Associations of Adipokine Levels With Levels of Remnant Cholesterol: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. METHODS AND RESULTS: We studied 1791 MESA (Multi-Ethnic Study of Atherosclerosis) participants who took part in an ancillary study on body composition with adipokine levels measured (leptin, adiponectin, and resistin) at either visit 2 or visit 3. RC was calculated as non-high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol, measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed-effects models were used to assess the cross-sectional and longitudinal associations between adipokines and log-transformed levels of RC. Mean±SD age was 64.5±9.6 years; mean±SD body mass index was 29.9±5.0 kg/m2; and 52.0% were women. In fully adjusted cross-sectional models that included body mass index, diabetes, low-density lipoprotein cholesterol, and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.6% (95% CI, 12.2-16.9) lower RC. With each 1-unit increment in leptin and resistin, there was 4.8% (95% CI, 2.7-7.0) and 4.0% (95% CI, 0.2-8.1) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5 (interquartile range, 4-8) years. CONCLUSIONS: Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for body mass index and low-density lipoprotein cholesterol.

Assessing the Accuracy of Estimated Lipoprotein(a) Cholesterol and Lipoprotein(a)-Free Low-Density Lipoprotein Cholesterol.

Background Accurate measurement of the cholesterol within lipoprotein(a) (Lp[a]-C) and its contribution to low-density lipoprotein cholesterol (LDL-C) has important implications for risk assessment, diagnosis, and treatment of atherosclerotic cardiovascular disease, as well as in familial hypercholesterolemia. A method for estimating Lp(a)-C from particle number using fixed conversion factors has been proposed (Lp[a]-C from particle number divided by 2.4 for Lp(a) mass, multiplied by 30% for Lp[a]-C). The accuracy of this method, which theoretically can isolate "Lp(a)-free LDL-C," has not been validated. Methods and Results In 177 875 patients from the VLDbL (Very Large Database of Lipids), we compared estimated Lp(a)-C and Lp(a)-free LDL-C with measured values and quantified absolute and percent error. We compared findings with an analogous data set from the Mayo Clinic Laboratory. Error in estimated Lp(a)-C and Lp(a)-free LDL-C increased with higher Lp(a)-C values. Median error for estimated Lp(a)-C <10 mg/dL was -1.9 mg/dL (interquartile range, -4.0 to 0.2); this error increased linearly, overestimating by +30.8 mg/dL (interquartile range, 26.1-36.5) for estimated Lp(a)-C ≥50 mg/dL. This error relationship persisted after stratification by overall high-density lipoprotein cholesterol and high-density lipoprotein cholesterol subtypes. Similar findings were observed in the Mayo cohort. Absolute error for Lp(a)-free LDL-C was +2.4 (interquartile range, -0.6 to 5.3) for Lp(a)-C<10 mg/dL and -31.8 (interquartile range, -37.8 to -26.5) mg/dL for Lp(a)-C≥50 mg/dL. Conclusions Lp(a)-C estimations using fixed conversion factors overestimated Lp(a)-C and subsequently underestimated Lp(a)-free LDL-C, especially at clinically relevant Lp(a) values. Application of inaccurate Lp(a)-C estimations to correct LDL-C may lead to undertreatment of high-risk patients.

The role of Lipoprotein(a) in cardiovascular disease: Current concepts and future perspectives.

High lipoprotein(a) [Lp(a)] levels are associated with the development of atherosclerotic cardiovascular disease (ASCVD) and with calcific aortic valve stenosis (CAVS) both observationally and causally from human genetic studies. The mechanisms are not well characterized but likely involve its role as a carrier of oxidized phospholipids (OxPLs), which are known to be increased in pro-inflammatory states, to induce pro-inflammatory changes in monocytes leading to plaque instability, and to impair vascular endothelial cell function, a driver of acute and recurrent ischemic events. In addition, Lp(a) itself has prothrombotic activity. Current lipid-lowering strategies do not sufficiently lower Lp(a) serum levels. Lp(a)-specific-lowering drugs, targeting apolipoprotein(a) synthesis, lower Lp(a) by up to 90% and are being evaluated in ongoing clinical outcome trials. This review summarizes the current knowledge on the associations of Lp(a) with ASCVD and CAVS, the current role of Lp(a) assessment in the clinical setting, and emerging Lp(a)-specific-lowering therapies.

Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia.

BACKGROUND: It is estimated that less than 10% of cases of familial hypercholesterolemia (FH) in the United States have been diagnosed. Low rates of diagnosis may in part be attributable to affected patients not meeting the clinical diagnostic criteria of the Dutch Lipid Clinic Network (DLCN), Simon Broome, or US MEDPED diagnostic criteria. OBJECTIVE: The objective of this study was to assess the utility of incorporating genetic testing into a patient's evaluation for FH. METHODS: We retrospectively reviewed patients seen in the Advanced Lipids Disorders Clinic at Johns Hopkins Hospital between January 2015 and May 2018. Between June 2018 and December 2018, patients were consented to a prospective registry. DLCN, Simon Broome, and MEDPED criteria were applied to each patient, before and after genetic testing. Genetic testing included sequencing and deletion duplication analysis of four genes (LDLR, PCSK9, APOB, and LDLRAP1). RESULTS: The retrospective review and prospective study identified 135 adult probands who were seen in our clinic for evaluation of heterozygous FH. Twenty-nine individuals (21%) were heterozygous for a pathogenic or likely pathogenic monogenic variant. Before genetic testing, using the DLCN criteria, 35 (26%) individuals met criteria for a definite diagnosis of FH. Thirty patients (22%) met criteria using Simon Broome, and 29 (21%) patients met criteria using US MEDPED before genetic analysis. Depending on the criteria, incorporating genetic testing identified 11-14 additional patients with FH. CONCLUSIONS: Incorporating genetic testing diagnosed almost 50% more patients with definite FH in comparison to classification solely on clinical grounds.

High-density Lipoprotein-cholesterol Subfractions and Coronary Artery Calcium: The ELSA-Brasil Study.

BACKGROUND: Although elevated high-density lipoprotein cholesterol (HDL-C) is considered protective against atherosclerotic cardiovascular disease, no causal relationship has been demonstrated. HDL-C comprises a group of different subfractions that might have different effects on atherosclerosis. Our objective was to investigate the association between HDL-C subfractions with the coronary artery calcium (CAC) score. METHODS: We included 3,674 (49.8 ± 8.3 years, 54% women) participants from the ELSA-Brasil study who had no prior history of CVD and were not currently using lipid-lowering medications. We measured the fasting lipoprotein cholesterol fractions (in mmol/l) by a zonal ultracentrifugation method (VAP). We analyzed the independent predictive values of total HDL-C, HDL2-C, and HDL3-C subfractions and in the HDL2-C/HDL3-C ratio using linear regression to predict Ln(CAC+1) and logistic regression to predict the presence of CAC. RESULTS: Overall 912 (24.8%) of the participants had CAC>0, and 294 (7.7%) had CAC>100. The mean total HDL-C, HDL2-C, and HDL3-C were: 1.42 ± 0.37, 0.38 ± 0.17 and 1.03 ± 0.21 mmol/l, respectively. Individuals with CAC>0 had lower levels of total HDL-C as well as of each subfraction (p < 0.001). When adjusted for age, gender, smoking, hypertension, alcohol use, physical activity, and LDL-C, we observed an inverse association between HDL-C and its subfractions and CAC (p < 0.05). However, by adding triglycerides in the adjustment, neither total HDL-C nor its subfractions remained independently associated with the presence or extent of CAC. CONCLUSION: In this cross-sectional analysis, neither the total HDL-C nor its subfractions (HDL2-C and HDL3-C, as well as HDL2-C/HDL3-C ratio) measured by VAP are independently associated with the presence or extent of coronary calcification.

Associations between cardiovascular disease, cancer, and very low high-density lipoprotein cholesterol in the REasons for Geographical and Racial Differences in Stroke (REGARDS) study.

Aims: Relatively little is known about the health outcomes associated with very low plasma concentrations of high-density lipoprotein cholesterol (HDL-C) mainly because of the small numbers of individuals with such extreme values included in clinical trials. We, therefore, investigated the association between low and very low HDL-C concentration at baseline and incident all-cause-mortality, death from malignant disease (i.e. cancer), and with fatal or non-fatal incident coronary heart disease (CHD) in individuals from the Reasons for Geographical And Racial Differences in Stroke (REGARDS) study. Methods and results: Analysis was based on 21 751 participants from the REGARDS study who were free of CHD, other cardiovascular disease, and cancer at baseline and were categorized by baseline HDL-C into <30 mg/dL (very low), 30-<40 mg/dL (low), and ≥40 mg/dL (reference). A series of incremental Cox proportional hazards models were employed to assess the association between the HDL-C categories and outcomes. Statistical analysis was performed using both complete case methods and multiple imputations with chained equations. After adjustment for age, race, and sex, the hazard ratios (HRs) comparing the lowest and highest HDL-C categories were 1.48 [95% confidence interval (CI) 1.28-1.73] for all-cause mortality, 1.35 (95% CI 1.03-1.77) for cancer-specific mortality and 1.39 (95% CI 0.99-1.96) for incident CHD. These associations became non-significant in models adjusting for demographics, cardiovascular risk factors, and treatment for dyslipidaemia. We found evidence for an HDL paradox, whereby low HDL (30-<40 mg/dL) was associated with reduced risk of incident CHD in black participants in a fully adjusted complete case model (HR 0.63; 95% CI 0.46-0.88) and after multiple imputation analyses (HR 0.76; 95% CI 0.58-0.98). HDL-C (<30 mg/dL) was significantly associated with poorer outcomes in women for all outcomes, especially with respect to cancer mortality (HR 2.31; 95% CI 1.28-4.16) in a fully adjusted complete case model, replicated using multiple imputation (HR 1.81; 95% CI 1.03-3.20). Conclusion: Low HDL-C was associated with reduced risk of incident CHD in black participants suggesting a potential HDL paradox for incident CHD. Very low HDL-C in women was significantly associated with cancer mortality in a fully adjusted complete case model.

Coronary Endothelial Dysfunction Is Associated With Elevated Serum PCSK9 Levels in People With HIV Independent of Low-Density Lipoprotein Cholesterol.

Background HIV + people are at increased risk of coronary artery disease, but the responsible mechanisms are incompletely understood. Proprotein convertase subtilisin/kexin type 9 ( PCSK 9) is traditionally recognized for its importance in cholesterol metabolism; however, recent data suggest an additional, low-density lipoprotein receptor-independent adverse effect on endothelial cell inflammation and function. We tested the hypotheses that PCSK 9 levels are increased and that abnormal coronary endothelial function is related to PCSK 9 serum levels in HIV + individuals. Methods and Results Forty-eight HIV + participants receiving antiretroviral therapy with suppressed viral replication, without coronary artery disease, and 15 age- and low-density lipoprotein cholesterol-matched healthy HIV- subjects underwent magnetic resonance imaging to measure coronary endothelial function, quantified as percentage change in coronary artery cross-sectional area during isometric handgrip exercise, an endothelial-dependent stressor; and blood was obtained for serum PCSK 9 and systemic vascular biomarkers. Data are presented as mean±SD. Mean serum PCSK 9 was 65% higher in the HIV + subjects (302±146 ng/ mL ) than in the HIV - controls (183±52 ng/ mL , P<0.0001). Coronary endothelial function was significantly reduced in the HIV + versus HIV - subjects (percentage change in coronary artery cross-sectional area, 2.9±9.6% versus 11.1±3.7%; P<0.0001) and inversely related to PCSK 9 ( R=-0.51, P<0.0001). Markers of endothelial activation and injury, P-selectin and thrombomodulin, were also significantly increased in the HIV + subjects; and P-selectin was directly correlated with serum PCSK 9 ( R=0.31, P=0.0144). Conclusions Serum PCSK 9 levels are increased in treated HIV + individuals and are associated with abnormal coronary endothelial function, an established measure of vascular health.

Association between high-density lipoprotein subfractions and low-grade inflammation, insulin resistance, and metabolic syndrome components: The ELSA-Brasil study.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) can be divided into subfractions, which may have variable effects in atherogenesis. The results about the association between HDL-C subfractions and risk factors for cardiovascular disease are mixed. OBJECTIVE: The objective of this study was to analyze the association between HDL-C subfractions and each metabolic syndrome component, homeostasis model assessment-estimated insulin resistance (HOMA-IR) and C-reactive protein (CRP). METHODS: Four thousand five hundred thirty-two individuals between 35 and 74 years old without previous manifest cardiovascular disease not using fibrates were enrolled. HDL-C subfractions were separated by vertical ultracentrifugation (vertical auto profile-in mg/dL) into HDL2-C and HDL3-C. HDL2-C/HDL3-C ratio, HOMA-IR, and high-sensitivity CRP were also included in the analysis. RESULTS: Mean age of participants was 51 ± 9 years, and 54.8% were women. In univariate analysis, HDL-C, HDL2-C, and HDL3-C were all inversely associated with each of the metabolic syndrome defining factors, HOMA-IR values, and serum CRP. We also observed a negative association between HDL2-C/HDL3-C ratio with the variables aforementioned even after adjusting for smoking, alcohol use, physical activity, and HDL-C levels (P < .01). CONCLUSION: HDL-C and its subfractions (HDL2-C and HDL3-C) are inversely associated with the defining features of metabolic syndrome, insulin resistance, and systemic inflammation. In addition, the HDL2-C/HDL3-C ratio measured by vertical auto profile is significantly associated with the former factors even after comprehensive adjustment for HDL-C and other confounding variables.

Association Between Smoking and Serum GlycA and High-Sensitivity C-Reactive Protein Levels: The Multi-Ethnic Study of Atherosclerosis (MESA) and Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND: Inflammation is suggested to be a central feature of atherosclerosis, particularly among smokers. We studied whether inflammatory biomarkers GlycA and high-sensitivity C-reactive protein are associated with cigarette smoking. METHODS AND RESULTS: A total of 11 509 participants, 6774 from the MESA (Multi-Ethnic Study of Atherosclerosis) and 4735 from ELSA-Brasil (The Brazilian Longitudinal Study of Adult Health) were included. We evaluated the cross-sectional association between multiple measures of smoking behavior and the inflammatory biomarkers, GlycA and high-sensitivity C-reactive protein, using regression models adjusted for demographic, anthropometric, and clinical characteristics. Participants were 57.7±11.1 years old and 46.4% were men. Never, former, and current smokers comprised 51.7%, 34.0%, and 14.3% of the population, respectively. Multivariable-adjusted mean absolute difference in GlycA levels (µmol/L) with 95% confidence interval (CI) were higher for former (4.1, 95% CI, 1.7-6.6 µmol/L) and current smokers (19.9, 95% CI, 16.6-23.2 µmol/L), compared with never smokers. Each 5-unit increase in pack-years of smoking was associated with higher GlycA levels among former (0.7, 95% CI, 0.3-1.1 µmol/L) and current smokers (1.6, 95% CI, 0.8-2.4 µmol/L). Among former smokers, each 5-year increase in time since quitting smoking was associated with lower GlycA levels (-1.6, 95% CI, -2.4 to -0.8 µmol/L) and each 10-unit increase in number of cigarettes/day was associated with higher GlycA among current smokers (2.8, 95% CI, 0.5-5.2 µmol/L). There were similar significant associations between all measures of smoking behavior, and both log-transformed GlycA and high-sensitivity C-reactive protein. CONCLUSIONS: Acute and chronic exposure to tobacco smoking is associated with inflammation, as quantified by both GlycA and high-sensitivity C-reactive protein. These biomarkers may have utility for the study and regulation of novel and traditional tobacco products.

Vitamin D deficiency and non-lipid biomarkers of cardiovascular risk.

INTRODUCTION: Deficient 25-hydroxyvitamin D (25(OH)D) levels have been associated with dyslipidemia and cardiovascular diseases, though the underlying mechanism of these associations is uncertain. We analyzed associations between vitamin D and other non-lipid biomarkers of cardiovascular risk to better elucidate possible relationships between deficient 25(OH)D and cardiovascular disease. MATERIAL AND METHODS: We performed a cross-sectional analysis of 4,591 adults included in a clinical laboratory database from 2009 to 2011 with available measurements for 25(OH)D and the following biomarkers: homocysteine (Hcy), high-sensitivity C-reactive protein (hs-CRP), cystatin-C, creatinine, γ-glutamyltransferase (GGT), uric acid, and hemoglobin A1c (HbA1c). We calculated odds ratios (OR) of having high levels of each biomarker associated with 25(OH)D deficiency (< 20 ng/ml) compared to optimal levels (≥ 30 ng/ml) using logistic regression adjusted for age, sex, and lipids. RESULTS: The mean ± SD age was 60 ±14 years and 46% of patients were women. In multivariable-adjusted models, adults with deficient 25(OH)D compared to those with optimal levels had increased odds of elevated biomarkers as follows: Hcy (OR = 2.53, 95% CI: 1.92-3.34), hs-CRP (1.62, 1.36-1.93), cystatin-C (2.02, 1.52-2.68), creatinine (2.06, 1.35-3.14), GGT (1.39, 1.07-1.80), uric acid (1.60, 1.31-1.95), and HbA1c (2.47, 1.95-3.13). In analyses evaluating women and men separately, 25(OH)D deficient women but not men had increased odds of elevated levels of all biomarkers studied. There were significant interactions based on sex between 25(OH)D and Hcy (p = 0.003), creatinine (p = 0.004), uric acid (p = 0.040), and HbA1c (p = 0.037). CONCLUSIONS: Deficient 25(OH)D is associated with elevated levels of many biomarkers of cardiovascular risk, particularly among women, in a United States population.

The Effects of Tamoxifen on Plasma Lipoprotein(a) Concentrations: Systematic Review and Meta-Analysis.

INTRODUCTION: Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of breast cancer. Tamoxifen therapy is associated with lower circulating low-density lipoprotein cholesterol and increased triglycerides, but its effects on other lipids are less well studied. AIMS: We aimed to investigate the effect of tamoxifen on circulating concentrations of lipoprotein(a) [Lp(a)] through a meta-analysis of available randomized controlled trials (RCTs) and observational studies. METHODS: This study was registered in the PROSPERO database (CRD42016036890). Scopus, MEDLINE and EMBASE were searched from inception until 22 March 2016 to identify studies investigating the effect of tamoxifen on Lp(a) values in humans. Meta-analysis was performed using an inverse variance-weighted, random-effects model with standardized mean difference (SMD) as the effect size estimate. RESULTS: Meta-analysis of five studies with 215 participants suggested a statistically significant reduction of Lp(a) levels following tamoxifen treatment (SMD -0.41, 95% confidence interval -0.68 to -0.14, p = 0.003). This effect was robust in the sensitivity analysis. CONCLUSIONS: Meta-analysis suggested a statistically significant reduction of Lp(a) levels following tamoxifen treatment. Further well-designed trials are required to validate these results.

Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies.

BACKGROUND: Remnant lipoproteins (RLPs), the triglyceride-enriched precursors to low-density lipoprotein, are an emerging risk factor for coronary heart disease (CHD). We sought to determine the association of RLP cholesterol (RLP-C) levels with incident CHD in 2 diverse, prospective, longitudinal observational US cohorts. METHODS AND RESULTS: We analyzed cholesterol levels from serum lipoprotein samples separated via density gradient ultracentrifugation in 4114 US black participants (mean age 53.8 years, 64% women) from the Jackson Heart Study and a random sample of 818 predominantly white participants (mean age 57.3 years, 52% women) from the Framingham Offspring Cohort Study. Multivariable-adjusted hazard ratios (HRs) for RLP-C (the sum of very low-density lipoprotein3 cholesterol and intermediate-density lipoprotein cholesterol) were derived to estimate associations with incident CHD events consisting of myocardial infarction, CHD death, and revascularizations for each cohort separately and as a combined population. There were 146 CHD events in the combined population. After adjustments for age, sex, body mass index, smoking, blood pressure, diabetes, and lipid-lowering therapy for the combined population, RLP-C (HR 1.23 per 1-SD increase, 95% CI 1.06-1.42, P<0.01) and intermediate-density lipoprotein cholesterol (HR 1.26 per 1-SD increase, 95% CI 1.08-1.47, P<0.01) predicted CHD during an 8-year follow-up. Associations were attenuated by high-density lipoprotein cholesterol and ultimately lost significance with inclusion of real low-density lipoprotein cholesterol, which excludes Lp(a) and IDL cholesterol fractions. Similar associations were seen in multivariable analyses within each cohort. CONCLUSION: RLP-C levels are predictive of incident CHD in this diverse group of primary prevention subjects. Interventions aimed at reducing RLP-C to prevent CHD warrant further intensive investigation. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00415415.

Screening and advanced lipid phenotyping in familial hypercholesterolemia: The Very Large Database of Lipids Study-17 (VLDL-17).

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant dyslipidemia characterized by defective low-density lipoprotein (LDL) clearance. The aim of this study was to compare Friedewald-estimated LDL cholesterol (LDL-C) to biologic LDL-C in individuals screening positive for FH and then further characterize FH phenotypes. METHODS: We studied 1,320,581 individuals from the Very Large Database of Lipids, referred from 2009 to 2011 for Vertical Auto Profile ultracentrifugation testing. Friedewald LDL-C was defined as the cholesterol content of LDL-C, intermediate-density lipoprotein cholesterol, and lipoprotein(a) cholesterol (Lp(a)-C), with LDL-C representing biologic LDL-C. Using Friedewald LDL-C, we phenotypically categorized patients by the National Lipid Association guideline age-based screening thresholds for FH. In those meeting criteria, we categorized patients using population percentile-equivalent biologic LDL-C cutpoints and explored Lp(a)-C and remnant lipoprotein cholesterol (RLP-C) levels. RESULTS: Overall, 3829 patients met phenotypic criteria for FH by Friedewald LDL-C screening (FH+). Of those screening FH+, 78.8% were above and 21.2% were below the population percentile-equivalent biologic LDL-C. The mean difference in Friedewald biologic LDL-C percentiles was -0.01 (standard deviation, 0.17) for those above, and 1.92 (standard deviation, 9.16) for those below, respectively. Over 1 of 3 were found to have an elevated Lp(a)-C and over 50% had RLP-C greater than 95th percentile of the entire VLDL population. CONCLUSIONS: Of those who screened FH+, Friedewald and biologic LDL-C levels were closely correlated. Large proportions of the FH+ group had excess levels of Lp(a)-C and RLP-C. Future studies are warranted to study these mixed phenotypic groups and determine the role for further risk stratification and treatment algorithms.

Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the multi-ethnic study of atherosclerosis.

BACKGROUND: Worldwide clinical practice guidelines for dyslipidemia emphasize allocating statin therapy to those at the highest absolute atherosclerotic cardiovascular disease (CVD) risk. METHODS AND RESULTS: We examined 5534 Multi-Ethnic Study of Atherosclerosis (MESA) participants who were not on baseline medications for dyslipidemia. Participants were classified by baseline coronary artery calcium (CAC) score (>0, ≥ 100) and the common clinical scheme of counting lipid abnormalities (LA), including low-density lipoprotein cholesterol ≥ 3.36 mmol/L (130 mg/dL), high-density lipoprotein cholesterol <1.03 mmol/L (40 mg/dL) for men or <1.29 mmol/L (50 mg/dL) for women, and triglycerides ≥ 1.69 mmol/L (150 mg/dL). Our main outcome measure was incident CVD (myocardial infarction, angina resulting in revascularization, resuscitated cardiac arrest, stroke, cardiovascular death). Over a median follow-up of 7.6 years, more than half of events (55%) occurred in the 21% of participants with CAC ≥ 100. Conversely, 65% of events occurred in participants with 0 or 1 LA. In those with CAC ≥ 100, CVD rates ranged from 22.7 to 29.5 per 1000 person-years across LA categories. In contrast, with CAC=0, CVD rates ranged from 2.7 to 5.9 per 1000 person-years across LA categories. Individuals with 0 LA and CAC ≥ 100 had a higher event rate compared with individuals with 3 LA but CAC=0 (22.7 versus 5.9 per 1000 person-years). Similar results were obtained when we classified LA using data set quartiles of total cholesterol/high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, or low-density lipoprotein particle concentration and guideline categories of low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. CONCLUSIONS: CAC may have the potential to help match statin therapy to absolute CVD risk. Across the spectrum of dyslipidemia, event rates similar to secondary prevention populations were observed for patients with CAC ≥ 100.

Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association.

The term "fat" may refer to lipids as well as the cells and tissue that store lipid (ie, adipocytes and adipose tissue). "Lipid" is derived from "lipos," which refers to animal fat or vegetable oil. Adiposity refers to body fat and is derived from "adipo," referring to fat. Adipocytes and adipose tissue store the greatest amount of body lipids, including triglycerides and free cholesterol. Adipocytes and adipose tissue are active from an endocrine and immune standpoint. Adipocyte hypertrophy and excessive adipose tissue accumulation can promote pathogenic adipocyte and adipose tissue effects (adiposopathy), resulting in abnormal levels of circulating lipids, with dyslipidemia being a major atherosclerotic coronary heart disease risk factor. It is therefore incumbent upon lipidologists to be among the most knowledgeable in the understanding of the relationship between excessive body fat and dyslipidemia. On September 16, 2012, the National Lipid Association held a Consensus Conference with the goal of better defining the effect of adiposity on lipoproteins, how the pathos of excessive body fat (adiposopathy) contributes to dyslipidemia, and how therapies such as appropriate nutrition, increased physical activity, weight-management drugs, and bariatric surgery might be expected to impact dyslipidemia. It is hoped that the information derived from these proceedings will promote a greater appreciation among clinicians of the impact of excess adiposity and its treatment on dyslipidemia and prompt more research on the effects of interventions for improving dyslipidemia and reducing cardiovascular disease risk in overweight and obese patients.

Low-risk lifestyle, coronary calcium, cardiovascular events, and mortality: results from MESA.

Unhealthy lifestyle habits are a major contributor to coronary artery disease. The purpose of the present study was to investigate the associations of smoking, weight maintenance, physical activity, and diet with coronary calcium, cardiovascular events, and mortality. US participants who were 44-84 years of age (n = 6,229) were followed in the Multi-Ethnic Study of Atherosclerosis from 2000 to 2010. A lifestyle score ranging from 0 to 4 was created using diet, exercise, body mass index, and smoking status. Coronary calcium was measured at baseline and a mean of 3.1 (standard deviation, 1.3) years later to assess calcium progression. Participants who experienced coronary events or died were followed for a median of 7.6 (standard deviation, 1.5) years. Participants with lifestyle scores of 1, 2, 3, and 4 were found to have mean adjusted annual calcium progressions that were 3.5 (95% confidence interval (CI): 0.0, 7.0), 4.2 (95% CI: 0.6, 7.9), 6.8 (95% CI: 2.0, 11.5), and 11.1 (95% CI: 2.2, 20.1) points per year slower, respectively, relative to the reference group (P = 0.003). Unadjusted hazard ratios for death by lifestyle score were as follows: for a score of 1, the hazard ratio was 0.79 (95% CI: 0.61, 1.03); for a score of 2, the hazard ratio was 0.61 (95% CI: 0.46, 0.81); for a score of 3, the hazard ratio was 0.49 (95% CI: 0.32, 0.75); and for a score of 4, the hazard ratio was 0.19 (95% CI: 0.05, 0.75) (P < 0.001 by log-rank test). In conclusion, a combination of regular exercise, healthy diet, smoking avoidance, and weight maintenance was associated with lower coronary calcium incidence, slower calcium progression, and lower all-cause mortality over 7.6 years.

A point-by-point response to recent arguments against the use of statins in primary prevention: this statement is endorsed by the American Society for Preventive Cardiology.

Recently, a debate over the merits of statin therapy in primary prevention was published in the Wall Street Journal. The statin opponent claimed that statins should only be used in secondary prevention and never in any primary-prevention patients at risk for cardiovascular events. In this evidence-based rebuttal to those claims, we review the evidence supporting the efficacy of statin therapy in primary prevention. Cardiovascular risk is a continuum in which those at an elevated risk of events stand to benefit from early initiation of therapy. Statins should not be reserved until after a patient suffers the catastrophic consequences of atherosclerosis. Contrary to the assertions of the statin opponent, this principle has been demonstrated through reductions in heart attacks, strokes, and mortality in numerous randomized controlled primary-prevention statin trials. Furthermore, data show that once a patient tolerates the initial treatment period, the few side effects that subsequently emerge are largely reversible. Accordingly, every major guidelines committee endorses statin use in secondary prevention and selectively in primary prevention for those with risk factors. The foundation for prevention remains increased physical activity, better dietary habits, and smoking cessation. However, prevention of heart attacks, strokes, and death from cardiovascular disease does not have to be all or none-all statin or all lifestyle. In selected at-risk individuals, the combination of pharmacotherapy and lifestyle changes is more effective than either alone. Future investigation in prevention should focus on improving our ability to identify these at-risk individuals.

Statin therapy in the prevention and treatment of atrial fibrillation.

Atrial fibrillation (AF) is the most common adult rhythm disorder, and it is associated with a substantial rate of morbidity and economic burden. There is an increasing body of literature in which the authors investigated the pleiotropic effects of statin therapy in relation to AF. In this comprehensive review, we examine the mechanism of AF as well as potential mechanisms supporting statin use in both the prevention and treatment of AF. In clinical studies, statin therapy appears to be useful in the prevention of AF in patients with coronary artery disease and possibly congestive heart failure and in the prevention of perioperative AF in cardiac surgery. Its utility in patients with paroxysmal AF may be limited to the prevention of incident AF, but it does not appear to inhibit the progression of paroxysmal AF to chronic AF. Further large scale, randomized, placebo-controlled studies are needed in perioperative use in noncardiac surgery and in patients undergoing ablation or cardioversion of AF.

Coronary artery calcium progression: an important clinical measurement? A review of published reports.

Baseline coronary artery calcification (CAC) accurately identifies coronary atherosclerosis and might improve prediction of future cardiac events. Serial assessment of CAC scores has been proposed for monitoring atherosclerosis progression and for assessing the effectiveness of medical therapies aimed at reducing cardiac risk. However, whether knowledge of progression of CAC scores over time further improves risk prediction is unclear. Several trials relating medical therapies to CAC progression have been performed without any formal guidelines on the definition of CAC progression and how it is best quantified. We conducted a comprehensive review of published reports on CAC progression. Increased CAC progression is associated with many known cardiac risk factors. We found that CAC progression correlates with worsening atherosclerosis and may facilitate prediction of future cardiac events. These findings support the notion that slowing CAC progression with therapeutic interventions might provide prognostic benefit. However, despite promising early data, such interventions (most notably with statin therapy) have not been shown to slow the progression of CAC in any randomized controlled trial to date, outside of post hoc subgroup analyses. Thus, routine quantification of CAC progression cannot currently be recommended in clinical practice. First, standards of how CAC progression should be defined and assessed need to be developed. In addition, there remains a need for further studies analyzing the effect of other cardiac therapies on CAC progression and cardiac outcomes.