Lipoprotein (a) [Lp(a)] is a lipoprotein similar to low-density lipoprotein (LDL), which binds to a characteristic component: apolipoprotein (a). The plasma Lp(a) level is mainly determined by genetic factors, with variations across ethnic groups. In adults, various epidemiological and genetic studies have shown that elevated Lp(a) levels are an independent risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis, associated with inflammatory, atherogenic, and thrombotic mechanisms. Given that the distribution, variability, and prognostic value of this marker in the pediatric population have been less investigated, the objective of this review is to analyze the available evidence on the behavior of Lp(a) as a risk marker in children and adolescents, current recommendations for its measurement in pediatrics, and treatment prospects.

To evaluate the comparative effectiveness of dulaglutide or semaglutide versus tirzepatide on cardiovascular outcomes in adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). Two target trial emulations included commercially insured adults (June 2022-December 2024) with T2D and ASCVD who initiated subcutaneous tirzepatide, dulaglutide, or semaglutide. The primary outcome was modified major adverse cardiovascular events (MACE), defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause death. First, new users of tirzepatide and dulaglutide were propensity score (PS) matched one to one. Second, new users of tirzepatide and semaglutide were PS matched one to one. Incidence rates (IRs) per 1,000 person-years and hazard ratios (HRs) were estimated. After PS matching, 9,233 pairs of tirzepatide or dulaglutide initiators and 25,266 pairs of tirzepatide or semaglutide initiators were identified. Tirzepatide initiators experienced a lower rate of modified MACE versus dulaglutide initiators (IR 31.3 vs. 39.4, respectively; HR 0.80 [95% CI 0.65-0.99]), which seemed to be driven by lower all-cause mortality among tirzepatide versus dulaglutide initiators (HR 0.60 [95% CI 0.43-0.83]). In post hoc analyses, tirzepatide was associated with lower rates of pneumonia-related hospitalization when compared with dulaglutide. Rates of modified MACE were similar among tirzepatide and semaglutide initiators (IR 23.7 vs. 23.2, respectively; HR 1.03 [95% CI 0.90-1.17]). Among adults with T2D and ASCVD in routine care, tirzepatide was associated with a lower risk of modified MACE when compared with dulaglutide, driven by reduction in all-cause mortality. Risks of modified MACE seemed similar with tirzepatide and semaglutide.

Low-density lipoprotein cholesterol (LDL-C) is the major lipid target to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with hypercholesterolemia and in those with mixed dyslipidemia. Lifestyle and diet modification should always be the first approach to management, but pharmacological intervention is often required. This article discusses the current therapies to reduce LDL-C and introduces some of the new drugs in late-stage development. The articles reviewed were identified by a PubMed search up to the current time. Statins remain the primary therapy to reduce LDL-C, but statins are often insufficient to achieve the more aggressive LDL-C targets. Ezetimibe is the next recommended therapy to add, and bempedoic acid provides another oral drug that can be added or substituted for the statins. The injectable proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are the most effective drugs in reducing LDL-C, but their uptake has not met expectations because of issues of cost and patients' reluctance to take injection therapy. The oral PCSK9 inhibitors in development and obicetrapib appear safe and very effective and if approved they should provide useful alternatives for reaching LDL-C goals but the problem of long-term adherence to therapy will remain.

PCSK9 inhibitors (PCSK9i) are indicated in combination with statins and/or ezetimibe to intensify LDL-cholesterol lowering and reduce the risks of atherosclerotic cardiovascular disease. We aimed at investigating PCSK9i (alirocumab and evolocumab) patterns of use in France by characterizing PCSK9i new-users and describing lipid-lowering agents (LLA) use before and after PCSK9i initiation. A cross-sectional study of PCSK9i users and a cohort study including PCSK9i new-users between 2018 and 2021 were conducted using the nationwide French healthcare insurance system database (SNDS). PCSK9i use increased greatly after the indication extension rapidly slowed by introduction of agreement prior to reimbursement in Dec-20. Among the 6891 PCSK9i new-users, 65.7% were men, 63.7% were at very-high cardiovascular risk, median age was 64years (IQR: 56-71). Trajectories of cholesterol-lowering treatment prior to PCSK9i initiation showed high intensity treatment for 50.5% of patients, low/moderate treatment for 37.3% and no prior treatment for 12.2%. LLA discontinuation after PCSK9i initiation was most frequent in patients with no prior treatment (17.3%) than in those with prior low/moderate or high-intensity treatment (4.9 and 1.3% respectively). Agreement prior to reimbursement seemed effective in contributing to control the appropriate use of PCSK9i with almost two-thirds of patients at very-high cardiovascular risk, and high treatment persistence.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality globally. Low-density lipoprotein cholesterol is a causal risk factor for atherosclerotic cardiovascular disease, with multiple classes of cholesterol-lowering therapies effective at reducing atherosclerotic cardiovascular disease risk. Despite robust efficacy data from randomized trials, real-world implementation of guideline-recommended lipid-lowering therapies is suboptimal. Barriers to the implementation of guideline lipid-lowering therapy recommendations exist at the healthcare systems level, the medical therapy level, and the patient level. A combination of strategies, including the incorporation of quality improvement and cost-effectiveness analysis among payers, pharmacist-based educational initiatives, digital health tools directed towards patients, the simplification of drug regimens via polypill, and emerging novel therapies, including PCSK9 gene silencing and editing technologies, may bridge these implementation gaps. This review highlights challenges and solutions to alleviating barriers to optimal implementation of guideline-recommended lipid-lowering therapies.

We aimed to investigate the challenges Korean physicians face in assisting their high-risk atherosclerotic cardiovascular disease (ASCVD) patients in achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) levels. We performed a prospective, implementation science study including 704 patients at very high risk of ASCVD with baseline LDL-C ≥ 70 mg/dL (1.8 mmol/L) while receiving maximally tolerated statins and/or ezetimibe for secondary prevention between 2020 and 2022. The primary evaluation criteria were the proportions of participants achieving LDL-C < 70 mg/dL at each visit. The secondary evaluation criteria included the proportions of participants in diverse situations associated with guideline adoption. The proportions of participants achieving LDL-C < 70 mg/dL at visits 2 (week 6-16) and 3 (week 18-30) were 56.3% and 58.7%, respectively. Among 307 patients on maximally tolerated statins and 397 patients on maximally tolerated statins and ezetimibe at baseline, physicians did not have an intention to intensify the lipid-lowering treatment regimen of 171 patients (55.7%) and 299 patients (75.3%) at visit 1, respectively. In both groups, physician disagreement with the guidelines was the major reason for not adopting the recommended therapy (70.8% and 46.2%, respectively), followed by patient refusal for reasons other than the cost, medical limitations such as comorbidities, and drug costs. This implementation science study for secondary prevention involving very high-risk ASCVD patients revealed that the proportion of patients achieving LDL-C < 70 mg/dL via lipid-lowering therapy was less than 60%. The main reason for not adopting the recommended LDL-C-lowering therapy was physician disagreement with the guidelines. Clinical Research Information Service Identifier: KCT0005488.

Automated Abdominal Aortic Calcification Scores and Atherosclerotic Cardiovascular Disease in the UK Biobank Imaging Study.

Residual cardiovascular risk remains substantial in patients with atherosclerotic cardiovascular disease (ASCVD) despite high-intensity statin therapy. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), including monoclonal antibodies and small-interfering RNA agents, offer additional risk reduction, yet comparative evidence across individual regimens remains limited. We conducted a systematic review and network meta-analysis of randomized controlled trials evaluating approved PCSK9i dosages in patients with ASCVD. The primary outcome was major adverse cardiovascular events (MACE); the secondary outcomes included myocardial infarction, stroke, coronary revascularization, cardiovascular mortality, and all-cause death. A total of eight trials involving 49,847 patients were included. Evolocumab (140 mg every 2 weeks or 420 mg monthly) and alirocumab 150 mg every 2 weeks significantly reduced MACE compared with placebo (risk ratios (RR): 0.78, 95% confidence intervals (CI): 0.66-0.93 and RR: 0.47, 95% CI 0.25-0.86, respectively). Evolocumab was also associated with reductions in myocardial infarction, stroke, and revascularization. Alirocumab 150 mg demonstrated the most pronounced effect on revascularization and was superior to both evolocumab and the lower alirocumab dose in this outcome. No regimen significantly reduced cardiovascular or all-cause mortality. These findings suggest that PCSK9 inhibitors are effective in ASCVD, with generally similar efficacy across agents; however, regimens achieving lower and sustained low-density lipoprotein cholesterollevels may confer greater benefit, in line with the concept that "the lower, the better." PROSPERO identifier no. CRD420251022108.

Metabolomic aging clock predicts risk of different cardiovascular diseases in the UK Biobank.

Association between Semaglutide 2.4 mg and Risk of Cardiovascular Events in People with Overweight or Obesity without Atherosclerotic Cardiovascular Disease in the Real-world: The SCORE – Primary Prevention Study

Sex-specific differences in cardiovascular risk factors and their management.

Optimal antithrombotic therapy for post-ischemic stroke patients with atrial fibrillation and atherosclerotic cardiovascular disease: A frequentist network meta-analysis

Cholesterol-Inflammation Fusion Hypothesis in Atherosclerosis: An Evolving Paradigm in Pathogenesis and Therapy.

Recent literature indicates that the benefits of aspirin use for primary prevention of atherosclerotic cardiovascular disease (ASCVD) may be equivocal to the risk. This has resulted in several organizations making updates to their clinical practice guidance on appropriate use. Despite this narrower scope, specific guidance on how to deprescribe aspirin in patients already on therapy for primary prevention is lacking. The purpose of this paper is two-fold: to provide a systematic review of the literature on aspirin deprescribing strategies and propose a practical aspirin deprescribing algorithm when used discordantly with current recommendations for primary prevention. We conducted searches in databases including EMBASE, PubMed, Web of Science, Scopus, and CINAHL from January 2018 to March 2025. One hundred and sixty-seven studies were screened, and 13 articles were included. The studies utilized a variety of interventions to impact aspirin deprescribing. In each of the studies included, there was at least some type of prompt to trigger deprescribing aspirin. However, a consistent approach was not defined. A multidisciplinary model occurred in half of the studies included, which resulted in the highest reported deprescribing rate of 78%. However, there were limited descriptions of patient-related outcomes as a result of deprescribing, warranting additional studies. A deprescribing algorithm can assist in guiding aspirin deprescribing for primary prevention of ASCVD while considering patient preferences in an individually tailored approach.

Clonal hematopoiesis (CH) refers to the presence of somatic variants in hematopoietic stem and progenitor cells (HSPC) that result in expansion over time. CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in oncogenic driver genes occurring in HSPCs at variant allele frequencies ≥ 2%. CH is associated with increased risk for progressive cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and nonhematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease. CH is linked to numerous other diseases including venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, and gout, with a potential protective impact in Alzheimer's disease (AD). CH detection is becoming increasingly common due to the ubiquitous use of somatic and germline sequencing in clinical practice, particularly, in oncology. The clinical implications of CH are most relevant in therapy-related myeloid neoplasms (t-MN), with antecedent CH clones in genes such as TP53, PPM1D, and/or CHEK2 having a clear selection advantage. Furthermore, genetic predisposition to CH has provided some clarity on the origin and evolution of CH. We are currently defining the role for CH assessment in individuals with persistent (≥ 4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation or chimeric antigen receptor T cell (CAR-T) therapy, and to work-up potentially germline mosaic variants.

Meteorin-like protein inhibits vascular smooth muscle cell-derived foam cell formation and atherosclerosis via KIT- endoplasmic reticulum stress signaling.

Endothelial versus global METRNL reveals importance of endothelial METRNL against atherosclerosis via mitochondrial homeostasis.

Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of early atherosclerosis-related cardiovascular disease. This review discusses the genetics, epidemiology, diagnosis, and novel therapeutic approaches for FH. Mutations in the LDL receptor gene are the primary cause of FH. Less common causes include mutations in proprotein convertase subtilisin/kexin type 9 and apolipoprotein B-100. In extremely rare cases, LDLR adaptor protein 1 mutations can also cause FH. Epidemiological data indicate that FH is frequently underdiagnosed, particularly within certain ethnic populations. Diagnostic criteria often rely on clinical manifestations and family history, although genetic testing is increasingly advocated for confirmation. Recent advancements in pharmacotherapy offer substantial opportunities for effective low-density lipoprotein cholesterol control and management of FH, providing new hope for affected patients. This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin. However, some of these newer agents are specifically designed to lower elevated Lp(a), which often occurs in patients with FH, and triglycerides. Furthermore, gene-editing approaches, such as clustered regularly interspaced short palindromic repeats -Cas9 and meganuclease, as well as vaccines targeting key components of cholesterol metabolism, represent promising future directions for FH treatment. SIGNIFICANCE STATEMENT: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels, which increase the risk of atherosclerotic cardiovascular disease. Conventional therapies, such as statins, often have limited efficacy in patients with FH. Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment.

Unanswered Questions About the Relationship Between Lipoprotein(a) and Atherosclerotic Cardiovascular Disease.

Lipoprotein(a) [Lp(a)] is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), but the shape and potential nonlinearity of its association remain uncertain. We assessed the linear and nonlinear associations between Lp(a) levels and ASCVD risk using observational and Mendelian randomization (MR) approaches. We analyzed 351,858 UK Biobank participants (2006-2023), stratified into Lp(a) percentiles: <70th, 70th-<80th, 80th-<90th, and ≥90th. Outcomes included ASCVD events from hospital, primary care, self-report, and death registry data. Cox models estimated the hazard ratios (HRs). MR analyses used a polygenic risk score from 10 Lp(a)-associated single-nucleotide polymorphisms, with nonlinearity tested by doubly ranked MR. Higher Lp(a) levels were associated with increased ASCVD risk. Compared with the <70th percentile, adjusted HRs (95% confidence interval) were 1.11 (1.07-1.16), 1.18 (1.14-1.22), and 1.25 (1.21-1.30) for the 70th-<80th, 80th-<90th, and ≥90th groups. Kaplan-Meier curves diverged early by group. Spline models suggested nonlinearity with an inflection near 130 nmol/L (P=0.007). MR showed a 2% higher ASCVD risk per 10 nmol/L genetically predicted Lp(a) (P<2×10-16). Nonlinear MR suggested steeper gradients at higher levels, though not statistically significant (P=0.087). Elevated Lp(a) concentrations were causally associated with ASCVD risk, showing a predominantly graded relationship with possible nonlinearity at very high levels, supporting routine Lp(a) measurement and the development of Lp(a)-lowering therapies.