Assessment of Subclinical Atherosclerosis in Asymptomatic People In Vivo: Measurements Suitable for Biomarker and Mendelian Randomization Studies.

BACKGROUND: One strategy to reduce the burden of cardiovascular disease is the early detection and treatment of atherosclerosis. This has led to significant interest in studies of subclinical atherosclerosis, using different phenotypes, not all of which are accurate reflections of the presence of asymptomatic atherosclerotic plaques. The aim of part 2 of this series is to provide a review of the existing literature on purported measures of subclinical disease and recommendations concerning which tests may be appropriate in the prevention of incident cardiovascular disease. METHODS: We conducted a critical review of measurements used to infer the presence of subclinical atherosclerosis in the major conduit arteries and focused on the predictive value of these tests for future cardiovascular events, independent of conventional cardiovascular risk factors, in asymptomatic people. The emphasis was on studies with >10 000 person-years of follow-up, with meta-analysis of results reporting adjusted hazard ratios (HRs) with 95% CIs. The arterial territories were limited to carotid, coronary, aorta, and lower limb arteries. RESULTS: In the carotid arteries, the presence of plaque (8 studies) was independently associated with future stroke (pooled HR, 1.89 [1.04-3.44]) and cardiac events (7 studies), with a pooled HR, 1.77 (1.19-2.62). Increased coronary artery calcium (5 studies) was associated with the risk of coronary heart disease events, pooled HR, 1.54 (1.07-2.07) and increasing severity of calcification (by Agaston score) was associated with escalation of risk (13 studies). An ankle/brachial index (ABI) of <0.9, the pooled HR for cardiovascular death from 7 studies was 2.01 (1.43-2.81). There were insufficient studies of either, thoracic or aortic calcium, aortic diameter, or femoral plaque to synthesize the data based on consistent reporting of these measures. CONCLUSIONS: The presence of carotid plaque, coronary artery calcium, or abnormal ankle pressures seems to be a valid indicator of the presence of subclinical atherosclerosis and may be considered for use in biomarker, Mendelian randomization and similar studies.

Aspirin and lipoprotein(a) in primary prevention.

PURPOSE OF REVIEW: Lipoprotein(a) [Lp(a)] is causally associated with cardiovascular diseases, and elevated levels are highly prevalent. However, there is a lack of available therapies to address Lp(a)-mediated risk. Though aspirin has progressively fallen out of favor for primary prevention, individuals with high Lp(a) may represent a high-risk group that derives a net benefit. RECENT FINDINGS: Aspirin has been demonstrated to have a clear benefit in secondary prevention of cardiovascular disease, but recent primary prevention trials have at best demonstrated a small benefit. However, individuals with elevated Lp(a) may be of high risk enough to benefit, particularly given interactions between Lp(a) and the fibrinolytic system / platelets, and the lack of available targeted medical therapies. In secondary analyses of the Women's Health Study (WHS) and the Aspirin in Reducing Events in the Elderly (ASPREE) trial, aspirin use was associated with a significant reduction in cardiovascular events in carriers of genetic polymorphisms associated with elevated Lp(a) levels. Further studies are needed, however, as these studies focused on narrower subsets of the overall population and genetic markers. SUMMARY: Individuals with elevated Lp(a) may benefit from aspirin therapy in primary prevention, but further study with plasma Lp(a) levels, broader populations, and randomization of aspirin are needed.

Efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation and chronic kidney disease.

BACKGROUND: Direct oral anticoagulants (DOACs) are effective alternatives to warfarin for stroke prevention in patients with atrial fibrillation (AF) including patients with CKD III. However, data on patient outcomes with DOACs for advanced CKD are limited, while warfarin use is controversial. METHODS: A retrospective study of patients with AF using DOACs and CKD stages III-V was conducted. The primary outcomes were stroke or systemic embolism and major bleeding while on DOAC therapy among CKD IV and V patients. Rates of outcomes from the DOAC trials and from previous studies of warfarin in CKD were referenced. RESULTS: Of 316 patients reviewed, 152 were included with mean CrCl of 38.8 mL/min. Stroke and systemic embolism occurred at a rate of 1.17 per 100 person-years, with no significant difference between CKD IV/V and CKD III (P = .567). Rates were comparable to DOAC use from the DOAC trials, and lower than rates in studies of warfarin in CKD IV/V patients. There was a nonstatistically significant trend toward increased major bleeding in CKD IV/V patients. Rates of major bleeding in CKD III to V subjects were comparable to published rates for warfarin users with similar levels of renal impairment. CONCLUSIONS: In our study, DOACs appeared to be as efficacious and safe in CKD IV and V as in CKD III. In addition, DOACs appeared to be more effective than, and as safe as warfarin when compared with reference studies of patients with advanced CKD. Our findings support the use of DOACs for thromboembolism prevention in patients with advanced CKD and AF.

X-ray crystal structure of rivoglitazone bound to PPARγ and PPAR subtype selectivity of TZDs.

Thiazolidinedione (TZD) compounds targeting the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) demonstrate unique benefits for the treatment of insulin resistance and type II diabetes. TZDs include rosiglitazone, pioglitazone and rivoglitazone, with the latter being the most potent. The TZDs are only marginally selective for the therapeutic target PPARγ as they also activate PPARα and PPARδ homologues to varying degrees, causing off-target effects. While crystal structures for TZD compounds in complex with PPARγ are available, minimal structural information is available for TZDs bound to PPARα and PPARδ. This paucity of structural information has hampered the determination of precise structural mechanisms involved in TZD selectivity between PPARs. To help address these questions molecular dynamic simulations were performed of rosiglitazone, pioglitazone and rivoglitazone in complex with PPARα, PPARδ, and PPARγ in order to better understand the mechanisms of PPAR selectivity. The simulations revealed that TZD interactions with residues Tyr314 and Phe318 of PPARα and residues Phe291 and Thr253 of PPARδ as well as the omega loop, are key determinants of TZD receptor selectivity. Notably, in this study, we solve the first X-ray crystal structure of rivoglitazone bound to any PPAR. Rivoglitazone forms a unique hydrogen bond network with the residues of the PPARγ co-activator binding surface (known as AF2) and makes more extensive contacts with helix 3 and the ß-sheet as compared to model TZD compounds such as rosiglitazone.

Long-term exposures to di-n-butyl phthalate inhibit body growth and impair gonad development in juvenile Murray rainbowfish (Melanotaenia fluviatilis).

The aim of the present study was to evaluate whether long-term exposures to environmentally relevant concentrations of di-n-butyl phthalate (DnBP) disrupt the reproduction-based endpoints in juvenile Murray rainbowfish (Melanotaenia fluviatilis). Fish were exposed to 5, 15 or 50 µg l(-1) DnBP for 30, 60 and 90 days each, and the effects on survival, body growth, whole-body concentrations of sex steroid hormones and gonadal development were investigated. The lowest observed effective concentration to affect the condition factor after 90 days was 5 µg l(-1). Complete feminization of the gonad was noted in fish exposed to 5 µg l(-1) for 90 days and to 15 and 50 µg l(-1) of DnBP for 30 or 60 days. After 90 days of exposure to DnBP, the ovaries were regressed and immature as opposed to the control fish which were in early-vitellogenic stage. Testes, present only in fish exposed to 5 µg l(-1) of DnBP for 30 or 60 days, were immature in comparison to the control fish that contained testes in the mid-spermatogenic phase. The E2/11-KT ratio was significantly higher only after exposures to 5 µg l(-1) DnBP for 90 days and 50 µg l(-1) DnBP for 30 days. Our data suggest that exposures to 5 µg l(-1) DnBP for 30 days did not have profound effects on body growth and gonadal differentiation of fish. However, 30 days of exposure to 15 µg l(-1) could interfere with the gonad development and to 50 µg l(-1) could compromise the hormonal profile of juvenile fish.

Co-treatment with the non-steroidal anti-androgen drug, flutamide and the natural estrogen, 17ß-estradiol does not lead to additive reproductive impairment in juvenile Murray rainbowfish (Melanotaenia fluviatilis).

The aim of this study was to investigate if the anti-androgen, flutamide, and the estrogen, 17ß-estradiol work together to feminize juvenile Murray rainbowfish (Melanotaenia fluviatilis). Fish (60 days post-hatch) were exposed to 25 ng/L 17ß-estradiol (E2), 25 µg/L flutamide (Flu low), 250 µg/L flutamide (Flu high), E2 + Flu low and E2 + Flu high. After 35 days of exposure, concentrations of sex steroid hormones, 17ß-estradiol and 11-keto testosterone (11-KT), were determined in the head; and vitellogenin (VTG) concentration was measured in the tail. The abdomens were used for histological investigation of the gonads. Treatment with E2 + Flu high resulted in reduction in body weights and lengths in males and condition factor in females. Intersex was noted in Flu high and E2 + Flu high treatments. Exposures to E2 and/or Flu (low and high) resulted in precocious oocyte development but inhibited sperm development. The 17ß-estradiol levels decreased significantly in the heads of both sexes after exposures to E2 and/or Flu (high and low). Flu high and E2 alone increased the 11-KT levels in both sexes. However, E2 + Flu low decreased 11-KT levels in males and increased them in females. Flutamide (low and high) induced VTG protein in the tails of both sexes. In males, VTG was not induced in the tail after exposure to E2. No significant effect of flutamide on E2-induced VTG concentration was noted. We conclude that co-treatment with flutamide and 17ß-estradiol does not lead to additive reproductive impairment in juvenile Murray rainbowfish.

Effects of short-term exposure to the model anti-androgen, flutamide on reproductive function based endpoints in female Murray rainbowfish (Melanotaenia fluviatilis).

The aim of the present study was to evaluate the responses of female Murray rainbowfish (Melanotaenia fluviatilis) to the model anti-androgen, flutamide in a short-term exposure. Adult female Murray rainbowfish were exposed to nominal (measured) concentrations of 125 (104), 250 (163), 500 (378) and 1000 (769) µg/L of flutamide for seven days in a semi-static set-up. Plasma vitellogenin (VTG), 11-keto testosterone (11-KT) and 17ß-estradiol (E2) concentrations, brain aromatase activity and ovarian histology were assessed following the exposure. No treatment-related mortality was found in rainbowfish and there was no effect of flutamide on the developmental stage of the ovaries. Histological investigation revealed absence of mature oocytes in flutamide-treated fish. In addition, a significant reduction in the sizes of the vitellogenic oocytes was found after treatment with 500 and 1000 µg/L flutamide. The circulating levels of VTG and the activity of aromatase in the brain were also significantly reduced in fish treated with 500 and 1000 µg/L flutamide. Treatment with higher concentrations of flutamide reduced the levels of 11-KT and E2 in plasma. The results from this study demonstrate that a short-term exposure to the model anti-androgen, flutamide can adversely affect the reproductive function based on end-points such as plasma VTG, 11-KT and E2; brain aromatase activity and sizes of the oocytes in female Murray rainbowfish. Further, a positive correlation between these experimental variables suggests hormonal imbalance.

Aspirin and Cardiovascular Risk in Individuals With Elevated Lipoprotein(a): The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Effective therapies for reducing cardiovascular disease (CVD) risk in people with elevated lipoprotein(a) are lacking, especially for primary prevention. Because of the potential association of lipoprotein(a) with thrombosis, we evaluated the relationship between aspirin use and CVD events in people with elevated lipoprotein(a). METHODS AND RESULTS: We used data from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of baseline cardiovascular disease. Due to potential confounding by indication, we matched aspirin users to nonusers using a propensity score based on CVD risk factors. We then evaluated the association between aspirin use and coronary heart disease (CHD) events (CHD death, nonfatal myocardial infarction) stratified by baseline lipoprotein(a) level (threshold of 50 mg/dL) using Cox proportional hazards models with adjustment for CVD risk factors. After propensity matching, the study cohort included 2183 participants, including 1234 (57%) with baseline aspirin use and 423 (19%) with lipoprotein(a) >50 mg/dL. Participants with lipoprotein(a) >50 mg/dL had a higher burden of CVD risk factors, more frequent aspirin use (61.7% versus 55.3%, P=0.02), and higher rate of incident CHD events (13.7% versus 8.9%, P<0.01). Aspirin was associated with a significant reduction in CHD events among those with elevated lipoprotein(a) (hazard ratio, 0.54 [95% CI, 0.32-0.94]; P=0.03). Those with lipoprotein(a) >50 mg/dL and aspirin use had similar CHD risk as those with lipoprotein(a) ≤50 mg/dL regardless of aspirin use. CONCLUSIONS: Aspirin use was associated with a significantly lower risk for CHD events in participants with lipoprotein(a) >50 mg/dL without baseline CVD. The results of this observational propensity-matched study require confirmation in studies with randomization of aspirin use.

Lipoprotein(a), platelet function and cardiovascular disease.

Lipoprotein(a) (Lp(a)) is associated with atherothrombosis through several mechanisms, including putative antifibrinolytic properties. However, genetic association studies have not demonstrated an association between high plasma levels of Lp(a) and the risk of venous thromboembolism, and studies in patients with highly elevated Lp(a) levels have shown that Lp(a) lowering does not modify the clotting properties of plasma ex vivo. Lp(a) can interact with several platelet receptors, providing biological plausibility for a pro-aggregatory effect. Observational clinical studies suggest that elevated plasma Lp(a) concentrations are associated with worse long-term outcomes in patients undergoing revascularization. Furthermore, in these patients, those with elevated plasma Lp(a) levels derive more benefit from prolonged dual antiplatelet therapy than those with normal Lp(a) levels. The ASPREE trial in healthy older individuals treated with aspirin showed a reduction in ischaemic events in those who had a single-nucleotide polymorphism in LPA that is associated with elevated Lp(a) levels in plasma, without an increase in bleeding events. In this Review, we re-examine the role of Lp(a) in the regulation of platelet function and suggest areas of research to define further the clinical relevance to cardiovascular disease of the observed associations between Lp(a) and platelet function.

Effectiveness of cognitive retraining intervention on weight loss and lifestyle-related behaviours among adults: A systematic review and meta-analysis.

INTRODUCTION: The review explores the potential benefits of cognitive retraining interventions in improving healthy lifestyle-related behaviours, and its possible use as an alternative or complementary approach to traditional weight loss interventions. METHOD: Studies were selected using different electronic databases (PubMed, Web of Science, Scopus, Embase), to identify RCTs published in the last 23 years on cognitive retraining interventions for weight loss. A total of 12 studies were finalized for systematic review and six for meta-analysis based on the inclusion criteria. The risk of bias was assessed by the two reviewers independently using the criteria outlined in the Joanna Briggs Institute Critical Appraisal Tool for RCTs. The R software was used to perform meta-analysis. RESULT: The overall effect estimates slightly favoured the intervention group, with a standardised mean difference (SMD) of -0.26 [95% CI (-0.58- 0.06) P < 0.05; I2 = 0.00%]. This suggests that although the effect was not statistically significant, cognitive retraining interventions may have a small effect on weight loss. The findings of the systematic review revealed that cognitive retraining interventions may be effective in modifying lifestyle behaviours and these changes may contribute in achieving and maintaining weight loss in the long run. CONCLUSION: Interventions exhibited a positive effect on weight loss. These interventions demonstrated promise in modifying lifestyle behaviours, suggesting a potential role in achieving and sustaining long-term weight loss. Further research is warranted to refine and validate these findings.

Aspirin use for primary prevention among US adults with and without elevated Lipoprotein(a).

Objective: Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic lipoprotein associated with atherosclerotic cardiovascular disease (ASCVD). We assessed the association between regular aspirin use and ASCVD mortality among individuals with versus without elevated Lp(a) in a nationally representative US cohort. Methods: Eligible participants were aged 40-70 years without clinical ASCVD, reported on aspirin use, and had Lp(a) measurements from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), the only cycle of this nationally representative US cohort to measure Lp(a). Regular aspirin use was defined as taking aspirin ≥30 times in the previous month. Using NHANES III linked mortality records and weighted Cox proportional hazards regression, the association between regular aspirin use and ASCVD mortality was observed in those with and without elevated Lp(a) (≥50 versus <50 mg/dL) over a median 26-year follow-up. Results: Among 2,990 persons meeting inclusion criteria (∼73 million US adults), the mean age was 50 years, 86% were non-Hispanic White, 9% were non-Hispanic Black, 53% were female, and 7% reported regular aspirin use. The median Lp(a) was 14 mg/dL and the proportion with elevated Lp(a) was similar among those with versus without regular aspirin use (15.1% versus 21.9%, p = 0.16). Among individuals with elevated Lp(a), the incidence of ASCVD mortality per 1,000 person-years was lower for those with versus without regular aspirin use (1.2, 95% CI: 0.1-2.3 versus 3.9, 95% CI: 2.8-4.9). In multivariable modeling, regular aspirin use was associated with a 52% lower risk of ASCVD mortality among individuals with elevated Lp(a) (HR=0.48, 95% CI: 0.28-0.83), but not for those without elevated Lp(a) (HR=1.01, 95% CI: 0.81-1.25; p-interaction=0.001). Conclusion: Regular aspirin use was associated with significantly lower ASCVD mortality in adults without clinical ASCVD who had elevated Lp(a). These findings may have clinical and public health implications for aspirin utilization in primary prevention.

Atherothrombotic and thrombolytic biomarkers in incident stroke and atrial fibrillation-related stroke: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Although several biomarkers have been studied in thromboembolic stroke, measuring the balance between thrombus formation and thrombolysis and data on its role in predicting stroke and atrial fibrillation (AF)-related stroke is limited. We sought to assess atherothrombotic biomarkers grouped into composite factors that reflect thrombotic and thrombolytic potential, and the balance between these factors as it relates to incident stroke or transient ischemic attack (TIA) and stroke/TIA in AF. METHODS: A Thrombotic Factor, derived from fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a); and a Thrombolytic Factor, derived from plasminogen and oxidized phospholipids on plasminogen, were evaluated at baseline in 5,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We evaluated the association between these two factors representative of thrombotic and thrombolytic potential and incident stroke/TIA (n = 402), and AF-related stroke/TIA (n = 82) over a median of 13.9 and 3.7 years, respectively. Cox proportional hazard models adjusted for medication use, cardiovascular risk factors and CHA2DS2-VASc score were utilized. Harrell's C-index was estimated to evaluate model performance. RESULTS: In models including both factors, Thrombotic Factor was positively while Thrombolytic Factor was inversely associated with incident stroke/TIA and AF-related stroke/TIA. Incorporating these factors along with the CHA2DS2-VASc in adjusted models resulted in a small improvement in risk prediction of incident stroke/TIA and AF-related stroke/TIA compared to models without the factors (C-index from 0.697 to 0.704, and from 0.657 to 0.675, respectively). CONCLUSIONS: Composite biomarker factors, representative of the balance between thrombotic and thrombolytic propensity, provided an improvement in predicting stroke/TIA beyond CHA2DS2-VASc score.

Lipoprotein(a) Testing Trends in a Large Academic Health System in the United States.

Background Despite its high prevalence and clinical significance, clinical measurement of lipoprotein(a) is rare but has not been systematically quantified. We assessed the prevalence of lipoprotein(a) testing overall, in those with various cardiovascular disease (CVD) conditions and in those undergoing cardiac testing across 6 academic medical centers associated with the University of California, in total and by year from 2012 to 2021. Methods and Results In this observational study, data from the University of California Health Data Warehouse on the number of individuals with unique lipoprotein(a) testing, unique CVD diagnoses (using International Classification of Diseases, Tenth Revision [ICD-10], codes), and other unique cardiac testing were collected. The proportion of total individuals, the proportion of individuals with a given CVD diagnosis, and the proportion of individuals with a given cardiac test and lipoprotein(a) testing any time during the study period were calculated. From 2012 to 2021, there were 5 553 654 unique adults evaluated in the University of California health system, of whom 18 972 (0.3%) had lipoprotein(a) testing. In general, those with lipoprotein(a) testing were more likely to be older, men, and White race, with a greater burden of CVD. Lipoprotein(a) testing was performed in 6469 individuals with ischemic heart disease (2.9%), 836 with aortic stenosis (3.1%), 4623 with family history of CVD (3.3%), 1202 with stroke (1.7%), and 612 with coronary artery calcification (6.1%). For most conditions, the prevalence of testing in the same year as the diagnosis of CVD was relatively stable, with a small upward trend over time. Lipoprotein(a) testing was performed in 10 753 individuals (1.8%) who had lipid panels, with higher rates with more specialized testing, including coronary computed tomography angiography (6.8%) and apolipoprotein B (63.0%). Conclusions Lipoprotein(a) testing persists at low rates, even among those with diagnosed CVD, and remained relatively stable over the study period.

Coronary Artery Calcium Density and Cardiovascular Events by Volume Level: The MESA.

BACKGROUND: The Agatston coronary artery calcium (CAC) score provides robust cardiovascular disease risk prediction but upweights plaque area by a density factor. Density, however, has been shown to be inversely associated with events. Using CAC volume and density separately improves risk prediction, but it is unclear how to apply this method clinically. We aimed to evaluate the association between CAC density and cardiovascular disease across the spectrum of CAC volume to better understand how to incorporate these metrics into a single score. METHODS: We performed an analysis of MESA (Multi-Ethnic Study of Atherosclerosis) participants with detectable CAC to evaluate the association between CAC density and events by level of CAC volume using multivariable Cox regression models. RESULTS: In a cohort of 3316 participants, there was a significant interaction (P<0.001) between CAC volume and density for coronary heart disease (CHD) risk (myocardial infarction, CHD death, resuscitated cardiac arrest). Models using CAC volume and density resulted in improvement in the C-index (0.703, SE 0.012 versus 0.687, SE 0.013) and a significant net reclassification improvement (0.208 [95% CI, 0.102-0.306]) compared with the Agatston score for CHD risk prediction. Density was significantly associated with lower CHD risk at volumes ≤130 mm3 (hazard ratio, 0.57 per unit of density [95% CI, 0.43-0.75]), but the inverse association at volumes >130 mm3 was not significant (hazard ratio, 0.82 per unit of density [95% CI, 0.55-1.22]). CONCLUSIONS: The lower risk for CHD associated with higher CAC density varied by level of volume, and volume ≤130 mm3 is a potentially clinically useful cut point. Further study is needed to integrate these findings into a unified CAC scoring method.

Small dense low-density lipoprotein cholesterol compared to other lipoprotein biomarkers for predicting coronary heart disease among individuals with normal fasting glucose: The Multi-Ethnic Study of Atherosclerosis.

Objective: This study compared small dense low-density lipoprotein cholesterol (sdLDL-C) with apolipoprotein B (apo B), and low-density lipoprotein particles (LDL-P) in predicting CHD risk in generally healthy adults with normal fasting glucose (NFG). Methods: This study was conducted among participants with NFG in the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort with measurements of sdLDL-C, LDL-P, and apo B available at baseline (2000-2002) and follow-up CHD data (through 2015) (N = 3,258). Biomarkers were evaluated as quartiles, and in categories using clinically and 75th percentile-defined cut-points. Discordance/concordance of sdLDL-C relative to other biomarkers was calculated using 75th percentile cut-points and linear regression residuals. Associations between individual biomarkers, sdLDL-C discordance and CHD incidence were evaluated using Cox proportional hazards regression. Results: There were 241 incident CHD events in this population through 2015. Higher sdLDL-C, apo B, LDL-P were similarly associated with increased CHD in individuals with NFG. Discordance of sdLDL-C with apo B or LDL-P by 75th percentiles was not significantly associated with CHD. Residuals discordantly higher/lower sdLDL-C relative to apo B (discordant high HR=1.26, 95% CI: 0.89, 1.78; discordant low HR=0.94, 95% CI: 0.68, 1.29) and LDL-P (discordant high HR=1.25, 95% CI: 0.88, 1.75; discordant low HR=0.84, 95% CI:0.60, 1.16), compared to those with concordant measures, had non-statistically significant higher/lower risk of CHD. Conclusions: Results suggest sdLDL-C, apo B and LDL-P are generally comparable for predicting CHD events in normoglycemic individuals. Larger studies are needed to confirm findings and to investigate whether measurement of sdLDL-C may be beneficial to evaluate as an additional risk-enhancing factor.

Lipoprotein(a) and coronary artery calcium in comparison with other lipid biomarkers: The multi-ethnic study of atherosclerosis.

BACKGROUND: Coronary artery calcium (CAC) scoring is often used for atherosclerotic cardiovascular disease (ASCVD) risk stratification in individuals with elevated lipoprotein(a) [Lp(a)]. OBJECTIVE: To evaluate associations between Lp(a) and baseline CAC (volume/density) and CAC progression compared to other lipid biomarkers. METHODS: We utilized data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of individuals without clinical ASCVD, excluding statin users. We evaluated the associations between Lp(a), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides, total cholesterol, apolipoprotein B, and non-HDL-C with baseline CAC and annual CAC progression using multivariable ordinal regression with adjustment for ASCVD risk factors. Analyses were also stratified by median age. RESULTS: In 5,597 participants (2,726 at median 9.5-year follow-up), Lp(a) was not associated with baseline CAC volume or density and was modestly associated with volume progression (OR 1.11, 95% CI 1.03-1.21). However, other biomarkers were positively associated with baseline volume and volume progression (LDL-C: OR 1.26, 95% CI: 1.19-1.33 and OR 1.22, 95% CI: 1.15-1.30, respectively), except HDL-C which was inversely associated. LDL-C, total cholesterol and non-HDL-C were inversely associated with baseline density. In participants <62 years of age, Lp(a) was modestly associated with baseline CAC volume (OR 1.10, 95% CI: 1.00-1.20) and volume progression (OR 1.16 95% CI: 1.04-1.30). CONCLUSIONS: In contrast to other lipid biomarkers, Lp(a) was not associated with baseline CAC volume or density and was only modestly associated with volume progression. Our findings suggest that Lp(a) is not as robustly associated with CAC as other lipid biomarkers.

Lipoprotein(a) and the pooled cohort equations for ASCVD risk prediction: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) but is not included in the Pooled Cohort Equations (PCE). We aimed to assess how well the PCE predict 10-year event rates in individuals with elevated Lp(a), and whether the addition of Lp(a) improves risk prediction. METHODS: We compared observed versus PCE-predicted 10-year ASCVD event rates, stratified by Lp(a) level and ASCVD risk category using Poisson regression, and evaluated the association between Lp(a) > 50 mg/dL and ASCVD risk using Cox proportional hazards models in the Multi-Ethnic Study of Atherosclerosis (MESA). We evaluated the C-index and net reclassification improvement (NRI) with addition of Lp(a) to the PCE. RESULTS: The study population included 6639 individuals (20%, n = 1325 with elevated Lp(a)). The PCE accurately predicted 10-year event rates for individuals with elevated Lp(a) with observed event rates falling within predicted limits. Elevated Lp(a) was associated with increased risk of CVD events overall (HR 1.27, 95% CI 1.00-1.60), particularly in low (HR 2.45, 95% CI 1.40-4.31), and high-risk (HR 1.41, 95% CI 1.02-1.96) individuals. Continuous NRI (95% CI) with the addition of Lp(a) to the PCE for CVD was 0.0963 (0.0158-0.1953) overall, and 0.2999 (0.0876, 0.5525) among low-risk individuals. CONCLUSIONS: The PCE performs well for event rate prediction in individuals with elevated Lp(a). However, Lp(a) is associated with increased CVD risk, and the addition of Lp(a) to the PCE improves risk prediction, particularly among low-risk individuals. These results lend support for increasing use of Lp(a) testing for risk assessment.

Association of Lp(a) (Lipoprotein[a]) and Hypertension in Primary Prevention of Cardiovascular Disease: The MESA.

BACKGROUND: This study explored the longitudinal relationship of Lp(a) (lipoprotein[a]) and hypertension to cardiovascular outcomes in a large multiethnic cohort free of baseline cardiovascular disease. METHODS: Individuals from the MESA (Multi-Ethnic Study of Atherosclerosis; N=6674) were grouped as follows: group 1: Lp(a) <50 mg/dL and no hypertension; group 2: Lp(a) ≥50 mg/dL and no hypertension; group 3: Lp(a) <50 mg/dL and hypertension; and group 4: Lp(a) ≥50 mg/dL and hypertension. Kaplan-Meier curves and multivariable Cox proportional hazard models were used to assess the relationship of Lp(a) and hypertension with time to cardiovascular disease events. RESULTS: Mean follow-up time was 13.9 (5.0) years and 809 participants experienced a cardiovascular disease event. A statistically significant interaction was found between Log[Lp(a)] and hypertension status (P=0.091). Compared with the reference group (Lp[a] <50 mg/dL and no hypertension), those with Lp[a] ≥50 mg/dL and no hypertension had no increased risk for cardiovascular disease events (hazard ratio, 1.09 [95% CI, 0.79-1.50]). However, those with Lp(a) <50 mg/dL and hypertension or Lp(a) ≥50 mg/dL and hypertension demonstrated a statistically significant increase in risk compared to the reference group (hazard ratio, 1.66 [95% CI, 1.39-1.98]) and (hazard ratio, 2.07 [95% CI, 1.63-2.62]), respectively. Among those with hypertension, Lp(a) was associated with a significant increase in cardiovascular disease risk (hazard ratio, 1.24 [95% CI, 1.01-1.53]). CONCLUSIONS: Although the major contribution to cardiovascular risk was hypertension, elevated Lp(a) significantly modified the association of hypertension with cardiovascular disease. More research is needed to understand mechanistic links among Lp(a), hypertension, and cardiovascular disease.

Diagnostic performance of 64-slice multidetector coronary computed tomographic angiography in women.

BACKGROUND: Diagnostic approach to chest pain in women is challenging, but still under-investigated. The purpose of this study was to assess the diagnostic performance of 64-slice multidetector coronary computed tomographic angiography (CCTA) in women with chest pain. METHODS AND RESULTS: We included 606 patients--255 women and 351 men (mean age 61 ± 12 years for both)--who had been referred for a CCTA and an invasive coronary angiography (diagnostic standard) because of chest pain, either as part of clinical work-up in two urban medical centers or as part of the multicenter ACCURACY trial. On a patient-based model, the sensitivity, specificity, and positive predictive value (PPV) and negative predictive value to detect ≥50% and ≥70% stenosis were 98%, 84%, 87%, and 97% and 96%, 83%, 77%, and 97%, respectively, for women and 97%, 83%, 89%, and 95% and 94%, 91%, 90%, and 94%, respectively, for men. There were no statistically significant differences between men and women in diagnostic performance measures except for the PPV of detecting a ≥70% stenosis (P = .007). CONCLUSION: In women with chest pain, 64-slice multidetector CCTA is at least as sensitive and specific as in men. Our findings suggest that CCTA is a promising diagnostic tool for timely detection and/or exclusion of CAD in symptomatic intermediate-risk female populations.