Pharmacogenetic aspects of thrombolytic therapy and early statin administration in patients with ST-segment elevation myocardial infarction

The dissertation is devoted to the study of pharmacogenetic aspects of the treatment of myocardial infarction with ST-segment elevation. It examines the efficacy of thrombolytic therapy and early statin administration depending on polymorphisms of hemostasis system genes (PAI-1, FXIII) and the apolipoprotein E gene. The frequency of successful myocardial reperfusion is assessed by indirect clinical and laboratory signs, the distribution of alleles and genotypes of the studied polymorphic markers is analyzed, and their association with the restoration of coronary blood flow and the development of complications is evaluated. In addition, the influence of early atorvastatin therapy on the dynamics of inflammation markers, lipid profile parameters, and the course of the in-hospital period of the disease is analyzed.

The data obtained are aimed at identifying groups of patients in whom standard thrombolytic therapy and early statin administration may be less effective, as well as at substantiating the expediency of genotyping for polymorphisms of hemostasis system genes and apoE in order to individualize treatment strategy.

Relevance: the overwhelming number of cases of MI development (95%) is caused by thrombosis resulting from the rupture of an unstable atherosclerotic plaque that has a large lipid core, a thin fibrous cap, and contains a large number of inflammatory cellular elements (T-lymphocytes, monocytes, macrophages) (79).

The main factors influencing the final size of MI are the time to myocardial reperfusion and the development of collaterals. This determines the treatment strategy, the goal of which is the restoration of blood flow through the occluded artery, which in practice is achieved either by the administration of a thrombolytic drug or by direct recanalization, possibly in combination with TLT. Despite the priority role of angioplasty in the treatment of MI patients demonstrated in recent clinical studies (49), in our country, due to the low availability of direct recanalization methods, TLT remains relevant at present.

The success of reperfusion is mainly judged by indirect criteria (a total ST-segment decline of more than 70% within 3 hours from the start of TLT, as well as an increase in the level of MB-CPK, CPK (20% or more of the initial value 6 hours after the start of TLT)). However, in 40–60% of MI patients systemic TLT is ineffective (under the same conditions of administration, including a similar duration of pain syndrome), which has not yet received a definitive explanation (15,38,66,174).

Taking into account the association revealed in a number of studies between gene polymorphisms and the plasma level and activity of the hemostasis system factors they encode, it may be assumed that there is a relationship between the polymorphism of these genes and the efficacy of TLT, which may play a role in the choice of treatment strategy. The influence of polymorphisms of hemostasis system factor genes on the efficacy of TLT has practically not been studied. In the available literature we encountered two studies devoted to the investigation of the relationship between FXIII gene polymorphism and the efficacy of TLT, in which less effective TLT was observed in carriers of the Leu34 allele (171). In two studies evaluating the influence of the 4G/5G polymorphism of the PAI-1 gene on the efficacy of TLT and stenting in MI patients, no differences in the efficacy of either method were revealed among carriers of different genotypes (178).

After TLT, one of the main tasks in the treatment of patients with ACS is the stabilization of the atherosclerotic lesion, and subsequently, if necessary, its elimination (stenting, CABG). New evidence on the mechanism of action of statins (they rapidly normalize impaired endothelial functions, inhibit platelet aggregation and thrombus formation, reduce vascular inflammation) suggests the expediency of early administration of this group of drugs to patients with acute MI. However, ACS, including MI with ST-segment elevation, which is characterized by significant mortality and a high risk of ischemic events, is still not considered as a generally accepted indication for statin prescription. There are contradictory data on the efficacy of statins in ACS patients with ST-segment elevation and the timing of initiation of therapy has not been determined (3,5,135).

The literature contains data on the association of hypolipidemic and pleiotropic effects of statins with apoE gene polymorphism. Thus, in a number of studies in a group of patients with familial forms of hypercholesterolemia, carriers of the E2 and less frequently E3 allele showed a more pronounced response to statin therapy, manifested in a greater reduction in TC and LDL-C levels than in carriers of at least one E4 allele (83,124). Data on the influence of the ApoE isoform on the efficacy of treatment of patients with stable CAD are generally consistent with those obtained in the treatment of patients with familial forms of hypercholesterolemia. However, in the available literature we did not encounter studies devoted to the investigation of the influence of the ApoE isoform on the efficacy of early statin administration in ACS.

Aim of the study: to investigate the efficacy of TLT and early statin administration in MI patients depending on the polymorphism of hemostasis system genes and apoE.

Objectives of the study:

1. To evaluate the frequency of successful myocardial reperfusion after TLT by indirect signs (dynamics of MB-CPK, CPK, total ST-segment decline 3 hours after the start of TLT) and its dependence on traditional risk factors.

2. To study the distribution of genotype and allele frequencies of hemostasis system genes (PAI-1, FXIII) in MI patients.

3. To evaluate the association of PAI-1 and FXIII gene polymorphisms with successful reperfusion and the development of complications.

4. To evaluate the efficacy of early atorvastatin administration in MI patients and the influence on the dynamics of inflammation markers (CRP, fibrinogen) and lipid profile parameters.

5. To study the distribution of genotype and allele frequencies of the apoE gene, as well as the association of atorvastatin efficacy depending on apoE gene polymorphism.

Scientific novelty.

It has been demonstrated that the frequency of effective blood flow after TLT in MI patients, assessed by a total ST-segment decline > 70% 3 hours after the start of TLT and an early increase in MB-CPK (20% or more of the initial value 6 hours after the start of TLT) in the blood, is 51% and depends on the waiting time for TLT and is more often observed in inferior MI localization and in patients with DM. Effective reperfusion is significantly more frequently recorded in women aged 60 years and older, including those with DM, obesity, and hypertension.

For the first time in MI patients, an assessment of the occurrence of alleles and genotypes of polymorphic variants of the PAI-1, FXIII, and apoE genes was carried out. The study did not reveal an association of the 4G/5G polymorphism of the PAI-1 gene with the restoration of blood flow in the IRA. A more frequent ineffective reperfusion was noted in the Leu/Leu genotype group of the FXIII gene.

A comparative assessment of the influence of early atorvastatin therapy on the course of the in-hospital period of MI and the dynamics of CRP and fibrinogen levels and lipid profile parameters was carried out. A more favorable course of the in-hospital period of MI was revealed, manifested in a reduced risk of MI recurrence, a lower frequency of the combined endpoint (ventricular rhythm disturbances + MI recurrence + death), as well as a significant decrease in CRP, TC, LDL-C, and TG levels on day 10 during early atorvastatin administration compared with the group of patients who did not receive a statin.

The association of atorvastatin efficacy with apoE gene polymorphism was studied. A more pronounced decrease in CRP level was noted in the group of carriers of the E3E3 genotype than in the group of the "non-E3E3" genotype.

Practical significance.

Assessment of the degree of blood flow restoration in the IRA by the degree of total ST-segment decline on ECG 3 hours after the start of TLT, as well as by the dynamics of MB-CPK and CPK levels in the blood, makes it possible to identify a high percentage of ineffective reperfusion and, consequently, to distinguish a group of high-risk patients for choosing the most preferable further management strategy, including the use of angioplasty.

The data obtained in the study on a more favorable course of the in-hospital period of MI, as well as a significant decrease in CRP levels and atherogenic lipids during early atorvastatin administration, make it possible to recommend the use of atorvastatin from the first day of MI development.

A more pronounced decrease in CRP level during atorvastatin treatment in the group of carriers of the E3E3 genotype allows discussion of the expediency of genotyping for apoE polymorphism in order to evaluate the efficacy of statin therapy.