Clinical and prognostic significance of polymorphism of certain candidate genes and markers of endothelial dysfunction in patients who have experienced acute coronary syndrome

The dissertation is devoted to the study of the clinical and prognostic significance of polymorphisms of candidate genes associated with vascular tone regulation and of biochemical markers of endothelial dysfunction in patients who have experienced acute coronary syndrome. The study determined the I/D polymorphic marker of the ACE gene, the Glu298Asp marker of the NOS3 gene, and the Lys198Asn marker of the EDN1 gene, as well as the plasma concentrations of nitric oxide and endothelin-1. The relationship between genotype and clinical and anamnestic data, cardiovascular risk factors, and the course of coronary artery disease within 12 months after acute coronary syndrome was assessed. On the basis of the data obtained, a mathematical model was developed for predicting an unfavourable outcome of the disease within one year after ACS, incorporating genetic and clinical predictors.

Relevance of the study

In the majority of economically developed countries, coronary artery disease (CAD) occupies one of the leading positions in terms of prevalence among the population and frequency of fatal outcomes. A characteristic feature of this pathology is its wave-like course, in which periods of relative stability alternate with episodes of exacerbation accompanied by the development of acute coronary syndrome (ACS) [8]. Even after stabilisation of their condition, patients who have experienced ACS remain at an increased risk of an unfavourable outcome. Thus, death or non-fatal myocardial infarction (MI) within one year is recorded in 4–5% of patients with stable angina pectoris, whereas during the year after ACS such coronary events occur three times more often, amounting to 14–15% of cases according to different sources. In this regard, the identification of predictors of an unfavourable outcome in the group of patients with an unstable course of CAD is one of the pressing problems of modern cardiology [56].

One of the promising approaches to identifying groups at high risk of death and non-fatal myocardial infarction, predicting the course of the pathological process and the development of complications, as well as choosing therapy, is the analysis of candidate gene polymorphisms [61]. Genetic characteristics do not change throughout life and may be classified as non-modifiable risk factors. At the same time, the influence of the genotype on the onset and course of the pathological process is realised through its additive interaction with environmental factors. More active intervention aimed at the modifiable causes of CAD progression in individuals with a genetic predisposition to a severe course of the disease may prevent the realisation of adverse genetic factors. Therefore, the identification of genes responsible for the progression of coronary pathology is undoubtedly of scientific and clinical interest.

A leading role in the pathogenesis of ACS is attributed to the impairment of vascular endothelial function [108, 198]. In endothelial dysfunction, the production of virtually all substances synthesised by the endothelium is disturbed, including such regulators of vascular tone as nitric oxide (NO), endothelin-1 (ET-1), and angiotensin-converting enzyme (ACE). Endothelial dysfunction may have a genetic basis. The identification of associative links between polymorphic markers of genes encoding substances that regulate vascular tone, the plasma content of their active products, and the risk factors for the development and unfavourable course of CAD will clarify certain pathogenetic aspects of the onset and progression of this disease.

Aim of the study

To determine the clinical and prognostic significance of polymorphisms of the angiotensin-converting enzyme (ACE), endothelin-1 (EDN1), and endothelial nitric oxide synthase (NOS3) genes, as well as the biochemical markers of endothelial function, nitric oxide and endothelin-1, in patients with CAD after an experienced acute coronary syndrome.

Objectives of the study:

1. To identify the variability of candidate genes associated with the development of endothelial dysfunction: I/D polymorphism of the angiotensin-converting enzyme gene, Glu298Asp polymorphism of the NOS3 gene, and Lys298Asn polymorphism of the endothelin-1 gene in patients who have experienced ACS.

2. To determine the status of endothelial mechanisms regulating vascular tone by assessing plasma concentrations of endothelin-1 and nitric oxide.

3. To evaluate the relationship between genotype and the clinical and anamnestic characteristics of patients, as well as the plasma content of nitric oxide and endothelin-1.

4. To assess the influence of the studied parameters on the clinical course of CAD within 12 months after the exacerbation episode.

5. To identify predictors of CAD progression and to substantiate the possibility of their practical application for identifying patients at high risk of cardiovascular events.

Scientific novelty of the work

The determination of ACE, NOS3, and EDN1 genotypes in patients with CAD made it possible for the first time to assess the prevalence of different alleles of the studied genes among patients of the Stavropol Territory. For the first time, associations were revealed between the studied polymorphic markers and the features of the course of CAD: the D/D variant of the ACE gene was associated with the development of ACS in younger patients and with early destabilisation of the process; the Asp allele of the NOS3 gene showed a relationship with marked impairment of left ventricular systolic function; the Lys/Lys variant of the EDN1 gene was interrelated with such a cardiovascular risk factor as excess body weight. For the first time, data were obtained on the association between the I/D polymorphism of the ACE gene—the D/D genotype—and the plasma level of nitric oxide in patients who had experienced ACS. For the first time, a dependence was established of the plasma content of endothelin-1 on the EDN1 genotype and the variant of ACS, as well as a relationship between the level of nitric oxide and the number of risk factors and the frequency of reaching endpoints within one year after acute coronary syndrome. For the first time, the distribution of genotypes of polymorphic markers of the ACE, NOS3, and EDN1 genes and the plasma level of vascular tone regulators were studied in patients with different outcomes within 12 months after ACS. For the first time, an association was shown between the D allele and D/D genotype of the ACE gene, a low plasma level of nitric oxide together with arterial hypertension and reduced left ventricular ejection fraction, and an unfavourable prognosis in patients with CAD—frequent episodes of destabilisation and low survival. Based on the results of the study, a mathematical model was created that makes it possible to predict the probability of an unfavourable outcome within 12 months after ACS.

Key propositions of the dissertation submitted for defence:

1. The association of the Glu298Asp polymorphic marker of the NOS3 gene and the Lys198Asn polymorphic marker of the EDN1 gene with certain clinical characteristics and risk factors of CAD.

2. The association of endothelin-1 level with the severity of CAD exacerbation and the relationship between plasma nitric oxide content and the number of risk factors and the course of CAD after an experienced ACS.

3. The influence of genetic factors on the plasma content of nitric oxide and endothelin-1 in patients with CAD.

4. The association of the I/D polymorphic marker of the ACE gene with the course of CAD and the risk of an unfavourable outcome within 12 months after ACS.

5. A mathematical model for predicting the probability of an unfavourable outcome of CAD within one year after ACS based on a set of independent predictors.

Scientific and practical significance of the work

The established fact of the association of the ACE genetic marker with a low level of nitric oxide and early destabilisation of CAD makes it possible to identify patients predisposed to the development of ACS at the early stages of the disease. The detection of the Asp allele of the Glu298Asp marker of the endothelial nitric oxide synthase gene may indicate the possibility of developing left ventricular dysfunction in patients with CAD. The revealed associations between homo- and heterozygosity for the D allele of the ACE gene and a low plasma level of NO in patients after ACS, on the one hand, and a high frequency of CAD destabilisation in the form of unstable angina pectoris, myocardial infarction, and comparatively lower survival, on the other, provide an opportunity to use these parameters for predicting the course of the disease over the next year. The proposed mathematical model for assessing prognosis after an experienced ACS, which includes, along with arterial hypertension and reduced left ventricular ejection fraction, the D/D genotype of the ACE gene and the NO level, can be used at the inpatient and post-inpatient stages to develop an optimal treatment strategy.