👤 Stylianos L Rallidis

Apolipoprotein B (apoB) is a recognized risk factor for acute coronary syndrome (ACS); however, its prognostic value in secondary prevention and superiority over other lipid biomarkers, especially in younger populations, remains uncertain. To investigate whether elevated baseline apoB predicts recurrent cardiovascular events in patients who experienced an ACS at ≤40 years of age and compare its incremental predictive value with that of other lipid biomarkers. We recruited 405 consecutive patients who survived an ACS at ≤40 years of age. Clinical endpoints included major adverse cardiovascular events (MACE): cardiac death, readmission for ACS or ventricular arrhythmias, ischemic stroke, and coronary revascularization due to clinical deterioration. The association between baseline lipid biomarkers and recurrent MACE risk was assessed using multivariable Cox regression. Model performance was evaluated based on discrimination and reclassification. Of 378 young ACS survivors (33.7 ± 4.3 years) with follow-up data, 139 (36.8%) experienced a MACE over a median 8-year (5.2-12.5 years) follow-up. Elevated baseline apoB was independently associated with a higher risk of recurrent MACE (hazard ratio per 10 mg/dL: 1.082, P= .007). This association remained significant even after additionally accounting for low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C). Conversely, apoB adjustment attenuated the LDL-C and non-HDL-C associations. Compared with LDL-C and non-HDL-C, apoB was associated with greater risk of recurrent MACE, and upon addition to conventional cardiovascular risk factors, yielded the greatest improvement in discrimination and reclassification. Baseline apoB may act as a driver for long-term recurrence of MACE in very young ACS survivors, highlighting its potential clinical utility to improve risk stratification beyond traditional lipid measurements. Show less

Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease, and it is particularly associated with premature acute coronary syndrome (ACS). We investigated whether elevated Lp(a) can predict recurrent cardiovascular events in patients who experienced their first ACS less than or equal to 40 years of age. Within the STudy of eArly Myocardial INfArction registry, we recruited 405 consecutive patients who survived their first ACS less than or equal to 40 years of age; of them 378 had complete follow-up data. Clinical endpoint was the development of major adverse cardiovascular events (MACE; i.e. cardiac death, readmission for ACS or malignant ventricular arrhythmias, ischemic stroke, or coronary revascularization due to clinical deterioration). Multi-adjusted Cox regression was used to assess the association between Lp(a) and first recurrent MACE risk. Of the 378 ACS survivors (33.7 ± 4.3 years), 139 (36.8%) experienced a MACE over a median 8-year (5.2-12.5 years) follow-up. Elevated Lp(a) showed a borderline independent association with higher recurrent MACE [hazard ratio per 1 mg/dl: 1.004, 95% confidence interval (CI): 0.999-1.009, P = 0.051]. Moreover, patients with baseline Lp(a) levels greater than or equal to 50 mg/dl had 82.6% higher risk of MACE as compared with those below (hazard ratio 1.826, 95% CI: 1.141-2.925, P = 0.012); similarly, patients with Lp(a) ≥ 70 mg/dl had 118% higher risk as compared with those below (hazard ratio 2.180, 95% CI: 1.330-3.573, P = 0.002). Elevated Lp(a) concentrations demonstrate an independent association with recurrent MACE among very young ACS survivors. Until targeted Lp(a)-lowering treatments become clinically available, an aggressive lipid-lowering approach may be warranted to partially attenuate Lp(a)-related residual cardiovascular risk. Show less

Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off. Show less

High-Density Lipoprotein cholesterol (HDL-C) levels do not correlate well with Coronary Artery Disease (CAD) risk, while HDL functionality affects atherogenesis and is a better prognostic marker for CAD. Often, the extreme HDL-C levels have a multigenic origin. Here, we searched for single-nucleotide polymorphisms (SNPs) in ten genes of HDL metabolism in a Greek cohort with very low (<10th percentile, n = 13) or very high (>90th percentile, n = 21) HDL-C. We also evaluated the association between HDL-C levels, HDL functionality (anti-oxidant capacity) and CAD in the subjects of this cohort. Individuals with low HDL-C levels had higher triglyceride levels, lower apoA-I levels, decreased HDL anti-oxidant capacity and higher incidence of CAD compared with individuals with control or high HDL-C levels. With next generation sequencing we identified 18 exonic SNPs in 6 genes of HDL metabolism and for selected amino acid changes we performed computer-aided structural analysis and modeling. A previously uncharacterized rare apolipoprotein A-IV variant, apoA-IV [V336M], present in a subject with low HDL-C (14 mg/dL) and CAD, was expressed in recombinant form and structurally and functionally characterized. ApoA-IV [V336M] had similar α-helical content to WT apoA-IV but displayed a small thermodynamic stabilization by chemical unfolding analysis. ApoA-IV [V336M] was able to associate with phospholipids but presented reduced kinetics compared to WT apoA-IV. Overall, we identified a rare apoA-IV variant in a subject with low HDL levels and CAD with altered biophysical and phospholipid binding properties and showed that subjects with very low HDL-C presented with HDL dysfunction and higher incidence of CAD in a Greek cohort. Show less