Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis.

BACKGROUND: Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate. OBJECTIVES: The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle. METHODS: Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed. RESULTS: The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis. CONCLUSIONS: We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.

Acute myocardial infarction preferentially alters low-abundant, long-chain unsaturated phospholipid and sphingolipid species in plasma high-density lipoprotein subpopulations.

Aim: High-density lipoprotein (HDL) particles in ST-segment elevation myocardial infarction (STEMI) are deficient in their anti-atherogenic function. Molecular determinants of such deficiency remain obscure. Methods: Five major HDL subpopulations were isolated using density-gradient ultracentrifugation from STEMI patients (n = 12) and healthy age- and sex-matched controls (n = 12), and 160 species of phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, sphingomyelin and ceramide were quantified by LC-MS/MS. Results: Multiple minor species of proinflammatory phosphatidic acid and lysophosphatidylcholine were enriched by 1.7-27.2-fold throughout the majority of HDL subpopulations in STEMI. In contrast, minor phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin and ceramide species were typically depleted up to 3-fold in STEMI vs. control HDLs, while abundances of their major species did not differ between the groups. Intermediate-to-long-chain phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol species were more affected by STEMI than their short-chain counterparts, resulting in positive correlations between their fold decrease and the carbon chain length. Additionally, fold decreases in the abundances of multiple lipid species were positively correlated with the double bond number in their carbon chains. Finally, abundances of several phospholipid and ceramide species were positively correlated with cholesterol efflux capacity and antioxidative activity of HDL subpopulations, both reduced in STEMI vs controls. KEGG pathway analysis tied these species to altered glycerophospholipid and linoleic acid metabolism. Conclusions: Minor unsaturated intermediate-to-long-chain phospholipid and sphingolipid species in HDL subpopulations are most affected by STEMI, reflecting alterations in glycerophospholipid and linoleic acid metabolism with the accumulation of proinflammatory lysolipids and maintenance of homeostasis of major phospholipid species.

Pitavastatin treatment remodels the HDL subclass lipidome and proteome in hypertriglyceridemia.

HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in nondiabetic hypertriglyceridemia (HTG) involves subnormal HDL-cholesterol and apoAI levels. Metabolic anomalies may impact the qualitative features of both the HDL lipidome and proteome. Whether particle content of bioactive lipids and proteins may differentiate HDL subclasses (HDL2b, 2a, 3a, 3b, and 3c) in HTG is unknown. Moreover, little is known of the effect of statin treatment on the proteolipidome of hypertriglyceridemic HDL and its subclasses. Nondiabetic, obese, HTG males (n = 12) received pitavastatin calcium (4 mg/day) for 180 days in a single-phase, unblinded study. ApoB-containing lipoproteins were normalized poststatin. Individual proteolipidomes of density-defined HDL subclasses were characterized prestatin and poststatin. At baseline, dense HDL3c was distinguished by marked protein diversity and peak abundance of surface lysophospholipids, amphipathic diacylglycerol and dihydroceramide, and core cholesteryl ester and triacylglycerol, (normalized to mol phosphatidylcholine), whereas light HDL2b showed peak abundance of free cholesterol, sphingomyelin, glycosphingolipids (monohexosylceramide, dihexosylceramide, trihexosylceramide, and anionic GM3), thereby arguing for differential lipid transport and metabolism between subclasses. Poststatin, bioactive lysophospholipid (lysophosphatidylcholine, lysoalkylphosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylinositol) cargo was preferentially depleted in HDL3c. By contrast, baseline lipidomic profiles of ceramide, dihydroceramide and related glycosphingolipids, and GM3/phosphatidylcholine were maintained across particle subclasses. All subclasses were depleted in triacylglycerol and diacylglycerol/phosphatidylcholine. The abundance of apolipoproteins CI, CII, CIV, and M diminished in the HDL proteome. Statin treatment principally impacts metabolic remodeling of the abnormal lipidome of HDL particle subclasses in nondiabetic HTG, with lesser effects on the proteome.

Sphingosine-1-phosphate: metabolism, transport, atheroprotection and effect of statin treatment.

PURPOSE OF REVIEW: To better define the metabolism of sphingosine-1-phosphate (S1P), its transport in plasma and its interactions with S1P receptors on vascular cells, and to evaluate the effect of statin treatment on the subnormal plasma levels of high-density lipoprotein (HDL)-bound S1P characteristic of the atherogenic dyslipidemia of metabolic syndrome (MetS). RECENT FINDINGS: Neither clinical intervention trials targeted to raising high-density lipoprotein-cholesterol (HDL-C) levels nor human genome-wide association studies (GWAS) studies have provided evidence to support an atheroprotective role of HDL. Recently however a large monogenic univariable Mendelian randomization on the N396S mutation in the gene encoding endothelial lipase revealed a causal protective effect of elevated HDL-C on coronary artery disease conferred by reduced enzyme activity. Given the complexity of the HDL lipidome and proteome, components of HDL other than cholesterol may in all likelihood contribute to such a protective effect. Among HDL lipids, S1P is a bioactive sphingolipid present in a small proportion of HDL particles (about 5%); indeed, S1P is preferentially enriched in small dense HDL3. As S1P is bound to apolipoprotein (apo) M in HDL, such enrichment is consistent with the elevated apoM concentration in HDL3. When HDL/apoM-bound S1P acts on S1P1 or S1P3 receptors in endothelial cells, potent antiatherogenic and vasculoprotective effects are exerted; those exerted by albumin-bound S1P at these receptors are typically weaker. When HDL/apoM-bound S1P binds to S1P2 receptors, proatherogenic effects may potentially be induced. Subnormal plasma levels of HDL-associated S1P are typical of dyslipidemic individuals at high cardiovascular risk and in patients with coronary heart disease. International Guidelines recommend statin treatment as first-line lipid lowering therapy in these groups. The cardiovascular benefits of statin therapy are derived primarily from reduction in low-density lipoprotein (LDL)-cholesterol, although minor contributions from pleiotropic actions cannot be excluded. Might statin treatment therefore normalize, directly or indirectly, the subnormal levels of S1P in dyslipidemic subjects at high cardiovascular risk? Our unpublished findings in the CAPITAIN study (ClinicalTrials.gov: NCT01595828), involving a cohort of obese, hypertriglyceridemic subjects (n = 12) exhibiting the MetS, showed that pitavastatin calcium (4 mg/day) treatment for 180days was without effect on either total plasma or HDL-associated S1P levels, suggesting that statin-mediated improvement of endothelial function is not due to normalization of HDL-bound S1P. Statins may however induce the expression of S1P1 receptors in endothelial cells, thereby potentiating increase in endothelial nitric oxide synthase response to HDL-bound S1P, with beneficial downstream vasculoprotective effects. SUMMARY: Current evidence indicates that S1P in small dense HDL3 containing apoM exerts antiatherogenic effects and that statins exert vasculoprotective effects through activation of endothelial cell S1P1 receptors in response to HDL/apoM-bound S1P.

Reducing residual cardiovascular risk in Europe: Therapeutic implications of European medicines agency approval of icosapent ethyl/eicosapentaenoic acid.

Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Hypertriglyceridemia, a major risk factor for premature ASCVD, is present in more than 20% of the European population, and is a key feature of atherogenic dyslipidemia. Recent findings from the Progression of Early Subclinical Atherosclerosis (PESA) cohort in Spain showed that even in apparently healthy, middle-aged individuals without a history of cardiovascular (CV) risk, elevated triglyceride levels are associated with subclinical atherosclerosis and arterial inflammation. Emerging evidence from epidemiologic and genetic studies supports an independent causative role of triglycerides, triglyceride-rich lipoproteins, and their remnants in this pathology. Icosapent ethyl (IPE) is a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) that was initially approved by the United States Food and Drug Administration to treat severe hypertriglyceridemia, and subsequently received an expanded indication to reduce the risk of CV events in adult statin-treated patients. Approval was based on the pivotal, randomized, placebo-controlled, double-blind Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), which showed that high-dose IPE (4 g/day) significantly reduced the risk of primary and secondary composite endpoints comprising major CV events and CV death relative to placebo. In 2021, the European Medicines Agency (EMA) approved IPE to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated triglyceride levels (≥1.7 mmol/L [≥150 mg/dL]) and established CV disease, or diabetes and at least one other CV risk factor. Clinical studies in Europe, which included patients with acute myocardial infarction, coronary artery disease, and those undergoing cardiac rehabilitation, established that 12.5% to 23.3% of these high-risk populations may benefit from treatment with IPE. Such clinical benefit may in part result from the moderate triglyceride-lowering properties of IPE/EPA; equally however, concentrations of atherogenic remnant particle-cholesterol are markedly reduced. Furthermore, IPE/EPA exerts pleiotropic actions beyond its lipid-lowering properties, which include modulation of endothelial function, attenuation of intra-plaque inflammation and oxidative stress, and reduction in macrophage accumulation. Plasma phospholipids, into which EPA is primarily incorporated and transported, appear to serve as precursors for a series of anti-inflammatory metabolites involving the resolvins RvE1 to RvE3, a pathway which may confer cardioprotective benefits. In addition, plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials show that plaque stabilization may be favorably affected. These factors may act synergistically to stabilize atherosclerotic plaques and reduce CV risk. In addition to robust efficacy data, multiple cost-utility studies across several countries indicate that IPE/EPA is a cost-effective treatment option that is favorably situated relative to some common willingness-to-pay thresholds. This review will evaluate the relevance of hypertriglyceridemia to residual ASCVD burden in statin-treated dyslipidemic patients, the potential of IPE/EPA to reduce the risk of ASCVD and cardiovascular mortality in high-risk patient populations, and the mechanisms which may underlie these effects. Finally, the clinical implications of the EMA label for IPE will be critically appraised in light of the updated 2019 European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidemia and the recent European Atherosclerosis Society consensus statement on triglyceride-rich lipoproteins and their remnants, together with considerations of its cost-effectiveness across several countries.

HDL functionality in type 1 and type 2 diabetes: new insights.

PURPOSE OF REVIEW: To critically appraise new insights into HDL structure and function in type 1 diabetes (T1DM) and type 2 diabetes (T2DM). RECENT FINDINGS: In young T1DM patients with early renal impairment and a high inflammatory score, both HDL antioxidative activity and endothelial vasodilatory function were impaired, revealing a critical link between HDL dysfunction, subclinical vascular damage, systemic inflammation and end organ damage. HDL may inhibit development of T2DM by attenuating endoplasmic reticulum (ER) stress and apoptotic loss of pancreatic ß-cells, an effect due in part to ABC transporter-mediated efflux of specific oxysterols with downstream activation of the hedghehog signalling receptor, Smoothened. The apoM-sphingosine-1-phosphate complex is critical to HDL antidiabetic activity, encompassing protection against insulin resistance, promotion of insulin secretion, enhanced ß-cell survival and inhibition of hepatic glucose production. Structure-function studies of HDL in hyperglycemic, dyslipidemic T2DM patients revealed both gain and loss of lipidomic and proteomic components. Such changes attenuated both the optimal protective effects of HDL on mitochondrial function and its capacity to inhibit endothelial cell apoptosis. Distinct structural components associated with individual HDL functions. SUMMARY: Extensive evidence indicates that both the proteome and lipidome of HDL are altered in T1DM and T2DM, with impairment of multiple functions.

Differentiating EPA from EPA/DHA in cardiovascular risk reduction.

None of the clinical trials of omega-3 fatty acids using combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were able to show any effect on cardiovascular outcomes, despite reductions in triglyceride levels. In contrast, the Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT), which employed high-dose (4 g) purified EPA, demonstrated a 25% reduction in atherosclerotic cardiovascular disease-related events compared with placebo (hazard ratio 0.75; 95% confidence interval 0.68-0.83; P < 0.001). Moreover, REDUCE-IT is the first clinical trial using a lipid-lowering agent as adjuvant therapy to a statin to show a significant reduction in cardiovascular mortality. Significant reductions in stroke, need for revascularization, and myocardial infarction were also observed. The pharmacology of EPA is distinct from that of DHA, with a differential effect on membrane structure, lipoprotein oxidation, and the production of downstream metabolites that promote the resolution of inflammation. Attained plasma levels of EPA may be an important determinant of efficacy, with a substudy of REDUCE-IT suggesting that the threshold for clinical benefit of EPA is approximately 100 µg/mL, a level achieved in only a minority of patients in other studies. No similar clinical trials of DHA monotherapy have been conducted, so no such threshold has been established. The results of the REDUCE-IT and the Japan EPA Lipid Intervention Study (JELIS) together affirm the efficacy of EPA therapy for cardiovascular disease risk reduction in certain patient populations.

Lipoprotein(a): Pathophysiology, measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d'Athérosclérose (NSFA).

Lipoprotein(a) is an apolipoprotein B100-containing low-density lipoprotein-like particle that is rich in cholesterol, and is associated with a second major protein, apolipoprotein(a). Apolipoprotein(a) possesses structural similarity to plasminogen but lacks fibrinolytic activity. As a consequence of its composite structure, lipoprotein(a) may: (1) elicit a prothrombotic/antifibrinolytic action favouring clot stability; and (2) enhance atherosclerosis progression via its propensity for retention in the arterial intima, with deposition of its cholesterol load at sites of plaque formation. Equally, lipoprotein(a) may induce inflammation and calcification in the aortic leaflet valve interstitium, leading to calcific aortic valve stenosis. Experimental, epidemiological and genetic evidence support the contention that elevated concentrations of lipoprotein(a) are causally related to atherothrombotic risk and equally to calcific aortic valve stenosis. The plasma concentration of lipoprotein(a) is principally determined by genetic factors, is not influenced by dietary habits, remains essentially constant over the lifetime of a given individual and is the most powerful variable for prediction of lipoprotein(a)-associated cardiovascular risk. However, major interindividual variations (up to 1000-fold) are characteristic of lipoprotein(a) concentrations. In this context, lipoprotein(a) assays, although currently insufficiently standardized, are of considerable interest, not only in stratifying cardiovascular risk, but equally in the clinical follow-up of patients treated with novel lipid-lowering therapies targeted at lipoprotein(a) (e.g. antiapolipoprotein(a) antisense oligonucleotides and small interfering ribonucleic acids) that markedly reduce circulating lipoprotein(a) concentrations. We recommend that lipoprotein(a) be measured once in subjects at high cardiovascular risk with premature coronary heart disease, in familial hypercholesterolaemia, in those with a family history of coronary heart disease and in those with recurrent coronary heart disease despite lipid-lowering treatment. Because of its clinical relevance, the cost of lipoprotein(a) testing should be covered by social security and health authorities.

Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.

Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges.

Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of 'lower is better'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.

Efficacy and safety of icosapent ethyl in hypertriglyceridaemia: a recap.

Although low-density lipoprotein cholesterol lowering is effective in atherosclerotic cardiovascular disease (ASCVD) prevention, considerable 'lipid-associated' residual risk remains, particularly in patients with mild-to-moderate hypertriglyceridaemia (2-10 mmol/L; 176-880 mg/dL). Triglyceride (TG)-rich lipoproteins carry both TGs and cholesterol (remnant-cholesterol). At TG levels >5 mmol/L (440 mg/dL) vs. <1 mmol/L (88 mg/dL) or remnant-cholesterol >2.3 mmol/L (89 mg/dL) vs. <0.5 mmol/L (19 mg/dL), risk is ∼1.5-fold elevated for aortic stenosis, 2-fold for all-cause mortality, 3-fold for ischaemic stroke, 5-fold for myocardial infarction (MI), and 10-fold for acute pancreatitis. Furthermore, Mendelian randomization studies indicate that elevated TG-rich lipoproteins are causally related to increased risk of ASCVD and even all-cause mortality. While genetic and epidemiological data strongly indicate that TG-rich lipoproteins are causally linked to ASCVD, intervention data are ambiguous. Fibrates, niacin and low-dose omega-3 fatty acids have all been used in outcome trials, but have failed to demonstrate clear benefit in combination with statins. Whether the lack of additional benefit relates to methodological issues or true failure is indeterminate. Importantly, a recent intervention trial evaluating a high dose of eicosapentaenoic-acid showed clear benefit. Thus, REDUCE-IT evaluated the effect of icosapent ethyl (4 g/day) on cardiovascular outcomes in 8179 high-risk patients with moderate TG elevation on statin therapy. Over a median duration of 4.9 years, the relative risk for the primary endpoint (composite of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina) was reduced by 25% (absolute risk 17.2% vs. 22.0%; P < 0.0001; number needed to treat 21). High-dose icosapent ethyl intervention therefore confers substantial cardiovascular benefit in high-risk patients with moderate hypertriglyceridaemia on statin therapy.

Beyond cardiovascular medicine: potential future uses of icosapent ethyl.

The REDUCE-IT trial demonstrated that icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), reduced cardiovascular events in an at-risk population by a substantial degree. While the cardiovascular protective properties of this compound are now proven, several other potential uses are being actively explored in clinical studies. These areas of investigation include cancer, inflammatory bowel disease, infections, Alzheimer's disease, dementia, and depression. The next decade promises to deepen our understanding of the beneficial effects that EPA may offer beyond cardiovascular risk reduction.

Targeting RNA With Antisense Oligonucleotides and Small Interfering RNA: JACC State-of-the-Art Review.

There is an unmet clinical need to reduce residual cardiovascular risk attributable to apolipoprotein B-containing lipoproteins, particularly low-density lipoprotein and remnant particles. Pharmacological targeting of messenger RNA represents an emerging, innovative approach. Two major classes of agents have been developed-antisense oligonucleotides and small interfering RNA. Early problems with their use have been overcome by conjugation with N-acetylgalactosamine, an adduct that targets their delivery to the primary site of action in the liver. Using these agents to inhibit the translation of key regulatory proteins such as PCSK9, apolipoprotein CIII, apolipoprotein(a), and angiopoietin-like 3 has been shown to be effective in attenuating dyslipidemic states. Cardiovascular outcome trials with N-acetylgalactosamine-conjugated RNA-targeting drugs are ongoing. The advantages of these agents include long dosing intervals of up to 6 months and the potential to regulate the abundance of any disease-related protein. Long-term safety has yet to be demonstrated in large-scale clinical trials.

SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population. METHODS: Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population. RESULTS: We included HeFH (n = 1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively). CONCLUSIONS: This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients.

Remnant lipoproteins: are they equal to or more atherogenic than LDL?

PURPOSE OF REVIEW: To critically appraise new insights into the biology of remnant lipoproteins and their putative role in the pathophysiology of atherosclerotic cardiovascular disease, and to compare the atherogenicity of remnant particles with that of low-density lipoproteins (LDL). RECENT FINDINGS: New in-vivo stable isotope tracer studies of the kinetics of apoB48 and apoB100-containing lipoproteins in postprandial conditions have revealed that apoB48-containing very low-density lipoproteins (VLDL) accumulated markedly in hypertriglyceridemic patients. These intestinally-derived particles were cleared slowly, and represented up to 25% of circulating VLDL; as part of the remnant particle population, they may increase cardiovascular risk. Importantly, the PCSK9 inhibitor, evolocumab, was shown to reduce remnant levels (-29%) during the postprandial period in diabetic patients on statin therapy - an effect which may be additive to that of LDL-cholesterol reduction in conferring cardiovascular benefit. In recent Mendelian randomization studies, the effect of lowering triglyceride-rich lipoproteins or LDL-cholesterol translated to similar clinical benefit per unit of apoB. Finally, in randomized trials involving statin-treated patients with atherosclerotic cardiovascular disease, remnant cholesterol levels were associated with coronary atheroma progression independently of LDL-cholesterol. SUMMARY: Overall, data from observational studies in large cohorts, Mendelian randomization studies, meta-regression analyses, and post-hoc analyses of randomized trials are consistent with the contention that remnants are highly atherogenic particles and contribute to the atherosclerotic burden in an equivalent manner to that of LDL.

LDL subclass lipidomics in atherogenic dyslipidemia: effect of statin therapy on bioactive lipids and dense LDL.

Atherogenic LDL particles are physicochemically and metabolically heterogeneous. Can bioactive lipid cargo differentiate LDL subclasses, and thus potential atherogenicity? What is the effect of statin treatment? Obese hypertriglyceridemic hypercholesterolemic males [n = 12; lipoprotein (a) <10 mg/dl] received pitavastatin calcium (4 mg/day) for 180 days in a single-phase unblinded study. The lipidomic profiles (23 lipid classes) of five LDL subclasses fractionated from baseline and post-statin plasmas were determined by LC-MS. At baseline and on statin treatment, very small dense LDL (LDL5) was preferentially enriched (up to 3-fold) in specific lysophospholipids {LPC, lysophosphatidylinositol (LPI), lysoalkylphosphatidylcholine [LPC(O)]; 9, 0.2, and 0.14 mol per mole of apoB, respectively; all P < 0.001 vs. LDL1-4}, suggesting elevated inflammatory potential per particle. In contrast, lysophosphatidylethanolamine was uniformly distributed among LDL subclasses. Statin treatment markedly reduced absolute plasma concentrations of all LDL subclasses (up to 33.5%), including LPC, LPI, and LPC(O) contents (up to -52%), consistent with reduction in cardiovascular risk. Despite such reductions, lipotoxic ceramide load per particle in LDL1-5 (1.5-3 mol per mole of apoB; 3-7 mmol per mole of PC) was either conserved or elevated. Bioactive lipids may constitute biomarkers for the cardiometabolic risk associated with specific LDL subclasses in atherogenic dyslipidemia at baseline, and with residual risk on statin therapy.