Influence of Pelacarsen on Patients After Myocardial Infarction With High Lp(a) Values (PEMILA)

Overview

The aim of study is to examine the relationship between lipid subfractions, inflammation and structural-functional properties of the arterial wall in patients after myocardial infarction with high lipoprotein (a) (Lp (a)) levels, to study genetic polymorphisms that determine lipid subfractions concentration on the functional and morphological properties of the arterial vascular wall in patients after myocardial infarction with high Lp (a) levels, to study the effect of pelacarsen on lipid subfractions, inflammation and structural-functional properties of arterial wall in patients after myocardial infarction with high Lp (a) levels and to study the influence of NOS-3 gene expression on the functional and morphological properties of the arterial vascular wall in the same patients. Impaired blood fat metabolism and chronic inflammation represent possible causes of atherosclerosis. Lp (a) is an independent risk factor for cardiovascular disease and a prognostic predictor in patients after myocardial infarction. Despite recommended screening for elevated Lp (a), there is no specific drug treatment approved to reduce cardiovascular risk through lowering Lp (a). Besides subtilisin-kexin convertase type 9 (PCSK9) inhibitors, antisense oligonucleotides (ASOs) are currently only therapeutic agents that significantly reduce serum Lp (a) concentration. Pelacarsen by using an ASO directed against the messenger ribonucleic acid (mRNA) of apolipoprotein (a), reduces the production of apolipoprotein (a) in the liver and thus, the level of Lp (a). However, there are no data on the relationship between Lp (a) values and polymorphisms for Lp (a), indicators of inflammation and impaired arterial function, and response to treatment with pelacarsen in patients after myocardial infarction with extremely high Lp (a) levels.

Impaired blood fat metabolism and chronic inflammation represent possible causes of atherosclerosis. The early stage of the atherosclerosis process is characterized by endothelial cell damage, which results in impaired release and function of nitric oxide (NO) from the endothelium. NO is formed by endothelial NO synthetase (NOS-3) from the amino acid L-arginine, which is most pronounced in the vascular wall and is also most important in the process of atherosclerosis. The NOS-3 gene is located on chromosome 7; in the region 7q35-7q36. Functional polymorphisms are those that alter the expression or activity of NOS-3. Among functional polymorphisms, rs2070744, rs3918226 and rs1799983 single nucleotide polymorphisms (SNP) are important. Variations in the NOS-3 genes cause diversity in NO bioavailability and are responsible for endothelial dysfunction. Lipoprotein (a) (Lp (a)) is a specific subfraction of lipoprotein that is an independent risk factor for cardiovascular disease and predicts the residual risk in patients with pre-existing atherosclerosis, regardless of serum LDL-cholesterol concentration. Circulating levels of Lp(a) are mainly genetically determined and varies according to ethnic group. Lp(a) has atherosclerotic, prothrombotic and pro-inflammatory effects. The gene encoding apo (a); LPA, is located on the long arm of chromosome 6 (6q2,6-2,7) and most variants in Lp (a) can be explained by genetic diversity in LPA. To date, the most studied genetic variant is the Kringle-IV type-2 (KIV2) polymorphism, which explains 30-70% of the diversity in Lp (a) in the population. Some KIV2 replicates are associated with smaller isoforms and higher plasma concentrations of Lp (a) which are causally and independently associated with coronary heart disease. Within LPA, the number of KIV2 copies, as well as one nucleotide polymorphism (SNP), rs3798220 and rs10455872, are associated with Lp (a) concentration and coronary heart disease. Besides subtilisin-kexin convertase type 9 (PCSK9) inhibitors, antisense oligonucleotides (ASOs) are currently only therapeutic agents that significantly reduce serum Lp (a) concentration and that have shown effectiveness in clinical trials, to provide reductions in cardiovascular morbidity and mortality. Pelacarsen by using an ASO directed against the mRNA of apolipoprotein (a), reduces the production of apolipoprotein (a) in the liver and thus, the level of Lp (a). A 6-month randomized, double-blind, parallel group and placebo-controlled study will include 60 patients with established cardiovascular disease (CVD) (including myocardial infarction, ischemic stroke or symptomatic peripheral artery disease) and Lp (a) levels above 700 mg / L. The investigators will do anamnesis, targeted clinical examination, take blood samples for laboratory measurements, ultrasound measure endothelium-dependent dilatation of the brachial artery and beta stiffness of carotid arteries. Patients will be divided into two groups according to the randomization list. The first group will receive pelacarsen 80 mg subcutaneously and the second group will receive corresponding placebo. After 6 months, the investigators will repeat all the mentioned investigations. Patients will be informed about the purpose and course of the study before starting the study. All patients will participate voluntarily, without pressure or inappropriate instigation and will give consent by signing the consent form. The investigators hypotheses that in patients after myocardial infarction and high levels of Lp (a), Lp (a) and Lp (a) polymorphisms are associated with indicators of inflammation and structural-functional properties of the arterial wall; in patients after myocardial infarction and extremely high levels of Lp (a), pelacarsen reduces the value of Lp (a), indicators of inflammation and structural and functional involvement of the arterial wall; in patients after myocardial infarction and extremely high levels of Lp (a), the influence of pelacarsen on Lp (a), indicators of inflammation and structural-functional properties of the arterial wall depends on the presence of specific polymorphisms for Lp (a).