RU2801684C1 - Method of predicting the development of left ventricular aneurysm in patients after myocardial infarction, taking into account genetic factors - Google Patents

Abstract

FIELD: medicine; cardiology.

SUBSTANCE: invention is intended to determine the risk of left ventricular aneurysm in patients with myocardial infarction. To predict the development of left ventricular aneurysm in patients with myocardial infarction, blood is taken for genetic analysis and polymorphisms rs2238296 of the POLG gene and rs4673 of the CYBA gene are determined. In the presence of a combination of the CC rs2238296 genotype of the POLG gene and the CC genotype of the rs4673 polymorphism of the CYBA gene, the development of left ventricular aneurysm in the postinfarction period is predicted.

EFFECT: use of the invention improves the accuracy of predicting the development of left ventricular aneurysm in patients with myocardial infarction, taking into account genetic factors.

1 cl, 3 tbl, 2 ex

Description

The invention relates to medicine, namely to cardiology.

Postponed myocardial infarction (MI) is one of the main causes of chronic heart failure (CHF) and is recorded in 15-30% of patients with CHF [1,2]. The process of postinfarction heart remodeling is largely determined by the expression of a certain set of genes, leading to molecular, cellular and interstitial changes, and clinically manifested as a change in the size, shape and function of the heart [3]. As is known, the main mechanisms of postinfarction heart remodeling are cell death, disruption of energy and ion metabolism, inflammation, imbalance in collagen synthesis and breakdown, neurohormonal activation, and oxidative stress. As a result of acute ischemic damage, mitochondrial dysfunction occurs, which leads to increased apoptosis of cardiomyocytes due to the accumulation of free radicals that are not adequately utilized [4]. Enzymes of the body's antioxidant system, such as catalase, superoxide dismutase, glutathione peroxidase, paraoxonase, and others, are of great importance in the processes of synthesis and utilization of free radicals [5], in turn, the activity of these enzymes is largely determined by genetic factors [6, 7].

The search for exact genetic predictors of left ventricular aneurysm development in patients with myocardial infarction, with the creation of an effective method for predicting this complication even in the acute period of a heart attack, is an urgent and promising area of medical science and practice.

There is a well-known "Method for predicting the likelihood of developing an acute aneurysm of the heart" [8], however, it is applicable only for patients with type 2 diabetes mellitus and takes into account indicators of clinical and laboratory status on the first day of admission to a hospital with acute myocardial infarction (thickness of the interventricular septum, triglyceride level, total cholesterol, heart rate per minute, end diastolic size, Killip class of acute heart failure, duration of history of arterial hypertension, blood glucose level, glycated hemoglobin level, type of remodeling, sex, age, duration of diabetes mellitus). However, this method does not include the analysis of genetic factors that may contribute to the development of adverse post-infarction remodeling of the heart with the development of left ventricular aneurysm.

Known "Method for predicting cardiovascular complications in patients with coronary heart disease in combination with postinfarction aneurysm of the left ventricle" [9]. The method takes into account the concentration in the blood serum of the aminoterminal fragment of the brain natriuretic peptide and allows predicting cardiovascular complications after coronary artery bypass grafting. However, this method is applicable in patients with already diagnosed left ventricular aneurysm, and cannot be used to predict the development of this complication.

The "Method for predicting the course of acute myocardial infarction" [10] is known, which takes into account the characteristics of platelet aggregation in the acute period of myocardial infarction and allows predicting a high probability of developing postinfarction complications, including left ventricular aneurysm. At the same time, the method allows to predict only a combination of complications (cardiac arrhythmias, thrombus formation in the cavity of the left ventricle, aneurysm, recurrent myocardial infarction), while individual parameters characterizing the high probability of developing an aneurysm of the left ventricle in this method are not presented, except for this , predictors of complications do not include genetic factors.

Thus, in the analyzed scientific, medical and patent literature, an adequate prototype was not found.

The objective of the invention is to create a method for predicting the development of left ventricular aneurysm in patients with myocardial infarction, taking into account genetic factors.

The problem is solved by determining the totality of factors influencing the development of left ventricular aneurysm in patients with MI, based on the formation of a cohort of patients of 153 people (137 men and 16 women), aged 56 (50; 60.5) years. To solve this problem, a retrospective case-control study was conducted in patients with obstructive multivessel coronary disease who had a history of myocardial infarction. The inclusion criteria were: the fact of myocardial infarction not earlier than 6 months before inclusion in the study and multivessel atherosclerotic lesions of the coronary arteries as an indication for surgical myocardial revascularization [11]. All patients were examined according to a single algorithm, including the collection of complaints and anamnesis of the disease, a clinical examination with the determination of body mass index, symptoms and signs of chronic heart failure. Instrumental examination included electrocardiography (ECG), echocardiography (EchoCG). Conducted laboratory blood tests. Coronary angiography was performed according to clinical indications on the angiographic complex "Siemens Axion Aptos" not earlier than 2 months before inclusion in the study. Patients were divided into 2 groups depending on the characteristics of postinfarction left ventricular (LV) remodeling: group 1 - patients with a history of myocardial infarction without LV aneurysm (n = 97), group 2 - patients with developed LV aneurysm after myocardial infarction (n = 56).

The material for genetic analysis was samples of genomic DNA of patients stored in the biocollection of the Tomsk National Scientific and Research Center "Biobank of the Population of Northern Eurasia". Genomic DNA was isolated from venous blood leukocytes of patients by phenol-chloroform extraction. Genotyping was carried out using polymerase chain reaction followed by restriction fragment length polymorphism analysis (PCR-RFLP). As part of the work, genotyping of 8 single nucleotide polymorphisms of 7 genes was performed: mitochondrial DNA polymerase gamma ( POLG (rs2238296 - T/C)), mitochondrial transcription factor A ( TFAM (rs1937 - Ser12Thr)), superoxide dismutase ( SOD2 (rs4880 - Ala16Val)), glutathione peroxidase ( GPX1 (rs1050450 - Pro198Leu)), catalase ( CAT (rs1001179 - C-262T)), paraoxonase 1 (PON1 (rs854560 - Leu55Met, rs662 - Gln192Arg)) and NADP-H oxidase ( CYBA (rs4673 - His72Tyr) ).

As a result of the analysis, it was found that patients with left ventricular aneurysm and without aneurysm did not have significant differences in gender and age parameters and comorbid background. Symptoms of chronic heart failure were most pronounced in the cohort of patients with left ventricular aneurysm, which was also confirmed by more pronounced changes in echocardiographic parameters (Table 1). Drug therapy of patients in both study groups was also comparable.

Table 1. Clinical and anamnestic characteristics of patients

Analyzed feature Group 1 (no aneurysm; n= 97) Group 2 (there is aneurysm; n=56) R Gender, male/female, n (%) 85/12 (87.6/12.4) 52/4 (92.9/7.1) 0.3 Average age, Me (Q25; Q75), years 55 (50; 60.5) 57 (50;60) 0.8 FC IHD, n (%)
I
II
III 10 (10.3)
53 (54.6)
34 (35.1) 11 (19.6)
27 (48.2)
18 (32.1) 0.1
0.4
0.7 FC CHF (NYHA), n (%)
I
II
III
IV 6 (6.2)
43 (44.3)
46 (47.4)
2 (2.1) 2 (3.6)
15 (26.7)
38 (67.9)
1 (1.8) 0.4
0.03
0.01
0.9 Diabetes mellitus, n (%) 19 (19.6) 8 (14.3) 0.4 Obesity, n (%) 40 (41) 20 (38.5) 0.3 Peripheral atherosclerosis, n (%) 58 (59.8) 27 (49.1) 0.18 Acute cerebrovascular accident, n (%) 8 (8.2) 5(9) 0.4 Chronic obstructive pulmonary disease, n (%) 28 (28.8) 13 (23.2) 0.5 Heart rhythm disorders, n (%) 13 (13.4) 14 (25) 0.04 Body mass index, Me (Q25; Q75) 28 (25.75;31) 27 (24;31) 0.15 Age at the time of the first myocardial infarction, Me (Q25; Q75), months 51.3 (44.7; 56.7) 52.2 (47.6;58) 0.2 Time from last myocardial infarction to inclusion in the study, Me (Q25; Q75), months 12.5 (7.5;51) 13.5 (8.5; 47.5) 0.38 Number of myocardial infarctions, n (%)
1
2
3
4 66 (68%)
25 (25.8)
3 (3.1)
3 (3.1) 36 (64%)
15 (26.8)
3 (5.4)
2 (3.6) p>0.05 End diastolic volume, Me (Q25; Q75), ml 134 (104;175) 189 (140;229) 0.001 End systolic volume, Me (Q25; Q75), ml 58 (39;100.5) 112 (67.25;162.25) 0.001 Myocardial mass, Me (Q25; Q75), g 223 (181.25; 281.5) 250 (205;298.5) 0.053 Left ventricular ejection fraction, Me (Q25; Q75), % 54.5 (44; 64) 43 (30; 53.5) <0.001 Note: Me (Q25; Q75) - median and interquartile range, p - level of significance of differences, FC - functional class, CAD - coronary heart disease, CHF - chronic heart failure

When analyzing the distribution of genotype frequencies of polymorphisms of the studied genes, no significant difference was found in the SOD2, GPX1, CAT, PON1, and TFAM genes in the studied groups (Table 2). Whereas with respect to the POLG and CYBA genes, significant differences were established. Thus, the SS genotype rs2238296 of the POLG gene was found in every third patient with LV aneurysm (30.3%), while in the group without aneurysm it was found only in every eighth case (12.3%; p=0.006). The chance of developing an aneurysm of the left ventricle in the presence of the CC genotype of the rs2238296 polymorphism was 3 times higher (OR 3.1; 95% CI 1.3-7.0).

Table 2. Distribution of genotypes of the studied traits in groups of patients with and without aneurysm of the left ventricle

Gene/genotype no aneurysm There is an aneurysm Achieved level of significance SOD2 (SS/ST/TT) 19.6/49.5/30.9 16.1/62.5/21.4 p>0.05 GPX1 (SS/ST/TT) 46.4/40.2/13.4 46.4/37.5/16.1 p>0.05 CAT (SS/ST/TT) 52.6/43.3/4.1 57.1/37.6/5.3 p>0.05 PON1 (55) (AA/AT/TT) 10.4/45.3/44.3 10.7/51.8/37.5 p>0.05 PON1 (192) (AA/AG/GG) 52.6/39.2/8.2 48.2/41.1/10.7 p>0.05 TFAM (CC/CG/GG) 4.1/20.6/75.3 7.1/23.3/69.6 p>0.05 POLG (SS/ST/TT) 12.3*/52.6/35.1 30.3*/41.1/28.6 *p=0.006 CYBA (SS/ST/TT) 32*/58.8/9.2 51.8*/37.5/10.7 *p=0.01

The CC genotype rs4673 of the CYBA gene was found in every second patient with an aneurysm (51.8%) and in 32% without left ventricular aneurysm. At the same time, the odds ratio of aneurysm development in the presence of CC polymorphism of the CYBA gene was 2.3 (1.16; 4.5) (p=0.01). Thus, the CC rs2238296 genotype of the POLG gene and the CC rs4673 genotype of the CYBA gene were associated with the development of postinfarction left ventricular aneurysm in patients with obstructive coronary atherosclerosis.

Taking into account the obtained results, a group of patients with a combination of these polymorphisms in the genotype was analyzed separately (n=11; Table 3). Features of the study group were studied in comparison with patients with a different genotype from the study (n=142). Of the 11 patients, 8 were diagnosed with an aneurysm of the left ventricle (73%), while in the comparison group - only 34% (p=0.01). Thus, the chance of developing post-infarction aneurysm in patients with a combination of polymorphic variants CC rs2238296 of the POLG gene and CC rs4673 of the CYBA gene was increased by 5.6 (1.4; 22) times.

Table 3. Clinical and anamnestic characteristics of patients with a combination of genotypes CC rs2238296 of the POLG gene and CC rs4673 of the CYBA gene in comparison with other patients

sign Group 1 (CC POLG+CC CYBA; n=11) Group 2 (n=142) Achieved level of significance Gender, male/female, n (%) 11/0 (100%) 126/16 (88.7) 0.3 Age, Me (Q25; Q75), years 50(46;59) 56(50;61) 0.06 Left ventricular aneurysm, n (%) 8 (73%) 48 (34) 0.01 FC IHD, n (%)
I
II
III 3 (27.3)
7 (63.6)
1 (9.1) 18 (12.7)
73 (51.4)
51 (35.9) 0.2
0.4
0.4 FC CHF (NYHA), n (%)
I
II
III
IV 1 (9.1)
4 (36.4)
6 (45.5)
0 7 (4.9)
54 (38)
78 (55)
3 (2.1) 0.5
0.9
0.9
0.8 Left ventricular ejection fraction, Me (Q25; Q75), % 40 (27;52) 50(40;61) 0.006 Diabetes mellitus, n (%) 0 27 (19) 0.1 Obesity, n (%) 1 (10) 59 (41.5) 0.03 Arterial hypertension, n (%) 6 (54.5) 119 (84) 0.1 Peripheral atherosclerosis, n (%) 5 (45.5) 80 (56.3) 0.5 Acute cerebrovascular accident, n (%) 6 (54) 52 (36.6) 0.2 Chronic obstructive pulmonary disease, n (%) 6 (54) 76 (53.2) 0.9 Heart rhythm disorders, n (%) 3 (27.3) 14 (9.8) 0.1 Age at the time of the first myocardial infarction, Me(Q25;Q75), years 47.7 (44.7; 54.4) 51.4 (46.6;57) 0.3 Time from last myocardial infarction to inclusion in the study, Me(Q25;Q75) , months 25 (11;49) 15 (8.5; 48.7) 0.2 Number of myocardial infarctions, n (%)
1
2
3
4 7 (64)
3 (27)
0
1 (10) 95 (67)
14 (10)
6 (4.2)
4 (2.8) 0.8
0.1
0.6
0.3 Note: Me (Q25; Q75) - median and interquartile range, p - level of significance of differences, FC - functional class, CAD - coronary heart disease, CHF - chronic heart failure

Thus, after the development of acute myocardial infarction, blood is taken from the patient to determine the polymorphisms of the rs2238296 genePOLG and rs4673 geneCYBA.And if there is a combination SS genotype rs2238296 genePOLG and CC genotype of rs4673 gene polymorphismCYBA predict the development of left ventricular aneurysm in the postinfarction period. The positive predictive value is 73%, the negative predictive value is 67%. Thus, in the presence of a combination of the SS genotype rs2238296 genePOLG and CC genotype of rs4673 gene polymorphismCYBA in a patient who has undergone MI, a high probability of left ventricular remodeling with the development of an aneurysm is predicted.

New in the present invention is the identification of single nucleotide polymorphisms rs2238296 of the POLG gene and rs4673 of the CYBA gene associated with the development of left ventricular aneurysm in the postinfarction period, and the establishment of a specific genotype of these polymorphisms (a combination of genotypes SS rs2238296 of the POLG gene and SS polymorphism rs46 73 CYBA genes), which makes it possible to predict the development left ventricular aneurysms in patients with myocardial infarction.

Clinical example No. 1.

Patient K., 57 years old. 11 months ago suffered an acute myocardial infarction with ST segment elevation on the ECG. Thrombolytic therapy was performed with signs of reperfusion; coronary angiography was not performed at the time of infarction due to technical reasons. In the acute period of myocardial infarction, heart failure of class II according to Killip was recorded. The ejection fraction of the left ventricle was 54%, there was hypokinesis of the anterior wall of the left ventricle. In the postinfarction period, the patient noted an increase in shortness of breath, the appearance of retrosternal pain during normal physical activity. After 11 months, according to the ultrasound examination of the heart, the patient revealed dyskinesia of the apical segments of the anterior wall of the left ventricle (aneurysm), the ejection fraction was 45%. The patient was admitted to a specialized hospital for additional examination and choice of management tactics. Coronary angiography revealed multivessel obstructive lesion of the coronary arteries, and cardiosurgical revascularization with resection of the left ventricular aneurysm was recommended. A combination of the CC genotype rs2238296 of the POLG gene and the CC genotype of the rs4673 polymorphism of the CYBA gene was found in a genetic study, which is a criterion for the risk of post-infarction aneurysm development, according to the proposed method, and when studied in the acute period of myocardial infarction, it could affect the management of the patient in the post-infarction period.

Clinical example No. 2.

Patient F., male, 55 years old. Six months ago, he had a myocardial infarction with a rise in the ST segment on the ECG. The patient underwent successful thrombolytic therapy. Surgical or interventional revascularization of the coronary arteries at the time of myocardial infarction was not performed. The ejection fraction of the left ventricle was 58%; also, according to echocardiography, there was a zone of hypokinesis along the anterior wall of the left ventricle. When a technical possibility appeared - 6 months after MI - the patient underwent coronary angiography, a multi-vessel obstructive lesion of the coronary arteries was detected, and cardiosurgical revascularization was recommended. According to the results of ultrasound examination and intraoperative data, there were no signs of aneurysmal remodeling of the left ventricle. A combination of the TT genotype rs2238296 of the POLG gene and the TC genotype of the rs4673 polymorphism of the CYBA gene was found during a genetic study, which does not predict a high risk of developing postinfarction left ventricular aneurysm, which is confirmed by a clinical example.

The method proposed as an invention has been tested on 153 patients and its use will effectively predict the development of left ventricular aneurysm in patients with myocardial infarction, based on genetic analysis.

Bibliography

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Claims (1)

A method for predicting the development of an aneurysm of the left ventricle in patients with a myocardial infarction, taking into account genetic factors, characterized in that in patients with a myocardial infarction, blood is taken for genetic analysis and polymorphisms of the rs2238296 gene are determinedPOLG and rs4673 geneCYBA,and if there is a combination SS genotype rs2238296 genePOLG and CC genotype of rs4673 gene polymorphismCYBA predict the development of left ventricular aneurysm in the postinfarction period.