bluuebunny/crossref_metadata_2025 huggingface dataset:
Late gadolinium enhancement patterns in severe symptomatic high-gradient aortic stenosis
Authors: Maltes S , Abecasis J , Santos R R , Oliveira L , Mendes G S , Guerreiro S , Lima T , Freitas P , Ferreira A , Cardim N , Gil V M , Mendes M
Published: October 2022

Background

Left ventricular (LV) remodeling in patients with severe aortic valve stenosis (AS) is a complex process that goes beyond hypertrophic response and may involve reparative/replacement fibrosis. Currently, cardiac magnetic resonance (CMR) is the gold-standard imaging technique for detecting focal myocardial fibrosis through late gadolinium enhancement (LGE). However, myocardial fibrosis prevalence and distribution is quite variable among series. Our goal was to assess LGE prevalence and distribution pattern in severe symptomatic high-gradient AS.

Methodology

Single-center prospective cohort of 132 patients with severe symptomatic high-gradient AS (mean age 73±11 years; 48% male, mean valvular transaortic gradient 60±20 mmHg; mean aortic valve area 0.7±0.2 cm2/m2; mean LV ejection fraction by 2D echocardiogram 58±9%), all with normal flow (except one) undergoing surgical aortic valve replacement. Those with previous history of acute myocardial infarction, ischemic cardiomyopathy or other cardiomyopathy were excluded. All patients performed 1.5T CMR assessment with LV myocardium tissue characterization prior to surgery. Segmental LGE presence was assessed by two independent operators and classified according to the AHA 16 segment model, using 5-standard deviations from remote myocardium as the signal intensity cut-off for LGE identification and quantification.

Results

Overall, 96 patients (74%) had non-ischemic LGE (median LGE mass 3.2 g [IQR 0.2–8.3] g; median percentage of LGE myocardial mass 2.5% [IQR 0.1–6.1]%); 22 patients [17%] with exclusively junctional LGE); in one patient an incidental ischemic scar (subendocardial distribution) was identified. No cases of subepicardial distribution were found. Intramyocardial LGE was most frequently observed in basal and mid-anterior and inferior interventricular septum – see Figure 1. In these segments, LGE was most often junctional at right-ventricular insertion points (54%), followed by mid-wall LGE (32%) or both sites involvement (14%).

Conclusion

LGE is frequent in symptomatic high-gradient AS patients with preserved left ventricular ejection fraction, most often presenting as junctional enhancement in basal/mid-anterior and inferior interventricular septum. Future studies may address whether distinct LGE patterns may impact patient prognosis.

Funding Acknowledgement

Type of funding sources: None.
Could cholesterol remnants predict long-term cardiovascular events after NSTACS?
Authors: Martinon-Martinez J , Alvarez Alvarez B , Gonzalez Ferrero T , Garcia-Rodeja Arias F , Otero Garcia O , Jimenez Ramos V , De La Fuente Rey A , Cacho Antonio C , Cid Alvarez B , Iglesias Alvarez D , Agra Bermejo R , Rigueiro Veloso P , Garcia Acuna J M , Gonzalez Juanatey J R
Published: October 2022

Introduction

The remnant cholesterol (RC) promotes atherosclerotic cardiovascular disease. However, the prognostic impact of elevated RC levels in patients with non-ST-elevation acute coronary syndrome have not been established in the current population. Then, our objetive is investigated the effect of RC in terms of long-term mortality in patients admitted for NSTACS

Methods

This is an observational study in which we included all patients discharged from cardiology for ACS in two centers from 2003 to 2018. Patients were classified by low RC values <23 mg/dL or high RC values ≥24 mg/dL in the first blood count performed during hospitalization. We analyzed the effect of RC (continuous variable) on all-cause mortality, cardiovascular mortality and MACE using the Cox regression model adjusted for several confounding variables.

Results

We included 5685 patients diagnosed with ACS, with a mean age of 66.50 (SD ±13.20) years, 27.1% female. The baseline, during admission and discharge characteristics are shown in table (1 and 2).

During follow-up (median 56 months, IQR 21–79 months) there was an increased risk of all-cause mortality in patients with higher levels os RC unadjusted and adjusted for several factors (age, sex, GRACE, early coronariography, hypertension, treatment at discharge), HR (1.003, CI 1.000–1.005, p 0.003). Similar results were observed for cardiovascular mortality (HR 1.003, CI 1.000–1.006, p 0.003), and MACE (HR 1.002, CI 1.000–1.003, p 0.002)

Conclusion

RC could have prognostic impact in the long-term follow up in patients with NSTACS, even after adjusting for risk factors and evidence-based treatments. There results should be taken under consideration for the treatment and management of NSTACS patients.

Funding Acknowledgement

Type of funding sources: None.
Heavy weekly alcohol consumption versus binge drinking after an acute coronary syndrome and risk of major adverse cardiovascular events at one year follow up
Authors: Tessitore E , Branca M , Heg D , Nanchen D , Auer R , Raber L , Klingenberg R , Windecker S , Luscher T F , Matter C M , Rodondi N , Carballo D , Mach F , Gencer B
Published: October 2022

Background

The association between heavy weekly alcohol consumption or binge drinking and the risk of major adverse cardiovascular events (MACE) after acute coronary syndromes (ACS) is still unclear.

Purpose

To determine the risks of MACE at one year follow up according to baseline alcohol consumption, especially in patients with heavy weekly alcohol consumption or binge drinking.

Methods

We analyzed data of 6053 patients hospitalized in 4 Swiss centres for an ACS and followed over 12 months. Data on alcohol consumption were collected at baseline and at one year follow up after ACS. Binge drinking was defined as the consumption of ≥6 units of alcohol on one occasion, for the 12-months period preceding the one-year follow up. We defined MACE as a composite of cardiac death, myocardial infarction, stroke or clinically indicated target vessel coronary revascularization. We applied Cox regression to assess the risk of MACE associated with heavy alcohol weekly consumption (>14 standard units/week) compared to light consumption (<1 standard unit/week) or abstinence, as well as the risk with binge drinking, compared to no binge drinking, adjusting for baseline differences (age, sex, body-mass index, smoking, diabetes, peripheral artery disease, stroke, hypertension, use of aspirin, anticoagulation, statin, beta-blocker, ACE-inhibitor or ATII receptor blocker).

Results

At baseline, 817 (13.4%) patients reported heavy weekly alcohol consumption and 717 (11.8%) reported to have at least one episode of binge drinking per month. The risk for MACE at one year follow up was not increased in those with heavy weekly consumption compared to light consumption (8.7% vs. 8.5%, HR 0.96, 95% CI 0.69–1.33, P=0.80) or no consumption (8.7% vs. 10.3%, HR 1.26, 95% CI 0.88–1.80, P=0.21). However, the risk of MACE was higher in those reporting binge drinking with less than one episode a month (9.4% vs. 7.7%, HR 1.67, 95% CI 1.32–2.12, P<0.001), as well as in those with at least one episode of binge drinking per month (13.4% vs. 7.7%, HR 2.07, 95% CI 1.62–2.65, P<0.001), when compared to no binge drinking.

Conclusion

In contrast to regular heavy alcohol consumption, binge drinking behavior is associated with significant increased risk of MACE 12 months after ACS.

Funding Acknowledgement

Type of funding sources: None.
Dementia in individuals with severe hypercholesterolemia: Korean nationwide cohort study
Authors: Lee S H , Lee C J , Park S , Han K
Published: October 2022

Background

Dementia risk and benefit of lipid lowering in individuals with severe hypercholesterolemia has not been well studied. The aim of this study was to evaluate the risk of dementia and effect of lipid lowering in this population using nationwide cohort.

Methods

This study was performed using the National Health Insurance Service database of Korea. Among individuals who took health check-up and were followed-up, 1,584,401 were enrolled and analyzed. Study population were categorized to three groups with severe hypercholesterolemia according to LDL-C levels, >260, 225–259, and 190–224 mg/dL groups, and a control group (<160 mg/dL). Risks of incident dementia (all dementia, Alzheimer's disease, and vascular dementia) were compared. In the subgroup with new statin users, the effect of statins was further analyzed according to post-treatment LDL-C levels (<70, 70–99, 100–129, >130 mg/dL).

Results

In the median follow-up of 6.1 years, all dementia occurred up to 5.41/1000 person-year in the groups with severe hypercholesterolemia. Adjusted hazard ratios (aHRs) of all dementia in the groups ranged from 1.05 to 1.34 (p=0.023) and were dependent of LDL-C categories. Alzheimer's disease developed up to 4.94/1000 person-year and aHRs ranged from 1.04 to 1.38 (p=0.040) with the same pattern to all dementia. Vascular dementia occurred up to 0.59/100 person-year and aHRs ranged from 1.03 to 1.57 without significant difference according to LDL-C categories. In the median follow-up of 6.2 years in new statin users, aHRs were 0.69 to 0.92 for all dementia and 0.74 to 0.92 for Alzheimer's disease, and 0.53 to 1.15 for vascular dementia according to post-treatment LDL-C levels. However, the risk was not significantly related to the levels.

Conclusions

This study newly showed elevated risk of dementia, particularly Alzheimer's disease, in patients with severe hypercholesterolemia. The benefit of active lipid lowering on this neurological disease needs to be proven by further studies.

Funding Acknowledgement

Type of funding sources: Other. Main funding source(s): Korean Society of Lipid and Atherosclerosis; National Research Foundation of Korea
Cholesterol remnants distribution in patients admitted for acute coronary syndrome
Authors: Cordero A , Escribano D , Alvarez-Alvarez B , Martinon J , Garcia-Rondeja F , Rodriguez-Manero M , Bertomeu-Gonzalez V , Cazorla D , Moreno-Arribas J , Quintanilla M A , Lopez Ayala J M , Zuazola P , Gonzalez-Juanatey J R
Published: October 2022

Background

Cholesterol remnants have been identified as one of leading lipid measurements associated with the incidence of coronary heart diseases. Nonetheless, there is scarce evidence on cholesterol remnants distribution in patients with acute coronary syndrome (ACS).

Methods

We included all consecutive patients admitted for ACS in two different centers. Cholesterol remnants were calculated by the equation: total cholesterol minus low-density lipoprotein cholesterol (LDLc) minus high-density lipoprotein cholesterol (HDLc) and values ≥30 were considered high. Premature ACS was defined in patients presenting with age <55 for men or <65 for women. Correlation weres assessed by linear regression and predictive models were obtained after logistic binary regression.

Results

We included 7,479 patients, mean age 66.68 (13.02), 2,062 (27.57%) women, mean body mass index (BMI) 28.60 (4.64) kg/m2, 2088 (27,92%) with diabetes and 2,726 (36.45%) admitted for ST-elevation ACS. Median (interquartile range) remnants level was 28 mg/dl (21–39) and 3,429 (45.85%) patients had levels ≥30 mg/dl. Significantly higher levels of remnants were observed in patients with diabetes, current smokers, BMI >30 kg/m2, absence of previous cardiovascular disease or premature ACS. No gender differences were observed in remnants level. Age (r: −0.29) and BMI (r: 0.44) were the variables more strongly correlated. As shown in the figures, at any given age, the risk of having cholesterol remnants ≥30 increased with higher BMI.

In-hospital mortality was 3.75% (280 patients). After adjustment by age, gender, previous cardiovascular disease and GRACE score, cholesterol remnants were not associated to higher mortality risk (OR: 0.89 95% CI 0.64–1.10; p=0.21)

Conclusions

Elevated cholesterol remnants is highly prevalent in patients admitted for ACS and their levels inversely correlate with age and positively with body mass index. We propose a risk matrix for estimating the probability of having cholesterol remnants ≥30. Elevated cholesterol remnants were not associated to higher in-hospital mortality risk.

Funding Acknowledgement

Type of funding sources: None.
Lipoprotein(a) testing in clinical practice: real-life data from a large health-care provider
Authors: Zafrir B , Aker A , Saliba W
Published: October 2022

Background

Evidence support a causal role of lipoprotein(a) [Lp(a)] in the development of atherosclerotic cardiovascular disease (ASCVD). Novel treatment options are emerging and recent guidelines recommend screening Lp(a) levels at least once during lifetime. However, significant variance exists regarding the incorporation of Lp(a) into patient care.

Purpose

To investigate patterns of Lp(a) measurement in a large health maintenance organization (HMO) and describe clinical characteristics associated with elevated Lp(a) levels.

Methods

Retrospective analysis of all Lp(a) laboratory tests performed between January 2015 and December 2021 in a single HMO providing health care for approximately 4.6 million insured members.

Results

Overall, 4,539 individuals were tested for Lp(a). Analysis was limited to the adult population (n=3900). Number of persons tested yearly increased progressively from 89 in the year 2015 to 1523 in 2021. Mean age was 55±15 years (39% females), 15% had family history of coronary disease, 40% ischemic heart disease, 7% prior stroke and 9% peripheral artery disease (PAD). Baseline low-density lipoprotein cholesterol (LDL-C) >190 mg/dl was evident in 21% of patients. Lp(a) level >125 nmol/l (∼50 mg/dl) was noted in 21.5%. In a multivariable logistic regression model, prior myocardial infarction (odds ratio 1.38, 95% confidence interval 1.16–1.64), PAD (1.29, 1–1.68), peak LDL-C>190 mg/dl (1.35, 1.12–1.62) and use of statins (1.54, 1.28–1.85), were independently associated with elevated Lp(a) levels >125 nmol/l, whereas an inverse association was seen with obesity (0.74, 0.62–0.88). Of the patients with elevated Lp(a), 72.4% were treated with statin and/or ezetimibe and 1.9% with PCSK9 inhibitors.

Conclusions

The reporting of Lp(a) levels is increasing, though it is still measured in a small portion of the population. Presence of ASCVD and severe hyperlipidemia may identify patients that should be considered for screening for increased Lp(a) levels. The use of PCSK9 inhibitors in those with elevated Lp(a) is yet considerably low.

Funding Acknowledgement

Type of funding sources: None.
Risk stratification and lipid evaluation in Mexican patients, evidence of lipid and cardiovascular analysis of a real world data registry (REMECAR)
Authors: De Los Rios Ibarra M O , Leiva-Pons J L , Rodriguez-Reyes H , Alcocer-Gamba M A , Cortes-Lawrenz J , Vizcaino-Rios F M , Barragan-Luna J , Farjat-Ruiz J I , Virgen-Carrillo L R , Lugo-Gavidia L M
Published: October 2022

Background and purpose

Dyslipidaemia is a significant risk factor for cardiovascular disease in the Mexican population. This analysis aims to describe the baseline LDL-c levels of patients at cardiovascular clinics and evaluate the proportion of them who achieved their risk-based LDL-c goals as recommended by 2021 ESC prevention guidelines.

Methods

The REMECAR registry is an observational study of patients attending a specialized cardiovascular clinic for their first visit. The cardiovascular risk was retrospectively determined using the 2021 ESC guideline stratification and the SCORE2 and SCORE-OP.

Results

A total of 5,443 patients were included in the analysis. Within this population, 55.96% presented as very high, 39.98% as high and 4.06% as moderate to low risk. 63% of the participants were not on any lipid lowering treatment at entry, while 12.4% were receiving high intensity statin therapy. Patients presenting with established atherosclerotic cardiovascular disease had a mean LDL-c of 90.9±40.7 mg/dL. Of these, 14.1% were achieving LDL-c levels of 70–50 mg/dL and 19.3% were achieving LDL-c levels <55mg/dL (Figure 1B) In diabetic patients at very high risk, only 25.7% reached their LDL-c goal. Finally, in patients without another risk factor and very high-risk evaluated by SCORE2 & SCORE-OP, only 14% of patients achieved their LDL-c goals.

Conclusions

A significant number of patients were not receiving lipid lowering therapy. Furthermore, in those who were, a significant portion did not achieve LDL-c recommended thresholds. Our results underline the urgent need to improve the prescription and optimisation of lipid lowering therapy as the current management appears to be insufficient for achieving optimal recommended goals. Identifying key barriers in lipid management is fundamental to establishing better strategies and health system policies to reduce cardiovascular risk.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): AMGEN
Quantification of left ventricular fibrosis in arrhythmic mitral valve prolapse patients: comparison of different semi-automated techniques assessed by cardiac magnetic resonance
Authors: Cecere A , Cipriani A , Ravagnin A , Graziano F , Brunetti G , De Conti G , Motta R , De Lazzari M , Iliceto S , Perazzolo Marra M
Published: October 2022

Background

Left ventricular (LV) fibrosis has a key role in arrhythmogenesis in mitral valve prolapse (MVP) patients. Cardiac magnetic resonance (CMR) demonstrated able to clearly identify LV fibrosis with the post-contrast late gadolinium enhancement (LGE) images. Despite the pivotal role of LV fibrosis in the arrhythmogenesis, a quantification and identification of reproducible method able to accurately measure LGE in arrhythmic MVP patients has not been recognized.

Purpose

We aimed to measure and compare different semi-quantitative methods for LGE quantification assessed by CMR, in order to identify the most reproducible one, in arrhythmic MVP patients.

Methods

66 arrhythmic MVP patients with normal systolic function and without significant regurgitation were enrolled. Semi-automated gray-scale thresholding technique using full with at half maximum (FWHM) and 2, 3 and 5 standard deviation (SD) above the remote myocardium were used and compared with visual assessment (Fig. 1).

Results

LGE was identified in 41 arrhythmic MVP patients (62%) and quantified (Fig. 2). The mean quantity of LGE visually assessed was 2.40±1.07% or 1.40±0.82 g. With FWHM, LGE resulted 3.56±1.23% or 1.99±1.13 g. Using thresholding, the mean LGE quantity was 9.2±3.1% or 4.82±2.28 g for 2-SD, 5.72±1.75% or 3.06±1.47 g for 3-SD and 2.36±0.99% or 1.29±0.79 g for 5-SD. The 5-SD measurement in percentage demonstrated a good correlation with LGE quantification visually assessed (2.402±1.075 vs 2.363±0.9909, p: 0.543). Despite all semi-quantitative methods for LGE quantification demonstrated a good intra and inter-observer agreement, the 5-SD threshold quantification, both in percentage and in grams, revealed the less intra-observer (respectively, ICC: 0.976 and 0.966) and inter-observer variability (respectively ICC: 0.948 and 0.935) when compared with visual assessment.

Conclusion

This is the first study that quantified and compared different CMR semi-automated methods for LGE assessment in a population of arrhythmic MVP patients. The 5-SD gray-scale threshold technique in percentage revealed the best correlation with the visual assessment and an optimal reproducibility.

Funding Acknowledgement

Type of funding sources: None.
The immunogenic potential of PCSK9 peptide vaccine in mice
Authors: Ataei S , Momtazi-Borojeni A A , Jaafari M R , Banach M , Sahebkar A A
Published: October 2022

Background

Proprotein convertase subtilisin/Kexin 9 (PCSK9) is a serum protein expressed by liver cells that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by modulating LDL receptors (LDLR). Recent studies of our group indicated the efficient immunogenicity of the nanoliposomal PCSK9 peptide vaccine in different animal models.

Purpose

Herein, we sought to evaluate the immunogenic potential of the non-liposomal form of the vaccine due to its simplicity of processing and lower production cost.

Methods

PCSK9 immunogenic peptide was prepared by linking a short PCSK9 peptide to a tetanus peptide as B and T cell epitopes, respectively. The immunogenic peptide and 0.4% alum adjuvant, in a 1:1 ratio, were mixed thoroughly and homogeneously prior to administration as vaccine formulation. In order to assess the humoral immune response, mice were inoculated subcutaneously four times at bi-week intervals. Immunized animals' blood was sampled two weeks after the last injection. The titers of the anti-PCSK9 antibodies in the serum of vaccinated mice were evaluated using the ELISA method. ELISA was also used to investigate the effects of anti-PCSK9 vaccination on PCSK9 serum concentrations and its interaction with LDL receptor (LDLR).

Results

ELISA analysis showed significant induction of IgG antibody titers by PCSK9 peptide vaccine in vaccinated mice compared to the control group (586±12000 and 642±11566 in male and female vaccinated mice, respectively, p<0.001). No significant difference was found between the male and female vaccine groups (p>0.05). Mechanistic analyses showed that vaccine-induced antibodies decreased serum PCSK9 concentration in vaccine groups compared to the control group (in male mice by 26±5 ng/mL, p<0.01 and female mice by 29±5 ng/mL, p<0.01). Serum concentrations of PCSK9 in control and vaccine groups were found to be 131±8.6 ng/mL and 102±8.1 ng/ml in male mice, and 124±6 ng/ml and 98±10 ng/ml in female mice, respectively. Moreover, vaccine-induced antibodies inhibited the PCSK9/LDLR interaction in the presence of serum from vaccinated mice compared to control mice serum (in male and female groups by 34% and 26%, respectively). The PCSK9 peptide vaccine significantly reduced LDL-C in immunized mice in both male (16.93±2.5 mg/dL, p=0.001) and female groups (22±2.7 mg/dL, p=0.001) compared with the control group.

Conclusions

According to our results, the PCSK9 peptide vaccine stimulates the humoral immune response in albino mice to produce active antibodies that inhibit plasma PCSK9 resulting in plasma LDL-C reduction.

Funding Acknowledgement

Type of funding sources: None.
Machine learning can accurately detect abnormal aortic valves in CMR
Authors: Vimalesvaran K , Uslu F , Zaman S , Howard J , Bharath A , Cole G
Published: October 2022

Background

Improving the efficiency of CMR by acquiring fewer, and more targeted sequences, would improve the diagnostic yield and reduce patient recalls. An AI-assisted clinical decision support system (CDSS) could deliver this efficiency using adaptive scanning protocols which replicate the expertise of highly trained clinicians. Normal aortic valve anatomy on the three-chamber (3CH) cine CMR is a guide to rationalising subsequent sequences, and therefore is a suitable base case for developing an AI-CDSS for CMR.

Purpose

We propose a machine learning approach to differentiate between normal and abnormal aortic valves from the 3CH cine.

Methods

We curated a unique expert-annotated dataset of 1221 frames from eighty CMR studies. For each frame, AV landmarks (two hinge points and two leaflets), and stenotic and regurgitant jets were labelled by three cardiologists.

We then tested two AI models (Figure 1) to detect these AV abnormalities: A) a convolutional neural network (CNN), and B) a random forest approach.

A) Using heat map regression, the AV was localised, and the jets (if present) were identified as pathological curves. We then tracked and quantified the curves in the estimated heatmaps based on their proximity, the length, orientation and angle with respect to the hinge points.

B) We used a random forest approach to classify cases as normal or abnormal by using the characteristics of estimated pathological curves obtained from the heat map regression output.

We trained and evaluated our models on an unseen dataset of 1017 CMR studies obtained from different scanner types across three NHS hospitals. Each CMR study report was manually assigned a binary ground truth label for a normal or abnormal AV. In total 496/1017 patients had an abnormal AV. Of those abnormal cases, 184 patients had aortic stenosis, 222 aortic regurgitation and 90 cases had mixed valve disease.

We assessed the classification performance of our method with accuracy and an F1 score – a composite of precision and recall, where 1 is perfect; and heatmap regression performance for curves with mean absolute error.

Results

This machine learning approach classified abnormal aortic valves with good agreement to the ground truth labels with mean accuracy of 0.93 (representing approximately 451/496 patients) and mean F1 score of 0.91. The AV hinge points were localised with a mean distance error of 3.5 pixels. This was despite the small size of expert labelled data.

Conclusion

This machine learning solution successfully differentiated between normal and abnormal aortic valves from routine 3CH cine CMR views. More labelled datasets will enable further classification of pathology and severity, and greater accuracy. Our results represent an important stepping stone towards an AI-assisted CDSS for CMR.

Funding Acknowledgement

Type of funding sources: Other. Main funding source(s): This work was supported by the UKRI CDT in AI for Healthcare http://ai4health.io
Patients with pseudoxanthoma elasticum (PXE) do not have dyslipidemia
Authors: Harmsen I M , Visseren F L J , Kok M , De Jong P A , Spiering W
Published: October 2022

Background

Pseudoxanthoma elasticum (PXE) is a rare genetic disease caused by low inorganic pyrophosphate and is characterized by medial arterial calcification, leading to peripheral arterial disease and ischemic cerebral disease. Animal studies and small human studies have reported an association between PXE and dyslipidemia and therefore suggest that atherosclerosis is a second pathway contributing to cardiovascular disease in PXE patients. The association between PXE and dyslipidemia was however not consistent across these studies and there are several biological hypotheses proposed where the affected gene in PXE (ABCC6) could affect the cholesterol pathway: ABCC might influence HMA-CoA reductase – and increase total cholesterol and LDL-c – on one hand, but there is also evidence that points toward influence of ABCC6 on the reversed cholesterol pathway, influencing HDL-c. This study is important to analyze if PXE subjects, from the larges PXE cohort in the world, indeed do have a different a different lipid profile compared to well matched controls.

Purpose

To evaluate whether PXE patients have a different lipid profile compared to non-PXE patients.

Methods

A cross-sectional patient-control study was done at the Dutch Expertise Center for PXE in the University Medical Center Utrecht. Patients were all diagnosed conform the Plomp cirteria. The control population consisted of acquaintances of PXE patients, excluding first and second-degree relatives. Total cholesterol, LDL-c, HDL-c and triglycerides were assessed in both patients and controls and if lipid-lowering treatment (LLT) was used pre-treatment levels were calculated using known effects of LLT on lipids.

To eliminate the imbalances between patients and controls, we used Coursened Exact Matching (CEM), to investigate the effect of PXE on lipids.

Results

The study population included 323 PXE patients and 57 controls. Their characteristics are displayed in Figure 1.

After CEM 186 patients (weighted means: age 57.8±9.9 years, 58% females, BMI 25.5±2.9 kg/m2) and 52 controls (age 57.3±43.1 years, 58% females, BMI 25.5±17 kg/m2) were left for analyses. The univariate, weighted regression analysis of the effect of having PXE on lipid profile shows that the differences in lipids between patients and controls were 0.22 mmol/L for total cholesterol (p=0.299), 0.15 mmol/L for LDL-c (p=0.524), 0.07 mmol/L for HDL-c (p=0.314) and 0.10 mmol/L for triglycerides (p=0.433).

A sensitivity analysis where only the crude values of untreated subjects were included in the analysis showed that LDL-c was sginficantly lower in PXE-patients. Probably due to the fact that only the very healthy PXE patients were included.

Conclusion

There are no differences in levels of total cholesterol, LDL-c, HDL-c, and triglycerides between PXE patients and matched controls.

Funding Acknowledgement

Type of funding sources: None.
Cost-effectiveness of cholesterol-lowering drugs for secondary cardiovascular prevention in the UK: ezetimibe, evolocumab, and alirocumab
Authors: Michaeli D T , Michaeli J C , Boch T , Michaeli T
Published: October 2022

Background

Despite statin treatment, patients with elevated low-density lipoprotein cholesterol (LDL-C) levels remain at high risk for acute cardiovascular events. Ezetimibe, evolocumab, and alirocumab were consequently developed to reduce the risk of recurrent ischemic events in patients with established cardiovascular diseases by 6%, 15%, and 15%, respectively. However, these novel treatments must demonstrate both clinical efficacy and cost-effectiveness to promote long-term adoption by patients, physicians, and insurers.

Objective

To assess the cost-effectiveness of statins in combination with ezetimibe, evolocumab, and alirocumab for secondary cardiovascular prevention from the perspective of England's National Health Service (NHS).

Methods

The incidence of major adverse cardiovascular events, including, myocardial infarction, stroke, angina, and coronary revascularization, was simulated with a Markov cohort model. The model was populated with transition probabilities and hazard ratios derived from cardiovascular outcome trials for statin combinations with ezetimibe (IMPROVE-IT), evolocumab (FOURIER), and alirocumab (ODYSSEY). Costs and utilities were retrieved from previous literature. Principle outcomes of interest were the incremental cost-effectiveness ratios (ICER) per quality-adjusted life year (QALY) gained in 2021 Great Britain Pounds (£). Univariate, scenario, willingness-to-pay, and probabilistic sensitivity analyses were conducted to assess the robustness of results.

Results

For secondary cardiovascular prevention, ezetimibe in combination with statins increased QALYs gained by 0.60 at cost reductions of −£2,529 (ICER: −4,231 £/QALY) per patients compared to statin monotherapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provided incremental QALYs of 0.53 and 0.86 at costs of £45,279 and £46,375 for evolocumab (ICER: 75,283 £/QALY) and alirocumab (ICER: 40,708 £/QALY), respectively. At the NHS' willingness-to-pay threshold of 30,000 £/QALY, there is 100% probability for ezetimibe and 0% probability for PCSK9 inhibitors to be cost-effective in secondary prevention. Results remained robust under univariate, scenario, and probabilistic sensitivity analyses.

Conclusions

Ezetimibe is cost-effective for secondary cardiovascular prevention at an annual price of £346 in the UK. For PCSK9 inhibitors, discounts of −37% to −53% on alirocumab's (£4,412) and evolocumab's (£4,467) prices are necessary to achieve cost-effectiveness.

Funding Acknowledgement

Type of funding sources: None.
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

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

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<0.001), while higher eicosapentaenoic acid (EPA) levels caused a decrease of AF risk (OR 0.85, 95% CI [0.80–0.90], P<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

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<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<0.0001) and in total events (rate ratio, 0.71 [95% CI, 0.61–0.82]; P<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

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

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) >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<0.05), while serum levels of KTR and PAr were higher only compared to fit men (p<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

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.