RESUMEN
BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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]). CONCLUSION: 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.
Asunto(s)
Aneurisma de la Aorta Abdominal , Aterosclerosis , Enfermedades Cardiovasculares , Trastornos Cerebrovasculares , Enfermedad de la Arteria Coronaria , Enfermedad Arterial Periférica , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Autoinforme , Prevalencia , Dieta con Restricción de Grasas , Factores de Riesgo , Enfermedad de la Arteria Coronaria/epidemiología , Aterosclerosis/epidemiología , Trastornos Cerebrovasculares/diagnóstico , Trastornos Cerebrovasculares/epidemiología , Trastornos Cerebrovasculares/prevención & control , Enfermedad Arterial Periférica/epidemiología , Aneurisma de la Aorta Abdominal/epidemiología , Dieta Vegetariana , Cloruro de Sodio Dietético/efectos adversosRESUMEN
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.
Asunto(s)
Apolipoproteínas E , Hiperlipoproteinemia Tipo III , Apolipoproteínas E/genética , Genotipo , Humanos , Hiperlipoproteinemia Tipo III/diagnóstico , Hiperlipoproteinemia Tipo III/genética , Hiperlipoproteinemia Tipo III/metabolismo , FenotipoRESUMEN
Familial dysbetalipoproteinemia (FD) is a genetic disorder associated with impaired postprandial lipid clearance. The effect of adding bezafibrate to standard lipid-lowering therapy on postprandial and fasting lipid levels in patients with FD is unknown. In this randomized placebo-controlled double-blind crossover trial, 15 patients with FD received bezafibrate and placebo for 6 weeks in randomized order in addition to standard lipid-lowering therapy (statin, ezetimibe, and/or lifestyle). We assessed post-fat load lipids, expressed as incremental area under the curve (iAUC) and area under the curve (AUC), as well as fasting levels and safety, and found that adding bezafibrate did not reduce post-fat load non-HDL-cholesterol (non-HDL-C) iAUC (1.78 ± 4.49 mmol·h/l vs. 1.03 ± 2.13 mmol·h/l, P = 0.57), but did reduce post-fat load triglyceride (TG) iAUC (8.05 ± 3.32 mmol·h/l vs. 10.61 ± 5.92 mmol·h/l, P = 0.03) and apoB (0.64 ± 0.62 g·h/l vs. 0.93 ± 0.71 g·h/l, P = 0.01). Furthermore, bezafibrate significantly improved AUC and fasting levels of non-HDL-C, TG, total cholesterol, HDL-C, and apoB. Bezafibrate was associated with lower estimated glomerular filtration rate (78.4 ± 11.4 ml/min/1.73 m2 vs. 86.1 ± 5.85 ml/min/1.73 m2, P = 0.002). In conclusion, in patients with FD, the addition of bezafibrate to standard lipid-lowering therapy resulted in improved post-fat load and fasting plasma lipids. Combination therapy of statin/fibrate could be considered as standard lipid-lowering treatment in FD.
Asunto(s)
Bezafibrato/farmacología , Grasas de la Dieta/efectos adversos , Hiperlipoproteinemia Tipo III/sangre , Hiperlipoproteinemia Tipo III/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Lípidos/sangre , Anciano , Bezafibrato/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Ayuno/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , SeguridadRESUMEN
BACKGROUND AND AIMS: Body adiposity is known to affect mortality risk in patients with coronary artery disease (CAD). We examined associations of body mass index (BMI) and waist circumference (WC) with long term mortality in Dutch CAD patients, and potential and effect modification of these associations by lifestyle and health determinants. METHODS: 10,370 CAD patients (mean age â¼65 y; 20% female; >80% on cardiovascular drugs) from the prospective Alpha Omega Cohort and Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease study were included. Cox models were used to estimate categorical and continuous associations (using restricted cubic splines) of measured BMI and WC with all-cause and cardiovascular mortality risk, adjusting for age, sex, smoking, alcohol, physical activity and educational level. Analyses were repeated in subgroups of lifestyle factors (smoking, physical activity, diet quality), education and health determinants (diabetes, self-rated health). RESULTS: During â¼10 years of follow-up (91,947 person-years), 3,553 deaths occurred, including 1,620 from cardiovascular disease. U-shaped relationships were found for BMI and mortality risk, with the lowest risk for overweight patients (BMI â¼27 kg/m2). For obesity (BMI ≥30), the HR for all-cause mortality was 1.31 (95% CI: 1.11, 1.41) in male patients and 1.10 (95% CI: 0.92, 1.30) in female patients, compared to BMI 25-30 kg/m2. WC was also non-linearly associated with mortality, and HRs were 1.18 (95%CI:1.06, 1.30) in males and 1.31 (95%CI:1.05, 1.64) in females for the highest vs. middle category of WC. Results for cardiovascular mortality were mostly in line with the results for all-cause mortality. U-shaped associations were found in most subgroups, associations were moderately modified by physical activity, smoking and educational level. CONCLUSIONS: CAD patients with obesity and a large WC were at increased risk of long-term CVD and all-cause mortality, while mildly overweight patients had the lowest risk. These associations were consistent across subgroups of patients with different lifestyles and health status.
Asunto(s)
Índice de Masa Corporal , Enfermedad de la Arteria Coronaria , Estilo de Vida , Circunferencia de la Cintura , Humanos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/mortalidad , Factores de Riesgo , Estudios Prospectivos , Obesidad/mortalidad , Obesidad/complicaciones , Ejercicio Físico , Países Bajos/epidemiologíaRESUMEN
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 â¼10 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.
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 â¼10 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.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Factores de Riesgo , Estudios Prospectivos , Estilo de VidaRESUMEN
AIMS: The efficacy of a healthy lifestyle in secondary prevention of cardiovascular disease (CVD) is well established and a first-line recommendation in CVD prevention guidelines. The aim of this study was to assess if they are also cost-effective in patients with established CVD. METHODS: A cost-utility analysis (CUA) was performed comparing a combined Mediterranean diet and physical activity intervention to usual care in CVD patients. The CUA had a healthcare perspective and lifetime horizon. Costs and utilities were estimated using a microsimulation on a cohort of 100,000 CVD patients sampled from the UCC-SMART study (N = 8,947, mean age 62 ±8.7 years and 74% male). Cost-effectiveness was expressed as incrementalcost-effectiveness ratio (ICER), incremental net health benefit (INHB) and incremental net monetary benefit (INMB). RESULTS: Mediterranean diet and physical activity yielded 2.0 incremental quality-adjusted life years (QALYs) and cost reductions of 1,236 per person compared to usual care, resulting in an ICER of -626/QALY (95%CI -1,929 to 2,673). At a willingness-to-pay of 20,000/QALY, INHB was 2.04 (95%CI 0.99-3.58) QALY and INMB was 40,757 (95%CI 19,819-71,605). The interventions remained cost-effective in a wide range of sensitivity analyses, including worst-case scenarios and scenarios with reimbursement for food and physical activity costs. CONCLUSION: In patients with established CVD, a combined Mediterranean diet and physical activity intervention was cost-saving and highly cost-effective compared to usual care. These findings strongly advocate for the incorporation of lifestyle interventions as integral components of care for all CVD patients.
Lifestyle optimization, including physical activity and healthy diet, is a central recommendation for preventing recurrent cardiovascular events. In this study, we assessed if improving physical activity habits and adherence to a heart-healthy Mediterranean diet would also be a cost-effective option. The results were remarkable - following the Mediterranean diet and engaging in physical activity was expected to result in an increase of 2.0 quality-adjusted life years (QALYs, equal to a life year in perfect health) and cost savings. This means that lifestyle optimization in secondary CVD prevention improves population health, while reducing overall health care costs. These findings underscore the importance of implementing lifestyle changes in the care for all individuals with CVD. A health lifestyle is not only effective in improving health but also a prudent financial decision. Key messages A combined Mediterranean diet and physical activity intervention is expected to result in two additional QALYs and three additional life years free of recurrent cardiovascular events per patient with with established CVDTargeting a healthy lifestyle is expected to lead to costs savings compared to usual care, due to the low costs of the intervention and the high efficacy in preventing recurrent cardiovascular events.Lifestyle optimization in secondary CVD prevention was shown to result in a dominant incremental cost-effectiveness ratio (ICER) of -626/QALY, which strongly advocates for healthy policy targeted at implementing lifestyle interventions in regular care for CVD patients.
RESUMEN
AIM: To quantify the relationship of neutrophil-to-lymphocyte ratio (NLR) with cardiovascular events and all-cause mortality in patients with type 2 diabetes (T2D), independent of C-reactive protein (CRP). METHODS: Patients with T2D from the UCC-SMART-cohort were studied using multivariable-adjusted Cox regression. The relationship of NLR and CRP with vascular events (cerebrovascular events, myocardial infarction and vascular death) and all-cause mortality was quantified. RESULTS: During 10,833 person-years, 232 vascular events and 302 deaths occurred in 1,239 patients with T2D. Risk of vascular events and all-cause mortality increased per standard deviation (SD) in NLR (hazard ratio (HR) 1.27; 95 % confidence interval (CI):1.11-1.46) and 1.15; 95 % CI:1.02-1.30) after adjustment for CRP. CRP was not associated with vascular events after adjustment for NLR, (HR per SD 1.03; 95 % CI: 0.90-1.19), but was associated with all-cause mortality (HR per SD 1.18; 95 % CI: 1.04-1.33). Notably, NLR was related to vascular events in patients with CRP < 2 mg/L (HR per unit 1.45; 95 % CI: 1.19-1.77). CONCLUSION: In patients with T2D, NLR is related to higher risk of CVD and all-cause mortality, independently from CRP. NLR is related to CVD even when CRP is low, indicating that NLR is a marker of CVD-risk in addition to CRP. Both NLR and CRP are independently related to all-cause mortality in T2D patients.
Asunto(s)
Proteína C-Reactiva , Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Linfocitos , Neutrófilos , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/mortalidad , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Masculino , Femenino , Persona de Mediana Edad , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/sangre , Anciano , Factores de RiesgoRESUMEN
BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.
Asunto(s)
Enfermedades Cardiovasculares , Conducta Alimentaria , Política Nutricional , Cooperación del Paciente , Humanos , Masculino , Femenino , Persona de Mediana Edad , Enfermedades Cardiovasculares/prevención & control , Cooperación del Paciente/estadística & datos numéricos , Estudios Prospectivos , Anciano , Países Bajos , Estudios de Cohortes , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Clearance of triglyceride-rich lipoproteins (TRLs) is mediated by several receptors, including heparan sulfate proteoglycans (HSPGs). Sulfate glucosamine-6-O-endosulfatase-2 is a gene related to the regulation of HSPG. A variant in this gene, rs2281279, has been shown to be associated with triglycerides and insulin resistance. Objective: To determine the relationship between rs2281279, metabolic parameters and vascular events, and type 2 diabetes mellitus (T2DM) in patients at high cardiovascular risk and whether APOE genotype modifies this relationship. Methods: Patients (n = 4386) at high cardiovascular risk from the Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease study were stratified according to their imputed rs2281279 genotype: AA (n = 2438), AG (n = 1642) and GG (n = 306). Effects of rs2281279 on metabolic parameters, vascular events and T2DM were analyzed with linear regression and Cox models. Results: There was no relationship between imputed rs2281279 genotype and triglycerides, non-high-density lipoprotein (HDL)-cholesterol, insulin and quantitative insulin sensitivity check index. During a median follow-up of 11.8 (IQR, 9.3-15.5) years, 1026 cardiovascular events and 320 limb events occurred. The presence of the G allele in rs2281279 did not affect the risk of vascular events [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.94-1.14] or limb events (HR, 0.92; 95% CI, 0.77-1.10). The presence of the G allele in rs2281279 did not affect the risk of T2DM (HR, 1.09; 95% CI, 0.94-1.27). The presence of the minor G allele of rs2281279 was associated with a beneficial risk profile in ε2ε2 patients, but not in ε3ε3 patients. Conclusions: Imputed rs2281279 genotype is not associated with metabolic parameters and does not increase the risk of vascular events or T2DM in patients at high risk for cardiovascular disease.
RESUMEN
OBJECTIVE: In healthy populations, leisure-time physical activity (LTPA) improves health outcomes, while, paradoxically, occupational physical activity (OPA) is associated with detrimental health effects. This study aimed to investigate the associations of LTPA and OPA with mortality, cardiovascular events and type 2 diabetes (T2D) in patients with cardiovascular disease (CVD). METHODS: In 7058 outpatients with CVD (age 61±10 years, 75% male) from the prospective Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort, Cox models were used to quantify the associations between self-reported LTPA and OPA and all-cause mortality, cardiovascular events and T2D. RESULTS: Over 8.6 years (IQR: 4.6-12.5) of follow-up, 1088 vascular events, 1254 deaths and 447 incident T2D cases occurred. The top LTPA quarter had a lower risk of all-cause mortality (HR 0.63, 95% CI 0.54 to 0.74), recurrent cardiovascular events (HR 0.72, 95% CI 0.60 to 0.84) and incident T2D (HR 0.71, 95% CI 0.55 to 0.93), compared with the lowest quarter. The continuous LTPA associations were reverse J-shaped for all-cause mortality and vascular events and linear for T2D. OPA (heavy manual vs sedentary) showed a trend towards an increased risk of all-cause mortality (HR 1.08, 95% CI 0.86 to 1.35), cardiovascular events (HR 1.15, 95% CI 0.91 to 1.45) and T2D (HR 1.04, 95% CI 0.72 to 1.50). The detrimental effects of higher OPA were more pronounced in men, never-smokers, people with higher education and active employment. CONCLUSIONS: In patients with CVD, LTPA was associated with lower risk of all-cause mortality, recurrent cardiovascular events and incident T2D. In contrast, OPA seemed to increase the risk of these outcomes. These findings support the existence of a physical activity paradox in patients with CVD.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Enfermedades Cardiovasculares/epidemiología , Estudios Prospectivos , Diabetes Mellitus Tipo 2/epidemiología , Ejercicio Físico , Actividades Recreativas , Evaluación de Resultado en la Atención de Salud , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to effectively reduce blood pressure and body weight, but its effectiveness for reducing (cardiovascular) mortality rates has never been assessed in a clinical trial. Causal effects of dietary interventions are difficult to measure, due to practical limitations of randomized controlled diet trials. Target trial emulation can be used to improve causal inference in observational data. The aim of this study was to emulate a target trial assessing the relationship between compliance with the DASH diet and cardiovascular and all-cause mortality risk in patients with established CVD. METHODS: Using data from the Alpha Omega Cohort, we emulated a DASH diet trial in patients with a history of myocardial infarction (MI). Inverse probability of treatment weighting (IPTW) was used to balance confounders over DASH-compliant and non-DASH-compliant participants. Hazard ratios (HRs) were estimated with IPT-weighted Cox models. RESULTS: Of 4365 patients (79% male, median age 69 years, >80% treated with lipid- and blood pressure-lowering medication), 598 were classified as DASH-compliant (compliance score ≥5 out of 9). During a median follow-up of 12.4 years, 2035 deaths occurred of which 903 (44%) were of cardiovascular origin. DASH compliance was not associated with all-cause mortality (HR 0.92, 95%CI 0.0.80-1.06) and cardiovascular mortality (HR 0.90, 95%CI 0.72-1.11). CONCLUSIONS: In an emulated target trial on the DASH diet in the Alpha Omega cohort no relation was found between DASH compliance and risk of all-cause and cardiovascular mortality in patients with a history of MI. The DASH diet's effects may have been modified in this population by concomitant use of blood pressure-lowering medications.
Asunto(s)
Enfermedades Cardiovasculares , Enfoques Dietéticos para Detener la Hipertensión , Hipertensión , Infarto del Miocardio , Humanos , Masculino , Anciano , Femenino , Dieta , Infarto del Miocardio/complicaciones , Cooperación del Paciente , Presión Sanguínea , Hipertensión/epidemiologíaRESUMEN
BACKGROUND: Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options. OBJECTIVES: To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD. METHODS: A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins. RESULTS: In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Æ2Æ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load. CONCLUSIONS: Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.
Asunto(s)
Anticolesterolemiantes , Enfermedades Cardiovasculares , Hiperlipoproteinemia Tipo III , Anciano , Humanos , Persona de Mediana Edad , Anticolesterolemiantes/uso terapéutico , Apolipoproteínas B , Enfermedades Cardiovasculares/tratamiento farmacológico , Ayuno , Hiperlipoproteinemia Tipo III/tratamiento farmacológico , Lipoproteínas , Proproteína Convertasa 9 , Resultado del Tratamiento , Metabolismo de los LípidosRESUMEN
AIM: 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. 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. RESULTS: Mean age of the 28 FD patients was 62 ± 9 years, 43 % were female and 93 % had an É2É2 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. CONCLUSION: 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.
Asunto(s)
Hiperlipoproteinemia Tipo III , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , LDL-Colesterol , Hiperlipoproteinemia Tipo III/tratamiento farmacológico , Colesterol , Lipoproteínas , Triglicéridos , HDL-ColesterolRESUMEN
Aims: To estimate the relation between physical exercise volume, type, and intensity with all-cause mortality and recurrent vascular events in patients with cardiovascular disease (CVD) and to quantify to what extent traditional cardiovascular risk factors mediate these relations. Methods and results: In the prospective UCC-SMART cohort (N = 8660), the associations of clinical endpoints and physical exercise volume (metabolic equivalent of task hours per week, METh/wk), type (endurance vs. endurance + resistance), and intensity (moderate vs. vigorous) were estimated using multivariable-adjusted Cox models. The proportion mediated effect (PME) through body mass index, systolic blood pressure, low-density lipoprotein cholesterol, insulin sensitivity, and systemic inflammation was assessed using structural equation models. Sixty-one percent of patients (73% male, age 61 ± 10 years, >70% receiving lipid-lowering and blood pressure-lowering medications) reported that they did not exercise. Over a median follow-up of 9.5 years [interquartile range (IQR) 5.1-14.0], 2256 deaths and 1828 recurrent vascular events occurred. The association between exercise volume had a reverse J-shape with a nadir at 29 (95% CI 24-29) METh/wk, corresponding with a HR 0.56 (95% CI 0.48-0.64) for all-cause mortality and HR 0.63 (95% CI 0.55-0.73) for recurrent vascular events compared with no exercise. Up to 38% (95% CI 24-61) of the association was mediated through the assessed risk factors of which insulin sensitivity (PME up to 12%, 95% CI 5-25) and systemic inflammation (PME up to 18%, 95% CI 9-37) were the most important. Conclusion: Regular physical exercise is significantly related with reduced risks of all-cause mortality and recurrent vascular events in patients with CVD. In this population with high rates of lipid-lowering and blood pressure--lowering medication use, exercise benefits were mainly mediated through systemic inflammation and insulin resistance.
RESUMEN
BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown. OBJECTIVE: To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition. METHODS: Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE. RESULTS: PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41-59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29-63%; and VLDL-TG 20%, 95%CI 6.3-41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons. CONCLUSION: PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.
Asunto(s)
Hiperlipoproteinemia Tipo III , Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/metabolismo , Hiperlipoproteinemia Tipo III/tratamiento farmacológico , Lipoproteínas , Lipoproteínas VLDL , Colesterol , Anticuerpos Monoclonales/efectos adversos , Apolipoproteínas B , Lipoproteínas LDLRESUMEN
Abnormalities in the lipid profile are common, but it is often not easy to determine their cause. After exclusion of secondary causes, a primary (genetic) cause of dyslipidaemia should be considered. The most common monogenic dyslipidaemia is familial hypercholesterolemia (FH), but there are other clinically relevant genetic dyslipidaemias, including familial dysbetalipoproteinaemia (FD), monogenic chylomicronaemia and hypoalphalipoproteinemia. It is important to make a genetic diagnosis because it may influence the prognosis of the patient, for determining appropriate treatment goals and because it is relevant for family members. This clinical viewpoint explains the diagnostic process of genetic dyslipidaemias using two cases.
Asunto(s)
Dislipidemias , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/complicaciones , Dislipidemias/diagnóstico , Dislipidemias/genética , Dislipidemias/complicaciones , LípidosRESUMEN
Chylomicronaemia accompanies hypertriglyceridaemia, usually due to a polygenic predisposition in combination with secondary risk factors. Monogenic chylomicronaemia represents a small subgroup of patients with hypertriglyceridaemia. This article describes three patients and illustrates the heterogeneity in the presentation of monogenic chylomicronaemia. The first case is a man with mild hypertriglyceridaemia who is a compound heterozygote for two variants in the LMF1 gene, without relevant medical history. The second case is a woman who is a double heterozygote of variants in the LPL and APOA5 genes. She experienced pancreatitis. The third case is a man, with recurrent pancreatitis attributed to severe hypertriglyceridaemia and homozygous for a variant in the APOC2 gene. This article highlights that in patients with hypertriglyceridaemia, the absence of pancreatitis or the presence of mild hypertriglyceridaemia does not exclude monogenic chylomicronaemia. Genetic screening should be considered in patients with unexplained or severe hypertriglyceridaemia, to determine appropriate treatment and follow-up.
Asunto(s)
Hipertrigliceridemia , Pancreatitis , Masculino , Femenino , Humanos , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/genética , Pancreatitis/etiología , Homocigoto , Pruebas Genéticas , GenotipoRESUMEN
BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: In patients with vascular disease, LDL-C PRS and SBP PRS, both separately and in combination, were not significantly associated with recurrent CVD.
Asunto(s)
Enfermedades Cardiovasculares , Infarto del Miocardio , Presión Sanguínea/genética , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , LDL-Colesterol , Humanos , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Asunto(s)
Apolipoproteína E2 , Diabetes Mellitus Tipo 2 , Dislipidemias , Adiposidad/genética , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Estudios Transversales , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Dislipidemias/genética , Humanos , Estudios ProspectivosRESUMEN
INTRODUCTION: Apolipoprotein B containing lipoproteins are atherogenic. There is evidence that with low plasma low density lipoprotein cholesterol (LDL-C) levels residual vascular risk might be caused by triglyceride rich lipoproteins such as very-low density lipoproteins (VLDL), chylomicrons and their remnants. We investigated the relationship between VLDL-cholesterol (VLDL-C) and recurrent major adverse cardiovascular events (MACE), major adverse limb events (MALE) and all-cause mortality in a cohort of patients with cardiovascular disease. METHODS: Prospective cohort study in 8057 patients with cardiovascular disease from the UCC-SMART study. The relation between calculated VLDL-C levels and the occurrence of MACE, MALE and all-cause mortality was analyzed with Cox regression models. RESULTS: Patients mean age was 60 ± 10 years, 74% were male, 4894 (61%) had coronary artery disease, 2445 (30%) stroke, 1425 (18%) peripheral arterial disease and 684 (8%) patients had an abdominal aorta aneurysm at baseline. A total of 1535 MACE, 571 MALE and 1792 deaths were observed during a median follow up of 8.2 years (interquartile range 4.512.2). VLDL-C was not associated with risk of MACE or all-cause mortality. In the highest quartile of VLDL-C the risk was higher for major adverse limb events (MALE) (HR 1.49; 95%CI 1.16-1.93) compared to the lowest quartile, after adjustment for confounders including LDL-C and lipid lowering medication. CONCLUSION: In patients with clinically manifest cardiovascular disease plasma VLDL-C confers an increased risk for MALE, but not for MACE and all-cause mortality, independent of established risk factors including LDL-C and lipid-lowering medication.