bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomics associated with coronary high-risk plaque features on optical coherence tomography
Authors: Niida T , Yuki H , Suzuki K , Kinoshita D , Nakajima A , Mcnulty I , Lee H , Tanriverdi K , Shah R , Freedman J , Nakamura S , Jang I K
Published: November 2023

Introduction

Cardiovascular disease is the major cause of death worldwide. The physiological status of the cardiovascular system is reflected in plasma proteins and a newly developed technique based on proximity extension assays has enabled the analysis of a broad range of protein biomarkers associated with cardiovascular disease. However, biomarkers for coronary high-risk plaques, including lipid-rich plaques, macrophages, cholesterol crystals, and microvessels, have not yet been found.

Purpose

This study aimed to identify proteins specific for coronary high-risk plaques.

Methods

We analyzed 57 patients (71.1 ± 10.6 years, male: 68.4%) who underwent intracoronary optical coherence tomography and provided blood samples for proteomic analysis. Forty-seven patients (86.0%) had lipid-rich plaques, 46 patients (80.7%) had macrophages, 16 patients (28.1%) had cholesterol crystals, and 27 patients (47.4%) had microvessels. A total of 1,470 plasma proteins were analyzed using the Olink® Explore 1,536 Reagent Kit and P2 100 cycle reagent kit on a NextSeq 2000 sequencer.

Results

In patients with lipid-rich plaques, the protein expressions of Interstitial collagenase (MMP1), Wiskott-Aldrich syndrome protein family member 1 (WASF1), and Protein phosphatase 1 regulatory subunit 12A (PPP1R12RA) were significantly increased, while the expressions of Fc receptor-like protein 3 (FCRL3), Folate receptor gamma (FOLR3), Cobalamin binding intrinsic factor (CBLIF), Glutathione S-transferase A1 (GSTA1), and Keratin, type I cytoskeletal 18 (KRT18) were significantly decreased (Figure A). In patients with macrophages, the protein expressions of MMP1, WASF1, PPP1R12RA, and Scavenger receptor cysteine-rich domain-containing group B protein (SSC4D) were significantly increased, while the expressions of Fatty acid-binding protein, intestinal (FABP2), FOLR3, CBLIF, GSTA1, and Fibroblast growth factor 21 (FGF21) were significantly decreased (Figure B). In patients with cholesterol crystals, the protein expressions of FOLR3, Secreted frizzled-related protein 1 (SFRP1), and Anterior gradient protein 2 homolog (AGR2) were significantly decreased (Figure C). In patients with microvessels, the expression of FOLR3 was significantly decreased (Figure D).

Conclusion

These proteins might be new biomarkers in patients with coronary high-risk plaques.
Low-density lipoprotein cholesterol reduction and short-term incidence of ASCVD in the population-based cohort study LATINO
Authors: Seabra Carvalho D , Gavina C , Afonso-Silva M , Canelas-Pais M , Araujo F
Published: November 2023

Background/Introduction

In Portugal, 25,000 people die from atherosclerotic cardiovascular diseases (ASCVD) every year, accounting for more than 20% of all deaths in 2019. Reducing low-density lipoprotein cholesterol (LDL-C) is an effective intervention to lower the risk of CV events, including ischemic stroke (IS), coronary heart disease (CHD) and Peripheral Artery Disease (PAD).

Purpose

This study aims to assess the extent of ASCVD risk prevention associated with different levels of LDL-C lowering in an unselected population in Portugal.

Methods

We used electronic health records to conduct a population-level retrospective cohort study of individuals aged 40–80 years who were followed in 1 hospital and 14 primary care facilities in Portugal from 1/1/2012 to 31/12/2020. Patients started being followed when they fulfilled criteria to be exclusively characterised as high CV risk at the index date (defined according to the ESC/EAS 2019 guidelines).

This analysis focused on the 24-month risk of developing ASCVD, by percentual LDL-C reduction between 360 and 540 days from the maximum LDL-C. The primary endpoint of ASCVD included the risk of IS, CHD or PAD, as defined by the corresponding ICD-9-CM/ICD-10-CM codes. IS, CHD and PAD were also analysed separately as secondary endpoints. LDL-C values were obtained from laboratory results and CV and diabetes medications’ use from prescription data registered according to the Anatomical Therapeutic Chemical Classification System recorded. A Cox regression model adjusted for sex, age, all relevant CV risk variables, risk-enhancing factors, and CV and diabetes medications was developed.

Results

The total cohort at 24 months of follow-up consisted of 21,101 observations corresponding to 16,055 distinct patients. Higher LDL-C percentual reduction was associated with a lower risk of ASCVD, with adjusted hazard ratios (aHR) (95% confidence intervals (CI)) of 0.82 (0.66-1.02), 0.86 (0.66-1.11) and 0.44 (0.24-0.79) per reduction of ]0,30%], ]30,50%] and ]50,90%] of LDL-C respectively, versus having no reduction or increase. IS was the secondary endpoint that contributed the most to the reduction of risk of ASCVD with an aHR (95% CI) of 0.89 (0.69-1.15), 0.67 (0.47-0.96) and 0.41 (0.19-0.86) for the same corresponding LDL-C reduction categories. However, these results were not statistically significant for PAD or CHD when assessed isolated.

Conclusion

This real-world evidence study shows that, independently of age, sex, and other CV risks and medications, reductions of >50% in LDL-C significantly reduced by 56% the risk of ASCVD at 24 months in high CV risk patients. This reduction was more striking for ischemic stroke. Therefore, LDL-C reductions >50% should be a paramount objective in public health policies worldwide.
Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: a meta-analysis of 59 trials
Authors: Burger P M , Dorresteijn J A N , Koudstaal S , Mosterd A , Visseren F L J
Published: November 2023

Background

Therapies lowering low-density lipoprotein cholesterol (LDL-c) are widely used to reduce cardiovascular disease (CVD) risk in patients with or at high risk of CVD. Therapy is usually continued lifelong, but whether the effects of LDL-c reduction remain stable over time is uncertain. This study aimed to establish the course of the relative treatment effects of LDL-c reduction on cardiovascular risk over time, i.e. treatment duration and age.

Methods

Randomized controlled trials (RCTs) of LDL-c lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). RCTs of guideline-recommended therapies (i.e. statins, ezetimibe, and proprotein convertase subtilisin–kexin type 9 inhibitors [PCSK9i]) were selected for the primary analyses, with RCTs of other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the average relative risk (RR) for major vascular events (cardiovascular death, myocardial infarction or other acute coronary syndrome, coronary revascularization, or stroke) per 1 mmol/L LDL-c reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the RR for major vascular events per 1 mmol/L LDL-c reduction. Analyses were also stratified for primary and secondary prevention.

Results

A total of 59 trials (26 statin trials, 2 ezetimibe trials, 3 statin/ezetimibe combination trials, 7 PCSK9i trials, and 21 other trials) were selected, including 394,989 participants and 49,642 major vascular events. Mean follow-up was 3.9 years (range 0.9-9.7), and age was 63.8 years (range 48.0-77.0). The average RR for major vascular events per 1 mmol/L LDL-c reduction was 0.78 (95% confidence interval [CI] 0.75-0.81), with slightly larger risk reductions in primary (RR 0.74; 95% CI 0.68-0.81) as compared to secondary prevention (RR 0.80; 95% CI 0.77-0.83). Follow-up duration was not associated with the RR for major vascular events (p = 0.615), with the meta-regression line showing a stable RR over follow-up time (RR for change per year 0.994; 95% CI 0.971-1.017). The RR for major vascular events increased (i.e. risk reduction decreased) with age in primary prevention (RR for change per 5 years 1.094; 95% CI 1.028-1.165; p = 0.018), but remained largely unchanged in secondary prevention (RR for change per 5 years 0.986; 95% CI 0.943-1.031; p = 0.533). Consistent results were found for statin trials only, and all trials combined.

Conclusions

The relative treatment effects of LDL-c reduction are stable over time in secondary prevention, but may decrease with age in primary prevention.Meta-analysisMeta-regression analyses
Effects of icosapent ethyl on residual cardiovascular risk according to predicted baseline risk: results from REDUCE-IT
Authors: Burger P M , Bhatt D L , Dorresteijn J A N , Steg P G , Koudstaal S , Mosterd A , Martens F M A C , Visseren F L J
Published: November 2023

Background

Icosapent ethyl is recommended by the ESC CVD Prevention Guidelines as one of the intensified prevention strategies to be considered in patients with established CVD and a high residual risk.[1] Treatment effects of icosapent ethyl may vary between individual patients. This study aimed to determine the relative and absolute treatment effects of icosapent ethyl according to baseline CVD risk.

Methods

Participants from the REDUCE-IT trial with established CVD were included (n = 5,785).[2] Baseline 5-year risk of major adverse cardiovascular events (MACE), defined here as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was estimated using the ESC guideline-recommended SMART2 risk score.[3] Modification of the relative treatment effect of icosapent ethyl by baseline risk was assessed using a Cox proportional hazards model including a treatment-by-risk interaction. Next, relative treatment effects were derived stratified by quartiles of baseline risk. The observed 5-year absolute risk reduction (ARR) with icosapent ethyl within each risk quartile was assessed based on Kaplan-Meier estimates of the cumulative incidence of MACE.

Results

During a median follow-up of 4.8 years (interquartile range 3.2-5.3), 361 MACE events occurred in the icosapent ethyl group vs 489 in the placebo group (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.63-0.82). Mean predicted vs observed 5-year risk of MACE was 9.1% vs 10.2% in the first quartile (range 3.6-11.4%), 13.8% vs 14.6% in the second quartile (range 11.5-16.0%), 19.2% vs 19.5% in the third quartile (range 16.1-23.4%), and 33.4% vs 32.2% in the fourth quartile (range 23.5-83.0%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96) respectively (p for treatment-by-risk interaction = 0.06). The 5-year ARR (95% CI) with icosapent ethyl increased across risk quartiles, i.e. was 5.3% (1.8-8.7%), 5.6% (1.9-9.4%), 7.4% (3.0-11.8%), and 10.8% (5.3-16.2%) respectively (Figure). This translates to a number needed to treat (NNT; 95% CI) of 19 (11-54), 18 (11-52), 14 (8-34), and 9 (6-19).

Conclusions

Among CVD patients with elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE in individuals with a low, moderate, and high baseline risk. Absolute treatment benefits are largest for patients at the highest risk, as reflected by the twofold increase in ARR and decrease in NNT in the highest as compared to the lowest risk quartile.Icosapent ethyl effect in risk quartiles
Effect of smoking initiation age on nicotine dependence
Authors: Komiyama M , Swati M , Yamakage H , Morimoto T , Hasegawa K
Published: November 2023

Background

Tobacco is widely recognized as a risk factor for major cardiovascular morbidity and mortality worldwide. Although the legal smoking age to purchase tobacco is 18 years old (yo) in most countries in the world but it ranges from 15 to 21 yo. If a person does not start using tobacco until the age of 21, they are more likely to remain tobacco-free for the rest of their lives. In 2019, the Tobacco 21 [T21] federal law came into effect in 2019 in the US, where the US government raised the minimum age for purchasing tobacco products from 18 to 21 yo and saw a subsequent decline in tobacco use. People who start smoking at a young age show greater nicotine dependence, and lower quit rates. However, the details of the effect of smoking initiation age on the smoking cessation (SC) rates and nicotine dependence are not known.

Purpose

The purpose of this study is to demonstrate the effect of age at smoking initiation on SC rate, and nicotine dependence using 20 yo as the cut-off point, which is the legal smoking age in Japan. We also examined the effect of age at smoking initiation on various smoking related parameters.

Methods

Among smokers who visited our SC clinics, the participants (smokers) who visited our SC clinics were divided into 2 groups (<20 yo and ≥20 yo) and 4 groups (≤17 yo, 18-19 yo, 20-21 yo, ≥22 yo) based on their age of smoking initiation. The prevalence and association between the various parameters including CV biomarkers were compared between 2 groups by using Fisher’s exact test, and unpaired t-test.

Results

The study participants consisted of 1382 smokers [29.8% female] with a mean age of 58.2±13.1 yo at the time of first visit to our clinic. Compared with the group of smoking initiation age of ≥20 yo, the group of smoking initiation age group <20 yo reported a higher number of cigarettes/day (25±12 vs 22±12, p value<0.001 and adjusted p-value=0.002), higher respiratory CO levels (19.3±13.5 vs16.5±11.9), and higher FTND score (7.4±2.0 vs 6.3±2.2) with significant p-values and adjusted p-value of <0.001. The successful SC rate was lower in the group ≥20 yo with 56% as compared to the group <20 yo with 45.5% (p-value=0.001). When comparing the 4 groups, a further increase in the age of smoking initiation to ≥22 yo leads to an additional decrease in nicotine dependence.

Conclusions

The present study shows that smoking initiation at the age of 20 yo or older is associated with lower nicotine dependence and depressive tendency, and a higher rate of successful SC compared with smoking initiation at age <20 yo. A further increase in the age of smoking initiation age to 22 yo or older leads to a further decrease in nicotine dependence. Our study may explain the rationale for reducing smoking through the T21 policy in the USA. The present study underlines the importance of raising the legal age of tobacco purchase to 22 yo worldwide.
Increased inflammatory proteins in patients with severe obesity is associated with persistent myocardial dysfunction one year after bariatric surgery. The FatWest study
Authors: Grymyr L M , Mellgren G , Meyer K , Gerdts E , Nadirpour S , Ferno J , Nedrebo B , Cramariuc D
Published: November 2023

Background

Over half of patients with severe obesity have subclinical cardiac dysfunction and about 40% maintain impaired left ventricular (LV) mechanics one year after bariatric surgery despite impressive weight reduction.

Purpose

To investigate whether measurement of serum markers of chronic inflammation before bariatric surgery can help identify patients with persistent postoperative cardiac dysfunction.

Methods

In the prospective FatWest (Bariatric Surgery on the West Coast of Norway) study 75 patients with severe obesity (44±9 years, 72% women, body mass index [BMI] 41.5±4.7 kg/m², 56% with hypertension) underwent echocardiography before and 1 year after Roux-en-Y gastric bypass surgery. We assessed LV mechanics in the radial and longitudinal direction by the midwall shortening (MWS) and global longitudinal strain (GLS). Myocardial oxygen (O2) demand was derived from the LV mass-wall stress-heart rate product. Inflammation was assessed by high-sensitive C-reactive protein, serum amyloid A and calprotectin in biobank samples.

Results

Preoperatively, patients with low MWS (45% of the group) had increased high-sensitive C-reactive protein, total calprotectin, and several amyloid A isoforms, and patients with high myocardial O2 demand (20%) had high total calprotectin (all p<0.05). In the whole study population, bariatric surgery induced a significant improvement in both BMI (12.6±3.7 kg/m²), GLS (4.74±5.20%), myocardial O2 demand and inflammatory proteins (Figure A, all p<0.001). However, there were no significant improvement in MWS, and 33% of patients still had low MWS at the 1-year control.

In logistic regression analyses, after adjustment for sex, BMI and hypertension, increased preoperative serum total calprotectin was independently associated with high myocardial O2 demand both pre- and postoperatively (Nagelkerke R² 0.47 and 0.51, p<0.05). In similar analyses, higher preoperative serum total amyloid A was related to low MWS and high myocardial O2 demand 1 year after surgery (Nagelkerke R² 0.55 and 0.51, p<0.05). A simple preoperative risk score based on sex, hypertension, biplane ejection fraction, and serum total amyloid A above 4.0 mg/ml predicted low 1-year MWS with 79% sensitivity and 75% specificity at a value of 1.75 in Receiver Operating Characteristic (ROC) analysis (AUC 0.80, p<0.001) (Figure B). Low GLS was not predicted by inflammatory biomarkers at any timepoint.

Conclusion

Increased serum concentration of inflammatory proteins in patients with severe obesity is linked to persistently elevated myocardial O2 demand and impaired LV midwall mechanics 1 year after bariatric surgery.Figure AFigure B
Association between body mass index and outcomes in heart failure across the ejection fraction spectrum: data from the Swedish Heart Failure Registry
Authors: Ferrannini G , Rodolico D , Amario D D , Dahlstrom U , Lund L H , Savarese G
Published: November 2023

Background

Despite overweight/obesity being a well-known cardiovascular (CV) risk factor, high body mass index (BMI) has been suggested to be associated with longer survival in patients with heart failure (HF). Data on large populations are lacking, as well as whether this advantage might be consistent across the ejection fraction (EF) spectrum, i.e. reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF, where obesity may have a greater causative role).

Purpose

To assess the association between BMI and outcomes in a large and unselected contemporary cohort of patients with HF across the EF spectrum.

Methods

Patients with HF registered in the Swedish HF Registry (SwedeHF) between May 2000 and December 2021, with no missing values for EF and BMI, were selected. Linkage with the Cause of Death Registry and the National Patient Registry provided data on mortality, hospitalizations and comorbidities. Patients were categorised according to BMI class (underweight <18.5 kg/m2; normal weight 18.5-24.9 kg/m2; overweight 25.0-29.9 kg/m2; obesity>30-34.9 kg/m2).

The primary outcome was all-cause death, secondary outcomes were CV death and HF hospitalization (HHF). The associations between BMI categories and outcomes were analysed by univariable and multivariable Cox proportional hazards models, both in the whole cohort and according to EF classes; this association was also explored by modeling BMI as a continuous variable through restricted cubic splines. Missing data were handled by chained equation multiple imputation.

Results

69,874 patients (mean age 74 years, 36% females) were included, of whom 3% underweight, 35% with normal weight, 35 % overweight, obese 27%. Figure 1 reports the proportions of the different BMI categories according to EF: obesity was significantly more common in HFpEF. Regardless of EF, obese patients were younger, with lower N-terminal B-type natriuretic peptide, higher New York Heart Association class, and with diabetes and hypertension as compared with the other three BMI classes.

Compared with normal weight, both overweight and obesity were independently associated with lower mortality risk, while underweight with higher mortality, with consistent results in HFrEF, HFmrEF and HFpEF; the same associations were found for CV death or all three EF classes, while underweight only was associated with HHF in HFrEF. When BMI was modelled as restricted cubic splines, a reverse J-shaped adjusted association was found between BMI and risk of all-cause death (Figure 2).

Conclusion

HF patients with overweight and obesity had a lower mortality risk compared with patients with normal or underweight patients across all EF classes, at least up to BMI>40 kg/m2. Our results are consistent with the previously suggested potential survival benefit in overweight patients, calling for future research to understand this apparent paradox.Figure 1
Five-year changes in weight and risk of atrial fibrillation in women and men from the Danish diet, cancer, and health cohort
Authors: Frederiksen T C , Christiansen M C , Benjamin E J , Overvad K , Olsen A , Dahm C C , Jensen H K
Published: November 2023

Background

Overweight and obesity are causal risk factors for atrial fibrillation (AF).(1) Mendelian randomization studies indicated a higher risk of AF with each unit increase in body mass index (BMI).(1) In observational studies, weight gain was associated with a higher risk of incident AF compared to stable weight.(2,3) However, the results are conflicting regarding the association between weight loss and risk of incident AF.(4,5).

Purpose

We aimed to assess the association between five-year changes in weight and absolute and relative rates of incident AF in women and men from the Danish Diet, Cancer, and Health Cohort.

Methods

In the Danish cohort study Diet, Cancer, and Health, participants were invited to attend a recruitment research examination and a second examination 5 years later. Height, weight, and several lifestyle factors were assessed at both examinations. We calculated BMI and BMI changes between first and second examination. BMI changes were categorized into following groups: <-5 kg/m2, ≥-5 to <-2.5 kg/m2, ≥-2.5 to <2.5 kg/m2, ≥2.5 to <5 kg/m2 and ≥5 kg/m2. Diagnoses of AF and comorbidities were retrieved from the Danish National Patient Registry. We used multivariable-adjusted Cox proportional hazards models to assess hazard ratios (HR) of AF according to changes in BMI.

Results

43,758 participants without prior AF were included in the study. The median age was 62 (25th-75th percentile, 58-66) years and 54% were women. Over 15.7 years median follow-up time 5,312 participants had incident AF. From the first to the second measure, 39,076 (89%) of participants had stable weight, 2,627 (6%) lost weight, and 2,055 (5%) gained weight. The incidence rates of AF per 1,000 person-years were 8.4 (95% CI 8.1-8.6) among participants with stable weight, 12.4 (95% CI 9.6-16.1) among those with weight loss ≥5 kg/m2, and 15.4 (95% CI 11.7-20.2) among those who gained ≥5 kg/m2. Compared to participants with stable weight, individuals who gained ≥2.5 to <5 kg/m2 had a higher hazard of AF (HR 1.24, 95% CI 1.09-1.41). Among participants who gained ≥5 kg/m2 the rate of AF was also higher compared to stable weight (HR 1.95, 95% CI 1.48-2.56). There was no statistically significant association between weight loss, regardless of degree, and rate of AF. Figure 1 shows the HR of AF by BMI changes from first to second measure compared to stable weight using restricted cubic splines. In sex-stratified analyses, the association between weight gain of ≥5 BMI units (kg/m2) and higher AF rate was present for both women and men.

Conclusions

In this cohort study, five-year weight gain was associated with higher long-term risk of AF compared to stable weight. However, we found no associations between weight loss and long-term risk of AF.Figure 1
Prevalence of SELECT-eligibility and incidence of 5-year major adverse cardiovascular outcomes in non-diabetic patients with myocardial infarction
Authors: Maeng M , Gyldenkerne C , Thrane P , Hansen M K , Olesen K K W
Published: November 2023

Background

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) trial has randomized 17,605 non-diabetic patients with a body mass index (BMI) ≥27 kg/m2 to treatment with semaglutide versus placebo. Follow-up will be terminated on March 31, 2023. In consecutive myocardial infarction (MI) patients representing daily clinical practice, the prevalence of SELECT-eligible patients and the incidence of the three-point major adverse cardiovascular events (MACE; MI, ischemic stroke, and cardiovascular death) are not known.

Purpose

To assess the prevalence of SELECT-eligibility and the incidence of 5-year MACE in SELECT-eligible patients in a contemporary semi-nationwide European MI cohort representing daily clinical practice.

Methods

We identified 34,385 patients with a first-time MI and followed the in- and exclusion criteria for the SELECT trial as outlined in the Figure. Concordant with the SELECT trial, follow-up started on day 60 and maximum follow-up time was 5 years. We estimated adjusted hazard ratios (aHR) for the SELECT-eligible cohort using patients with a BMI from 20 to <27 kg/m2 as reference group. Moreover, we stratified the SELECT-eligible cohort by BMI ≥27 to <33 kg/m2 and ≥33 kg/m2.

Results

As depicted in the Figure, 10,769 patients with a BMI ≥27 kg/m2 were eligible for SELECT (SELECT-eligible cohort), which corresponds to a prevalence of 31% in the entire 34,385 MI cohort. The normoweight reference group included 11,011 patients. At baseline, the median age was 64 years for the SELECT-eligible cohort and 68 years for the reference group. Stratification of the SELECT-eligible cohort showed median age of 65 years for the BMI ≥27 to <33 kg/m2 and 63 years for the BMI ≥33 kg/m2 subgroups. The cumulative 5-year incidence of MACE was 10.7% for SELECT-eligible and 13.2% for reference patients (aHR 0.96, 95% CI 0.88-1.04). When stratifying the SELECT-eligible cohort, those with BMI ≥27 to <33 and ≥33 kg/m2 had cumulative 5-year incidence of 10.9% (aHR 0.95, 95% CI 0.87-1.04) and 9.9% (aHR 0.99, 95% CI 0.84-1.16).

Conclusions

In a large contemporary semi-nationwide cohort of consecutive MI patients, approximately 3 out of 10 were eligible for the SELECT trial and the estimated 5-year MACE incidence in SELECT-eligible patients was just above 10%. SELECT-eligible patients experienced the index MI up to 7 years earlier than the reference group. However, the 5-year incidence of MACE did not suggest that overweight/obese patients fulfilling SELECT eligibility criteria were associated with an excess MACE risk when compared to a normoweight reference group.
Association of dietary salt intake with diabetes mellitus in the Japanese general population
Authors: Nakano S , Takase H , Hayashi K , Kin F , Isogaki T , Takayama S , Dohi Y
Published: November 2023

Background/Introduction

Excess salt intake, one of the most important modifiable factors in our lifestyle, has been reported to be a risk of cardiovascular morbidity and mortality. Several mechanisms underlying the development of cardiovascular disease after excess salt intake are proposed, among which hypertension has been established. Diabetes mellitus (DM) is also a risk factor of cardiovascular disease and, thus, there may be some association between excess salt intake and DM.

Purpose

The present study was designed to investigate possible relationship between dietary salt intake and DM in the general population.

Methods

Dietary salt intake was estimated using a spot urine sample in 16018 subjects (male=9642, 52.0±12.3 year-old) who visited our hospital for a yearly physical checkup from July 2008 to March 2019 (baseline). A cross-sectional analysis for the relationship between salt intake and DM was performed at baseline. Then, subjects without DM (n=14715, male=8651, 51.3±12.3 year-old) were followed up until March 2020 (median 2107 days) with the endpoint being the development of DM. DM was defined as fasting plasma glucose (FPG) ≥126mg/dL, HbA1c≥6.5% or the use of antidiabetic medications.

Results

A cross-sectional analysis revealed that salt intake in subjects was 8.67±1.98 g/day. Salt intake was significantly higher in subjects with (n=1280) than without DM (9.55±2.17 vs. 8.61±1.94 g/day). Multivariate regression analysis adjusted for age, gender, body weight, systolic blood pressure, pulse rate, serum creatinine, uric acid, FPG, LDL-cholesterol, triglyceride, current smoking and frequent alcohol drink showed that salt intake was associated with the presence of DM (r=0.027, p<0.001). In the follow-up study, 861 subjects developed DM (10.1 per 1000 person-year), with the incidence being more frequent in males than in females (11.7 vs. 7.6 per 1,000 person-year). The incidence of DM was increased across the quartiles of salt intake at baseline (7.5, 7.6, 10.5 and 14.8 per 1000 person-year). In analysis where salt intake at baseline was taken as continuous variables, non-adjusted hazard ratio (HR) (95% confidence interval [CI]) of salt intake for the new onset of DM was 1.146 (1.109-1.184). Multivariate Cox-hazard analysis adjusted for possible risk factors showed that salt intake was a significant predictor for the future development of DM (HR: 1.037, 95%CI: 1.001-1.073), while additional adjustment for baseline body weight disappeared the statistical significance (HR: 0.994, 95%CI: 0.958-1.031).

Conclusions

Salt intake is associated with the development of DM and excess salt intake may predict future development of DM in the general population. Excess food intake which is usually accompanied by excess salt intake in individuals with increased body weight may be responsible for the development of DM. Maintenance of appropriate body weight as well as restriction of dietary salt may lead to the prevention from developing DM.
Association between intensity of glycemic control with GLP-1 receptor agonists and risk of atherosclerotic cardiovascular disease: a systematic review and meta-regression
Authors: Gomes D , Presume J , Ferreira J , De Araujo Goncalves P , Sousa Almeida M , Mendes M
Published: November 2023

Background

Several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown to reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (DM). However, this reduction has not been consistent among different GLP-1 RAs. We conducted a systematic review and meta-regression analyses to evaluate the association between the intensity of glycemic control achieved byGLP-1 RAs therapy in patients with type 2 DM and the reduction of MACE as well as to identify potential mechanisms involved.

Methods

Electronic databases (MEDLINE, CENTRAL, SCOPUS) were searched through November 2022. Studies were considered eligible if they were cardiovascular outcomes randomized trials (CVOTs) comparing GLP-1 RAs versus placebo in type 2 DM patients. Trials including non-diabetic patients and GLP-1 RAs refused by European Medicines Agency or US Food and Drug Administration were excluded. The outcome of interest was 3-point MACE (CV death, MI, or stroke). Random-effects meta-analyses and meta-regression evaluated associations between glycemic control withGLP-1 RAs and study outcomes. Secondary meta-regression analyses were performed for body weight and blood pressure (BP) variation.

Results

Overall, 8 CVOTs were included, with a total of 60080 patients (30694 treated withGLP-1 RAs). GLP-1 RAs were associated with a lower incidence of 3P-MACE (RR 0.876; 95% CI 0.821-0.935, p<0.001). Mean HbA1C reduction was 0.57% in patients treated withGLP-1 RAs vs. placebo. Meta-regression showed that higher reductions of HbA1C levels were associated with lower risk of 3P-MACE (Log RR -0.286 [95% CI-0.512; -0.056], p=0.015), which translates into an estimated relative risk reduction of 25% for each 1% reduction in HbA1C (Figure 1A). There was a non-significant association between glycemic control and each of the 3P-MACE outcomes analysed separately. Body weight reduction was also associated with a lower risk of 3P-MACE (Log RR -0.067 [95% CI-0.134; 0.001], p=0.053), despite not meeting statistical significance (Figure 1B). Systolic BP decrease was not associated with reduced risk of 3P-MACE.

Conclusions

The better the glycemic control withGLP-1 RAs in type 2 DM patients, the greater the reduction in 3P-MACE. Body weight reduction may also play a potential role.Figure 1
Insulin pump treatment vs. multiple daily insulin injections in patients with poorly controlled type 2 diabetes mellitus: a comparison of cardiovascular effects
Authors: Tremamunno S , Tartaglione L , Telesca A , Rizzi A , Felici T , Mazzotta F , De Vita A , Rizzo G E , Cambise N , Belmusto A , Lanza G A , Pitocco D
Published: November 2023

Background

Both hyper- and hypo-glycaemia, as well as large glycaemic variability (GV) are associated with increased cardiovascular events in patients with type 2 diabetes mellitus (T2DM); possible contributing mechanisms of the increased cardiovascular risk include endothelial dysfunction and cardiac sympatho-vagal imbalance. Recent studies suggest that continuous subcutaneous insulin infusion (CSII) improves glycaemic control compared to multiple daily insulin injections (MDI).

Purpose

In this study, we assessed whether CSII may improve cardiac autonomic and vascular dilation function compared to MDI.

Methods

We enrolled in a small randomized pilot study consecutive T2DM patients without cardiovascular disease with poor glycaemic control, despite optimized MDI therapy. Patients were randomized to CSII (Group 1) or to continue MDI (Group 2); insulin dose was adjusted to achieve optimal glycaemic target ranges. Patients were studied at baseline and after 6 months by: 1) assessment of flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) of the brachial artery; 2) heart rate variability (HRV) by 24-hour ECG Holter monitoring; 3) a 7-day continuous glucose monitoring (CGM) was performed at baseline and follow-up in 8 and 7 patients of Group 1 and 2, respectively.

Results

Overall, 21 patients were enrolled, 12 randomized to CSII and 9 to MDI. Daily insulin dose, glycated hemoglobin levels and CGM parameters did not differ significantly between the 2 groups, both at baseline and at follow-up. Both FMD (6.7±2.5 vs 4.6±2.0 %, p=0.51) and NMD (8.9±3.1 vs 7.0±3.0 %, p=0.18), as well as HRV parameters, showed no significant differences between the 2 groups at 6-month follow-up. No relation between GV and both peripheral dilator function and cardiac autonomic function was also detected.

Conclusions

In this small, randomized pilot study we show that, in T2DM patients, CSII achieves similar medium-term glycaemic control compared to MDI, without any significant adverse effect on the cardiovascular system.
Elevated remnant cholesterol in atherosclerotic cardiovascular disease in diabetes: a population-based prospective cohort study
Authors: Nilsson Wadstrom B , Monsted Pedersen K , Berg Wulff A , Gronne Nordestgaard B
Published: November 2023

Background

Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population; the association in individuals with diabetes is not known.

Purpose

We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of peripheral artery disease, myocardial infarction, ischemic stroke, and any ASCVD in individuals with diabetes.

Methods

We studied 4,569 individuals with diabetes and 102,674 individuals without diabetes from the Copenhagen General Population Study (2003-2015). In those with diabetes, during up to 15 years of follow-up, 236 were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischemic stroke, and 498 with any ASCVD in national Danish health registries. Remnant cholesterol was calculated from a standard lipid-profile as total cholesterol minus HDL cholesterol minus LDL cholesterol.

Results

Individuals with diabetes had higher levels of remnant cholesterol, but lower levels of LDL cholesterol, compared to individuals without diabetes (Figure 1). Statin use could explain the lower levels of LDL cholesterol but did not associate with levels of remnant cholesterol.

Multivariable adjusted hazard ratios (95% confidence interval) per doubling of remnant cholesterol and LDL cholesterol were 1.8 (1.2-2.5) and 0.9 (0.6-1.2) for peripheral artery disease, 1.8 (1.3-2.6) and 1.0 (0.7-1.4) for myocardial infarction, 1.6 (1.1-2.3) and 1.1 (0.8-1.6) for ischemic stroke, and 1.7 (1.4-2.2) and 0.9 (0.7-1.1) for any ASCVD, respectively.

Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischemic stroke, and 1.6-fold for any ASCVD. Elevated remnant cholesterol explained 14% (95% confidence interval: 6-23%) of excess risk of PAD; corresponding numbers were 26% (10-41%) for myocardial infarction, 34% (5-64%) for ischemic stroke, and 24% (12-36%) for any ASCVD (Figure 2). LDL cholesterol was lower in individuals with diabetes than in individuals without diabetes and could therefore not explain excess risk.

Conclusions

Elevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes and explained 24% of their excess risk of ASCVD. Clinical trials should determine if remnant cholesterol lowering can prevent ASCVD in individuals with diabetes.
Metabolic disorders predict future impairment of kidney function in the Japanese general population
Authors: Kin F , Takase H , Hayashi K , Nakano S , Isogaki T , Takayama S , Dohi Y
Published: November 2023

Background/Introduction

Metabolic syndrome (MetS) which is defined as accumulation of visceral fat followed by a cluster of metabolic disorders is one of the most important risk factors of cardiovascular morbidity and mortality. Although the close relationship between kidney dysfunction and cardiovascular events have also been reported, the association of kidney dysfunction with MetS remains unidentified.

Purpose

The present study investigated whether MetS or its components predict future deterioration of kidney function in the general population.

Methods

Consecutive 14917 subjects with normal estimated glomerular filtration rate (eGFR; ≥60mL/min/1.73m²) who visited our hospital for a physical check-up from 2008 to 2018 (male=8876, 51.3±12.4 year-old) were enrolled and followed up until 2019 for 1847 days (median) with the endpoint being the development of impaired kidney function (eGFR<60mL/min/1.73m²). Metabolic syndrome was defined based on the Japanese diagnostic criteria (2005; waist circumference ≥85 cm for males and ≥90 cm for females and ≥2 of the following three criteria: (1) triglyceride≥150 mg/dL and/or high-density lipoprotein cholesterol < 40 mg/dL; (2) systolic blood pressure≥130 mmHg and/or diastolic blood pressure ≥85 mmHg; and (3) fasting plasma glucose ≥110 mg/dL). Participants who had medication for each metabolic disorder were considered to meet each criterion.

Results

During the follow-up, 2150 subjects (25.9 per 1000 person-year) developed impaired kidney function. The incidence was more frequent in subjects with (39.3 per 1000 person-year) than without MetS (24.2 per 1000 person-year, p<0.001). Moreover, each component of MetS showed a significant impact on the incident impaired kidney function (obesity 23.0 vs. 31.2, lipid 23.3 vs. 34.2, blood pressure 19.9 vs. 35.9, glucose 24.8 vs. 35.2 per 1000 person-year) and the incidence was increased with increasing the number of metabolic disorders in individuals at baseline (0, 1, 2 and ≥3 factor(s); 17.3, 26.9, 32.9 and 39.7 per 1000 person-year, respectively). Non-adjusted hazard ratio (HR) (95% confidence interval [CI]) of MetS for the new onset of impaired kidney function was 1.619 (1.447-1.810). In multivariate Cox hazard analysis adjusted for sex, age, pulse rate, serum creatinine, uric acid, hemoglobin, current smoking and frequent alcohol consumption, MetS was an independent predictor of the development of impaired kidney function (HR=1.312, 95%CI [1.167-1.475]). Similar results were obtained in sub-analysis using subjects without any medications (n=11963) (data not shown).

Conclusions

Metabolic syndrome and its components are important predictors for the development of impaired kidney function in the general population. Prediction of the deterioration of kidney function may lead to effective prevention of chronic kidney disease and relating cardiovascular disease.
Combined therapy with SGLT2i and GLP-1ra improves cardiovascular prognosis in a population with diabetes and overweigh or obesity. A real-world clinical practice study
Authors: Garcia Vega D , Cinza-Sanjurjo S , Gonzalez-Juanatey J R , Eiras S
Published: November 2023

Background

Prior clinical trials found diabetic patients treated with SGLT2i and/or GLP1ra had lower rates of cardiovascular complications.

Purpose

This study (CardioCHUS-T2D) sought to determine the association between initiation of SGLT2i, GLP1ra or both, and major cardiovascular complications or death in high risk diabetic patients.

Materials and methods

The CardioCHUS-T2D study was an observational study in which adults with type 2 diabetes, older than 65 years old and overweight or obesity were identified in a Galician health area. Patients prescribed an SGLT2i, GLP1ra or both over the last 5 years were matched base on antidiabetic treatment, duration of treatment, sex, age, diabetes duration, arterial hypertension, hyperlipidemia, CAD, HF, atrial fibrillation, CVA and peripheral artery disease (PAD) and were included on a regression Cox for determining the main variables associated with outcomes.

After score matching, we selected 5132 patients who were taking SGLT2i, GLP-1ra or both. The data records were obtained from shared electronic patient dossier (EPD). Patients were classified in 3 groups according antidiabetic drugs, SGLT2i or/and GLP-1ra. During follow-up, after treatment intake, the main outcomes were recorded (hospitalization for coronary artery disease (CAD), heart failure (HF) or cerebrovascular accident (CVA) events, overall and cardiovascular death.

Results

The main clinical characteristics of patients regarding antidiabetic treatment are represented on table 1. No clinical relevant differences were observed between the group of patients treated with any of the monotherapies (SGLT2i or GLP-1ra) and the patients treated with the combined therapy. During the period of observation, the group of patients receiving the combined therapy (SGLT2 + GLP-1ra) were associated with a significant reduction in the risk of suffering heart failure (HF) events (composite of HF hospitalization and HF-related death): HR: 0,651 (95%CI: 0,457-0,927; p=0,017), and all-cause mortality (HR: 0,602 (95%CI:0,443-0,817; p=0,001) (Figure 1) without significative differences in cerebrovascular events.

Conclusions

In a real-world practice observational study (CardioCHUS-T2D) combined therapy with SGLT2i + GLP1ra in patients with T2D older than 65 years with overweight or obesity was associated with a significative reduction in major cardiovascular complications.Clinical characteristics of patientsKaplan-Meier curves
Comparison of plaque characteristics among different age groups in patients with acute coronary syndromes with or without diabetes
Authors: Suzuki K , Niida T , Yuki H , Kinoshita D , Lee H , Mcnulty I , Takano M , Kakuta T , Mizuno K , Jang I
Published: November 2023

Background

It has been reported that young patients with diabetes mellitus (DM) had a higher mortality rate after myocardial infarction. However, plaque characteristics among different age groups in patients with acute coronary syndromes (ACS) with or without DM are unknown.

Purpose

The aim of this study was to investigate the plaque characteristics among different age groups in ACS patients with or without DM in a large population.

Methods

Patients who presented with ACS and underwent preintervention OCT imaging were included. The culprit plaque was categorized as plaque rupture (PR), plaque erosion (PE) or calcified plaque (CP), and stratified by 5 age groups. Features of plaque vulnerability were also analyzed.

Results

Among 1394 patients, 482 (34.6%) had DM. DM patients had a higher prevalence of lipid-rich plaque (71.2% vs. 64.8%, p=0.016), macrophage (72.0% vs. 62.6%, p<0.001), and cholesterol crystal (27.6% vs. 19.7%, p<0.001) than non-DM patients. Non-DM patients showed a significant ascending trend with age in PR (p=0.004), lipid-rich plaque (p=0.018), whereas DM patients had a high prevalence of these vulnerable features at early age, which plateaued across the different age groups. Both DM and non-DM groups showed a significant decreasing trend in PE with age (non-DM patients, p<0.001; DM patients, p=0.020).

Conclusions

DM patients had a high prevalence of lipid-rich plaque and a high incidence of plaque rupture at early age. This pattern persisted across the different age groups.
Associations of built environment characteristic using NEWS questionnaires with major cardiovascular diseases and all-cause mortality
Authors: Li M , Li W
Published: November 2023

Background

The WHO of 2016 reports that cardiovascular diseases (CVDs) represent the leading cause of death in most countries and China has one of the highest prevalence of CVDs[1-2]. In order to reduce the burden of CVD risk factors, environmental interventions have become increasingly recognized as necessary approaches to health promotion and diseases prevention[3]. Pervious evidence mainly from the western countries, examined the effects of built environment on health (i.e. physical activity, mental health, self-reported health scale and CVD risk factors) , while the potential impact on CVDs has not been fully explored[4]. Thus, the aim of this study is to evaluate the longitudinal relationships between perceived built environment attributes using neighborhood environment walkability scale (NEWS) questionnaire and the CVDs in Chinese adults, to explore the different between urban and rural areas, and to provide a logical foundation for both research and policy making.

Methods

PURE-China is a prospective cohort study, recruiting participants aged 35–70 years from 115 urban and rural communities in 12 provinces of China between 2005 and 2009[5]. Baseline including NEWS information was collected using standardized questionnaires. Participants without any NEWS data and with baseline CVDs were excluded. The primary outcome is the composite of major CVD events and all-cause mortality. The main exposure variables including land use mix-diversity, land use-access, streets connectivity, infrastructure for walking and cycling, aesthetics, safety from traffic, safety from crime, and community satisfaction. Cox frailty model with random intercepts to account for cluster were used to assess the association between total built environment score/ subscales score and the time to occurrence of events. Based and fully-adjusted model were estimated and presented as HR and 95%CI. Interactions and stratified subgroup analysis were also tested.

Results

A total of 32,534 PURE participants were included with averaged 51 years old and 59.9% females. During a median follow-up period of 11.7 years (IQR 9.4 – 12.2), we documented 3298 (10.2%) new CVD events and 1639 (5.1%) all cause deaths. Table 1 summarizes based models and adjusted models results. For composite outcomes, higher level of land use access (HR, 1.06; 95%CI, 1.01-1.11), aesthetics (HR, 1.07; 95%CI, 1.02-1.12), safety from crime (HR, 1.06; 95%CI, 1.01-1.10), community satisfaction (HR, 1.04; 95%CI, 1.00-1.09), combined BE metrics (HR, 1.05; 95%CI, 1.01-1.10) were associated with a lower risk of composite outcome in adjusted model. For major CVD events more statistically significant differences were observed.

Conclusions and Relevance

High level of specific BE characteristics were associated with lower risk of all-cause mortality and CVD in China. Our findings may guide policy makers on how to implement BE measures to easing the burden of CVDs and premature deaths.Table 1