bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping renal impairment and cardiac structure and function: observation and genetic insights from 30,000 cardiac magnetic resonance images
Authors: Liu J , Huang H , Lu X , He Y , Tang N , Chen J , Liu Y 
Published: October 2024

Abstract

Background
The elevated risk of heart failure in kidney dysfunction is well-identified. However, the early alteration of renal impairment on cardiac structure and function, as well as genetic susceptibility associations have not been well reported. We sought to map the early effects of kidney dysfunction on cardiac remodeling with the cardiac magnetic resonance images (MRI) and identify share genetic correlation in community population.

Methods
Of 29,592 subjects underwent MRI test were recruited from the population-based UK Biobank study from 2006-2010. Renal function was assessed by historical identified chronic kidney disease (CKD), log-transfrom estimated glomerular filtration rate (eGFR) based on cystatin C (eGFRCysC) or serum creatine (eGFRSCr) and urine albumin-to-creatinine ratio (uACR). Multivariable generalized linear regression was used to analyse the association of 4 different kidney function indexes with six cardiac MRI-derived traits: left atria and ventricle, right atria and ventricle, and ascending and descending aortas. Genetic correlation between renal function decline and cardiac traits were evaluated by Mendelian randomization (MR).

Results
The mean (SD) age of subjects was 54.9 (7.5) years, and 51.1% were women. Observational and MR analysis showed a reliable relationship of lower level of eGFRCysC with reduced biventricular end systolic volume, biventricular ventricular end diastolic volume and left ventricular mass, and lower level of eGFRSCr with reduced left ventricular cardiac output.

Conclusions
Our study indicates the observational and genetic correlation between kidney function decline and cardiac measurements. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics.Renal function decline & Cardiac Imaging
Inhibition of ceramide de novo synthesis mitigates atherosclerosis
Authors: Chong S Y , Louise R A , Huang C , Ting H J , Seah F , Qi X , Pastorin G , Storm G , Wang J W 
Published: October 2024

Abstract

Background
Atherosclerosis is the primary underlying cause of cardiovascular disease. Plasma ceramides are positively correlated with an increased risk of major adverse cardiovascular events and serve as an alternative biomarker for cardiovascular disease. Importantly, ceramide levels are notably higher within atherosclerotic plaques. Therefore, inhibiting the ceramide de novo synthesis pathway in the plaques may serve as a potential therapeutic intervention for atherosclerosis.

Purpose
We aim to assess the therapeutic efficacy of a nano-formulation of myriocin, a targeted inhibitor of serine-palmitoyl transferase, the key enzyme in ceramide de novo synthesis, in treating atherosclerosis.

Methods
Myriocin was encapsulated within the hydrophobic core of lipid-based nanoparticles specifically designed for this study. Male and female ApoE-/- mice, subjected to an 8-week high-fat diet regimen, received either myriocin nanoparticles (treatment group) or empty nanoparticles (control group) intravenously once a week for 4 weeks at a dose of 1.3 mg/kg body weight while still on the high-fat diet. At the study endpoint, whole aortas were harvested and subjected to Oil Red O staining to quantify the total lesion area. Histological staining was performed on serial sections of the aortic root to analyze the cellular composition within the plaques. Plasma samples were collected for total cholesterol measurement and lipidomic analysis.

Results
Upon intravenous administration, myriocin nanoparticles exhibited preferential accumulation in atherosclerotic plaques. Compared to control mice, those treated with myriocin nanoparticles exhibited a 58.7% reduction in total lesion area in male ApoE-/- mice and a 64.6% reduction in female ApoE-/- mice (p&lt;0.0001). Consistently, the lesion areas in the aortic root were also reduced in the treated mice. Notably, myriocin nanoparticles enhanced collagen and alpha-smooth muscle content, while reducing macrophages and neutral lipids within the plaques, leading to a reduced plaque vulnerability index and preventing rupture events. TUNEL staining revealed reduced cellular apoptosis in the atherosclerotic plaques, resulting in a smaller necrotic area in the treated mice. In vitro experiments demonstrated that myriocin nanoparticles effectively inhibited lipopolysaccharide-induced inflammatory response and oxidative stress in bone marrow-derived macrophages. Furthermore, myriocin nanoparticles restored the gene expression of enzymes involved in the fatty acid beta-oxidation pathway, such as ACOX1 and CPT1A, in foam cells.

Conclusion
Using myriocin nanoparticles to inhibit excessive ceramide production due to inflammation reduces inflammation, and ROS production, while restoring fatty acid beta-oxidation in macrophages. This approach emerges as an effective strategy for targeting ceramide de novo synthesis within atherosclerotic plaques, thereby mitigating atherosclerosis progression and improving plaque stability.
Association between genetic predisposition of AF and the risk of ischemic stroke and thromboembolism
Authors: Lai Y , Li S , Li M , Jiang C , Sang C , Du X , Dong J , Ma C 
Published: October 2024

Abstract

Background
Ischemic stroke and thromboembolism are the major complications of atrial fibrillation (AF), however, its association with genetic background of AF remains unclear.
To investigate the association between genetic predisposition of AF underlying common variants and the risk of ischemic stroke and thromboembolism.

Methods
We included unrelated individuals with non-valvular AF from UK biobank. The polygenic risk scores of AF (PRSAF) was calculated for each individual using the effect weight from a previous study which has been validated in both European and mixed-ancestry population[1, 2]. The SNPs from the original score were lifted over to GRCh38 and 6514708 of 6730541 were available in the UK biobank genotype data. The clinical data was defined by ICD-10 code. The primary endpoint is ischemic stroke or thromboembolism resulting in hospitalization after first AF diagnosis.

Results
A total of 28810 unrelated patients were included in the study. Among them, 4064 had PRSAF over 90th percentile of the general population, and were considered having high genetic risk. The rest 18746 with per SD increase in PRSAF lower than 90th percentile of the general population were considered having lower genetic risk. Generally, age and sex adjusted model demonstrated that per standard deviation change in PRSAF is associated with 9% increase in the risk of stroke or thromboembolism (HR=1.09, 95%CI: 1.03-1.14), and patients with high genetic risk was associated with 15% increase in the risk of stroke or thromboembolism (HR=1.15, 95%CI: 1.02-1.31).The result remained stable when further adjusted for clinical risk factors (1.09, 95%CI: 1.04-1.15 per SD increase in PRSAF) and competing risk of death (1.10, 95%CI: 1.05-1.16 per SD increase in PRSAF). There was no interaction between CHA2DS2-VASc score risk stratification and the per SD increase in PRSAF (P interaction = 0.751, Figure 1A). However, the association between per SD increase in PRSAF and the event tended to be affected by age at AF onset (HR = 1.02 95%CI: 0.94, 1.11 for early onset AF; HR = 1.12 95%CI: 1.05, 1.19 for non-early onset AF, P for interaction = 0.062, Figure 1B). Multi-variate COX regression including PRSAF, components of CHA2DS2-VASc score, and other AF risk factors revealed that history of stroke/thromboembolism, age over 65 years, hypertension, diabetes and high AF genetic risk were significantly associated with the outcome (Figure 1C). To evaluate the importance of these risk factors, average population attributable fraction for 10-year risk of stroke/thromboembolism in the study population was calculated, indicating that genetic risk of AF is responsible for 3.26% (0.89%-5.63%) of the events (Figure 1D).

Conclusion
Genetic predisposition of AF underlying common variants is associated with ischemic stroke and thromboembolism independent of clinical risk factors. But its role in different AF populations, like early onset AF, remains further investigation.Figure 1
Direct oral anticoagulants exhibit lower risks of mortality and bleeding compared to vitamin-k antagonists in atrial fibrillation patients on chronic hemodialysis: a meta-analysis
Authors: Goyal A , Jain H , Maheshwari S , Fatima L , Javed B , Shrestha A B , Mahalwar G 
Published: October 2024

Abstract

Background
Atrial fibrillation (AF) is a common arrhythmia in patients with chronic kidney disease (CKD). Although direct oral anticoagulants (DOACs) are equally or more effective than vitamin K antagonists (VKAs) in patients with moderate CKD, evidence claiming the benefits of DOACs over VKAs in patients on hemodialysis (HD) is scarce.

Purpose
This meta-analysis aimed to assess the outcomes of patients with AF on chronic HD by comparing the clinical outcomes of DOACs versus VKAs.

Methods
A systematic literature search was conducted across various databases to retrieve studies focusing on efficacy and safety outcomes in patients with AF on chronic hemodialysis comparing DOACs and VKAs. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using the Mantel-Haenszel random-effects model in Review Manager 5.4. Statistical significance was set at p &lt;0.05.

Results
Nine studies with 39, 831 patients were included. The risk of all-cause mortality [RR: 0.73; 95% CI: 0.60, 0.88; p=0.001], major bleeding [RR: 0.63; 95% CI: 0.52, 0.76; p&lt;0.00001], gastrointestinal bleeding [RR: 0.67; 95% CI: 0.53, 0.85; p=0.0009], intracranial hemorrhage [RR: 0.57; 95% CI: 0.38, 0.84; p=0.004], all-cause stroke [RR: 0.64; 95% CI: 0.51, 0.81; p=0.0001], and ischemic stroke [RR: 0.53; 95% CI: 0.29, 0.96; p=0.04] were lower in the DOAC group than in the VKA group. The risk of cardiovascular-related death [RR: 1.34; 95% CI: 0.69, 2.60; p=0.39], and clinically relevant non-major bleeding [RR: 0.90; 95% CI: 0.75, 1.08; p=0.26] showed no significant differences.

Conclusion
The risks of all-cause stroke, ischemic stroke, all-cause mortality, major bleeding, gastrointestinal bleeding, and intracranial hemorrhage in the patients with AF undergoing chronic HD were lower in the DOAC group than in the VKA group. Further large-scale RCTs are needed to generate more robust evidence through adequately powered studies, leading to conclusive results that are applicable to real-world scenarios.
The high-dose statin treatment reduces neutrophil extracellular traps formation in patients with coronary artery disease
Authors: Stepien K , Natorska J , Zabczyk M , Zalewski J , Jawien J , Undas A 
Published: October 2024

Abstract

Background
Neutrophil extracellular traps formation (NETosis) is currently considered as an important mediator in atherosclerosis and atherothrombosis. However, the impact of high-dose statin treatment, as potent cholesterol-lowering agents with pleiotropic effects, on NETosis in coronary artery disease (CAD) has been poorly described.

Purpose
We sought to assess whether in CAD patients the recommended statin treatment intensification is associated with changes in NETs-related markers and if such changes can alter fibrin clot properties.

Methods
130 patients with advanced CAD, who did not achieve the target low-density lipoprotein cholesterol (LDL-C) were included. Before and at least 6 months after initiation of high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) citrullinated histone H3 (H3cit), myeloperoxidase (MPO) and neutrophil elastase (NE) as markers associated with NETosis were assessed in relation to C-reactive protein (CRP), thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis proteins.

Results
At baseline, NETosis did not differ depending on gender and cardiovascular risk factors but H3cit correlated with MPO (R=0.543, P&lt;0.001) and CRP (R=0.540, P&lt;0.001). All NETosis markers were inversely correlated with Ks. Median LDL-C reduction by 25% (P&lt;0.001) on high-dose statin treatment was independent from H3cit reduction by 30.4%, MPO by 28.1%, and NE by 25.5% (in all P&lt;0.001, Figure 1). The ΔH3cit and ΔMPO, but not ΔNE were associated with ΔCRP (R=0.855, P&lt;0.001; R=0.250, P=0.004, respectively), Δthrombin activatable fibrinolysis inhibitor (TAFI) (R=0.385, P&lt;0.001; R=0.245, P=0.005), and inversely with ΔKs (R=-0.315, P&lt;0.001; R=-0.395, P=0.001). In multivariable analysis the H3cit decrease was independently associated with ΔCRP (β=0.771, P&lt;0.001), ΔTAFI (β=0.125, P=0.013) and Δfibrinogen (β=0.106, P=0.034) but not with ΔLDL-C.

Conclusions
As has been shown for the first time high-dose statin treatment reduces levels of NETs-related markers, regardless of lipid-lowering effect in CAD patients.
Long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive intracerebral hemorrhage in mice
Authors: Bian X , Guo Y , Chen J , Song W , Dou K 
Published: October 2024

Abstract

Background
Intracerebral hemorrhage (ICH) is a catastrophic disease with limited treatment options. Statins and low low-density lipoprotein cholesterol (LDL-C) levels have been reported to be associated with increased risk of ICH. Safety concerns of statins were raised as statins become the cornerstone of anti-atherosclerosis therapy. To date, the effect of statins on the incidence of ICH still remains a controversial topic.

Purpose
The aim of this study was to investigate the effect of atorvastatin on the occurrence and progression of hypertensive ICH in mice.

Methods
Male wild-type C57BL/6J mice, 13 months old, were randomly divided into atorvastatin (Ato, n=20) group and vehicle (Veh, n=20) group. The atorvastatin group and vehicle group were given atorvastatin (20 mg/kg) and same volume of 0.5% sodium carboxymethylcellulose by oral gavage for 8 weeks, separately. Angiotensin II (Ang II) and L-NAME were then used to induce hypertensive ICH. The time of stroke symptom onset was documented. Hemorrhage volumes were measured by spectrophotometric hemoglobin assay.

Results
After 8 weeks of atorvastatin or vehicle administration, serum LDL-C levels were significantly lower in the mice treated with atorvastatin than vehicle controls (0.705 vs. 1.008 mmol/L, P&lt;0.001). The administration of atorvastatin did not show significant effects on the systolic blood pressure (SBP) levels when compared with the vehicle group (164 vs. 166 mmHg, P=0.497) after the induction of Ang II and L-NAME. Hemorrhage was observed in brain morphology, and was further verified by hematoxylin and eosin staining or MRI scans in mice that showed signs of stroke. During the 28-day experimental period, 75% (15/20) of mice in the atorvastatin group developed signs of ICH, and 70% (14/20) of mice in the vehicle group developed in the similar time window. The incidence of hypertensive ICH had no significant difference between atorvastatin and vehicle groups (Log-rank P=0.761). Hemorrhage volumes were also comparable between the two groups (1.462 vs. 1.392 uL, P=0.788).

Conclusion
Reducing serum LDL-C levels by long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive ICH in middle-aged mice.
Ezetimibe use and mortality after myocardial infarction: a nationwide cohort study
Authors: Kyto V , Tornio A 
Published: October 2024

Abstract

Background
Inhibition of intestinal cholesterol absorption by ezetimibe improves outcomes after myocardial infarction (MI), yet real-world data on ezetimibe is lacking.

Purpose
To study usage and outcome impact of ezetimibe after MI.

Methods
Consecutive MI patients in Finland (2010-2018) were retrospectively studied (N=57,505; 65% men; mean age 69 years). Study data were combined from national registries. The median follow-up was 4.5 (IQR 2.8-7.1) years. Differences between groups were adjusted with multivariable regression. Ezetimibe use was studied with competing risk analyses. Median follow-up was 4.5 (IQR 2.8-7.1) years.

Results
The cumulative incidence of ezetimibe use was 3.7% at 90-days, 13.4% at 5-years and 19.8% at 10-years. Younger age was the strongest predictor for ezetimibe use (adj. sHR 6.67; CI 5.88-7.69 for patients aged &lt;60 vs. ≥80 years). Women were more likely to use ezetimibe during follow-up than men. The average proportion of patients using ezetimibe during follow-up was 6.8%. (11.7% at 10-years). Ezetimibe was discontinued by 43.6% of patients during the follow-up. Patients with early ezetimibe after MI had lower all-cause mortality during follow-up (33.6% vs. 45.1%; adj. HR 0.77; CI 0.69-0.86; p&lt;0.0001). Early ezetimibe use was associated with lower mortality irrespective of sex, age, atrial fibrillation, diabetes, heart failure, malignancy, revascularization, or statin use. Ongoing ezetimibe therapy during follow-up was associated with lower mortality in time-dependent analysis (adj. HR 0.53; CI 0.48-0.59; p&lt;0.0001).

Conclusion
Ezetimibe is associated with lower risk of death after MI, but therapy use is limited and discontinuity is frequent.
SHR-1918, a monoclonal antibody against angiopoietin-like 3, in healthy subjects: a randomized, double-blind, placebo-controlled, phase 1 study
Authors: Xie Z , Ye L , Hu W , Lv C , Zhu M 
Published: October 2024

Abstract

Background
Low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) are important risk factors for atherosclerotic cardiovascular disease. Angiopoietin-like 3 (ANGPTL3) is involved in the regulation of lipid metabolism and can increase serum TG and LDL-C levels by reducing their clearance. SHR-1918 is an ANGPTL3 monoclonal antibody developed to inhibit ANGPTL3 activity, thereby reducing the level of TG and LDL-C.

Purpose
This phase 1 single ascending dose study aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1918 in healthy subjects.

Methods
Six dose cohorts were planned, including 100, 300, 450, 750, 900 (optional), and 1200 (optional) mg. For each cohort, 12 healthy subjects were enrolled and randomized (9:3) to receive single subcutaneous SHR-1918 or placebo. Subjects were observed for seven days post-dose and followed up to Day 148 for the 100 mg cohort and Day 190 for the other dose cohorts. The primary endpoints were safety and tolerability.

Results
A total of 72 subjects were enrolled in the six dose cohorts from 100 to 1200 mg (SHR-1918, n = 54; placebo, n = 18). SHR-1918 was well-tolerated at tested doses. Treatment-emergent adverse events (TEAEs) were reported in 49 (90.7%) subjects in the SHR-1918 group and 17 (94.4%) subjects in the placebo group. The most common TEAEs were upper respiratory tract infection (25.9% with SHR-1918 vs. 27.8% with placebo), protein urine present (22.2% vs. 22.2%), and blood uric acid increased (16.7% vs. 16.7%). All TEAEs were mild or moderate in severity. There were no serious adverse events or TEAEs leading to death. Serum concentration of SHR-1918 generally increased with increasing doses. Maximum serum concentration was reached 8.0 to 10.0 days after injection, and mean t½ was 29.4 to 53.3 days across the dose range. SHR-1918 exposure exhibited in a slightly greater-than-dose-proportional manner from 100 to 1200 mg. Serum LDL-C and TG levels markedly and rapidly decreased in all SHR-1918 dose cohorts and remained under the baseline value up to the end of follow-up period for the higher doses, whereas those in the placebo group were above baseline at most follow-up visits (Figure 1 and 2). In the 750 to 1200 mg cohorts, the largest decline in LDL-C from baseline ranged from -46.5% to -49.1%, and the maximum decrease in TG ranged from -67.4% to -82.8%. On Day 85, there remained to be 36.9% to 39.0% reduction in LDL-C and 59.9% to 79.1% reduction in TG for the higher doses. Anti-drug antibody was not detected in SHR-1918-treated subjects.

Conclusions
SHR-1918 was well-tolerated and showed promising efficacy in healthy subjects. A phase 2 study has initiated to evaluate SHR-1918 in hyperlipidemic patients (NCT06109831).Serum LDL-C after SHR-1918 injectionSerum TG after SHR-1918 injection
Impact of SGLT2 inhibitor dapagliflozin on myocardial protein profile in rats with long-standing Type 1 diabetes mellitus
Authors: Rodrigues E A , Dionizio A , Rosa C M , Campos D H S , Damatto F C , Borim P A , Pagan L U , Oliveira J P G , Souza L M , Gatto M , Araujo T T , Buzalaf M A , Cunha T M , Okoshi K , Okoshi M P 
Published: October 2024

Abstract

Background
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. However, as most trials have focused on Type 2 DM, the impact of SGLT2 inhibitors on Type 1 DM remains unclear.

Objective
To investigate the effects of long-term treatment with SGLT2 inhibitor dapagliflozin on the left ventricular (LV) proteome in Type 1 DM rats.

Methods
Male Wistar rats were divided into three groups: Control (C, n=7); Diabetes (DM, n=6); and Diabetes treated with Dapagliflozin (DM+DAPA, n=8) for 30 weeks. Diabetes was induced by streptozotocin (40 mg/kg). Dapagliflozin was added to chow at 5 mg/kg/day. Label-free mass spectrometry was used to assess LV proteome using a nanoAcquity UPLC-Xevo QTof MS system and ProteinLynx Global Server (PLGS) software. Cytoscape software, Cluster Marker, and Cluego plugins were used for bioinformatic analysis. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn.

Results
Dapagliflozin increased body weight (C 574±43; DM 339±31*; DM+DAPA 413±30*# g; p&lt;0.05: * vs C; # vs DM) and reduced glycemia [C 108 (101–111); DM 554 (529–562)*; DM+DAPA 343 (237–416)*# mg/dL; p&lt;0.05: * vs C; # vs DM]. One rat died in C and two in DM+DAPA. A total of 252 differentially expressed proteins were identified. Most proteins identified in the networks were downregulated in DM vs C and upregulated in DM+DAPA vs DM. Six proteins related to energy metabolism (Atp5j, P21571; CKm, P00564; Ak1, P39069; Atp5h, P31399; Mdh1, O88989; and Idh2, P56574), four involved in myocyte excitation-contraction (Act1, P68065; Casq2, P51868; SERCA1, Q64578; and SERCA2a, P11507), and two associated with oxidative stress (Sod1, P07632; and Sod2, P07895) were upregulated in DM+DAPA x DM. Comparing DM with C, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to gap junction (25.6%), necroptosis (25.6%), and fatty acid degradation (25.6%), and for downregulated proteins was related to Alzheimer disease (27.3%), cardiac muscle contraction (25%) and glycolysis/gluconeogenesis (13.6%). Comparing DM+DAPA with DM, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to Parkinson disease (18.3%), cardiac muscle contraction (14.2%), citrate acid cycle (9.47%), necroptosis (8.88%), and cGMP-PKG signaling (7.10 %), and for downregulated proteins was related to ketone bodies synthesis and degradation (100%).

Conclusion
Dapagliflozin is safe and prevents changes in the expression of proteins related to energy metabolism, cardiac muscle contraction, and oxidative stress in Type 1 diabetes mellitus rats. These results offer new insights into the cardioprotective mechanisms of dapagliflozin in Type 1 diabetes mellitus.