Research Articles

MTOR maintains endothelial cell integrity to limit lung vascular injury

The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify Mechanistic Target of Rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis of cell surface VE-Cadherin leading to disrupted barrier function. MTOR-depleted EC also exhibited reduced VE-Cadherin and VEGFR2 levels mediated in part by autophagy. Similarly, lungs from mice with EC-specific MTOR deficiency displayed spontaneous vascular leakage marked by decreased VE-Cadherin and VEGFR2 levels, indicating that MTOR deficiency in EC is sufficient to disrupt lung vascular integrity and may be a key pathogenic mechanism of ALI. Indeed, MTOR as well as VEGFR2 and VE-Cadherin levels were markedly reduced in injured mouse lungs or EC. Importantly, EC-targeted gene transfer of MTOR cDNA, either prophylactically or therapeutically, mitigated inflammatory lung injury, and improved lung function and survival in mouse models of ALI. These findings reveal an essential role of MTOR in maintaining EC function, identify loss of endothelial MTOR as a key mechanism of lung vascular injury, and show the therapeutic potential of EC-targeted MTOR expression in combating ALI and mortality in mice.

The gender difference in cause of death in Japanese atrial fibrillation patients: The Fushimi AF Registry

Abstract Background Previously we reported that incident rate of heart failure (HF) hospitalization was higher in female than male and stroke was comparable between female and male in Japanese atrial fibrillation (AF) patients. We also reported cardiovascular death was mainly related to HF but not stroke. However, the gender difference in cause of death in Japanese AF patients is little known. Method The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, which is a typical urban district of Japan. We started to enroll patients from March 2011, and follow-up data were available for 4,496 patients by the end of February 2022. In the entire cohort, 2,677 were male and 1,819 were female. We compared clinical characteristics and cause and incidence rate of death between two groups. Result Female patients were older (female vs. male; 76.7 years vs. 71.5 years, p<0.01), less in body weight (51.2 kg vs. 65.0 kg, p<0.01), had higher pulse rate (79.4 bpm vs. 77.5 bpm, p<0.01), less often persistent/permanent type (48.2% vs. 52.0%, p=0.04), less likely to have previous stroke/systemic embolism (18.6% vs. 21.1%, p=0.04), diabetes mellitus (19.9% vs. 26.2%, p<0.01), coronary artery disease (12.3% vs. 16.0%, p<0.01) and more likely to have prior HF (32.2% vs. 24.0%, p<0.01), chronic kidney disease (39.3% vs. 33.7%, p<0.01)and had higher CHADS2 score (2.15 vs. 1.96, p<0.01). In prescription data, female patients less often received oral anticoagulant (52.1% vs. 58.2%, p<0.01) and antiplatelet drug (23.8% vs. 29.0%, p<0.01). Systolic blood pressure, hypertension and major bleeding were comparable between two groups. During the median follow-up of 2,093 days, the incidence rate of all cause death was comparable between female group and male group (5.20 vs. 4.86 % per person-year, log rank p=0.32). The incidence rate of cardiac death was significantly higher in female group than male group (0.98 vs. 0.70 % per person-year, log rank p=0.02) and the incidence rate of vascular death was also significantly higher in female group than male group (0.43 vs. 0.26 % per person-year, log rank p=0.03). The incidence rate of death due to HF, which was main cause of cardiac death, was higher in female group but not significant (0.86 vs. 0.66 % per person-year, log rank p=0.08). We analyzed the proportion of cause of death in each gender, cardiac death and stroke were higher and non-cardiovascular death was lower in female than male group. Conclusion The incidence rates of cardiac death and vascular death were significantly higher in female group than male group, and death due to HF was non-significantly higher in female group. Concerning the proportion of cause of death in each gender, cardiac death and stroke were higher in female than male. The impact of cardiovascular events may be stronger and prevention of them may be more important in female.

A Systematic Review of Metabolic Syndrome: Key Correlated Pathologies and Non-Invasive Diagnostic Approaches.

Background and Objectives: Metabolic syndrome (MetS) is a condition marked by a complex array of physiological, biochemical, and metabolic abnormalities, including central obesity, insulin resistance, high blood pressure, and dyslipidemia (characterized by elevated triglycerides and reduced levels of high-density lipoproteins). The pathogenesis develops from the accumulation of lipid droplets in the hepatocyte (steatosis). This accumulation, in genetically predisposed subjects and with other external stimuli (intestinal dysbiosis, high caloric diet, physical inactivity, stress), activates the production of pro-inflammatory molecules, alter autophagy, and turn on the activity of hepatic stellate cells (HSCs), provoking the low grade chronic inflammation and the fibrosis. This syndrome is associated with a significantly increased risk of developing type 2 diabetes mellitus (T2D), cardiovascular diseases (CVD), vascular, renal, pneumologic, rheumatological, sexual, cutaneous syndromes and overall mortality, with the risk rising five- to seven-fold for T2DM, three-fold for CVD, and one and a half-fold for all-cause mortality. The purpose of this narrative review is to examine metabolic syndrome as a "systemic disease" and its interaction with major internal medicine conditions such as CVD, diabetes, renal failure, and respiratory failure. It is essential for internal medicine practitioners to approach this widespread condition in a "holistic" rather than a fragmented manner, particularly in Western countries. Additionally, it is important to be aware of the non-invasive tools available for assessing this condition. Materials and Methods: We conducted an exhaustive search on PubMed up to July 2024, focusing on terms related to metabolic syndrome and other pathologies (heart, Lung (COPD, asthma, pulmonary hypertension, OSAS) and kidney failure, vascular, rheumatological (osteoarthritis, rheumatoid arthritis), endocrinological, sexual pathologies and neoplastic risks. The review was managed in accordance with the PRISMA statement. Finally, we selected 300 studies (233 papers for the first search strategy and 67 for the second one). Our review included studies that provided insights into metabolic syndrome and non-invasive techniques for evaluating liver fibrosis and steatosis. Studies that were not conducted on humans, were published in languages other than English, or did not assess changes related to heart failure were excluded. Results: The findings revealed a clear correlation between metabolic syndrome and all the pathologies above described, indicating that non-invasive assessments of hepatic fibrosis and steatosis could potentially serve as markers for the severity and progression of the diseases. Conclusions: Metabolic syndrome is a multisystem disorder that impacts organs beyond the liver and disrupts the functioning of various organs. Notably, it is linked to a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors. Non-invasive assessments of hepatic fibrosis and fibrosis allow clinicians to evaluate cardiovascular risk. Additionally, the ability to assess liver steatosis may open new diagnostic, therapeutic, and prognostic avenues for managing metabolic syndrome and its complications, particularly cardiovascular disease, which is the leading cause of death in these patients.

MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome.

The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3-MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.

Biomarkers of Oxidative Stress in Diabetic Microvascular Complications Review Article

Reactive oxygen species (ROS) are produced as a result of biochemical processes that are not in balance with the body's antioxidant defense mechanism. This metabolic dysfunction is referred to the oxidative stress (OS). Metabolic dysfunction-associated diseases are affected by changes in the redox balance. It is now widely recognized that oxidative stress significantly affects diabetes mellitus (DM), particularly type 2 diabetes. The biochemical changes associated with DM could disturb the oxidative milieu, leading to several microvascular complications in diabetic patients. Thus, DM is a perfect disease to explore the harmful consequences of oxidative stress and how to treat it. Oxidative stress triggered by hyperglycemia is an important contributor to the effects of diabetic microvascular diseases. Uncontrolled hyperglycemia carried by deficiencies in insulin secretion or action produces a number of problems, such as peripheral vascular disorders, nephropathy, neuropathy, retinopathy, increased morbidity and/or mortality, as well as the incidence of diabetes mellitus (DM) are rising globally. The development and progression of diabetic problems are strongly correlated with reactive oxygen species and oxidative stress, according to a wide body of research. This review aims to explore various markers of oxidative stress and the role of ROS in the pathogenesis and progression of late diabetic microvascular complications.

Lipids and apolipoproteins and the risk of vascular disease and mortality outcomes in women and men with type 2 diabetes in the ADVANCE study.

Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very-low-density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. The aim of this study was to assess the association between established risk markers, apolipoproteins and the risk of macro- and microvascular disease and death in a large study of women and men with diabetes and to assess the potential sex differences in the associations. Established lipid risk markers were studied in 11 140 individuals with type 2 diabetes from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial, and apolipoproteins (A1, B, ApoB/ApoA1 ratio) and VLDL cholesterol from nuclear magnetic resonance (NMR) lipid analyses in biobanked samples from 3586 individuals included in the ADVANCE case-cohort study (ADVANCE CC). Primary outcomes were major macro- and microvascular events and death. Cox proportional hazards models adjusted for confounders were used to quantify the associations (hazard ratio [HR] and 95% confidence intervals [CIs]) between established lipid risk markers and apolipoproteins with study outcomes. To address potential effect modification by sex, we investigated the association between the lipid risk markers and outcomes in subgroup analyses by sex. There was a lower risk of macrovascular complications for high-density lipoprotein (HDL) cholesterol (HR [95%CI] 0.88 [0.82-0.95]), a higher risk for total cholesterol (1.10 [1.04-1.17]), low-density lipoprotein (LDL) cholesterol (1.15 [1.08-1.22]), non-HDL cholesterol (1.13 [1.07-1.20]) and the total cholesterol/HDL ratio (1.20 [1.14-1.27]) but no significant associations with triglycerides from ADVANCE. There was a higher risk of macrovascular complications for the ApoB/ApoA1 ratio (1.13 [1.03-1.24]) from the ADVANCE CC. Only the ApoB/ApoA1 ratio (1.19 [1.06-1.34]), but none of the established lipid risk markers, was associated with a higher risk of microvascular complications. There were no statistically significant sex differences for any of the established lipid risk markers or apolipoproteins with any outcome. Using C-statistics and net reclassification improvement (NRI) did not detect significant improvement in predicting all outcomes by adding lipids or apolipoproteins to the models with confounding factors only. All established lipid risk markers, except triglycerides, were predictors of macrovascular complications, but not microvascular complications, in patients with type 2 diabetes. The ApoB/ApoA1 ratio was associated with major macro- and microvascular complications, but there was no evidence that apolipoproteins are better than established lipid risk markers in predicting cardiovascular complications in patients with type 2 diabetes.

High Resting Heart Rate Is Associated with Cardiovascular Death in Patients with Stroke, Independent of Sex

Introduction: High resting heart rate (HRHR) is a surrogate marker of increased sympathetic outflow. In acute stroke patients, HRHR is more commonly observed in women than in men. We analyzed whether HRHR (>86 bpm) adds incremental prognostic value for stroke outcomes in women. Methods: We analyzed data of 6,024 patients (2,568 women, mean age 68.98 years) with acute ischemic stroke from the Virtual International Stroke Trials Archive (VISTA). Results: Patients with HRHR were more often female (45.3 vs. 41.8%, p = 0.017), younger (66.0 ± 13.2 vs. 67.8 ± 12.6 years, p < 0.001), had higher baseline systolic blood pressure and more often diabetes. The primary composite endpoint of recurrent ischemic stroke, transient ischemic attack, myocardial infarction, or cardiovascular death within 90 days occurred more often in patients with HRHR (19.3 vs. 14.6%, p < 0.001). HRHR was associated with worse functional outcome at 90 days as assessed by modified Rankin Scale (mRS90: 3.03 ± 1.98 vs. 2.82 ± 1.94, p = 0.001). As exclusion of deceased patients (mRS90 of 6) resulted in a loss of association of HRHR with mRS90, it can be assumed that HRHR is mainly associated with poststroke vascular mortality, but not disability. Female sex was not associated with the primary endpoint but with adverse functional outcome measured by mRS90. Conclusion: HRHR was associated with adverse events and mortality after stroke. Despite a higher prevalence of HRHR in women, they did not reach the primary endpoint more often. However, women had a worse functional outcome (mRS) 3 months after stroke, independent of HRHR.

Association between Timing of Vascular Access Creation and Mortality in Patients Initiating Hemodialysis: A Nationwide Cohort Study in Japan

Introduction: The optimal time for vascular access (VA) creation remains controversial. Methods: We conducted a cohort study using data from the Japanese Society for Dialysis Therapy Renal Data Registry. Adult patients who started receiving hemodialysis in 2007 and had a permanent VA created were included. The exposure of interest was the timing of VA creation, categorized into three groups: early VA creation (defined as creation at least 4 months before hemodialysis initiation), just prior VA creation (creation between 1 and 3 months before hemodialysis initiation), and late VA creation (creation within 1 month of or after hemodialysis initiation). Cox regression analyses were used to compare 1-year all-cause mortality, with late VA creation as the reference group. Owing to the violations of the proportional hazards assumptions, the follow-up period was divided into “early” (1–4 months follow-up) and “late” (5–12 months follow-up) periods. Results: Overall, 1,280 (15.4%) of 8,322 patients died. Both early creation and just prior creation were associated with lower all-cause mortality in the early period compared with late creation. In the late period, the hazard ratios (HRs) for all-cause mortality decreased with earlier VA creation (adjusted HRs [95% confidence intervals]: 0.49 [0.35–0.67] for the early creation group and 0.63 [0.51–0.79] for the just prior creation group). Conclusion: Our study suggests that VA creation at least 1 month before hemodialysis initiation is associated with lower all-cause mortality in the early period, with earlier VA creation resulting in further mortality reduction in the late period.

Impaired glucose metabolism and the risk of vascular events and mortality after ischemic stroke: A systematic review and meta-analysis

BackgroundDiabetes mellitus (DM), prediabetes, and insulin resistance are highly prevalent in patients with ischemic stroke (IS). DM is associated with higher risk for poor outcomes after IS.ObjectiveInvestigate the risk of recurrent vascular events and mortality associated with impaired glucose metabolism compared to normoglycemia in patients with IS and transient ischemic attack (TIA).MethodsSystematic literature search was performed in PubMed, Embase, Cochrane Library on 21st March 2024 and via citation searching. Studies that comprised IS or TIA patients and exposures of impaired glucose metabolism were eligible. Study Quality Assessment Tool was used for risk of bias assessment. Covariate adjusted outcomes were pooled using random-effects meta-analysis.Main outcomesRecurrent stroke, cardiac events, cardiovascular and all-cause mortality and composite of vascular outcomes.ResultsOf 10,974 identified studies 159 were eligible. 67% had low risk of bias. DM was associated with an increased risk for composite events (pooled HR (pHR) including 445,808 patients: 1.58, 95% CI 1.34–1.85, I2 = 88%), recurrent stroke (pHR including 1.161.527 patients: 1.42 (1.29–1.56, I2 = 92%), cardiac events (pHR including 443,863 patients: 1.55, 1.50–1.61, I2 = 0%), and all-cause mortality (pHR including 1.031.472 patients: 1.56, 1.34–1.82, I2 = 99%). Prediabetes was associated with an increased risk for composite events (pHR including 8,262 patients: 1.50, 1.15–1.96, I2 = 0%) and recurrent stroke (pHR including 10,429 patients: 1.50, 1.18–1.91, I2 = 0), however, not with mortality (pHR including 9,378 patients, 1.82, 0.73–4.57, I2 = 78%). Insulin resistance was associated with recurrent stroke (pHR including 21,363 patients: 1.56, 1.19–2.05, I2 = 55%), but not with mortality (pHR including 21,363 patients: 1.31, 0.66–2.59, I2 = 85%).DiscussionDM is associated with a 56% increased relative risk of death after IS and TIA. Risk estimates regarding recurrent events are similarly high between prediabetes and DM, indicating high cardiovascular risk burden already in precursor stages of DM. There was a high heterogeneity across most outcomes.

Neutrophil to lymphocyte ratio and five-year mortality in patients with acute ischemic stroke

BackgroundPrevious studies linked neutrophil to lymphocyte ratio (NLR) with short-term mortality after acute ischemic stroke (AIS), but its relationship with long-term mortality remains unclear. This study investigates the association between NLR and five-year mortality in AIS patients. MethodWe analyzed 416 AIS patients from April 2012 to January 2016 at Zhangjiagang TCM Hospital. Admission NLR was divided into quartiles: Q1 (<2.00), Q2 (2.00–3.05), Q3 (3.06–5.46), and Q4 (≥5.46). We assessed 5-year all-cause and vascular mortality using Kaplan-Meier, Cox regression, and receiver operating characteristic (ROC) curve analyses. ResultsOver five years, 134 (32.2 %) all-cause deaths and 114 (27.4 %) vascular deaths occurred. Elevated NLR was significantly associated with increased risks of all-cause and vascular mortality. Multivariate Cox analysis identified stroke history (HR: 1.57, 95 % CI 1.08–2.30), baseline National Institutes of Health Stroke Scale (NIHSS) score (HR: 1.09, 95 % CI 1.05–1.12), and NLR (HR: 1.09, 95 % CI 1.05–1.12) as independent risk factors for all-cause mortality. These factors also predicted 5-year vascular mortality: stroke history (HR: 1.65, 95 % CI 1.10–2.49), NIHSS score (HR: 1.10, 95 % CI 1.06–1.13), and NLR (HR: 1.08, 95 % CI 1.05–1.10). NLR quartiles were significantly linked to both outcomes: all-cause mortality HRs were Q2 (1.87, 95 % CI 1.00–3.51), Q3 (2.40, 95 % CI 1.31–4.39), Q4 (2.77, 95 % CI 1.47–5.24), P for trend = 0.001; vascular mortality HRs were Q2 (1.76, 95 % CI 0.88–3.55), Q3 (2.34, 95 % CI 1.14–4.40), Q4 (2.57, 95 % CI 1.28–5.16), P for trend = 0.002. Kaplan-Meier survival analysis revealed significantly higher mortality rates in higher NLR quartiles (log-rank p < 0.001). ROC analysis identified optimal NLR cutoff values of 3.42 for predicting 5-year all-cause mortality (AUC 0.689) and 3.51 for vascular-cause mortality (AUC 0.700), with moderate sensitivity and specificity. ConclusionsHigher NLR at admission was linked with five-year all-cause mortality and mortality attributed explicitly to vascular causes in AIS patients.

Recurrent vascular events and mortality outcomes in patients with known atrial fibrillation, compared to atrial fibrillation detected early after stroke.

Atrial fibrillation (AF) detected after stroke (AFDAS) may represent a distinct clinical entity to that of known AF (KAF). However, there is limited long-term outcome data available for patients with AFDAS. More information regarding prognosis in AFDAS is required to inform future trial design in these patients. We used data (2015-2019) from a national prospective stroke registry of consecutive patients with acute ischaemic stroke and AF. AFDAS was defined as a new diagnosis of AF after stroke detected on electrocardiograph or cardiac monitoring. The co-primary endpoints were: (1) all-cause mortality; (2) recurrent major adverse cardiovascular events (MACE) at 3 years. Secondary endpoints were: (1) recurrent stroke; (2) functional outcome at discharge; (3) presence of co-existing stroke mechanisms. 583 patients were included. After a median follow-up of 2.65 years (cumulative 1064 person-years) 309 patients died and 23 had recurrent MACE. Compared with AFDAS, KAF was associated with a higher risk of all-cause mortality (adjusted Hazard Ratio (aHR) 1.56, 95% CI 1.12-2.18), a higher prevalence of co-existing stroke mechanisms (adjusted odds ratio (aOR) 2.28, 95% CI 1.14-4.59), but not poor functional outcome (aOR 1.61, 95% CI 0.98-2.64). A trend towards a higher risk of MACE was observed in patients with KAF, but this was limited by statistical power (aHR 2.90, 95% CI 0.67-12.51). All 14 recurrent strokes occurred in the KAF group (Log-rank p = 0.03). These data provide further evidence that AFDAS differs to KAF with respect to risk of recurrent stroke, MACE, and all-cause mortality.

Valve-in-valve transcatheter mitral valve replacement versus redo-surgical mitral valve replacement for degenerated bioprosthetic mitral valves: A systematic review and meta-analysis

Bioprosthetic mitral valve degeneration is traditionally treated with Redo-SMVR, but the latest ViV-TMVR procedure offers a less invasive and lower risk alternative. A systematic literature search was conducted on Cochrane Central, Scopus, and Medline (PubMed interface) electronic databases from inception till 15th April 2024. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes. We included a total of eleven studies with 11,931 patients in the final quantitative and qualitative analysis. When comparing ViV-TMVR with Redo-SMVR, no significant difference was found for 30-day mortality (P = 0.13) and 1-year mortality (P = 0.91), whereas patients in the ViV-TMVR showed significantly reduced incidence of stroke (P < 0.00001), In-hospital mortality (P), bleeding complications (P = 0.003), AKI (P = 0.0006), arrhythmias (P = 0.01), LVOT obstruction (P = 0.04), and PPI (P < 0.00001). Furthermore, no significant difference was observed between either group when comparing vascular complications (P = 0.97), 2-year mortality (P = 0.60) and 3-year mortality. ViV-TMVR was associated with a significant risk of paravalvular leakage (P = 0.008). Although, ViV-TMVR reduces the risk of complications associated with Redo-SMVR, larger studies are imperative to reach conclusive results.

Conventional and genetic associations of BMI with major vascular and non-vascular disease incidence and mortality in a relatively lean Chinese population: U-shaped relationship revisited.

Higher body mass index (BMI) is associated with higher incidence of cardiovascular and some non-cardiovascular diseases (CVDs/non-CVDs). However, uncertainty remains about its associations with mortality, particularly at lower BMI levels. The prospective China Kadoorie Biobank recruited >512 000 adults aged 30-79years in 2004-08 and genotyped a random subset of 76 000 participants. In conventional and Mendelian randomization (MR) analyses, Cox regression yielded adjusted hazard ratios (HRs) associating measured and genetically predicted BMI levels with incident risks of major vascular events (MVEs; conventional/MR 68 431/23 621), ischaemic heart disease (IHD; 50 698/12 177), ischaemic stroke (IS; 42 427/11 897) and intracerebral haemorrhage (ICH; 7644/4712), and with mortality risks of CVD (15 427/6781), non-CVD (26 915/4355) and all causes (42 342/6784), recorded during ∼12years of follow-up. Overall, the mean BMI was 23.8 (standard deviation: 3.2) kg/m2 and 13% had BMIs of <20 kg/m2. Measured and genetically predicted BMI showed positive log-linear associations with MVE, IHD and IS, but a shallower positive association with ICH in conventional analyses. Adjusted HRs per 5 kg/m2 higher genetically predicted BMI were 1.50 (95% CI 1.41-1.58), 1.49 (1.38-1.61), 1.42 (1.31-1.54) and 1.64 (1.58-1.69) for MVE, IHD, IS and ICH, respectively. These were stronger than associations in conventional analyses [1.21 (1.20-1.23), 1.28 (1.26-1.29), 1.31 (1.29-1.33) and 1.14 (1.10-1.18), respectively]. At BMIs of ≥20 kg/m2, there were stronger positive log-linear associations of BMI with CVD, non-CVD and all-cause mortality in MR than in conventional analyses. Among relatively lean Chinese adults, higher genetically predicted BMI was associated with higher risks of incident CVDs. Excess mortality risks at lower BMI in conventional analyses are likely not causal and may reflect residual reverse causality.

Suture closure AFtEr large bore vein access (SAFE-VEIN): A randomized, prospective study of the efficacy and safety of venous closure device.

Perclose ProGlide (PPG) Suture-Mediated Closure System™ is safe and can reduce time to hemostasis following procedures requiring arterial access. We aimed to compare PPG to figure of 8 suture in patients who underwent interventional catheter procedures requiring large bore venous access (LBVA) (≥13 French). In this physician-initiated, randomized, single-center study [clinicaltrials.gov ID: NCT04632641], single-stick venous access was obtained under ultrasound guidance. Eligible patients were randomized 1:1, and 100 subjects received allocated treatment to either PPG (n = 47) or figure of 8 suture (n = 53). No femoral arterial access was used in any patient. Primary outcomes were time to achieve hemostasis (TTH) and time to ambulation (TTA). Secondary outcomes were time to discharge (TTD) and vascular-related complications and mortality. Wilcoxon rank-sum test was used to compare TTH, TTA, and TTD. TTH (minutes) was significantly lower in PPG versus figure of 8 suture [median, (Q1, Q3)] [7 (2,10) vs. 11 (10,15) respectively, p < 0.001]. TTA (minutes) was significantly lower in PPG compared to figure of 8 suture [322 (246,452) vs. 403 (353, 633) respectively, p = 0.005]. TTD (minutes) was not significantly different between the PPG and figure of 8 suture arms [1257 (1081, 1544) vs. 1338 (1171,1435), p = 0.650]. There was no difference in minor bleeding or access site hematomas between both arms. No other vascular complications or mortality were reported. PPG use had lower TTH and TTA than figure of 8 suture in a population of patients receiving LBVA procedures. This may encourage same-day discharge in these patients.

Signs of Hemolysis Predict Mortality and Ventilator Associated Pneumonia in Severe Acute Respiratory Distress Syndrome Patients Undergoing Veno-Venous Extracorporeal Membrane Oxygenation.

Cell-free hemoglobin (CFH) is used to detect hemolysis and was recently suggested to trigger acute lung injury. However, its role has not been elucidated in severe acute respiratory distress syndrome (ARDS) patients undergoing extracorporeal membrane oxygenation (ECMO). We investigated the association of carboxyhemoglobin (COHb) and haptoglobin-two indirect markers of hemolysis-with mortality in critically ill patients undergoing veno-venous ECMO (VV-ECMO) with adjusted and longitudinal models (primary aim). Secondary aims included assessment of association between COHb and haptoglobin with the development of ventilator-associated pneumonia (VAP) and with hemodynamics. We retrospectively collected physiological, laboratory biomarkers, and outcome data in 147 patients undergoing VV-ECMO for severe ARDS. Forty-seven patients (32%) died in the intensive care unit (ICU). Average levels of COHb and haptoglobin were higher and lower, respectively, in patients who died. Higher haptoglobin was associated with lower pulmonary (PVR) and systemic vascular resistance, whereas higher COHb was associated with higher PVR. Carboxyhemoglobin was an independent predictor of VAP. Both haptoglobin and COHb independently predicted ICU mortality. In summary, indirect signs of hemolysis including COHb and haptoglobin are associated with modulation of vascular tone, VAP, and ICU mortality in respiratory ECMO. These findings suggest that CFH may be a mechanism of injury in this patient population.

Garlic ameliorates atherosclerosis by regulating ferroptosis pathway: an integrated strategy of network pharmacology, bioinformatic and experimental verification.

Atherosclerosis (AS) is a chronic arterial pathology and a leading cause of vascular disease-related mortality. Fatty streaks in the arterial wall develop into atherosclerosis and characteristic plaques. Clinical interventions typically involve lipid-lowering medications and drugs for stabilizing vulnerable plaques, but no direct therapeutic agent specifically targets atherosclerosis. Garlic, also locally known as DASUAN, is recognized as a widely sold herbal dietary supplement esteemed for its cardiovascular benefits. However, the specific mechanisms of garlic's anti-atherosclerotic effects remain unclear. This study aims to elucidate the pharmacological mechanisms through which garlic ameliorates atherosclerosis. The study identified the major active components and targets of garlic by screening the TCMSP, TCM-ID, and, ETCM databases. Atherosclerosis-associated targets were obtained from the DisGeNET, GeneCards, and DiGSeE databases, and garlic intervention targets were determined through intersection. Utilizing the intersected genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using R software. A garlic component-disease target network was constructed using Cytoscape. RNA-seq datasets from the GEO database were utilized to identify differentially expressed genes (DEGs) associated with atherosclerosis. The target genes were intersected with DEGs and the FerrDb (ferroptosis database). Molecular docking predicted the binding interactions between active components and the core targets. In vitro and in vivo experiments validated the identified core targets. The integration of garlic drug targets with atherosclerotic disease targets identified 230 target genes. Intersection with RNA-seq DEGs revealed 15 upregulated genes, including 8 target genes related to ferroptosis. Molecular docking indicated favorable affinities between garlic active components [Sobrol A, (+)-L-Alliin, Benzaldoxime, Allicin] and target genes (DPP4, ALOX5, GPX4). Experimental validation showed that GARLIC reduces the expression of ferroptosis-related genes in AS, suggesting its therapeutic potential through the regulation of ferroptosis. Garlic ameliorates atherosclerosis by targeting intra-plaque ferroptosis and reducing lipid peroxidation. These findings provide novel insights into the pharmacological mechanisms underlying the efficacy of garlic in treating AS.

Synthesis of β-Amino Carbonyl 6-(Aminomethyl)- and 6-(Hydroxymethyl)pyrazolopyrimidines for DPP-4 Inhibition Study.

Type-2 diabetes is a chronic progressive metabolic disease resulting in severe vascular complications and mortality risk. Recently, DPP-4 inhibitors had been conceived as a favorable class of agents for the treatment of type 2 diabetes due to the minimal side effects. Sitagliptin is the first medicine approved for the DPP-4 inhibitor. Its structure involved three fragments: 2,4,5-triflorophenyl fragment pharmacophore, enantiomerically β-amino carbonyl linker, and tetrahydrotriazolopyridine. Herein, we are drawn to the possibility of substituting tetrahydrotriazolopyridine motif present in Sitagliptin with a series of new fused pyrazolopyrimidine bicyclic fragment to investigate potency and safety. Two series of fused 6-(aminomethyl)pyrazolopyrimidine and 6-(hydroxymethyl) pyrazolopyrimidine derivatives containing β-amino ester or amide as linkers were successfully designed for the new DPP-4 inhibitors. Most fused 6-methylpyrazolopyrimidines were evaluated against DPP-4 inhibition and selectivity capacity. Based on research study, β-amino carbonyl fused 6-(hydroxymethyl)pyrazolopyrimidine possesses the significant DPP-4 inhibition (IC50 ≤ 59.8 nM) and presents similar with Sitagliptin (IC50 = 28 nM). Particularly, they had satisfactory selectivity over DPP-8 and DPP-9, except for QPP. β-Amino esters and amides fused 6-(hydroxymethyl)pyrazolopyrimidine were developed as the new DPP-4 inhibitors. Those compounds with a methyl group or hydrogen in N-1 position and methyl substituted group in C-3 of pyrazolopyrimidine moiety showed better potent DPP-4 inhibition (IC50 = 21.4-59.8 nM). Furthermore, they had satisfactory selectivity over DPP-8 and DPP-9 Finally, the docking results revealed that compound 9n was stabilized at DPP-4 active site and would be a potential lead drug.

Lipid Profile and Ankle Brachial Index in Obese Male Subjects with Obstructive Sleep Apnea: Cross sectional analytical study

Background &amp; Objective: Obstructive sleep apnea (OSA) and dyslipidemia are common medical disorders that independently increase vascular morbidity and mortality. Currently, there is no conclusive data indicating that Obstructive Sleep Apnea serves as a risk factor for disrupted lipid profiles and subclinical atherosclerosis, as assessed by ankle-brachial index (ABI). The objective of this cross-sectional study was to assess lipid profiles, blood sugar levels, and ankle brachial index in obese male participants with OSA and to compare them with obese individuals lacking OSA. Methods: In the present study, 64 obese males with BMI &gt; 25kg/m2 were included between ages 20 - 45 years. Subjects having acute or chronic inflammatory conditions were excluded. Obstructive sleep apnea (OSA) diagnosis involved two subjective assessment tools, the Berlin and STOP BANG questionnaires, followed by overnight portable pulse oximetry. The study participants were partitioned into two distinct groups, 32 with OSA and 32 without OSA. Following an overnight fast lasting between 10 to 12 hours, blood samples were collected. Fasting blood glucose and lipid profiles were then analyzed using a spectrophotometer. ABI was measured by using a Doppler ultrasound device. The data was collected and then entered SPSS version 22 and analyzed. The study utilized both Independent Samples t-test as well as Mann-Whitney U test to analyze and compare the quantitative variables across the two groups. Results Comparison of ABI between the study groups showed a non-significant difference p-value= 0.435. Fasting blood sugar levels showed insignificant difference (p-value 0.778) among the study groups. Comparison between the groups showed a nonsignificant difference in triglyceride levels (p= 0.413) cholesterol (p-value 0.523), HDL (p-value 0.190), and LDL (p-value 0.888). Conclusion Normal lipid profile and normal ABI indicate the absence of detectable atherosclerosis in young apparently healthy OSA subjects without known comorbidities.

The use of technology in type 2 diabetes and prediabetes: a narrative review.

The increasing incidence of type 2 diabetes, which represents 90% of diabetes cases globally, is a major public health concern. Improved glucose management reduces the risk of vascular complications and mortality; however, only a small proportion of the type 2 diabetes population have blood glucose levels within the recommended treatment targets. In recent years, diabetes technologies have revolutionised the care of people with type 1 diabetes, and it is becoming increasingly evident that people with type 2 diabetes can also benefit from these advances. In this review, we describe the current knowledge regarding the role of technologies for people living with type 2 diabetes and the evidence supporting their use in clinical practice. We conclude that continuous glucose monitoring systems deliver glycaemic benefits for individuals with type 2 diabetes, whether treated with insulin or non-insulin therapy; further data are required to evaluate the role of these systems in those with prediabetes (defined as impaired glucose tolerance and/or impaired fasting glucose and/or HbA1c levels between 39 mmol/mol [5.7%] and 47 mmol/mol [6.4%]). The use of insulin pumps seems to be safe and effective in people with type 2 diabetes, especially in those with an HbA1c significantly above target. Initial results from studies exploring the impact of closed-loop systems in type 2 diabetes are promising. We discuss directions for future research to fully understand the potential benefits of integrating evidence-based technology into care for people living with type 2 diabetes and prediabetes.

The impact of small peripheral vessels on transcatheter aortic valve implantation outcomes: assessing vascular complications and mortality risk in a high-volume centre

The impact of small peripheral vessels on transcatheter aortic valve implantation outcomes: assessing vascular complications and mortality risk in a high-volume centre