Antiplatelet Effects of PCSK9 Inhibitors in Primary Hypercholesterolemia

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel group of hypolipidemic drugs that are recommended particularly for high-risk hypercholesterolemia patients, including those with primary hypercholesterolemia (PH), where lifelong exposure to high low-density lipoprotein (LDL) cholesterol levels results in an elevated risk of atherosclerosis at an early age. The onset and progression of atherosclerosis is significantly influenced by activated platelets. Oxidized LDL influences platelet activation by interacting with their surface receptors and remodeling the composition of their cell membrane. This results in platelet aggregation, endothelial cell activation, promotion of inflammation and oxidative stress, and acceleration of lipid accumulation in atherosclerotic plaques. PCSK9 inhibitors reduce platelet activation by both significantly lowering LDL levels and reducing the LDL receptor-mediated activation of platelets by PCSK9. They also work synergistically with other hypolipidemic and antithrombotic drugs, including statins, ezetimibe, acetylsalicylic acid, clopidogrel, and ticagrelor, which enhances their antiplatelet and LDL-lowering effects. In this review, we summarize the currently available evidence on platelet hyperreactivity in PH, the effects of PCSK9 inhibitors on platelets, and their synergism with other drugs used in PH therapy.

Oral Unsaturated Fat Load Impairs Postprandial Systemic Inflammation in Primary Hypercholesterolemia Patients

Context: Primary hypercholesterolemia (PH) is a lipid disorder characterized by elevated levels of cholesterol and low-density lipoprotein (LDL). Low-grade systemic inflammation is associated with PH, which might explain the higher incidence of cardiovascular diseases in this setting.Objective: To evaluate the effect of an oral unsaturated fat load (OUFL) on different immune parameters and functional consequences in patients with PH in postprandial state.Design: A commercial liquid preparation of long-chain triglycerides (Supracal®; ω6/ω3 ratio >20/1, OUFL) was administered to 20 patients and 10 age-matched controls. Whole blood was collected before (fasting state) and 4 h after administration (postprandial state). Flow cytometry was employed to determine platelet and leukocyte activation, and the levels of circulating platelet-leukocyte aggregates. Soluble markers were determined by ELISA, and the parallel-plate flow chamber was employed to study leukocyte adhesion to the dysfunctional arterial endothelium.Results: The PH group had a lower percentage of activated platelets and circulating type 1 monocytes, and blunted neutrophil activation after the OUFL, accompanied by a significant increase in the percentage of regulatory T lymphocytes. In this group, the OUFL led to a significant impairment of leukocyte adhesion to the dysfunctional [tumor necrosis factor α (TNFα)-stimulated] endothelium and reduced the plasma levels of soluble P-selectin, platelet factor-4 (PF-4)/CXCL4, CXCL8, CCL2, CCL5, and TNFα.Conclusion: The OUFL has a beneficial impact on the pro-thrombotic and pro-inflammatory state of PH patients and might be a promising macronutrient approach to dampen the systemic inflammation associated with PH and the development of further cardiovascular events.

Genetic basis of hypercholesterolemia in adults

We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.

Abstract 13826: Lipoprotein (a) Levels Among Children Diagnosed With a Primary Hypercholesterolemia

Introduction: The American Academy of Pediatrics (AAP) recommends universal lipid screening in all children beginning at nine years of age. Although not a component of the lipid profile, an elevated lipoprotein (a) (Lp(a)) (≥30 mg/dL) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in adults. Plasma Lp(a) levels are a product of the Lp (a) gene, which is fully expressed by 5 years of age, and remains relatively unchanged into adulthood. Limited number of studies have examined Lp(a) levels in children diagnosed with a primary hypercholesterolemia. Hypothesis: To determine the frequency of Lp(a) excess, defined as ≥30 mg/dL, among children diagnosed with a primary hypercholesterolemia (i.e., Familial Hypercholesterolemia (FH), Familial Combined Hyperlipidemia (FCH), Polygenic Hypercholesterolemia (PH). Methods: We reviewed the Ascension St. John Children’s Center Lipid Clinic database between 8/1/2012 and 12/31/2019. Only children diagnosed with a primary hypercholesterolemia and having a baseline Lp(a) assessment were included. FH was diagnosed using the Dutch Lipid Score. PH was diagnosed as an elevated LDL-C level not associated with a monogenic mutation or a secondary cause. FCH was diagnosed as an elevated LDL-C in combination with any triglyceride elevation in the absence of secondary causes. Results: One-hundred and twenty patients were evaluated (mean age: 12.1 ± 2.0 years). Seventy-eight percent (93) of the children were white and 52% (62) were male. The frequency of an Lp(a) excess was 44% (53) in this group. The frequencies of Lp(a) excess by diagnosis, and the median Lp(a) and mean LDL-C levels are displayed in Table 1. Conclusions: Lp(a) excess is relatively frequent among children diagnosed with a primary hypercholesterolemia. Since an Lp(a) excess is an ASCVD risk factor, it should be considered clinically relevant when determining the baseline LDL-C level at which a lipid-lowering agent is initiated in children.