Obesity phenotypes and atherogenic dyslipidemias.

Adverse cardiovascular (CV) events have declined in Western countries due at least in part to aggressive risk factor control, including dyslipidemia management. The American and European (Western) dyslipidemia treatment guidelines have contributed significantly to the reduction in atherosclerotic cardiovascular disease (ASCVD) incidence in the respective populations. However, their direct extrapolation to Indian patients does not seem appropriate for the reasons described below. In the US, mean low-density lipoprotein cholesterol (LDL-C) levels have markedly declined over the last 2 decades, correlating with a proportional reduction in CV events. Conversely, poor risk factor control and dyslipidemia management have led to increased CV and coronary artery disease (CAD) mortality rates in India. The population-attributable risk of dyslipidemia is about 50% for myocardial infarction, signifying its major role in CV events. In addition, the pattern of dyslipidemia in Indians differs considerably from that in Western populations, requiring unique strategies for lipid management in Indians and modified treatment targets. The Lipid Association of India (LAI) recognized the need for tailored LDL-C targets for Indians and recommended lower targets compared to Western guidelines. For individuals with established ASCVD or diabetes with additional risk factors, an LDL-C target of <50 mg/dL was recommended, with an optional target of ≤30 mg/dL for individuals at extremely high risk. There are several reasons that necessitate these lower targets. In Indian subjects, CAD develops 10 years earlier than in Western populations and is more malignant. Additionally, Indians experience higher CAD mortality despite having lower basal LDL-C levels, requiring greater LDL-C reduction to achieve a comparable CV event reduction. The Indian Council for Medical Research-India Diabetes study described a high prevalence of dyslipidemia among Indians, characterized by relatively lower LDL-C levels, higher triglyceride levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to Western populations. About 30% of Indians have hypertriglyceridemia, aggravating ASCVD risk and complicating dyslipidemia management. The levels of atherogenic triglyceride-rich lipoproteins, including remnant lipoproteins, are increased in hypertriglyceridemia and are predictive of CV events. Hypertriglyceridemia is also associated with higher levels of small, dense LDL particles, which are more atherogenic, and higher levels of apolipoprotein B (Apo B), reflecting a higher burden of circulating atherogenic lipoprotein particles. A high prevalence of low HDL-C, which is often dysfunctional, and elevated lipoprotein(a) [Lp(a)] levels further contribute to the heightened atherogenicity and premature CAD in Indians. Considering the unique characteristics of atherogenic dyslipidemia in Indians, lower LDL-C, non-HDL-C, and Apo B goals compared to Western guidelines are required for effective control of ASCVD risk in Indians. South Asian ancestry is identified as a risk enhancer in the American lipid management guidelines, highlighting the elevated ASCVD risk of Indian and other South Asian individuals, suggesting a need for more aggressive LDL-C lowering in such individuals. Hence, the LDL-C goals recommended by the Western guidelines may be excessively high for Indians and could result in significant residual ASCVD risk attributable to inadequate LDL-C lowering. Further, the results of Mendelian randomization studies have shown that lowering LDL-C by 5-10 mg/dL reduces CV risk by 8-18%. The lower LDL-C targets proposed by LAI can yield these incremental benefits. In conclusion, Western LDL-C targets may not be suitable for Indian subjects, given the earlier presentation of ASCVD at lower LDL-C levels. They may result in greater CV events that could otherwise be prevented with lower LDL-C targets. The atherogenic dyslipidemia in Indian individuals necessitates more aggressive LDL-C and non-HDL-C lowering, as recommended by the LAI, in order to stem the epidemic of ASCVD in India.

The objective of this study was to investigate the association between intake of seafood and plant-derived n-3 polyunsaturated fatty acids (PUFA) and development of total atherosclerotic cardiovascular disease (ASCVD) and acute major ischemic events. A total of 53,909 men and women were enrolled between 1993 and 1997 into the Danish Diet, Cancer and Health cohort and followed through nationwide Danish registries for development of total ASCVD defined as a first registration of myocardial infarction, peripheral artery disease, or ischemic stroke due to large artery atherosclerosis or small-vessel occlusion. At recruitment, the intake of the major marine n-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the plant-derived n-3 PUFA, alpha-linolenic acid (ALA), was assessed using a validated food frequency questionnaire. Statistical analyses were conducted using sex-stratified multivariable Cox proportional hazard regression models. During a median of 13.5years of follow-up, 3958 participants developed ASCVD including 3270 patients with an acute major ischemic event. In multivariable analyses including adjustment for established risk factors, we found no associations for intake of ALA, but indications of inverse associations between intake of EPA, DHA and EPA + DHA and the rate of total ASCVD and acute major ischemic events. A high intake of marine n-3 PUFA was associated with a lower risk of total ASCVD and acute major ischemic events, whereas no association could be demonstrated for the plant-derived ALA.

Elevated low-density lipoprotein-cholesterol (LDL-C) is a causal factor for the development of atherosclerotic cardiovascular disease (ASCVD); accordingly, LDL-C lowering is associated with a decreased risk of progression of atherosclerotic plaques and development of complications. Currently, statins play a central role in any ASCVD management and prevention strategies, in relation to their lipid-lowering action and potentially to pleiotropic effects. After coronary artery disease, stroke is the most frequent cause of ASCVD mortality and the leading cause of acquired disability, a major public health problem. There is often a tendency to aggregate all types of stroke (atherothrombotic, cardioembolic, and haemorrhagic), which have, however, different causes and pathophysiology, what may lead to bias when interpreting the results of the studies. Survivors of a first atherothrombotic ischemic stroke are at high risk for coronary events, recurrent stroke, and vascular death. Although epidemiological studies show a weak relationship between cholesterol levels and cerebrovascular disease as a whole compared with other ASCVD types, statin intervention studies have demonstrated a decrease in the risk of stroke in patients with atherosclerosis of other territories and a decrease in all cardiovascular events in patients who have had a stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated the benefit of high doses of atorvastatin in the secondary prevention of ischemic stroke. In this review, we discuss the evidence, use and recommendations of statins in the primary and secondary prevention of stroke, and their role in other scenarios such as the acute phase of ischemic stroke, cerebral hemorrhage, cardioembolic stroke, small vessel disease, and cognitive impairment.

Grundy, Scott M; Cleeman, James I; Daniels, Stephen R; Donato, Karen A; Eckel, Robert H; Franklin, Barry A; Gordon, David J; Krauss, Ronald M; Savage, Peter J; Smith, Sidney C Jr; Spertus, John A; Costa, Fernando Executive Summary

The metabolic syndrome has received increased attention in the past few years. This statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) is intended to provide up-to-date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults. The metabolic syndrome is a constellation of interrelated risk factors of metabolic origin— metabolic risk factors —that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD).1 Patients with the metabolic syndrome also are at increased risk for developing type 2 diabetes mellitus. Another set of conditions, the underlying risk factors , give rise to the metabolic risk factors. In the past few years, several expert groups have attempted to set forth simple diagnostic criteria to be used in clinical practice to identify patients who manifest the multiple components of the metabolic syndrome. These criteria have varied somewhat in specific elements, but in general they include a combination of both underlying and metabolic risk factors. The most widely recognized of the metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a pro-inflammatory state as well. Atherogenic dyslipidemia consists of an aggregation of lipoprotein abnormalities including elevated serum triglyceride and apolipoprotein B (apoB), increased small LDL particles, and a reduced level of HDL cholesterol (HDL-C). The metabolic syndrome is often referred to as if it were a discrete entity with a single cause. Available data suggest that it truly is a syndrome, ie, a grouping of ASCVD risk factors, but one that probably has more than one cause. Regardless of cause, the syndrome identifies individuals at an elevated risk for ASCVD. The magnitude of the increased risk can vary according to which components of the syndrome are …

Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of LDL-C metabolism, have emerged as promising approaches for reducing elevated LDL-C levels. Here, we evaluated the cholesterol-lowering efficacy of virus-like particle (VLP) based vaccines that target epitopes found within the LDL receptor (LDL-R) binding domain of PCSK9. In both mice and non-human primates, a bivalent VLP vaccine targeting two distinct epitopes on PCSK9 elicited strong and durable antibody responses and lowered cholesterol levels. In macaques, a VLP vaccine targeting a single PCSK9 epitope was only effective at lowering LDL-C levels in combination with statins, whereas immunization with the bivalent vaccine lowered LDL-C without requiring statin co-administration. These data highlight the efficacy of an alternative, vaccine-based approach for lowering LDL-C.

Current algorithms for assessing risk of atherosclerotic cardiovascular disease (ASCVD) and, in particular, the reliance on low-density lipoprotein (LDL) cholesterol in conditions where this measurement is discordant with apoB and LDL-particle concentrations fail to identify a sizeable part of the population at high risk for adverse cardiovascular events. This results in missed opportunities for ASCVD prevention, most notably in those with metabolic syndrome, prediabetes, and diabetes. There is substantial evidence that accumulation of ectopic fat and associated metabolic traits are markers for and pathogenic components of high-risk atherosclerosis. Conceptually, the subset of advanced lesions in high-risk atherosclerosis that triggers vascular complications is closely related to a set of coordinated high-risk traits clustering around a distinct metabolic phenotype. A key feature of this phenotype is accumulation of ectopic fat, which, coupled with age-related muscle loss, creates a milieu conducive for the development of ASCVD: atherogenic dyslipidemia, nonresolving inflammation, endothelial dysfunction, hyperinsulinemia, and impaired fibrinolysis. Sustained vascular inflammation, a hallmark of high-risk atherosclerosis, impairs plaque stabilization in this phenotype. This review describes how metabolic and inflammatory processes that are promoted in large measure by ectopic adiposity, as opposed to subcutaneous adipose tissue, relate to the pathogenesis of high-risk atherosclerosis. Clinical biomarkers indicative of these processes provide incremental information to standard risk factor algorithms and advanced lipid testing identifies atherogenic lipoprotein patterns that are below the discrimination level of standard lipid testing. This has the potential to enable improved identification of high-risk patients who are candidates for therapeutic interventions aimed at prevention of ASCVD.

Although there is no clarity on the precise definition of the metabolic syndrome, there is consensus that it is a cluster of inter-related risk factors (elevated blood pressure, elevated plasma glucose, atherogenic dyslipidaemia) that are due to mainly abdominal obesity and insulin resistance, and which appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD), and increase the risk for developing type 2 diabetes mellitus. The prevalence of the metabolic syndrome is increasing globally, including in the adolescent population. In developed countries the prevalence of the metabolic syndrome is about 30% of the adult population. The cornerstone of management of this syndrome is lifestyle intervention. Following a comprehensive initial assessment to risk-stratify patients, they are recommended to attend either a group-based programme (medically supervised or medically directed, depending on the severity of the disease and the presence of any co-morbidities) or a home...

Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia. The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefit on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors.

Atherosclerosis is a leading cause of cardiovascular disease and mortality worldwide. Alterations in the gut microbiota composition, known as gut dysbiosis, have been shown to contribute to atherosclerotic cardiovascular disease (ACVD) development through several pathways. Disruptions in gut homeostasis are associated with activation of immune processes and systemic inflammation. The gut microbiota produces several metabolic products, such as trimethylamine (TMA), which is used to produce the proatherogenic metabolite trimethylamine-N-oxide (TMAO). Short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, and certain bile acids (BAs) produced by the gut microbiota lead to inflammation resolution and decrease atherogenesis. Chronic low-grade inflammation is associated with common risk factors for atherosclerosis, including metabolic syndrome, type 2 diabetes mellitus (T2DM), and obesity. Novel strategies for reducing ACVD include the use of nutraceuticals such as resveratrol, modification of glucagon-like peptide 1 (GLP-1) levels, supplementation with probiotics, and administration of prebiotic SCFAs and BAs. Investigation into the relationship between the gut microbiota, and its metabolites, and the host immune system could reveal promising insights into ACVD development, prognostic factors, and treatments.

Background: Atherosclerosis is a multifactorial disease with an intrinsic inflammatory component, but it may also be influenced by systemic inflammation. There is cardiovascular risk associated with rheumatoid arthritis (RA), but there is still a need to clarify the contributions of traditional risk factors in those with inflammatory connective tissue diseases (CTD, which includes RA) in the development of atherosclerotic cardiovascular disease (ASCVD). It would also be useful to identify particular groups of patients that are at disproportionately greater conferred risk for ASCVD owing to their CTD. For these reasons, a cross-sectional analysis of a diverse patient population could help develop finer ASCVD risk estimations in those with and without CTD. Results: A systematically queried warehouse of de-identified data from over a quarter-million adult patients at our urban medical center over the past six years showed that prevalence of ASCVD steadily increases with age, consistent with rates found in other large cohorts, in both white and African-American patients. Amongst the ~9,000 patients with CTD (RA, other inflammatory polyarthropathy, lupus, Sjögren’s syndrome, systemic sclerosis, dermatomyositis, polymyositis), the overall prevalence of ASCVD was higher than amongst those without CTD with a rate ratio of 1.9 [95% CI 1.8-2.1] for white patients and 3.3 [95% CI 3.1-3.5] for African-American patients. Subgroup analysis revealed that the rate ratio was particularly high for young adults, and especially young African-American patients (ages 18-44; rate ratio for women: 10.7 [95% CI 8.5-13.5], for men: 9.9 [95% CI 6.8-14.5]). Rate ratios of ASCVD in those with vs. without CTD declined with age as traditional risk factors became more prevalent. Importantly, in those without any documented traditional risk factors (smoking, hypertension, diabetes, dyslipidemia), a diagnosis of ASCVD was found nearly three times more frequently in those with CTD than without [rate ratio 2.9, 95% CI 2.4-3.5]. Conclusions: CTD is associated with increased ASCVD rates, and major traditional risk factors do not fully account for these increased rates. African-Americans and young adults have a disproportionately strengthened association between CTD and ASCVD.

Non–high-density lipoprotein cholesterol target achievement in patients on lipid-lowering drugs and stratified by triglyceride levels in the Arabian Gulf

Whether cardiovascular risk scores geographically aggregate and inform on spatial development of atherosclerotic cardiovascular diseases (ASCVD) remains unknown. Our aim is to determine the spatial distribution of 10-year predicted cardiovascular risk and ASCVD, and to compare the overlap of the resulting spatial distributions. Using prospective data from the CoLaus|PsyCoLaus cohort study (2003–2021) we computed SCORE2 in participants free from ASCVD. Geographical distributions of predicted risk and events were determined using the Gi* Getis-Ord autocorrelation statistic. 6203 individuals (54% women, mean age 52.5 ± SD 10.7, ASCVD incidence rate 5.7%) were included. We identified clusters of high versus low predicted risk (4%, 6%, respectively) and ASCVD (5%, 5% respectively) at baseline. They persisted at follow-up. Overlap of SCORE2 and ASCVD clusters was marginal. Body-mass index and alcohol consumption explained most of the predicted risk distribution. For ASCVD, high clusters persisted or were reinforced after multivariate adjustment, while low incidence clusters were reduced, multifactorial determinants. Incidence rate of ASCVD was 2.5% higher (IC 95%, 1.4–3.7) in clusters of higher incidence of ASCVD. To develop up-to-date, geographically targeted prevention strategies, there is a need to study novel geographically risk factors affecting ASCVD and to update commonly used prediction models for a population approach.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Swiss National Science Foundation GlaxoSmithKline. Introduction Whether cardiovascular risk score geographically aggregates and informs on spatial development of atherosclerotic cardiovascular disease (ASCVD) remains unknown. Aims We first determined the spatial distribution of cardiovascular risk predicted in an urban population. Second, we compared risk maps with clustering of incident ASCVD over a 10-year follow-up. Sensitivity analyses were conducted to identify explanatory risk factors for both clusters of predicted risk and observed ASCVD. Methods Using data from a population-based cohort study, we computed the Systematic Coronary Risk Evaluation Score 2 (SCORE2 and SCORE2-OP) in participants free from ASCVD at baseline (2003-2006). Geographical distributions of predicted risk and incident ASCVD were determined using global and local spatial autocorrelation statistics. Different models were tested to identify explanatory variables (alcohol consumption, body mass index, socio-economic status, anxiety disorder, major depressive disorder, Mediterranean diet, sport activity, polygenic risk score, mean noise, concentration of PM2.5, normalized difference vegetation index, land surface temperature). Results 6203 individuals (56% women, mean age 52.5 ± SD 10.7) with a median follow-up of 10 years (IQR, 6-10) were included in the analyses. Over the period, there was persistent geographical clustering of predicted risk and ASCVD (Figures 1 and 2). Predicted risk and incident ASCVD marginally overlapped spatially. Body-mass index (BMI) and alcohol consumption explained most of the spatial distribution of predicted risk, reducing high-risk clusters from 286 to 5 and low-risk clusters from 391 to 44. For ASCVD, high clusters either persisted or were reinforced depending upon locations, after adjustment for potential risk factors, with an increase from 100 to 118. Low clusters reduced from 293 to 76 after the adjustment. Incidence rate of ASCVD was 2.5% (IC95%, 3.7-2.4%]) in high-risk clusters compared to the rest of the population. Conclusions Using a population-based cohort, we showed that in an urban area there exists clusters of high and low incidence of ASCVD. Geographical distribution of clusters of high clinical risk score was not congruent with that of incident ASCVD, limiting the use of clinical risk scores in identifying areas where ASCVD may develop.

Comparing Primary Prevention Recommendations: A Focused Look at United States and European Guidelines on Dyslipidemia.