👤 Jeroen J Bax

Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL cholesterol (LDL-C), and reduces apolipoprotein B (apoB) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. We conducted a coronary computed tomography angiography (CCTA) study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen vs. placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence or high risk for cardiovascular disease, and non-calcified plaque on baseline CCTA. The primary endpoint was percent change from baseline to 12 months in non-calcified plaque volume (NCPV). Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (IQR 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (IQR 197-331), and remnant cholesterol was 53 mg/dL (IQR 38-76). Median baseline NCPV was 125.3 mm Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. Show less

Cerebral small vessel disease (CSVD) contributes to the development of Alzheimer's disease (AD) dementia and co-occurs with AD-associated proteinopathies. However, how sex modulates the interaction between CSVD and AD-associated proteinopathies in the medial temporal lobe (MTL) remains unclear. One hundred fifty-two autopsy cases from the Massachusetts Alzheimer's Disease Research Center were included. Deep-learning and semiquantitative scores were applied to MTL histological sections to obtain quantitative measures of proteinopathies and CSVD (cerebral amyloid angiopathy [CAA] and arteriolosclerosis). The effect of sex on AD-associated proteinopathies and the interaction between sex, CSVD, and apolipoprotein E (APOE) genotype were analyzed using linear mixed-effect models. In women, higher CAA burden was associated with lower amyloid beta (Aβ) plaques but higher tau tangles density. No interaction effect was found for arteriolosclerosis. Women <75 years of age carrying the APOE ε4 allele had higher Aβ plaque burden than ε4 non-carriers. Our results highlight the complex effect of sex on microvascular and AD-associated pathologies in the MTL. Show less

There is a need for effective tools to stratify and modify cardiovascular risk associated with elevated lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPL). The objective of this analysis was to explore the modifying effects of low-grade inflammation on Lp(a)- and OxPL-associated risk in a secondary prevention cohort. Levels of Lp(a), OxPL associated with apolipoprotein(a) (OxPL-apo[a]) and apolipoprotein B (OxPL-apoB) were determined in the placebo-arm of the low-dose colchicine 2 trial. Patients were between 35 and 82 years, had established chronic coronary syndrome (CCS), and were clinically stable for at least six months prior to randomization. The outcome was the incidence of the composite endpoint of spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization stratified by biomarker levels using a Cox regression model. There was a significant interaction between Lp(a) and IL-6 <3.2 ng/L (median) and IL-6 ≥3.2 ng/L for the composite endpoint (HR 0.90; 95 %CI 0.78-1.03 vs HR 1.18; 95 %CI 1.01-1.39, P In patients with CCS, Lp(a), OxPL-apo(a) and OxPL-apoB associated cardiovascular risk was only pertinent in those with elevated IL-6 but not hsCRP levels. Show less

Inflammatory lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPLs) on lipoproteins convey residual cardiovascular disease risk. The low-dose colchicine 2 (LoDoCo2) trial showed that colchicine reduced the risk of cardiovascular events occurring on standard therapies in patients with chronic coronary syndrome (CCS). We explored the effects of colchicine on Lp(a)- and oxidized lipoprotein-associated risk in a LoDoCo2 biomarker subpopulation. Lipoprotein(a) and OxPLs on apolipoprotein(a) [OxPL-apo(a)] and apolipoprotein B-100 (OxPL-apoB) levels were determined in the biomarker population of the LoDoCo2 trial (n = 1777). The Cox regression analysis was used to compare the risk of the primary endpoint, consisting of myocardial infarction, ischaemic stroke, or ischaemia-driven revascularization by biomarker levels. Interactions between treatment, Lp(a), and OxPL levels were evaluated. Lipoprotein(a), OxPL-apo(a), and OxPL-apoB levels were similar between the colchicine and placebo groups. Consistent risk reduction by colchicine was observed in those with Lp(a) < 125 nmol/L and ≥125 nmol/L and the highest OxPL-apo(a) tertile compared with the lowest (Pinteraction = 0.92 and 0.66). The absolute risk reduction for those with Lp(a) ≥ 125 nmol/L appeared higher compared with those with Lp(a) < 125 nmol/L (4.4% vs. 2.4%). A treatment interaction for colchicine was found in those with the highest OxPL-apoB tertile vs. the lowest (Pinteraction = 0.04). In patients with CCS, colchicine reduces cardiovascular disease risk in those with and without elevated Lp(a) but absolute benefits appeared higher in those with Lp(a) ≥ 125 nmol/L. Patients with higher levels of OxPL-apoB experienced greater benefit of colchicine, suggesting that colchicine may be more effective in subjects with heightened oxidation-driven inflammation. Show less