bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the toxicity of the antiPCSK9 vaccine in the animal model
Authors: Momtazi-Borojeni A A , Ataei S , Sarborji M R , Hatamipour M R , Tabatabaei S A , Banach M , Sahebkar A 
Published: October 2022

Abstract

Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel cholesterol-lowering treatment for decreasing the risk of atherosclerosis. We have previously shown that active immunization using the antiPCSK9 vaccine could decrease hypercholesterolemia and impede the development of atherosclerotic lesions in the experimental model of atherosclerosis.

Purpose
Here, we intended to evaluate the toxicity of the vaccine in healthy mice.

Methods
Forty male and female mice were divided into 4 experimental groups, including vaccine female (10 mice) and male (10 mice) groups receiving the antiPCSK9 vaccine as well as corresponding control female (10 mice) and male (10 mice) groups receiving the phosphate buffer. Vaccination was planned based on 4 subcutaneous injections of the vaccine formulation (10 μg/mouse) in bi-weekly intervals. The toxicity study was performed by the sub-acute protocol, 28 days after the last vaccine injection. To this end, the plasma levels of lipid indexes, urea, creatinine, AST, ALT, ALP, and fasting plasma glucose (FPG), as well as the CBC test were measured using commercial kits. To evaluate histopathological alterations, various tissues including the heart, liver, kidneys, spleen, and brain were studied using hematoxylin & eosin (H&E) staining by an expert pathologist. The severity of damage to the tissue was considered based on the standard classification; grade 1 as light damage, grade 2 as moderate damage, grade 3 as the bit-intense damage, and grade 4 as the intense damage.

Results
The results showed the non-significant changes of total cholesterol, triglyceride, HDL-C, FBS, creatinine, urea, AST, ALP, ALT, and PAB in the vaccinated mice when compared with control mice. However, plasma levels of LDL-C were significantly decreased in vaccinated male (by16.93±2.5 mg/dL, p=0.001) and female mice (by 22±2.7 mg/dL, p=0.001) when compared with corresponding control mice. CBS test indicated that there were no significant changes in the levels of WBC, RBC, HGB, HCT, MCH, MCHC, PLT, LYM, NEUT, PDW, and MPV in the vaccinated mice when compared with control mice. However, the levels of MCV, RDW-SD, and P-LCR were significantly decreased by (4.6±1.2 fL, p=0.02), (4±0.6 fL, p=0.001), and (0.13±0.01%, p=0.001), respectively, in vaccinated male mice when compared with control male mice. Evaluating histopathological alterations in various tissues indicated no significant adverse effects in vaccinated mice when compared to control mice.

Conclusions
The findings of the present study indicate that the antiPCSK9 is safe and exerts no adverse effects on the function of different organs and blood levels of the cellular and biochemical biomarkers in healthy mice.

Funding Acknowledgement
Type of funding sources: None.
Fish oil supplements increase atrial fibrillation risk in healthy individuals: a population-based cohort study and Mendelian randomization analysis
Authors: Rhee T , Choi E K , Ahn H J , Lee S R , Oh S , Lip G Y H 
Published: October 2022

Abstract

Background
There is a paucity of information on the risk of atrial fibrillation (AF) in healthy individuals taking fish oil supplements.

Purpose
We aimed to investigate the epidemiologic and causal relationships between fish oil supplement intake and the long-term risk of AF.

Methods
From the population-based UK Biobank, we selected healthy individuals without a history of AF, other cardiac arrhythmias, or cardiovascular diseases, who were not taking lipid-lowering medications or dietary supplements other than fish oil. The 10-year risk of AF in Fish-Oil-Users vs. Non-Users was evaluated in the total population and propensity-score matched cohort. The causal relationship between n-3 polyunsaturated fatty acids (PUFA) and AF was evaluated using a two-sample summary-level Mendelian randomization analysis with fixed effects robust inverse-variance weighted method, using genetic instruments from previous studies genome-wide association studies for n-3 PUFA levels and AF, respectively.

Results
A total of 338,199 participants (aged 55.2±8.1, 44.3% men) were analysed. Of these, 35.0% (n=118,300) was taking fish oil supplements. The 10-year risk of AF was significantly higher in the Fish-Oil-Users than in the Non-Users (3.83% vs. 2.91%, adjusted hazard ratio [HR] 1.05, 95% CI [1.01–1.10], P=0.023). The result was consistent in the propensity-score matched cohort (propensity-score matched HR 1.06, 95% CI [1.00–1.12], P=0.043). The increased risk of AF by fish oil supplement was prominent in low-risk participants with healthy lifestyles. Among n-3 PUFA, the docosapentaenoic acid (DPA) showed significant causal estimates for the increased risk of AF (odds ratio [OR] 1.15, 95% CI [1.08–1.22], P&lt;0.001), while higher eicosapentaenoic acid (EPA) levels caused a decrease of AF risk (OR 0.85, 95% CI [0.80–0.90], P&lt;0.001).

Conclusion
Fish oil supplement intake significantly increased the long-term risk of AF in a healthy population. The causal effect of fish oil intake on the risk of AF may depend on the specific types of n-3 PUFA.

Funding Acknowledgement
Type of funding sources: None.
Icosapent Ethyl diminishes CVD risk in smokers: REDUCE-IT smoking
Authors: Miller M , Bhatt D L B , Steg P G S , Brinton E A B , Jacobson T A J , Jiao L J , Tardif J C T , Ballantyne C M B , Budoff M B , Mason R P M 
Published: October 2022

Abstract

Background/Introduction
Cigarette smoking is associated with increased risk of cardiovascular (CV) events with effective treatment currently limited to smoking cessation. REDUCE-IT, a multinational, double-blind trial, randomised 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and CV risk, to icosapent ethyl (IPE) 4 grams/day or placebo, with a median of 4.9 years of follow-up. IPE reduced the primary composite (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularisation, or hospitalisation for unstable angina) and key secondary composite (CV death, nonfatal MI, or nonfatal stroke) endpoints 25% and 26%, respectively (each P&lt;0.0001), and individual components including stroke (28%), MI (31%), cardiac arrest (48%), and sudden cardiac death (31%) (all P≤0.01).

Purpose
To evaluate the effects of IPE on the risk of CV events and safety measures in patients by history of smoking.

Methods
The effect of IPE on first and total primary and key secondary endpoints was evaluated in the REDUCE-IT study using post hoc analyses based upon smoking history. Groups were classified as never smokers (n=3264), former smokers (n=3672), and current smokers (n=1241).

Results
Compared with placebo, IPE use in combined current and former smokers (n=4913) was associated with significant reductions in time to the primary composite endpoint (hazard ratio, 0.77 [95% CI, 0.68–0.87]; P&lt;0.0001) and in total events (rate ratio, 0.71 [95% CI, 0.61–0.82]; P&lt;0.0001) (Figure 1). These benefits remained significant when subdivided into current and former smokers and were associated with reductions in the key secondary composite endpoint (P=0.04, P=0.005), and the individual components of CV death or nonfatal MI (P=0.04, P=0.01) and fatal or nonfatal MI (P=0.009, P=0.01, respectively). Never smokers also had a significant benefit from IPE for both the primary and key secondary endpoints. Overall, there were similar estimated rates of first occurrences of CV death, MI, stroke, coronary revascularisation, or hospitalisation for unstable angina in current smokers (23.8%) and former smokers (23.0%) assigned to IPE compared with never smokers on placebo (25.7%) (Figure 2).

Conclusions
In the REDUCE-IT study, IPE treatment significantly reduced the risk of CV events in current and former smokers to levels observed in never smokers. While smoking cessation should always be recommended, these data raise the possibility that IPE treatment may markedly attenuate the CV hazards attributable to smoking.

Funding Acknowledgement
Type of funding sources: None.
Atherogenic lipoprotein profile associated with anthropometric indices of obesity and their association with cardiometabolic risk markers: a cross-sectional study in community
Authors: Wei D , Melgarejo J , Vanassche T , Van Aelst L , Janssens S , Verhamme P , Redon J , Zhang Z Y 
Published: October 2022

Abstract

Background
Obesity, especially abdominal fat accumulation, is strongly associated with various metabolic comorbidities. Whether simple anthropometric measures are independently associated with atherogenic lipoproteins is not completely clear.

Methods
We randomly recruited 505 participants (51.5% women; mean age: 48.8 years) from the Flemish community, who had undergone lipoprotein particle measurements by nuclear magnetic resonance spectroscopy and conventional lipid measurements. Each lipoprotein fraction was subgrouped into large, medium, and small subclass. Anthropometric measures included body mass index (BMI) and waist-to-hip ratio (WHR), and defined BMI obesity as BMI ≥30 kg/m2, and WHR obesity as WHR ≥0.85 (women) or 0.9 (men).

Results
In the multivariable logistic regression analysis, total very-low-density lipoprotein (VLDL) particle and its subclasses were positively associated with BMI obesity (adjusted odds ratio [OR] for total VLDL: 2.37; 95% confidence interval [CI]: 1.70–3.31) and WHR obesity (OR for total VLDL: 2.06 [95% CI: 1.55–2.73]). The level of total high-density lipoprotein (HDL) particle and its subclass was negatively associated with BMI (OR for total HDL: 0.63 [95% CI: 0.45–0.90), but not with WHR (P≥0.11). None of the low-density lipoprotein (LDL) particles was associated with the two types of obesity (P≥0.092). BMI was inversely associated with the size of LDL and HDL particles, whereas high WHR was significantly associated with smaller VLDL and HDL sizes. For conventional lipid measures, both BMI and WHR were independently associated with high triglyceride and remnant cholesterol, both mainly driven from VLDL particles, and low HDL cholesterol (P≤0.008). These associations were confirmed in multivariable linear regression analysis, except the association of BMI with HDL number and the association of WHR with HDL size. With partial least squares analysis, the lipoprotein profiles of BMI and WHR were significantly associated with a high 10-year cardiovascular disease risk score, the homeostasis model assessment-estimated insulin resistance (HOMA-IR), and C-reactive protein.

Conclusion
BMI and WHR were independently associated with high triglyceride-rich lipoproteins, decreased HDL cholesterol. The size of LDL and HDL was more consistently associated with BMI than WHR. The lipoprotein alterations may link obesity with high cardiometabolic risk.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The European Research Council; the European Research Area Net for Cardiovascular Diseases
Inflammation and cardiorespiratory fitness in overweight women and men: the FATCOR study
Authors: Midtboe H , Ulvik A , Meyer K , Cramariuc D , Ueland P M , Halland H , Gerdts E 
Published: October 2022

Abstract

Background
Women have more body fat compared to men, and adipose tissue is associated with chronic inflammation. Cardiorespiratory fitness has on the other hand been postulated to lower chronic inflammation. However, sex-specific associations of inflammation with cardiorespiratory fitness is less studied.

Purpose
To assess inflammatory markers in overweight and obese women and men according to cardiorespiratory fitness in the FAT associated CardiOvasculaR dysfunction (FATCOR) study.

Methods
Cardiorespiratory fitness was assessed by maximal oxygen uptake (VO2max) by cardiopulmonary exercise testing in 566 subjects (mean age was 48±9 years, 60% women) with body mass index (BMI) &gt;27.0 kg/m2. Participants were grouped according to sex, and fitness status identified from sex and age specific VO2max thresholds. C-reactive protein (CRP) and serum amyloid A (SAA) were analysed using Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight mass spectrometry. Serum levels of the kynurenine:tryptophan ratio (KTR) and pyriodoxic acid ratio (PAr) were measured by liquid chromatography tandem mass spectrometry. All inflammatory markers were log transformed before inclusion in linear regression analyses.

Results
In the total study population, 63% had obesity and 74% were cardiorespiratory unfit. Unfit women had the highest fat percentage and the highest serum levels of CRP and SAA compared to the other groups (p&lt;0.05), while serum levels of KTR and PAr were higher only compared to fit men (p&lt;0.05). In multivariable linear regression analyses in women, higher CRP (β −0.15, p=0.001), SAA (β −0.10, p=0.03) and PAr (β −0.09, p=0.03) were associated with lower VO2max after adjusting for age, fat percentage, hypertension and metabolic syndrome. In men, only higher PAr (β −0.14, p=0.02) was associated with lower VO2max in multivariable analyses adjusted for age, fat percentage and metabolic syndrome. In multivariable analyses in obese women only (n=213), higher CRP (β −0.15, p=0.01) and PAr (β −0.13, p=0.03) remained associated with lower VO2max, while in obese men (n=144) there was no significant associations between inflammatory markers and VO2max.

Conclusion
Among overweight subjects participating in the FATCOR study, cardiorespiratory unfit women had the highest serum levels of inflammatory markers. The association of inflammation with reduced cardiorespiratory fitness was more pronounced in women than men, in particular when obesity was present.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Western Regional Health Authority of Norway
Comparison of mechanistic pathways of metabolic bariatric surgery in diabetic patients
Authors: Chew N W S , Lin C X , Yeong T , Lim W H , Ng C H , Chin Y H , Muthiah M , Loh P H , Mok S F , Shabbir A , Khoo C M , Foo R 
Published: October 2022

Abstract

Background and aims
Metabolic bariatric surgeries are potentially efficacious treatment options in patients with type 2 diabetes mellitus (T2DM). However, previous meta-analyses focused on individual operative approaches rather than the mechanistic pathways behind different bariatric procedures. Thus, this updated network meta-analysis aimed to synthesize new evidence and comparatively evaluate the efficacy of bypass against restrictive procedures and standard first-line treatment for patients with T2DM.

Methods
Embase, Medline and trial registries were searched for randomized controlled trials on bariatric surgeries in patients with T2DM. A Bayesian network meta-analysis was conducted to compare between bypass, restrictive bariatric procedures, medical therapy and lifestyle intervention. Primary outcomes were T2DM remission and improvements in glycated haemoglobin (HbA1c). Secondary outcomes included changes in body mass index (BMI), lipoprotein levels and blood pressure.

Results
Thirty-two articles comprising 2,071 patients were included. Bypass surgery was statistically superior to restrictive procedures (RR: 2.57, 95% CrI: 1.36 to 5.43), medical therapy (RR: 35.29, 95% Crl: 10.56 to 183.23), and lifestyle intervention (RR: 40.51, 95% Crl: 5.32 to 402.59) in T2DM remission. Both bypass surgery and restrictive procedures were largely comparable in lowering HbA1c (MD: 0.02, 95% Crl: −0.03 to 0.08). In addition, bypass surgery significantly lowered BMI and blood pressure compared to other interventions. While restrictive procedures significantly increased high-density lipoproteins compared to bypass surgery, lifestyle intervention and bypass surgery were statistically superior to restrictive procedures in reducing low-density lipoproteins.

Conclusion
This study demonstrates that bypass surgery is superior to restrictive bariatric procedures in diabetes remission and glycaemic control. Additionally, significant metabolic advantages support the choice of bypass surgery over restrictive bariatric procedures in T2DM management.

Funding Acknowledgement
Type of funding sources: None.
Does dulaglutide impact a composite outcome reflecting atherosclerosis? A post-hoc analysis of the REWIND trial
Authors: Ferrannini G , Mellbin L , Kirabo F , Ramasundarahettige C , Herstein H G , Ryden L 
Published: October 2022

Abstract

Background
It has been postulated that the cardioprotective effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 2 diabetes (T2DM) may retard the progression of atherosclerosis.

Purpose
The aim of this post-hoc analysis of the REWIND trial was to test the hypothesis that treatment with dulaglutide impacts a clinical outcome that reflects atherosclerosis in patients with type 2 diabetes (T2DM).

Methods
In the double-blind, placebo-controlled REWIND trial recruiting 9901 patients (46.3% women, mean age 66 years) with T2DM and cardiovascular disease (CVD) or varying levels of CV risk, a weekly subcutaneous injection of dulaglutide 1.5 mg reduced the hazard of MACE by 12% versus placebo. This post hoc analysis assessed the impact of dulaglutide on atherosclerosis-related outcomes comprising a composite of the first of CV death, nonfatal myocardial infarction, nonfatal ischaemic stroke and any revascularization including coronary, peripheral or carotid. Cox proportional hazards models were used to estimate the effect of randomized treatment. The effect in selected subgroups (Table 1) was estimated by including each subgroup and an interaction term in the model for the primary outcome. The composite of any component of the primary endpoint and non-cardiovascular death was considered as a secondary outcome.

Results
The primary endpoint occurred in 799 (16.1%) patients in the dulaglutide group and 870 (17.6%) patients in the placebo group (incidence rates: 3.25/100 person-years vs 3.58/100 person-years; HR 0.91, 95% CI 0.83–1.00; p=0.05) during a median follow-up of 5.4 years. This finding was consistent regardless of sex, body mass index, previous CVD or not and diabetes duration. The incidence of the secondary outcome was also lower in the dulaglutide group (HR; 95% CI: 0.91; 0.83–0.99; p=0.03).

Conclusion
Dulaglutide was associated with a 9% reduced index of atherosclerosis in patients with T2DM and CVD or high CV risk. This finding supports the hypothesis that dulaglutide may retard progression of atherosclerosis.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): EliLilly and Company
Causes of excess mortality in diabetes patients without coronary artery disease
Authors: Olesen K , Gyldenkerne C , Thrane P G , Maeng M 
Published: October 2022

Abstract

Background
Diabetes (DM) patients without coronary artery disease (CAD) by coronary angiography have a similar risk of myocardial infarction and cardiac death as non-DM patients without CAD. Yet, even with absence of CAD, patients with DM have higher mortality compared to non-DM patients.

Aims
To examine the underlying causes of death in patients undergoing coronary angiography depending on DM and CAD.

Methods
We included every patient with no previous history of CAD who underwent coronary angiography in Western Denmark between 2003–2016. Patients were stratified by DM and CAD and followed for a maximum of 10 years. We estimated the 10-year cumulative risk of all-cause death and cause-specific death. Causes of death were categorized as “cardiovascular”, “pulmonary”, “cancer”, “renal”, “bleeding-related”, and “other” based on ICD-10 codes listed as underlying causes of death obtained from death certificates. Deaths where DM was listed as the underlying cause of death (i.e. ICD-10 code DE1) were included in the category “other”.

Results
We included 132,432 patients, of whom 33% had neither DM nor CAD, 5% had DM only, 51% had CAD only, and 11% had both DM and CAD. Mean age was 64 years. Median follow-up was 6.3 year (inter-quartile range 3.8–10.0). During follow-up, 35,036 (26.5%) patients died. Patients with both DM and CAD had the highest 10-year mortality (47.4%, 95% CI 46.3–48.4), followed by CAD only (33.3%, 95% CI 32.8–33.7), DM only (30.7%, 95% CI 29.3–32.2), and patients with neither DM nor CAD (21.6%, 95% CI 21.1–22.1). The proportion of cardiovascular deaths were similar in patients with DM only (29.2%, 95% CI 27.0–31.5, Figure) and patients with neither DM nor CAD (29.7%, 95% CI 28.8–30.7). Patients with DM were more likely to die from causes categorized as “other” compared to patients with neither DM nor CAD [38.4% (95% CI 36.0–40.9) versus 30.2% (95% CI 29.3–31.2)]. Among patients with DM only, 43.7% of deaths classified as “other” were attributable to DM-related complications such as ketoacidosis and diabetic nephropathy.

Conclusion
Despite absence of CAD, DM remained associated with increased mortality. Excess mortality was primarily driven by patients dying of DM-related microvascular complications and ketoacidosis. Thus, despite absence of CAD, patients with DM require continued preventative measures to reduce DM-related mortality.

Funding Acknowledgement
Type of funding sources: Public hospital(s). Main funding source(s): Aarhus University Hospital