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.
10,370 CAD patients (mean age ∼65 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).
During ∼10 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 ∼27 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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Abstract Introduction The apolipoprotein E gene ( APOE ) is associated with coronary heart disease and stroke, but the relation with peripheral artery disease (PAD) is unknown. We investigated the ...relation of APOE genotype with PAD and other types of vascular disease. Methods The cross-sectional association between APOE genotype and ankle-brachial index (ABI) and vascular disease prevalence; and the prospective relation with incident PAD and other types of vascular disease (coronary artery disease, stroke and vascular mortality) were evaluated in 7418 patients from the Secondary Manifestations of ARTerial disease (SMART) study. This is a prospective cohort study in patients with cardiovascular disease or a cardiovascular risk factor. Analyses were adjusted for age and sex. Results Mean age was 56.7 ± 12.4 years and 68% of the patients was male. APOE genotype frequencies were ε2ε2 1.3%; ε2ε3 9.9%; ε2ε4 2.4%; ε3ε3 56.9%; ε3ε4 26.7% and ε4ε4 2.8%. Median follow-up time was 8.1 years (IQR 5.4–11.4) in which 452 new PAD events occurred. The ε2ε2 genotype was significantly associated with a lower ABI (regression coefficient −0.04, 95%CI −0.07 to −0.01), increased PAD prevalence (prevalence ratio 1.54, 95%CI 1.01–2.17) and a higher risk of incident PAD (HR 2.31, 95%CI 1.29–4.12) compared with ε3ε3. No relations between APOE genotypes and other vascular disease were observed. Conclusion Of the six APOE genotypes, the ε2ε2 variant is associated with an increased risk for PAD in patients at high risk for cardiovascular disease. No association was observed between APOE genotype and coronary artery disease, stroke or vascular mortality in this population.
Abstract Familial dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism associated with an increased risk for premature cardiovascular disease. In about 10% of the cases, FD is ...caused by autosomal dominant mutations in the apolipoprotein E gene ( APOE ). This review article provides a pathophysiological framework for autosomal dominant FD (ADFD) and discusses diagnostic challenges and therapeutic options. The clinical presentation and diagnostic work-up of ADFD are illustrated by two cases: a male with premature coronary artery disease and a p.K164Q mutation in APOE and a female with mixed hyperlipidemia and a p.R154H mutation in APOE . ADFD is characterized by a fasting and postprandial mixed hyperlipidemia due to increased remnants. Remnants are hepatically cleared by the low-density lipoprotein receptor and the heparan sulfate proteoglycan receptor (HSPG-R). Development of FD is associated with secondary factors like insulin resistance that lead to HSPG-R degradation through sulfatase 2 activation. Diagnostic challenges in ADFD are related to the clinical presentation; lipid phenotype; dominant inheritance pattern; genotyping; and possible misdiagnosis as familial hypercholesterolemia. FD patients respond well to lifestyle changes and to combination therapy with statins and fibrates. To conclude, diagnosing ADFD is important to adequately treat patients and their family members. In patients presenting with mixed hyperlipidemia, (autosomal dominant) FD should be considered as part of the diagnostic work up.
Abstract Tendon xanthoma are most commonly associated with Familial Hypercholesterolemia, but the differential diagnosis includes sitosterolemia and cerebrotendinous xanthomatosis (CTX). The case ...presented here is of a 48-year old male with large tendon xanthomas attributable to CTX. CTX is a rare, recessive disorder caused by mutations in the CYP27A1 gene. The resultant defect in bile acid synthesis leads to cholestanol deposition in different tissues in the body, including tendons. CTX is associated with neurologic symptoms and a reduced life expectancy. Treatment consists of bile acid supplementation in combination with a statin. When patients present with tendon xanthomas and FH is ruled out, clinicians should consider CTX as a possible diagnosis.
To review pathophysiological, epidemiological and clinical aspects of familial dysbetalipoproteinemia; a model disease for remnant metabolism and remnant-associated cardiovascular risk.
Familial ...dysbetalipoproteinemia is characterized by remnant accumulation caused by impaired remnant clearance, and premature cardiovascular disease. Most familial dysbetalipoproteinemia patients are homozygous for apolipoprotein ε2, which is associated with decreased binding of apolipoprotein E to the LDL receptor. Although familial dysbetalipoproteinemia is an autosomal recessive disease in most cases, 10% is caused by autosomal dominant mutations. Of people with an ε2ε2 genotype 15% develops familial dysbetalipoproteinemia, which is associated with secondary risk factors, such as obesity and insulin resistance, that inhibit remnant clearance by degradation of the heparan sulfate proteoglycan receptor. The prevalence of familial dysbetalipoproteinemia ranges from 0.12 to 0.40% depending on the definition used. Clinical characteristics of familial dysbetalipoproteinemia are xanthomas and mixed hyperlipidemia (high total cholesterol and triglycerides); the primary lipid treatment goal in familial dysbetalipoproteinemia is non-HDL-cholesterol; and treatment consists of dietary therapy and treatment with statin and fibrate combination.
Familial dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination.
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).
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
•In patients with vascular disease VLDL-C levels are associated with MALE.•This risk is independent of conventional risk factors including LDL-C levels and use of lipid-lowering therapy.•Especially in patients with CAD, there is a relationship with VLDL-C and MACE, MALE and MI.•VLDL-C could attribute to the residual CV risk in patients with vascular disease.
•NLR is related to CVD in patients with T2D, independently from CRP.•In patients with T2D and a low CRP, NLR remains related to CVD.•Both NLR and CRP are independently related to mortality in T2D ...patients.•Measuring both NLR and CRP might identify patients at high CVD risk.•This might help select patients with T2D for anti-inflammatory therapy.
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).
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.
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).
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.
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