👤 E Björnson

The comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in abdominal aortic aneurysm (AAA) pathogenesis are unclear. To evaluate the putative causal role of TRLs in AAA, quantify the relative effect on AAA risk ("aneurysmogenicity") of TRL vs LDL particles, and prioritize lipid-lowering drug targets for AAA prevention and treatment. We performed summary-level and individual-level Mendelian randomization (MR) analyses. Genetic variants were selected from 383,983 UK Biobank participants and ranked into 10 sets of variants where set 1 predominantly affected LDL cholesterol (LDL-C) and set 10 predominantly affected TRL cholesterol (TRL-C; and with mixed effects for intermediate variant sets). AAA outcome data were obtained from AAAgen (37,214 cases), FinnGen (4,439 cases), and the VA Million Veteran Program (MVP; 23,848 cases). Multivariable MR was used to assess the independent roles of LDL-C and TRL-C in AAA. For each set of variants, MR or logistic regression was used to estimate AAA odds ratios (ORs) per 10 mg/dL higher apolipoprotein B (apoB). Interaction analyses were conducted between a statin-like LDL-C-lowering variant set (set 3) and a TRL-C-lowering variant set (set 10). Drug-target MR was performed to evaluate lipid-lowering targets relevant to LDL-C- and TRL-C-lowering. Genetically predicted LDL-C and TRL-C concentrations were each associated independently with genetic liability for AAA after mutual adjustment, with 3.0 to 5.5 times stronger associations for TRL-C compared to LDL-C on a per-cholesterol basis. In AAAgen, the AAA OR per 10 mg/dL increased apoB concentrations were 1.10 (95% CI, 1.05-1.14) for variant set 1 (LDL-C-predominant) and 1.89 (95% CI, 1.69-2.11) for variant set 10 (TRL-C-predominant). Using the ratio of log(OR) per 10 mg/dL apoB for set 10 versus set 1 as a conservative estimate of relative aneurysmogenicity, TRLs were approximately 3.2 to 6.9 times more aneurysmogenic than LDLs across the three studies. No evidence of interaction was observed between LDLs and TRLs, indicating additive contribution to AAA risk. Drug-target MR supported strong protective associations for genetically proxied inhibition of TRL-pathway targets, particularly TRLs are at least threefold more aneurysmogenic than LDLs on a per-particle basis. Therapeutic strategies targeting TRL-C -especially via Show less

Circulating apoB-containing lipoproteins fall into three principal categories- low-density lipoproteins (LDLs), triglyceride-rich lipoproteins (TRLs) and lipoprotein(a) [Lp(a)]. These three different lipoproteins are all causally related to atherosclerotic cardiovascular disease (ASCVD) and together account for the full spectrum of apoB-related atherogenic risk. They vary substantially in metabolic and kinetic properties, size and lipid composition and may affect the atherosclerotic pathogenic process differently. Indeed, genetic evidence indicates that TRLs and Lp(a) are several-fold more atherogenic per particle than LDL in terms of ASCVD risk. On the other hand, Lp(a) and TRLs are typically much less abundant than LDL. How should these countervailing factors be balanced to understand their net contribution to risk? In this review, we summarize the evidence relating to the atherogenicity of LDLs, TRLs and Lp(a) and explore the implications for risk stratification and therapeutic strategies. We argue that LDL lowering will remain the cornerstone of apoB-related risk reduction, but eradication of residual risk necessitates combination therapies targeting TRLs and/or Lp(a) in addition to LDL. Show less

LDL-C and non-HDL-C do not fully capture coronary heart disease (CHD) risk attributed to all apoB-containing lipoproteins. Use of apolipoprotein B (apoB) as a marker of total atherogenic particle number improves risk prediction, but risk may still be underestimated when triglyceride-rich lipoproteins (TRL/remnants) and lipoprotein(a) [Lp(a)] are elevated. The aim was to formulate a new metric-risk-weighted apoB (RW-apoB)-designed to capture risk from LDL, TRL/remnants, and Lp(a) in a single number. Based on previously published estimates of the relative atherogenicity of LDL, TRL/remnant, and Lp(a) particles, RW-apoB was developed (using UK Biobank data) as an atherogenicity-weighted apoB-sum calculated as: RW-apoB = 11.65×TG(mmol/L) + 0.215×lipoprotein(a)(nmol/L) + 0.736×apoB(mg/dL). Assigning RW-apoB to individuals substantially reclassified their risk status. Compared with ranking by measured apoB, 52% of individuals were up- or down-ranked by ≥10 percentiles. About one-third of those in the top RW-apoB quintile-with elevated TRL and Lp(a) and a CHD event rate of 5.4%-were misclassified as lower risk by apoB. Conversely, individuals in the top measured apoB quintile but with low TRL and Lp(a) had a lower event rate (3.9%) and were correctly down-ranked. RW-apoB improved risk prediction, significantly increasing Harrell's C-index relative to apoB (P < .0001). In statin-treated subjects, RW-apoB was potentially a better index of residual risk. RW-apoB consistently outperformed apoB as a risk predictor in Cox models across the UK Biobank and three other large population cohorts. RW-apoB represents not only particle number but also accounts for the higher atherogenicity of TRL and Lp(a). It offers clinically meaningful improvements in CHD risk stratification. Show less

Apolipoprotein C-III (apoC-III) has emerged as a pivotal regulator of triglyceride metabolism and a key factor in cardiovascular risk. This review explores the physiological and pathological roles of apoC-III, focusing on kinetic mechanisms, genetic data, and the therapeutic potential of targeting apoC-III. Loss-of-function mutations in APOC3 significantly lower plasma triglyceride levels and coronary heart disease risk, validating apoC-III as a therapeutic target. Kinetic studies indicate that increased hepatic secretion of apoC-III raises triglyceride levels, particularly in individuals with type 2 diabetes. Beyond lipid metabolism, apoC-III promotes lipoprotein retention and amplifies arterial inflammation. Novel inhibitors, such as antisense oligonucleotides targeting APOC3, have been shown to markedly reduce plasma apoC-III and triglyceride concentrations in both preclinical and clinical studies. Genetic and mechanistic evidence together establish the inhibition of apoC-III as a promising strategy for patients at high risk of persistent hypertriglyceridemia and cardiovascular disease. ApoC-III not only controls lipid metabolism but also exerts direct pro-atherogenic and pro-inflammatory effects, supporting its role as a multifaceted therapeutic target in cardiometabolic medicine. Show less

Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis. The level is genetically determined and remains stable during life, and elevated levels may be inherited. The 2025 ESC/EAS Management of Dyslipidaemias Focused Update recommends measuring Lp(a) at least once in adulthood. It further recommends considering Lp(a) >105 nmol/L (>50 mg/dL) as a risk-enhancing factor to refine risk classification, particularly near treatment thresholds. In Sweden, an estimated 10-20 procent of the population (1-2 million people) exceed the 105 nmol/L or 50 mg/dL threshold, hundreds of thousands of whom may be reclassified as being eligible for primary preventive treatment, according to the updated guidelines. While specific Lp(a)-lowering therapies are not yet available, individuals with elevated Lp(a) should receive intensified management of traditional risk factors, primarily lower LDL cholesterol. Scalable approaches are needed to identify and follow high-risk individuals without overburdening primary care. Show less

Apolipoprotein B-containing triglyceride-rich lipoproteins (TRLs) -chylomicrons, very low-density lipoproteins (VLDL), their remnants, and intermediate-density lipoproteins (IDL) - are recognised as key contributors to atherosclerotic cardiovascular disease (ASCVD). On a per particle basis, genetic and clinical evidence indicates that TRL/remnants exhibit a greater atherogenic potential than LDL and evidence points to this being mediated by enhanced arterial wall retention of TRLs, the pro-inflammatory actions of their constituent apolipoproteins and cargo of cholesterol and bioactive lipids, and their capacity to induce endothelial dysfunction. Despite the strong association between plasma triglyceride levels and ASCVD, TRL-lowering trials have produced inconsistent, often negative results. The answer to this conundrum, as explored here, likely lies in the complexity of TRL structure, composition and metabolism, and in the dynamic influence that TRLs have on the properties of LDL, the most abundant atherogenic lipoprotein. The substantial heterogeneity in the TRL/remnant/IDL spectrum means that these particles present a wide range of potentially pathogenic factors to the artery wall in the form of major and minor lipids and a variety of surface apolipoproteins. Significant gaps exist in our knowledge: how are TRL remodelled during their lifetime in the bloodstream to become cholesterol-enriched lipoproteins; which are the most relevant TRL subspecies or TRL constituents, that initiate and progress the formation of atherosclerotic lesions; and what are the prime targets for effective intervention. Critical to the design of future triglyceride-lowering prevention trials will be the development of superior biomarkers of TRL/remnant atherogenicity and the development of a precision medicine approach to ASCVD prevention. Show less

Conventional statistical approaches are not designed to compare highly correlated variables such as low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB). Discordance analysis was designed to overcome this limitation by creating groups in which the predictions of 2 markers differ. This systematic review compiled all discordance studies that compare the predictive powers of LDL-C and non-HDL-C vs LDL particle number (LDL P) or apoB as markers of atherosclerotic disease risk to determine which is the most accurate marker of cardiovascular risk. A PubMed search completed September 30, 2024, identified 15 studies involving 593,354 participants. These studies encompassed diverse populations, and included patients with and without statin therapy. Several variations of discordance analysis were used including median-based, percentile-based, residual-based, and variance-based approaches. ApoB outperformed LDL-C in 9 of 9 studies whereas LDL P was superior to LDL-C in 2 of 3 comparisons. In 1 study, non-HDL-C was superior to apoB, in 1 study apoB and non-HDL-C were equivalent, whereas in 7 studies, apoB, overall, was a significantly more accurate marker of atherosclerotic cardiovascular disease risk than non-HDL-C. Discordance analysis provides robust evidence that apoB is a more accurate marker of cardiovascular risk than either LDL-C or non-HDL-C, notwithstanding these variables are highly intercorrelated. Thus, neither LDL-C nor non-HDL-C are adequate clinical surrogates for apoB. Accordingly, apoB should be the primary measure in clinical care to estimate the cardiovascular risk attributable to the apoB lipoproteins and the adequacy of lipid-lowering therapy to reduce this risk. Show less

Apolipoprotein C-III (apoC-III) is an important regulator of triglyceride (TG) metabolism and a target for intervention. The present study examined the effects of gain-of-function (GOF) variants in APOC3 on apolipoprotein B kinetics to understand further how changes in the synthesis of this apolipoprotein impact triglyceride-rich lipoprotein (TRL) metabolism. Two groups of subjects were recruited by population screening, 9 carriers of known APOC3 GOF variants and 9 age-, sex- and BMI-matched non-carriers. The kinetics of TRL were determined using stable isotope tracers of apoprotein and triglyceride metabolism in a non-steady-state protocol involving administration of a fat-rich meal. APOC3 GOF carriers had 47 % higher plasma apoC-III levels compared to non-carriers (P = 0.022) and higher production rates for the apolipoprotein. Post-prandial response (total area-under-curve) for plasma TG was 108 % greater in GOF carriers compared to non-carriers (P = 0.002) due specifically to higher levels of VLDL APOC3 GOF carriers showed specific alterations in TRL metabolism (compared to matched non-carriers), namely slower lipolysis and delayed clearance of VLDL Show less

The per-particle pathogenicity of very-low-density lipoprotein (VLDL) and lipoprotein(a) [Lp(a)] with risk of valvular heart diseases (VHD) other than aortic stenosis compared with low-density lipoprotein (LDL) remains unclear. Single-nucleotide polymorphism specific clusters associated with LDL cholesterol (LDL-C), VLDL cholesterol (VLDL-C) and Lp(a) were identified. The relationships of genetically predicted variation in apolipoprotein B (apoB) in these lipoproteins with risk of VHD and its major types (aortic stenosis, aortic regurgitation, and mitral regurgitation) were evaluated to determine the comparative pathogenicity by Mendelian randomization (MR) analyses. The VHD odds ratio (OR) per 1 g/L higher apoB was 1.09 [95 % confidence interval (CI) 1.04-1.15] in LDL vs. 1.45 (95 % CI 1.25-1.69) in VLDL vs. 2.71 (95 % CI 1.92-3.82) in Lp(a) based on the cluster-based MR analyses. The polygenic scores for each lipoprotein weighted by apoB similarly showed a greater OR of VHD per 1 g/L apoB in VLDL [1.20 (95 % CI 1.06-1.37)] and in Lp(a) [2.54, (95 % CI 1.95-3.32)] compared with that in LDL [1.05 (95 % CI 1.01-1.08)]. Multivariable MR analyses further revealed the strong effects of VLDL-C and Lp(a) on VHD risk independent of LDL-C. In addition, significant associations between Lp(a) and all three major types of VHD were observed, while LDL and VLDL had no impact on aortic and mitral regurgitation. VLDL and Lp(a) appear to have significantly greater per-particle pathogenicity in VHD compared to LDL. The distinct impacts of lipoproteins on different VHD subtypes suggest the inadequacy of just focusing on LDL-lowering treatment for valve disorders. Show less

Triglyceride-rich lipoproteins (TRLs) and remnants are established causal risk factors for coronary heart disease (CHD). APOC3 gene-silencing agents reduce TRL/remnant concentrations but the consequent quantitative effect on CHD risk is not yet defined. We used a polygenic score (PGS)-based model to investigate if the degree of TRL/remnant reduction seen on APOC3 silencing would lead to a meaningful reduction in CHD risk. A TRL/remnant-specific PGS was used to select two groups (each >4,150 individuals) from the UK Biobank. CHD event rates were compared between the group with the highest PGS with genetically higher TRL/remnant levels (mimicking placebo) and the group with the lowest PGS with lower levels (mimicking APOC3 silencing). Compared with the high PGS group, the low PGS group had lower plasma triglycerides (-34%), TRL/remnant cholesterol (-22.5%), non-HDL cholesterol (-7.5%) and apolipoprotein B (-6.0%), with a small reduction in LDL cholesterol (-3.9%) and a 15.3% increase in HDL cholesterol. These differences were similar to those seen with APOC3 silencing agents, but with about a third of the absolute effect size. The low PGS group had a 28% lower lifetime CHD event rate (HR = 0.72, 95% CI:0.56-0.91). Extrapolating to a 5-year trial, an APOC3 silencing agent achieving a 16-23 mg/dL decrease in TRL/remnant cholesterol is predicted to reduce CHD risk by approximately 25%. Based on our genetic modelling, the degree of TRL/remnant lowering seen on APOC3 silencing would produce a meaningful CHD risk reduction of around 25 % over a 5-year outcomes trial. Show less

Triglyceride-rich lipoproteins and remnants (TRL/remnants) have a causal, but not yet quantified, relationship with coronary heart disease (CHD): myocardial infarction plus revascularization. The authors sought to estimate TRL/remnant per-particle atherogenicity, investigate causal relationships with inflammation, and determine whether differences in the atherogenicity of TRL/remnants and low-density lipoprotein (LDL) impact the causal association of non-high-density lipoprotein cholesterol (non-HDL-C) with CHD. Single nucleotide polymorphisms (SNPs) (N = 1,357) identified by genome-wide association in the UK Biobank were ranked into 10 clusters according to the effect on TRL/remnant-C vs LDL-C. Mendelian randomization analysis was used to estimate for each SNP cluster CHD ORs per 10 mg/dL apolipoprotein B (apoB) and per 0.33 mmol/L non-HDL-cholesterol, and to evaluate association of TRL/remnants with biomarkers of systemic inflammation. SNPs in cluster 1 predominantly affected LDL-C, whereas SNPs in cluster 10 predominantly affected TRL/remnant-C. CHD risk per genetically predicted increase in apoB and in non-HDL-C rose across clusters. ORs per 10 mg/dL higher apoB was 1.15 (95% CI: 1.11-1.19) in cluster 1 vs 1.70 (95% CI: 1.52-1.90) in cluster 10. Comparing ORs between these TRL/remnant-predominant and LDL-predominant clusters, we estimated that TRL/remnants were at least 3.9 (95% CI: 2.8-5.4) times more atherogenic than LDL on a per-particle basis. For non-HDL-C, CHD ORs per 0.33 mmol/L rose from 1.15 (95% CI: 1.11-1.19) for cluster 1 to 1.40 (95% CI: 1.30-1.50) for cluster 10. TRL/remnants exhibited causal relationships with inflammation, but this did not explain their greater atherogenicity. TRL/remnants are about 4 times more atherogenic than LDL. Variation in the causal association of non-HDL-C with CHD indicates that adjustment for percentage TRL/remnant-C may be needed for accurate risk prediction. Show less

BackgroundApolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.MethodsWe investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.ResultsCompared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.ConclusionThese findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention.Trial registrationClinicalTrials.gov NCT04209816 and NCT01445730.FundingSwedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation. Show less

To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5- Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III. Show less