👤 Gary Gerstenblith

People with HIV (PWH) and undetectable virus experience elevated cardiovascular risk independent of traditional risk factors. Vascular inflammation may contribute to this residual risk. The perivascular fat attenuation index (FAI), derived from coronary computed tomography angiography (CCTA), is a biomarker of coronary inflammation. Lipoprotein(a) [Lp(a)] carries oxidized phospholipids that may promote inflammation. Statins have demonstrated cardiovascular benefit in PWH, including pleiotropic anti-inflammatory effects. This study assessed the associations of Lp(a) and of statin use with coronary inflammation (FAI) in men with HIV (MWH). We analysed FAI of the left anterior descending (LAD) and the right coronary arteries (RCA) in 583 men from the Multicenter AIDS Cohort Study, a prospective, multicentre cohort study, including 280 with undetectable HIV RNA, <50 copies/ml. Associations between log Lp(a) was associated with increased coronary inflammation, independent of traditional cardiovascular risk factors, in MWH with undetectable virus. Statin therapy did not modify the relationship between coronary inflammation and Lp(a). Show less

Lipoprotein(a) [Lp(a)] is a primarily genetically determined, causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) levels are stable, unaffected by lifestyle, and best measured using isoform-insensitive, molar-based assays. Current guidelines from the European Atherosclerosis Society and U.S. National Lipid Association recommend a one-time Lp(a) measurement in all adults. Cascade testing is advised in affected families. Elevated Lp(a) levels are associated with increased risk of coronary artery disease, myocardial infarction incidence and recurrence, and aortic stenosis onset and progression. In cerebrovascular disease, high Lp(a) is linked to large artery ischemic stroke incidence and recurrence, as well as poor functional outcomes. Associations with venous thromboembolism are limited to prothrombotic states and extreme Lp(a) concentrations. Elevated levels (≥50 mg/dL or ≥125 nmol/L) should prompt intensified risk factor modification. There are no currently approved lipid-lowering therapies that substantially reduce Lp(a) levels. Novel agents to lower Lp(a) include antisense oligonucleotides, small interfering ribonucleic acid and small molecules, all of which have shown promising results in phase 2 trials. Ongoing phase 3 trials will evaluate the causal relationship between Lp(a) and ASCVD, and whether lowering Lp(a) reduces cardiovascular outcomes. Show less

Lipoprotein(a) [Lp(a)] is a primarily genetically determined, low-density lipoprotein-like particle that plays an important role in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Despite optimal control of traditional lipid levels, elevated lipoprotein(a) [Lp(a)] remains a significant contributor to residual cardiovascular risk, affecting up to 20% of the global population. We performed a literature search of PubMed/Medline and Google Scholar until July 2025 to provide a comprehensive overview of the genetics, structure, metabolism, and molecular mechanisms underlying Lp(a)'s pathogenicity. Structurally, Lp(a) consists of an LDL-like core covalently bound to apolipoprotein(a) [apo(a)], a polymorphic glycoprotein characterized by kringle IV type 2 (KIV-2) repeat variability. This copy number variation is the primary determinant of apo(a) isoform size and plasma Lp(a) levels. Small isoforms are produced more efficiently, resulting in higher concentrations. Lp(a) is synthesized in hepatocytes, and its plasma levels are predominantly governed by production rather than clearance. It carries a high burden of oxidized phospholipids (OxPLs), which confer pro-inflammatory and pro-atherogenic properties. Lp(a) promotes arterial inflammation, endothelial dysfunction, monocyte activation and impaired fibrinolysis via competition with plasminogen. It also plays a direct pathogenic role in valvular calcification by delivering OxPLs and autotaxin to valve interstitial cells, triggering osteogenic signaling cascades. While environmental factors such as inflammation and hormonal status can transiently modulate levels, genetic variation overwhelmingly dictates lifelong Lp(a) burden. As novel agents targeting Lp(a) enter late-stage clinical trials, mechanistic insights into Lp(a) biology will be essential to risk stratification and future clinical management. Show less

The peri- and early post-infarction period carries an increased risk of recurrent ischemic events. Oxidized phospholipids (OxPLs) are pro-inflammatory and contribute to plaque instability and thrombosis. This study aimed to: (1) assess changes, during the early post-MI period in OxPL-apo(a) and OxPL-apoB, (2) evaluate the effect of PCSK9 inhibition on these changes, and (3) explore their relationships with the changes in Lp(a) and LDL-C. Ninety-six participants with NSTEMI or STEMI were randomized to receive placebo (n = 48) or 420 mg subcutaneous evolocumab (n = 48) within 24 h of admission. OxPL-apo(a), OxPL-apoB, Lp(a), and LDL-C levels were measured at baseline and 30 days post-MI. In the placebo group, OxPL-apo(a) increased from 52.6 [19.3, 106.5] nmol/L at baseline to 61.7 [31.5, 116.9] nmol/L at 30 days (p = 0.014), and OxPL-apoB rose from 6.7 [3.1, 21] nmol/L to 8.8 [3.7, 23] nmol/L (p = 0.0045). In contrast, no significant changes were observed for OxPL-apo(a) (p = 0.17) or OxPL-apoB (p = 0.058) in the evolocumab group. OxPL-apo(a) correlated strongly with Lp(a) at baseline (r = 0.93, p < 0.001) and 30 days (r = 0.94, p < 0.001), and OxPL-apoB correlated similarly (baseline: r = 0.92, p < 0.001; 30 days: r = 0.93, p < 0.001). No correlation was observed between OxPLs and LDL-C. OxPL-apo(a) and OxPL-apoB levels were strongly correlated with Lp(a) and increased during the early post-infarction period. This increase was prevented by in-hospital administration of a PCSK9 inhibitor. These findings provide new insights into early changes in OxPLs following acute MI and suggest a protective role for PCSK9 inhibition during this critical period. Show less