👤 Ece Yurtseven

Lipoprotein(a) [Lp(a)] is a genetically determined, proatherogenic, and prothrombotic lipoprotein associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Elevated Lp(a) levels are associated with progressive ASCVD even when guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets are achieved under optimal lipid-lowering therapy. There is currently no approved pharmacological therapy specifically targeting Lp(a) reduction in routine clinical practice; therefore, current management strategies for patients with elevated Lp(a) primarily focus on aggressive control of modifiable cardiovascular risk factors and intensive LDL-C lowering. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a modest reduction in Lp(a) levels and have been associated with greater cardiovascular benefit in patients with high baseline Lp(a); however, this degree of reduction is often insufficient in individuals with markedly elevated Lp(a) levels and progressive ASCVD. At present, lipoprotein apheresis remains the only therapeutic option capable of achieving substantial and sustained reductions in Lp(a) concentrations and is recommended in selected high-risk patients with progressive ASCVD despite optimal medical therapy. Meanwhile, Lp(a)-specific therapies, including antisense oligonucleotides and small interfering RNA agents, are in advanced clinical development and have shown marked reductions in Lp(a) levels in early phase trials. These emerging therapies are expected to significantly change future treatment strategies for patients with Lp(a)-driven residual cardiovascular risk. Show less

Advanced age is a well-recognized risk factor for atherosclerotic cardiovascular disease (ASCVD). Given the ongoing debate regarding the initiation of statin therapy in elderly individuals, identifying those with underlying coronary artery disease (CAD) who may benefit from lipid-lowering treatment is essential. This study aimed to identify predictors of CAD in statin-naïve adults aged ≥ 70 years with elevated low-density lipoprotein cholesterol (LDL-C), with particular emphasis on risk assessment, cumulative LDL-C burden, and lipoprotein(a) [Lp(a)] levels. The analysis included consecutive patients aged ≥ 70 years with LDL-C ≥ 160 mg/dL, available Lp(a) measurements, no prior history of ASCVD or diabetes, who underwent evaluation for CAD by coronary imaging or functional stress testing. Global ASCVD risk was estimated using the Systematic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) and the Spanish Familial Hypercholesterolemia Cohort Study (SAFEHEART) risk scores. A total of 202 patients were included (mean age 76 years; 68.3% female). CAD was diagnosed in 30.7% of participants. In multivariable analysis, male sex (odds ratio [OR]: 2.109), Lp(a) level (OR: 1.012 per mg/dL), and cumulative LDL-C (OR: 1.155 per g/dL) were independently associated with CAD. The highest CAD prevalence was observed among individuals with cumulative LDL-C ≥ 14 g/dL and Lp(a) ≥ 50 mg/dL. While the SCORE2-OP algorithm failed to predict CAD, the SAFEHEART risk score was significantly associated with CAD. In statin-naïve elderly individuals with elevated LDL-C levels, male sex, cumulative LDL-C exposure, and high Lp(a) levels were independently associated with CAD. These findings underscore the potential utility of incorporating cumulative LDL-C and Lp(a) into risk stratification for older adults. Show less

Subclinical atherosclerosis is a key predictor of cardiovascular events. While inflammation plays a crucial role in atherosclerosis, the involvement of Human Neutrophil Peptides 1-3 (HNP1-3) in its progression remains unclear. The study investigates the association of HNP1-3 and PCSK9 with coronary atherosclerotic burden and explores the potential mediatory role of PCSK9 in HNP1-3's effect on atherogenesis. Patients who underwent coronary computed tomographic angiography (CCTA) and had subclinical atherosclerosis (luminal stenosis < 50%) or normal coronary arteries were included in this cross-sectional study. HNP1-3 and PCSK9 levels were measured using ELISA, and coronary plaque burden was quantified using the modified Gensini score. Patients with subclinical atherosclerosis had significantly higher levels of HNP1-3 (p < 0.001), PCSK9 (p < 0.001), and lipoprotein(a) [Lp(a)] (p < 0.001) compared to controls. HNP1-3 was an independent predictor of subclinical atherosclerosis (p < 0.001), and its levels positively correlated with the modified Gensini score (p < 0.001). In multinomial logistic regression, higher levels of HNP1-3, PCSK9, and Lp(a) were independently associated with higher modified Gensini score tertiles. Mediation analysis revealed that PCSK9 mediated 48.7% of the effect of HNP1-3 on the modified Gensini score. After adjusting for hsCRP and cardiovascular risk factors, the direct effect of HNP1-3 became statistically insignificant, while the indirect effect via PCSK9 remained significant, suggesting that PCSK9 fully mediates the pro-atherogenic effects of HNP1-3. In conclusion, HNP1-3 is a novel independent predictor of subclinical atherosclerosis and coronary plaque burden, with its effects being mediated through PCSK9. These findings suggest that targeting PCSK9 could mitigate the inflammatory actions of HNP1-3, offering potential therapeutic insights for atherosclerosis prevention. Show less