Familial dysbetalipoproteinemia (FD), characterized by remnant lipoprotein accumulation and premature cardiovascular disease, occurs in homozygous carriers of the APOE ε2 allele, but genetic ...predisposition alone does not suffice for the clinical phenotype. Cross-sectional studies suggest that a second metabolic hit – notably adiposity or insulin resistance – is required, but the association between these risk factors and development of FD has not been studied prospectively.
For this study, we evaluated 18,987 subjects from two large prospective Dutch population-based cohorts (PREVEND and Rotterdam Study) of whom 118 were homozygous APOE ε2 carriers. Of these, 69 subjects were available for prospective analyses. Dyslipidemia – likely to be FD – was defined as fasting triglyceride (TG) levels >3 mmol/L in untreated subjects or use of lipid lowering medication. The effect of weight, body mass index (BMI), waist circumference, type 2 diabetes mellitus and non-TG metabolic syndrome on development of dyslipidemia was investigated.
Eleven of the 69 ε2ε2 subjects (16%) developed dyslipidemia – likely FD – during follow-up. Age-, sex- and cohort-adjusted risk factors for the development of FD were BMI (OR 1.19; 95%CI 1.04–1.39), waist circumference (OR 1.26 95%CI 1.01–1.61) and presence of non-TG metabolic syndrome (OR 4.39; 95%CI 1.04–18.4) at baseline. Change in adiposity during follow-up was not associated with development of dyslipidemia.
Adiposity increases the risk of developing an FD-like lipid phenotype in homozygous APOE ε2 subjects. These results stress the importance of healthy body weight in subjects at risk of developing FD.
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•Baseline adiposity increases the risk of developing dyslipidemia – likely familial dysbetalipoproteinemia (FD) – in ε2ε2 subjects from the general population.•Change in adiposity during follow-up was not associated with the development of dyslipidemia – likely FD.•This suggests that in ε2ε2 subjects the ‘switch’ to FD-like lipid phenotype is a gradual process that starts early in life.
In clinical trials, treatment with fenofibrate did not reduce the incidence of major cardiovascular events (MCVE) in patients with type 2 diabetes mellitus (T2DM). However, treatment effects reported ...by trials comprise patients who respond poorly and patients who respond well to fenofibrate. Our aim was to use statistical modeling to estimate the expected treatment effect of fenofibrate for individual patients with T2DM.
To estimate individual risk, the FIELD risk model, with 5-year MCVE as primary outcome, was externally validated in T2DM patients from ACCORD and the SMART observational cohort. Fenofibrate treatment effect was estimated in 17,142 T2DM patients from FIELD, ACCORD, and SMART. Individual treatment effect, expressed as absolute risk reduction (ARR), is the difference between treated and untreated MCVE risk. Results were stratified for patients with and without dyslipidemia (i.e., high triglycerides and low LDL cholesterol).
External validation of the FIELD risk model showed good calibration and moderate discrimination in ACCORD (C-statistic 0.67 95% CI 0.65-0.69) and SMART (C-statistic 0.66 95% CI 0.63-0.69). Median 5-year MCVE risk in all three studies combined was 6.7% (interquartile range IQR 4.0-11.7) in patients without (
= 13,224) and 9.4% (IQR 5.4-16.1%) in patients with (
= 3,918) dyslipidemia. The median ARR was 2.15% (IQR 1.23-3.68) in patients with dyslipidemia, corresponding with a number needed to treat (NNT) of 47, and 0.22% (IQR 0.13-0.38) in patients without dyslipidemia (NNT 455).
In individual patients with T2DM, there is a wide range of absolute treatment effect of fenofibrate, and overall the fenofibrate treatment effect was larger in patients with dyslipidemia. The method of individualized treatment effect prediction of fenofibrate on MCVE risk reduction in T2DM can be used to guide clinical decision making.
Abstract
Aims
To quantify the relationship between self-reported, long-term lifestyle changes (smoking, waist circumference, physical activity, and alcohol consumption) and clinical outcomes in ...patients with established cardiovascular disease (CVD).
Methods and results
Data were used from 2011 participants (78% male, age 57 ± 9 years) from the Utrecht Cardiovascular Cohort—Second Manifestations of ARTerial disease cohort who returned for a re-assessment visit (SMART2) after ∼10 years. Self-reported lifestyle change was classified as persistently healthy, improved, worsened, or persistently unhealthy. Cox proportional hazard models were used to quantify the relationship between lifestyle changes and the risk of (cardiovascular) mortality and incident Type 2 diabetes (T2D). Fifty-seven per cent of participants was persistently healthy, 17% improved their lifestyle, 8% worsened, and 17% was persistently unhealthy. During a median follow-up time of 6.1 (inter-quartile range 3.6–9.6) years after the SMART2 visit, 285 deaths occurred, and 99 new T2D diagnoses were made. Compared with a persistently unhealthy lifestyle, individuals who maintained a healthy lifestyle had a lower risk of all-cause mortality hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.36–0.63, cardiovascular mortality (HR 0.57, 95% CI 0.38–0.87), and incident T2D (HR 0.46, 95% CI 0.28–0.73). Similarly, those who improved their lifestyle had a lower risk of all-cause mortality (HR 0.52, 95% CI 0.37–0.74), cardiovascular mortality (HR 0.46, 95% CI 0.26–0.81), and incident T2D (HR 0.50, 95% CI 0.27–0.92).
Conclusion
These findings suggest that maintaining or adopting a healthy lifestyle can significantly lower mortality and incident T2D risk in CVD patients. This study emphasizes the importance of ongoing lifestyle optimization in CVD patients, highlighting the potential for positive change regardless of previous lifestyle habits.
Lay Summary
In this study, we investigated whether lifestyle changes were related to improved health outcomes in individuals with cardiovascular disease (CVD). We assessed self-reported lifestyle behaviours (smoking, waist circumference, alcohol consumption, and physical activity), at inclusion in the cohort and again ∼10 years later. The results emphasize the importance of making healthy lifestyle choices, even for individuals already diagnosed with CVD, and suggest that it is never too late to improve one’s lifestyle.
Polygenic risk scores (PRSs) can be used to quantify the effect of genetic contribution to LDL-cholesterol (LDL-C) and systolic blood pressure (SBP). Several PRSs for LDL-C and SBP have been shown to ...be associated with cardiovascular disease (CVD) in the general population. This study aimed to evaluate the effect of an LDL-C PRS and an SBP PRS on the risk of recurrent CVD in patients with CVD.
Genotyping was performed in 4,416 patients included in the UCC-SMART study. Weighted LDL-C PRS (279 LDL-C-related SNPs) and SBP PRS (425 SBP-related SNPs) were calculated. Linear regression models were used to evaluate the relation between both PRSs and LDL-C and SBP. The effects of the LDL-C PRS and SBP PRS, and its combination on the risk of recurrent CVD (stroke, myocardial infarction, and vascular death) were analyzed with Cox proportional-hazard models.
Per SD increase in LDL-C PRS, LDL-C increased by 0.18 mmol/L (95%CI 0.15–0.21). Per SD increase in SBP PRS, SBP increased by 3.19 mmHg (95%CI 2.60–3.78). During a follow-up of 11.7 years (IQR 9.2–15.0) 1,198 recurrent events occurred. Neither the LDL-C nor the SBP PRS were associated with recurrent CVD (HR 1.05 per SD increase in LDL-C PRS (95%CI 0.99–1.11) and HR 1.04 per SD increase in SBP PRS (95%CI 0.98–1.10)). The combination of both scores was neither associated with recurrent CVD (HR 1.09; 95%CI 0.93–1.28).
In patients with vascular disease, LDL-C PRS and SBP PRS, both separately and in combination, were not significantly associated with recurrent CVD.
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•Low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) are highly heritable traits•Few studies have reported on the association between polygenic risk scores (PRSs) for LDL-C and SBP and recurrent CVD•RS for LDL-C and PRS SBP were associated with LDL-C and SBP in patients with CVD•Both PRS were not significantly associated with the risk of recurrent CVD•Genetically determined LDL-C and SBP do not explain residual cardiovascular risk in patients with CVD
Unhealthy dietary habits are an important risk factor for cardiovascular disease (CVD) and adopting a healthy diet is a central recommendation in CVD prevention. This study assessed the dietary ...habits of patients with established CVD, their compliance to dietary guidelines, and the relationship between guideline-compliance and recurrent cardiovascular event risk.
2656 patients with established CVD from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART) prospective cohort study, were included between 1996 and 2022. Data on dietary intake was retrospectively collected for all participants in December 2022 using a 160-item food frequency questionnaire. Compliance with dietary guidelines was quantified using an amended version of the Dutch Healthy Diet 2015 (DHD-15) index (range: 0-135). Cox proportional hazard models were used to quantify the relationship with cardiovascular events (stroke and myocardial infarction).
Among 2656 CVD patients (77% male, mean age 59 ± 9 years), median energy intake was 1922 IQR: 1536-2351 kcal/day. The median DHD-15 index was 81.7 IQR 71.2-92.0, with high compliance scores for recommendations on legumes and fish, and low scores for recommendations on whole grains, red meat, processed meat, and dairy. A higher DHD-15 score was associated with lower stroke risk (HR 0.78, 95% CI 0.66-0.92 per 10-point increase) but not with myocardial infarction.
Compliance with dietary guidelines was suboptimal in patients with established CVD. High compliance was associated with a clinically significant reduction in stroke risk in patients with established CVD, emphasizing the importance of dietary counseling.
Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol‐enriched remnant lipoproteins. FD is ...usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow‐up, and family counseling.
•For this study data from a randomized trial performed in 28 patients with FD were used.•Friedewald, Martin-Hopkins, direct assay and gels to determine LDL-C were compared to UC.•All methods over- or ...underestimated LDL-C concentrations compared to UC.•UC probably overestimates LDL-C concentrations as well.•Non-HDL-C measured by standard assays performed well compared to non-HDL-C by UC.
To compare LDL-C concentrations using the Friedewald formula, the Martin-Hopkins formula, a direct assay and polyacrylamide gradient gel electrophoresis (PGGE) to the reference standard density gradient ultracentrifugation in patients with Familial Dysbetalipoproteinemia (FD) patients. We also compared non-HDL-cholesterol concentrations by two methods.
For this study data from 28 patients with genetically confirmed FD from the placebo arm of the EVOLVE-FD trial were used. Four different methods for determining LDL-C were compared with ultracentrifugation. Non-HDL-C was measured with standard assays and compared to ultracentrifugation. Correlation coefficients and Bland-Altman plots were used to compare the methods.
Mean age of the 28 FD patients was 62 ± 9 years, 43 % were female and 93 % had an ɛ2ɛ2 genotype. LDL-C determined by Friedewald (R2 = 0.62, p <0.01), Martin-Hopkins (R2 = 0.50, p = 0.01) and the direct assay (R2 = 0.41, p = 0.03) correlated with density gradient ultracentrifugation. However, Bland-Altman plots showed considerable over- or underestimation by the four methods compared to ultracentrifugation. Non-HDL-C showed good correlation and agreement.
In patients with FD, all four methods investigated over- or underestimated LDL-C concentrations compared with ultracentrifugation. In contrast, standard non-HDL-C assays performed well, emphasizing the use of non-HDL-C in patients with FD.
Guidelines no longer recommend low-fat diets and currently recommend more plant-based diets to reduce atherosclerotic cardiovascular disease (ASCVD) risk. Furthermore, these guidelines have ...consistently recommended salt-reduced diets. This article describes current self-reported use and time-trends in the self-reported use of low-fat, low-salt and vegetarian diets in ASCVD patients and examines patient characteristics associated with each diet.
9005 patients with ASCVD included between 1996 and 2019 in the UCC-SMART cohort were studied. The prevalence of self-reported diets was assessed and multi-variable logistic regression was used to identify the determinants of each diet. Between 1996-1997 and 2018–2019, low-fat diets declined from 22.4 % to 3.8 %, and low-salt diets from 14.7 % to 4.6 %. The prevalence of vegetarian diets increased from 1.1 % in 1996–1997 to 2.3 % in 2018–2019. Patients with cerebrovascular disease (CeVD) and peripheral artery disease or an abdominal aortic aneurysm (PAD/AAA) were less likely to report a low-salt diet than coronary artery disease (CAD) patients (OR 0.62 95%CI 0.49–0.77 and 0.55 95%CI 0.41–0.72).
In the period 1996 to 2019 amongst patients with ASCVD, the prevalence of self-reported low-fat diets was low and decreased in line with changes in recommendations in major guidelines. The prevalence of self-reported vegetarian diets was low but increased in line with societal and guideline changes. The prevalence of self-reported low-salt diets was low, especially in CeVD and PAD/AAA patients compared to CAD patients, and decreased over time. Renewed action is needed to promote low-salt diets in ASCVD patients.
•A small and decreasing proportion of patients with ASCVD reports a low-salt diet.•Renewed efforts are needed to promote low-salt diets in this population.•While still low, an increasing number of CVD patients reports a vegetarian diet.•Further research is needed on the vegetarian diet's health impact in CVD patients.
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