Baseline coronary artery calcification has been shown to be associated with dementia. However, the value of coronary artery calcium (CAC) progression in the prediction of dementia remains unclear. In ...this study, we examined the association between CAC progression and dementia in the Multi-Ethnic Study of Atherosclerosis. The Multi-Ethnic Study of Atherosclerosis is a prospective study consisting of 6,814 participants 45 to 84 years of age, free of overt cardiovascular disease at baseline. A total of 5,570 subjects had baseline and follow-up CAC scans approximately 2.5 years apart and were included this analysis. A total of 4,173 of these participants completed cognitive testing with the Cognitive Abilities Screening Instrument (CASI) approximately 10 years after the baseline CAC scan. Dementia diagnoses were identified using International Classification of Diseases codes from hospitalizations, death certificates, and medications used to treat dementia. The absolute change between baseline and follow-up CAC was used to assess CAC progression. Cox proportional hazards and multivariable linear regression models were used to examine the association of CAC progression with incident dementia and with CASI score. Over a median follow-up of 13.2 (interquartile range: 11.2 to 15.3) years, 350 participants developed incident dementia. CAC progression showed no association with dementia risk after adjustment for age, gender, race/ethnicity, vascular risk factors, and baseline CAC score. There was no association of CAC progression with CASI score in any adjusted model. In conclusion, progression of CAC over approximately 2.5 years was not associated with increased risk of dementia after adjustment for demographic variables, vascular risk factors, and baseline CAC.
This study sought to characterise the main dyslipidaemic phenotypes present in chronic kidney disease (CKD) and their association with coronary heart disease (CHD) risk.
Analyses included 6612 ...individuals in the multiethnic study of atherosclerosis free of CHD at baseline. CKD was defined as an estimated glomerular filtration rate (eGFR) of 15 to <60 mL/min/1.73 m
(stages 3-4). Principal component analyses were used to characterise the main dyslipidaemic phenotypes of CKD accounting for the correlation among different lipoproteins and lipoprotein particles. CHD was defined as incident myocardial infarction, angina followed by revascularisation, resuscitated cardiac arrest or CHD death.
CHD developed in 303 individuals (5%) with eGFR ≥60 and in 72 individuals (12%) with CKD (p for difference <0.001). A dyslipidaemic phenotype (principal component 1 (PC1)) consisting of elevations in triglycerides, triglyceride-rich lipoproteins (VLDL particles), small LDL particles and reductions in HDL particles, was more common in those with CKD, compared with those without CKD (p for difference <0.001). This phenotype was also more strongly associated with CHD in those with CKD: adjusted HRs (95% CIs) per SD increase in PC1 1.13 (95% CI 1.00 to 1.27; P=0.05) and 1.51 (95% CI 1.17 to 1.94; P<0.001) in eGFR ≥60 and CKD, respectively (P for interaction=0.05).
In individuals with mainly stage 3 CKD, a dominant lipid phenotype consisting of triglyceride-rich lipoproteins and other closely correlated lipoproteins is strongly associated with CHD risk. Future studies should investigate whether modification of the components of this phenotype leads to a reduction in the CHD burden in individuals with CKD.
HDL (high-density lipoprotein) contains functional proteins that define single subspecies, each comprising 1% to 12% of the total HDL. We studied the differential association with coronary heart ...disease (CHD) of 15 such subspecies. Approach and Results: We measured plasma apoA1 (apolipoprotein A1) concentrations of 15 protein-defined HDL subspecies in 4 US-based prospective studies. Among participants without CVD at baseline, 932 developed CHD during 10 to 25 years. They were matched 1:1 to controls who did not experience CHD. In each cohort, hazard ratios for each subspecies were computed by conditional logistic regression and combined by meta-analysis. Higher levels of HDL subspecies containing alpha-2 macroglobulin, CoC3 (complement C3), HP (haptoglobin), or PLMG (plasminogen) were associated with higher relative risk compared with the HDL counterpart lacking the defining protein (hazard ratio range, 0.96-1.11 per 1 SD increase versus 0.73-0.81, respectively;
for heterogeneity <0.05). In contrast, HDL containing apoC1 or apoE were associated with lower relative risk compared with the counterpart (hazard ratio, 0.74;
=0.002 and 0.77,
=0.001, respectively).
Several subspecies of HDL defined by single proteins that are involved in thrombosis, inflammation, immunity, and lipid metabolism are found in small fractions of total HDL and are associated with higher relative risk of CHD compared with HDL that lacks the defining protein. In contrast, HDL containing apoC1 or apoE are robustly associated with lower risk. The balance between beneficial and harmful subspecies in a person's HDL sample may determine the risk of CHD pertaining to HDL and paths to treatment.
Apo CIII (apolipoprotein CIII) is an important regulator of triglyceride metabolism and was associated with cardiovascular risk in several cohorts. It is present in 4 major proteoforms, a native ...peptide (CIII
), and glycosylated proteoforms with zero (CIII
), 1 (CIII
, most abundant), or 2 (CIII
) sialic acids, which may differentially modify lipoprotein metabolism. We studied the relationships of these proteoforms with plasma lipids and cardiovascular risk.
Apo CIII proteoforms were measured by mass spectrometry immunoassay in baseline plasma samples of 5791 participants of Multi-Ethnic Study of Atherosclerosis, an observational community-based cohort. Standard plasma lipids were collected for up to 16 years and cardiovascular events (myocardial infarction, resuscitated cardiac arrest, or stroke) were adjudicated for up to 17 years.
Apo CIII proteoform composition differed by age, sex, race and ethnicity, body mass index, and fasting glucose. Notably, CIII
was lower in older participants, men and Black and Chinese (versus White) participants, and higher in obesity and diabetes. In contrast, CIII
was higher in older participants, men, Black, and Chinese persons, and lower in Hispanic individuals and obesity. Higher CIII
to CIII
ratio (CIII
/III
) was associated with lower triglycerides and higher HDL (high-density lipoprotein) in cross-sectional and longitudinal models, independently of clinical and demographic risk factors and total apo CIII. The associations of CIII
/III
and CIII
/III
with plasma lipids were weaker and varied through cross-sectional and longitudinal analyses. Total apo CIII and CIII
/III
were positively associated with cardiovascular disease risk (n=669 events, hazard ratios, 1.14 95% CI, 1.04-1.25 and 1.21 1.11-1.31, respectively); however, the associations were attenuated after adjustment for clinical and demographic characteristics (1.07 0.98-1.16; 1.07 0.97-1.17). In contrast, CIII
/III
was inversely associated with cardiovascular disease risk even after full adjustment including plasma lipids (0.86 0.79-0.93).
Our data indicate differences in clinical and demographic relationships of apo CIII proteoforms, and highlight the importance of apo CIII proteoform composition in predicting future lipid patterns and cardiovascular disease risk.
In this study, we aimed to establish whether age-sex-specific percentiles of coronary artery calcium (CAC) predict cardiovascular outcomes better than the actual (absolute) CAC score.
The presence ...and extent of CAC correlates with the overall magnitude of coronary atherosclerotic plaque burden and with the development of subsequent coronary events.
MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective cohort study of 6,814 asymptomatic participants followed for coronary heart disease (CHD) events including myocardial infarction, angina, resuscitated cardiac arrest, or CHD death. Time to incident CHD was modeled with Cox regression, and we compared models with percentiles based on age, sex, and/or race/ethnicity to categories commonly used (0, 1 to 100, 101 to 400, 400+ Agatston units).
There were 163 (2.4%) incident CHD events (median follow-up 3.75 years). Expressing CAC in terms of age- and sex-specific percentiles had significantly lower area under the receiver-operating characteristic curve (AUC) than when using absolute scores (women: AUC 0.73 versus 0.76, p = 0.044; men: AUC 0.73 versus 0.77, p < 0.001). Akaike's information criterion indicated better model fit with the overall score. Both methods robustly predicted events (>90th percentile associated with a hazard ratio HR of 16.4, 95% confidence interval CI: 9.30 to 28.9, and score >400 associated with HR of 20.6, 95% CI: 11.8 to 36.0). Within groups based on age-, sex-, and race/ethnicity-specific percentiles there remains a clear trend of increasing risk across levels of the absolute CAC groups. In contrast, once absolute CAC category is fixed, there is no increasing trend across levels of age-, sex-, and race/ethnicity-specific categories. Patients with low absolute scores are low-risk, regardless of age-, sex-, and race/ethnicity-specific percentile rank. Persons with an absolute CAC score of >400 are high risk, regardless of percentile rank.
Using absolute CAC in standard groups performed better than age-, sex-, and race/ethnicity-specific percentiles in terms of model fit and discrimination. We recommend using cut points based on the absolute CAC amount, and the common CAC cut points of 100 and 400 seem to perform well.
Elevated plasma lipoprotein (a) Lp(a) and coronary artery calcification (CAC) are established cardiovascular risk factors that correlate with each other. We hypothesized that other cardiovascular ...risk factors could affect their relationship.
We tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years in 5975 Multi-Ethnic Study of Atherosclerosis (MESA) participants, free of apparent cardiovascular disease at baseline.
Elevated Lp(a) was associated with larger absolute increase in CAC volume (3.21 and 4.45 mm3/year higher for Lp(a) ≥30 versus <30 mg/dL, and Lp(a) ≥50 versus <50 mg/dL, respectively), but not relative change in CAC volume. No association was found with change in CAC density when assessing continuous ln-transformed Lp(a). The association between elevated Lp(a) (≥30 mg/dL) and absolute change in CAC volume was greater in participants with higher circulating levels of interleukin-2 soluble receptor α, soluble tumor necrosis factor alpha receptor 1 and fibrinogen (15.33, 11.81 and 7.02 mm3/year in quartile 4, compared to −3.44, −0.59 and 1.91 mm3/year in quartile 1, respectively). No significant interaction was found for other study variables. Similar interactions were seen when assessing Lp(a) levels ≥50 mg/dL.
Elevated Lp(a) was associated with an absolute increase in CAC volume, especially in participants with higher levels of selected markers of inflammation and coagulation. These results suggest Lp(a) as a potential biomarker for CAC volume progression.
•Higher Lp(a) was related to a higher annual absolute increase in CAC volume.•The relationship was stronger in participants with inflammation and procoagulation.•Baseline Lp(a) was not related to change in the density of CAC.
Elevated coronary artery calcium (CAC) score, as assessed by the Agatston method, is associated with incident atrial fibrillation (AF). We aimed to evaluate the associations of CAC volume and density ...with incident AF. Participants from the Multiethnic Study of Atherosclerosis without baseline AF and CAC >0 were included. The associations between baseline and progression (average annual change) of CAC measures and incident AF were evaluated using Cox proportional hazards models. CAC volume and Agatston scores were natural log (ln)-transformed, and hazard ratios (HRs) were calculated per standard deviation increment. The baseline analysis included 3,332 participants; 2,643 were included in the progression analysis. In multivariable models adjusted for cardiovascular risk factors, volume (HR 1.24, 95% confidence interval CI 1.14 to 1.36), density (HR 1.14, 95% CI 1.05 to 1.25), and Agatston score (HR 1.24, 95% CI 1.14 to 1.35) were associated with increased risk of incident AF. In models including both volume and density, the magnitude of association between volume and incident AF was unchanged, whereas the density association was eliminated (HR 0.99, 95% CI 0.89 to 1.11). Median time to follow-up CAC assessment was 1.9 (interquartile range 1.3, 3.0) years. Similar results were observed for the association of incident AF with annual change in volume and Agatston score. CAC volume, but not density, is associated with risk for incident AF when adjusting for both. In conclusion, our findings suggest that, although CAC may be a risk marker for AF, the association between CAC and AF appears to be independent of plaque density.
Apolipoprotein C-III (apoC-III) proteoform composition shows distinct relationships with plasma lipids and cardiovascular risk. The present study tested whether apoC-III proteoforms are associated ...with risk of peripheral artery disease (PAD).
ApoC-III proteoforms, i.e., native (C-III0a), and glycosylated with zero (C-III0b), one (C-III1) or two (C-III2) sialic acids, were measured by mass spectrometry immunoassay on 5,734 Multi-Ethnic Study of Atherosclerosis participants who were subsequently followed for clinical PAD over 17 years. Ankle-brachial index (ABI) was also assessed at baseline and then 3 and 10 years later in 4,830 participants.
Higher baseline C-III0b/C-III1 and lower baseline C-III2/C-III1 were associated with slower decline in ABI (follow-up adjusted for baseline) over time, independently of cardiometabolic risk factors, and plasma triglycerides and HDL cholesterol levels (estimated difference per 1 SD was 0.31 % for both, p < 0.01). The associations between C-III2/C-III1 and changes in ABI were stronger in men (−1.21 % vs. −0.27 % in women), and in Black and Chinese participants (−0.83 % and −0.86 % vs. 0.12 % in White). Higher C-III0b/C-III1 was associated with a trend for lower risk of PAD (HR = 0.84 95%CI: 0.67–1.04) that became stronger after excluding participants on lipid-lowering medications (0.73 95%CI: 0.57–0.94). Neither change in ABI nor clinical PAD was related to total apoC-III levels.
We found associations of apoC-III proteoform composition with changes in ABI that were independent of other risk factors, including plasma lipids. Our data further support unique properties of apoC-III proteoforms in modulating vascular health that go beyond total apoC-III levels.
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•Higher glycosylated-asialylated (C-III0b) and lower disialylated (C-III2) apoC-III were related to slower decline in ankle-brachial index (ABI).•Higher C-III0b was also associated with lower risk of clinical peripheral artery disease (PAD).•The associations of apoC-III proteoforms with ABI or PAD were weaker in individuals with prevalent diabetes.•Neither change in ABI nor clinical PAD was related to total apoC-III levels.
Age-related macular degeneration (AMD) shares many similarities with cardiovascular disease (CVD) pathophysiology. We sought to determine the relationship of AMD to the progression of coronary artery ...calcium (CAC) using data from the Multi-Ethnic Study of Atherosclerosis (MESA).
Our cohort consisted of 5803 adults aged 45 to 84 years free of known cardiovascular disease (CVD). Retinal photographs were taken during visit 2 (Aug 2002-Jan 2004). CAC was measured with computed tomography at visit 1 (July 2000-Aug 2002) and visit 5 (April 2010-Dec 2011) and changes between visits were determined.
Participants were categorized as with (n = 244) and without AMD (n = 5559) at visit 2. At visit 5, 92 participants with and 2684 without AMD had CAC scores. Among those with detectable CAC at baseline (>0 at visit 1), CAC progression was greater in persons with compared to those without AMD after multivariable adjustment (530 ± 537 vs. 339 ± 426 Agatston units, P<0.01).
The presence of AMD in a diverse population without known clinical CVD independently predicted higher 10-year CAC progression in participants with baseline CAC >0. The retinal exam might be a useful tool for pre-clinical assessment and prevention of CVD events.
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