S-EPMC10073288 - Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry. - OmicsDI

Unknown

Dataset Information

Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry.

ABSTRACT:

Background

Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC.

Methods

The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the National Heart, Lung, and Blood Institute-funded Multi-Ethnic Study of Atherosclerosis.

Results

During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04-1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06-1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87-1.18]). Similarly, a very high LDL-C level (>193 mg/dL) versus LDL-C <116 mg/dL was associated with ASCVD in patients with CAC>0 (aHR, 2.42 [95% CI, 1.59-3.67]) but not in those without CAC (aHR, 0.92 [0.48-1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis.

Conclusions

LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis.

SUBMITTER: Mortensen MB

PROVIDER: S-EPMC10073288 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry.

Mortensen Martin Bødtker MB Dzaye Omar O Bøtker Hans Erik HE Jensen Jesper Møller JM Maeng Michael M Bentzon Jacob Fog JF Kanstrup Helle H Sørensen Henrik Toft HT Leipsic Jonathon J Blankstein Ron R Nasir Khurram K Blaha Michael J MJ Nørgaard Bjarne Linde BL

Circulation 20230109 14

<h4>Background</h4>Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and w ...[more]

Similar Datasets

Project description:ObjectivesThe purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD).BackgroundHDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors.MethodsIn a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking.ResultsHDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = -0.38, -0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were - 26.1 (95% confidence interval [CI]: -34.7 to -17.4) μm and -30.1 (95% CI: -38.8 to - 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: - 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (-22.2; 95% CI: - 33.8 to -10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant.ConclusionsAdjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk.

Project description:BackgroundHigh-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden.MethodsWe measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants.ResultsThe levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins.ConclusionsCholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).

Project description:Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-Ccorr30). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; P=0.005) but not for LDL-Ccorr30 (1.07; 95% CI, 0.93-1.22; P=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-Ccorr30 was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-Ccorr30 was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions "LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.

Project description:BACKGROUND: Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. METHODS: We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). RESULTS: Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q <or=0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values <or=0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD. CONCLUSION: Putatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma apo A-I level, severity of coronary atherosclerosis and its progression.

Project description:ImportanceElevated non-high-density lipoprotein cholesterol (non-HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non-HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown.ObjectiveTo examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events.Design, setting, and participantsIndividual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019.ExposuresChild (age 3-19 years) and adult (age 20-40 years) non-HDL-C age- and sex-specific z scores and categories according to clinical guideline-recommended cutoffs for dyslipidemia.Main outcomes and measuresIncident fatal and nonfatal CVD events adjudicated by medical records.ResultsOver a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non-HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non-HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non-HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non-HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non-HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non-HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]).Conclusions and relevanceIndividuals with persistent non-HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non-HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non-HDL-C levels may help prevent premature CVD.