High-density lipoproteins (HDLs) and their main protein, apolipoprotein A-I (apoA-I), are considered immunomodulators of the vascular wall. However, the precise mechanisms are incompletely understood. Using intravital microscopy, flow cytometry, experimental ex vivo models, and bulk RNA sequencing of cultured macrophages, this study reveals the immunomodulatory capacity of apoA-I, which is validated in representative inflammatory models. Intravital imaging in mice shows specific uptake of intravenously injected, lipid-free apoA-I by dermal perivascular macrophages. Supraphysiological doses of apoA-I alter key cellular pathways, involving mammalian target of rapamycin complex 1 (mTORC1) and interferon regulatory factor 8 (IRF8), in THP-1-derived macrophages. In lipopolysaccharide (LPS)-induced skin inflammation, apoA-I pretreatment dampens the inflammatory response and reduces immune cell trafficking in and out of the skin. Moreover, apoA-I inhibits joint inflammation in a mouse model of rheumatoid arthritis (RA). Overall, apoA-I acts as an integrator of vascular-immune interactions by modulating macrophage function in the vicinity of blood vessels. These findings open avenues for HDL-targeting strategies in a broad spectrum of autoimmune disorders, including RA.

Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.

BACKGROUND AND AIMS:Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder caused primarily by variants in both alleles of the gene encoding the low-density lipoprotein receptor (LDLR). This subanalysis of the ELIPSE open-label extension (OLE) study assessed the efficacy of evinacumab, an angiopoietin-like 3 inhibitor, by genotype and LDLR function in patients with HoFH. METHODS:Patients aged ≥12 years with HoFH on stable lipid-lowering therapies received evinacumab 15 mg/kg intravenously every 4 weeks. Patients were grouped according to genotype: bi-allelic monogenic identical variants (true homozygous) or bi-allelic monogenic different LDLR variants (compound heterozygous); and by LDLR function: null/null variants resulting in <15% LDLR activity or negative/negative variants predicted to result in <2% LDLR activity. RESULTS:One hundred and sixteen patients enrolled in the OLE. At baseline, 55 (47.4%) had either identical bi-allelic variants in LDLR (n = 53) or LDLRAP1 (n = 2), and 41 (35.3%) had different bi-allelic LDLR variants. Median (Q1, Q3) LDL-C levels were reduced by -53.8% (-42.6%, -67.0%) and -58.1% (-41.5%, -65.9%) by Week 8 of evinacumab treatment in the identical (LDLR or LDLRAP1) and different (LDLR) bi-allelic variant groups, respectively, and remained low at Week 104 (-50.9% [-34.9%, -60.3%] and -47.3% [-34.8%, -67.5%], respectively). At baseline, 36 (31.0%) patients had null/null LDLR variants, and 19 (16.4%) patients had negative/negative LDLR variants. Evinacumab treatment also resulted in rapid and sustained decreases in median LDL-C levels to Week 104 in these subgroups. CONCLUSIONS:Evinacumab treatment resulted in sustained LDL-C reduction in patients with HoFH irrespective of genotype or LDLR function.

AIMS:Both plasma levels of remnant cholesterol and low-density lipoprotein (LDL) cholesterol levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. In this study, we aimed to assess the extent to which inflammation mediates the effect of remnant and LDL cholesterol on (non)fatal major adverse cardiovascular events (MACE), comprising of coronary artery disease and ischaemic stroke. METHODS AND RESULTS:This prospective study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk study, with a mean age of 58.8 ± 9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher high-sensitivity C-reactive protein (hsCRP) levels [95% Confidence Interval (CI): 22.1, 37.4, P < 0.001], whereas LDL cholesterol was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, P < 0.001) for MACE, compared with an HR of 1.21 (95% CI: 1.13, 1.31, P < 0.001) for LDL cholesterol. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, P < 0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL cholesterol. CONCLUSION:Plasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease. LAY SUMMARY:This study finds that systemic inflammation does not influence the effect remnant cholesterol has on cardiovascular disease risk, suggesting the importance of addressing both remnant cholesterol and inflammation to manage cardiovascular health.

BACKGROUND:Hypertriglyceridemia is an established risk factor for cardiovascular disease and acute pancreatitis with postprandial elevations as an important contributor. Olezarsen, an investigational antisense oligonucleotide targeting plasma apolipoprotein C-III (apoC-III), markedly reduces fasting triglyceride levels, though its effect on postprandial triglyceride levels remains to be established. DESIGN:In a double-blind, placebo-controlled trial, 28 patients with fasting triglycerides ≥4 mmol/L received either 2 doses 80mg olezarsen (19 patients) or placebo (9 patients) every 4 weeks.Triglyceride levels were measured in the fasting state and postprandially both at baseline and 7 weeks into treatment. Postprandial triglyceride levels were assessed by calculating the area under the curve (AUC). RESULTS:The mean (±SD) age was 58.6±9.4 years, 82.1% (23) were male and the median [IQR] baseline fasting triglyceride levels were 5.9 [4.5, 9.2] mmol/L. At 7 weeks of olezarsen treatment led to a placebo adjusted triglyceride reduction of 59.3% (-77.3 to -41.2%, p<0.0001). The mean (95% CI) postprandial placebo-adjusted triglyceride AUC was reduced by 50.1% (-68.3 to -31.8%, p<0.0001). Mean (95% CI) incremental AUC (iAUC) was reduced by 30.3% (-56.2 to -4.3%, p=0.026) in the olezarsen versus baseline group; the placebo-adjusted iAUC remained unchanged. The proportion of patients reaching any triglyceride levels ≥10 mmol/L, indicative of increased risk estimation of acute pancreatitis, decreased from 47% to 5% after olezarsen treatment, a 96.6% (p<0.0001) reduction. CONCLUSION:Olezarsen significantly reduces both fasting and postprandial triglyceride levels, these findings highlight olezarsen as a promising intervention to managing hypertriglyceridemia and reducing the risk of hypertriglyceridemia induced acute pancreatitis.

Low-density lipoprotein cholesterol (LDL-C) is the pre-eminent target for the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). Despite the expansive evidence supporting therapeutic reductions in LDL-C with statin therapy, many high-risk patients do not achieve guideline-recommended treatment targets resulting in avoidable cardiovascular events and higher healthcare expenditures. Underutilization of effective LDL-C lowering is exacerbated by low adherence to statin therapy even among patients following an acute coronary event. Adjunctive therapies such as ezetimibe and PCSK9 monoclonal antibodies remain underutilized, and polypharmacy regimens used for the treatment of cardiovascular disease further increase challenges for patients. Although cardiovascular outcomes data are lacking, inclisiran, a small-interfering RNA (siRNA) targeting PCSK9 mRNA, is available for clinical use. Novel implementation approaches offer the opportunity for more durable or even potentially permanent solutions for lipoprotein-associated cardiovascular disease risk. As an adjunct to statins, these novel approaches may offer more durable approaches for the prevention of ASCVD events. In this review, we discuss the challenges of current LDL-C lowering therapies, achieving LDL-C targets and the necessity of novel approaches.

Inflammation is an important driver of disease in the context of atherosclerosis, and several landmark trials have shown that targeting inflammatory pathways can reduce cardiovascular event rates. However, the high cost and potentially serious adverse effects of anti-inflammatory therapies necessitate more precise patient selection. Traditional biomarkers of inflammation, such as high-sensitivity C-reactive protein, show an association with cardiovascular risk on a population level but do not have specificity for local plaque inflammation. Nowadays, advancements in non-invasive imaging of the vasculature enable direct assessment of vascular inflammation. Positron emission tomography (PET) tracers such as 18F-fluorodeoxyglucose enable detection of metabolic activity of inflammatory cells but are limited by low specificity and myocardial spillover effects. 18F-sodium fluoride is a tracer that identifies active micro-calcification in plaques, indicating vulnerable plaques. Gallium-68 DOTATATE targets pro-inflammatory macrophages by binding to somatostatin receptors, which enhances specificity for plaque inflammation. Coronary computed tomography angiography (CCTA) provides high-resolution images of coronary arteries, identifying high-risk plaque features. Measuring pericoronary adipose tissue attenuation on CCTA represents a novel marker of vascular inflammation. This review examines both established and emerging methods for assessing atherosclerosis-related inflammation, emphasizing the role of advanced imaging in refining risk stratification and guiding personalized therapies. Integrating these imaging modalities with measurements of systemic and molecular biomarkers could shift atherosclerotic cardiovascular disease management towards a more personalized approach.

BACKGROUND AND AIMS:Recent data from a large American cohort of women strongly support universal one-time screening for LDL cholesterol, high-sensitivity C-reactive protein (hsCRP), and lipoprotein(a) [Lp(a)] in primary prevention. This study addresses the validity and generalizability of this novel primary prevention strategy in a large prospective European cohort of initially healthy men and women. METHODS:Plasma levels of LDL cholesterol, hsCRP, and Lp(a) were measured at study entry in 17 087 participants from the EPIC-Norfolk study who were subsequently followed over a period of 20 years for major adverse cardiovascular events (MACEs). Competing risk- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MACE across quintiles of each biomarker and sought evidence of independent as well as additive effects over time were calculated. RESULTS:During the 20-year follow-up, a total of 3249 MACEs occurred. Increasing quintiles of baseline LDL cholesterol, hsCRP, and Lp(a) all predicted 20-year risks; the multivariable-adjusted HRs in a comparison of the top to bottom quintile were 1.78 (95% CI: 1.57-2.00) for LDL cholesterol, 1.55 (95% CI: 1.37-1.74) for hsCRP, and 1.19 (95% CI: 1.07-1.33) for Lp(a). Compared with individuals with no biomarker elevations, the multivariable-adjusted HRs for incident MACE were 1.33, 1.68, and 2.41 for those with one, two, or three biomarkers in the top quintile, respectively (all P < .001). Each biomarker demonstrated independent contributions to overall risk and findings were consistent in analyses stratified by sex. CONCLUSIONS:A single combined measure of LDL cholesterol, hsCRP, and Lp(a) among initially healthy European men and women was predictive of incident MACE during a 20-year period. These data replicate findings from a recent American cohort and strongly support universal screening for all three biomarkers in primary prevention.

BackgroundVisual assessment of coronary CT angiography (CCTA) is time-consuming, influenced by reader experience and prone to interobserver variability. This study evaluated a novel algorithm for coronary stenosis quantification (atherosclerosis imaging quantitative CT, AI-QCT).MethodsThe study included 208 patients with suspected coronary artery disease (CAD) undergoing CCTA in Perfusion Imaging and CT Coronary Angiography With Invasive Coronary Angiography-1. AI-QCT and blinded readers assessed coronary artery stenosis following the Coronary Artery Disease Reporting and Data System consensus. Accuracy of AI-QCT was compared with a level 3 and two level 2 clinical readers against an invasive quantitative coronary angiography (QCA) reference standard (≥50% stenosis) in an area under the curve (AUC) analysis, evaluated per-patient and per-vessel and stratified by plaque volume.ResultsAmong 208 patients with a mean age of 58±9 years and 37% women, AI-QCT demonstrated superior concordance with QCA compared with clinical CCTA assessments. For the detection of obstructive stenosis (≥50%), AI-QCT achieved an AUC of 0.91 on a per-patient level, outperforming level 3 (AUC 0.77; p<0.002) and level 2 readers (AUC 0.79; p<0.001 and AUC 0.76; p<0.001). The advantage of AI-QCT was most prominent in those with above median plaque volume. At the per-vessel level, AI-QCT achieved an AUC of 0.86, similar to level 3 (AUC 0.82; p=0.098) stenosis, but superior to level 2 readers (both AUC 0.69; p<0.001).ConclusionsAI-QCT demonstrated superior agreement with invasive QCA compared to clinical CCTA assessments, particularly compared to level 2 readers in those with extensive CAD. Integrating AI-QCT into routine clinical practice holds promise for improving the accuracy of stenosis quantification through CCTA.

BACKGROUND AND AIMS:Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear. METHODS:Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD. RESULTS:Globally, 52% of adults and 27% of children with HeFH were overweight or obese, with the highest prevalence noted in Northern Africa/Western Asia. A higher overweight/obesity prevalence was found in non-high-income vs. high-income countries. Median age at familial hypercholesterolaemia diagnosis in adults with obesity was 9 years older than in normal weight adults. Obesity was associated with a more atherogenic lipid profile independent of lipid-lowering medication. Prevalence of coronary artery disease increased progressively across body mass index categories in both children and adults. Compared with normal weight, obesity was associated with higher odds of coronary artery disease in children (odds ratio 9.28, 95% confidence interval 1.77-48.77, adjusted for age, sex, lipids, and lipid-lowering medication) and coronary artery disease and stroke in adults (odds ratio 2.35, 95% confidence interval 2.10-2.63 and odds ratio 1.65, 95% confidence interval 1.27-2.14, respectively), but less consistently with peripheral artery disease. Adjusting for diabetes, hypertension and smoking modestly attenuated the associations. CONCLUSIONS:Overweight and obesity are common in patients with HeFH and contribute to ASCVD risk from childhood, independent of LDL-C and lipid-lowering medication. Sustained body weight management is needed to reduce the risk of ASCVD in HeFH.

Background: VICTORION-1 PREVENT (V-1P) is an ongoing trial evaluating inclisiran for lipid lowering in patients with high cardiovascular (CV) risk without established atherosclerotic CV disease (ASCVD). This study evaluates the generalizability of V-1P enrollment criteria to the US population and their clinical comorbidity and CV risk factor burden. Methods: Data from National Health and Nutrition Examination Surveys (2015-March 2020) were used to determine nationally representative estimates. Inclusion criteria were low-density lipoprotein cholesterol (LDL-C) of 70–189 mg/dL and a 10-year ASCVD risk of ≥20% or 7.5%-19.9% with two CV risk enhancers. The pooled cohort equations (PCE) was used to stratify ASCVD risk in primary analysis. Estimates of the US population were compared with the V-1P eligible population. Results: The V-1P eligible population included 23,837,940 adults. Compared with US adults ages 40-79 years, V-1P eligible adults had higher mean 10-year ASCVD risk by PCE (21.1% [95% CI: 20.1%-22.2%] vs 10.0% [95% CI: 9.4%-10.6%]). The V-1P eligible population also had higher rates of hypertension (85.4% [95% CI: 81.6%-89.1%] vs 59.4% [95% CI: 56.7%-62.2%], diabetes (35.6% [95% CI: 31.3%-40.0%] vs 18.7% [95% CI: 16.9%- 20.5%]) and metabolic syndrome (81.6% [95% CI: 78.4%-84.7%] vs 51.1% [48.3%- 53.9%]). Adults meeting V-1P eligibility had high levels of LDL-C (117.8 mg/dL [95% CI: 114.3 mg/dL-121.2 mg/dL]) and low statin use (36.7% [95% CI: 31.9%-41.5%]). Conclusions: Many primary prevention patients have high CV risk, significant comorbidity burden, and are eligible for lipid-lowering therapy, yet rates of treatment are low. Public health interventions to improve CV risk factor management are necessary.

PURPOSE OF REVIEW:The aim of this review is to examine recent advancements in RNA-targeted therapies for the management of severe hypertriglyceridemia (sHTG) and prevention of sHTG-associated acute pancreatitis. RECENT FINDINGS:Recent developments in RNA-targeted therapies, aimed at inhibiting apolipoprotein C-III (apoC-III), have demonstrated substantial and sustained reductions in triglyceride levels. Novel therapies, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), such as volanesorsen, olezarsen, and plozasiran, have shown promising results in recent trials. These therapies not only effectively lower plasma triglyceride levels but also significantly reduce the incidence of acute pancreatitis. SUMMARY:SHTG is a high-burden metabolic disorder that is associated with a significantly increased incidence and severity of acute pancreatitis. Traditional lifestyle interventions and conventional therapies, including fibrates and n-3 fatty acids, often provide only modest reductions in triglycerides and fail to prevent sHTG-associated acute pancreatitis. The emergence of novel and targeted RNA-therapies represents a potential breakthrough in the management of sHTG and acute pancreatitis prevention.

BACKGROUND AND AIMS:Identification of individuals affected by familial hypercholesterolaemia (FH) is suboptimal when genetic tests are unavailable. Relying only on low-density lipoprotein cholesterol (LDL-C) is challenging as it may not allow distinguishing individuals with FH from hypercholesterolaemic (HC) individuals from the general population. The aim of this study was to determine whether biomarkers associated with cardiovascular disease and/or inflammation identify FH individuals and distinguish them from HC individuals. METHODS:A panel of 264 proteins in plasma was measured and machine learning was used to search for those that can distinguish FH individuals, either genetically proven (genFH) or clinically diagnosed (clinFH) from HC and control individuals. RESULTS:Both genFH and clinFH had elevated plasma levels of fibroblast growth factor 5 (FGF-5) compared with controls (mean area under the curve [AUC] > .990 for both, P < .001) or HC individuals (mean AUC >.990, P < .001), even after matching for LDL-C levels. An immunoenzymatic assay confirmed that FGF-5 was elevated in genFH and clinFH in all cohorts analysed. CONCLUSIONS:This analysis suggests that FGF-5 could be a biomarker to discriminate individuals living with FH from HC individuals.

Funding This study was sponsored by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Medical writing and editorial support were provided by Elisabetta Lauretti, PhD, of Red Nucleus, and funded by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Background/Synopsis Familial chylomicronemia syndrome (FCS) is a rare genetic disorder of deficient lipolytic capacity causing severe hypertriglyceridemia and increased acute pancreatitis risk. Olezarsen is a triantennary N-acetyl galactosamine–conjugated antisense oligonucleotide that targets hepatic APOC3 mRNA for degradation. In Balance (NCT04568434), a phase 3 study in patients with genetically-identified FCS, olezarsen 80 mg vs placebo significantly reduced triglycerides and was associated with reduced acute pancreatitis events. Olezarsen 80 mg is approved in United States as an adjunct to diet to reduce triglycerides in adults with FCS. In clinical laboratories, genetic testing results for FCS are reported as “positive” (or “pathogenic/likely pathogenic”) “indeterminate” or “negative.” However, publicly available databases may be incomplete or not up to date for all potentially pathogenic variants. Objective/Purpose This post hoc analysis from Balance examined the prevalence, baseline characteristics, and reclassification of initially indeterminate genetic test results in patients with suspected FCS. Methods After eligibility assessment and screening for enrollment in Balance, genetic testing was performed by a commercial laboratory (Prevention Genetics, Marshfield, WI). Prior to randomization, initial laboratory results were further adjudicated by a core laboratory (Western University, London, ON, Canada) using independent bioinformatics and non-public research registry data. Results Of 131 patients tested, 67 (51%) were initially designated positive, 10 (8%) negative, and 54 (41%) indeterminate for FCS, the latter because of “variants of uncertain significance” (VUSs). Compared with positive patients, initially indeterminate patients were more likely to be male, non-White, have a lower prevalence of pancreatitis, and have a lower value for chylomicron-triglycerides and higher values for ApolipoproteinC-III (ApoC-III), low-density lipoprotein-C (LDL-C), and apolipoprotein B (apoB) (Table 1). All initially positive and negative patients were adjudicated as such by the core laboratory. However, indeterminate laboratory results were subsequently reclassified as pathogenic/likely pathogenic in 15/54 (28%) patients and as negative in 39/54 (72%). Over 53 weeks, 7 initially positive (13%; 1 olezarsen 80 mg, 1 olezarsen 50 mg, 5 placebo) and 2 initially indeterminate patients (17%; both placebo) had adjudicated acute pancreatitis episodes. Conclusions Of patients with suspected FCS initially reported as indeterminate, a substantial proportion (28%) had genetically-confirmed FCS using a more comprehensive assessment. In patients with indeterminate genetic results, pending refinement of genetic testing, consideration should be given for using clinical risk scores to diagnose FCS. A global curated public database of FCS-related DNA variants in racially diverse populations may allow more accurate classification of pathogenic FCS variants.