👤 Sascha N Goonewardena

Elevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized. We sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured Year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using LASSO regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident CHD, and hs-CRP over 27 years of follow-up. External replication was performed in the UK Biobank (n=37,996). Lp(a) was associated with CAC (OR 1.23 [1.13-1.34]; p<0.0001) and incident CHD (HR 1.23 [1.07-1.41]; p=0.004). Lp(a) correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a) proteomic score was independently associated with incident CAC (standardized beta = 0.40, p<0.0001) and hs-CRP (standardized beta = 0.11, p = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomic score was associated with CRP, incident CHD, and all-cause mortality. In young adults, Lp(a) is associated with distinct proteomic features that independently predict ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk. Show less

Lipoprotein(a) [Lp(a)] is an inherited cardiovascular risk factor. However, its association with coronary plaque characteristics beyond traditional risk enhancers remains unclear. We aimed to evaluate the association between Lp(a) levels and coronary plaque characteristics in asymptomatic primary prevention patients, and to compare its predictive value against other risk enhancers, including LDL particle concentration (LDL-P), high-sensitivity C-reactive protein (hsCRP), and coronary artery calcium (CAC) score. We retrospectively analyzed 547 asymptomatic patients undergoing coronary computed tomography angiography (CCTA) between 2018-2024. Plaque characteristics were assessed using artificial intelligence-based quantitative CCTA. Associations between Lp(a), LDL-P, hsCRP, CAC score, and plaque features were evaluated using multivariable regression adjusted for age and sex. Median age was 56 years, 69.8% were male. Higher Lp(a) was associated with greater total plaque volume (β=23.1 mm³, p=0.006), calcified plaque (β=11.1 mm³, p=0.014), non-calcified plaque (β=12.0 mm³, p=0.027), and low-density non-calcified plaque (LDNCP; β=0.4 mm³, p<0.001) volumes, as well as increased area stenosis (β=1.9%, p=0.031) and remodeling index (β=0.02, p=0.017). In multivariable models, CAC score was the strongest predictor of overall plaque burden including calcified and non-calcified plaque (p<0.000) but was not associated with LDNCP. Lp(a) remained independently associated with LDNCP (β=0.45 mm³, p=0.013), while LDL-P and hsCRP showed no significant associations. In asymptomatic primary prevention patients, Lp(a) was independently associated with high-risk coronary plaque features, specifically LDNCP, beyond traditional risk enhancers. These findings highlight the unique role of Lp(a) in identifying coronary plaque vulnerability and suggest complementary roles for Lp(a) and CAC in refining cardiovascular risk stratification. Show less

Lipoprotein(a) (Lp[a]) is an apolipoprotein B100 (apoB)-containing lipoprotein with a single apolipoprotein(a) (apo[a]) covalently bound to apoB via a disulfide bond and oxidized phospholipids linked to apoB and apo(a), which is associated with proinflammatory, prothrombotic, and proatherogenic mechanisms. Elevated Lp(a) (≥125 nmol/L [≥50 mg/dL]) is an independent, causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD), affecting >1.4 billion individuals worldwide. There are no pharmacological Lp(a)-lowering therapies approved in the United States; however, lipoprotein apheresis may be considered under certain circumstances. Germany is the only country where apheresis is approved for patients with elevated Lp(a) and progressing ASCVD. Existing lipid-lowering therapies including proprotein convertase subtilisin/kexin type 9 inhibitors have shown modest effects on Lp(a) levels but fallen short of clinically meaningful reductions of >50 to 100 mg/dL. Several Lp(a)-lowering, RNA-targeted agents are in development, including antisense oligonucleotides (ASOs) and small interfering RNAs. Pelacarsen is a second-generation ASO that targets the production of apo(a) and includes chemical modifications such as triantennary N-acetylgalactosamine that improve biostability, decrease off-target toxicity compared with unmodified ASOs, and allow rapid, specific uptake by hepatocytes, the site of apo(a) synthesis. A phase 2b study of pelacarsen showed ≥80% reduction in Lp(a) concentration with a favorable safety profile in patients with established ASCVD. The ongoing phase 3 Lp(a)HORIZON study is evaluating whether the Lp(a)-lowering effects of pelacarsen translate into reductions in the incidence of major cardiovascular events, also in patients with established ASCVD. Herein, we review the mechanism of action of pelacarsen and evidence for its Lp(a)-lowering effects. Show less