RU2601381C1 - Diagnostic technique for developing painless myocardial ischemia in young females with estrogen deficiency with arterial hypertension in late fertile period depending on intergenic interactions - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiovascular diagnostics. Young women with estrogen deficiency with arterial hypertension in late fertile period are subject to echocardiographic, laboratory examination, and the obtained results are processed. On the obtained data Z number is determined by a developed formula. If Z<0 and in presence of gene polymorphism painless myocardial ischemia is diagnosed. If Z>0 and with no gene polymorphism absence of painless myocardial ischemia is diagnosed.

EFFECT: method enables preventing development of complications of cardiovascular system in the following periods of a woman's life - during menopause and postmenopause due to timely diagnosis of the risk of developing painless ischemia at the pre-hospital stage.

1 cl, 2 ex

Description

The invention relates to medicine, it is possible to use in areas such as general therapy, cardiology, endocrinology, gynecology.

Clinical and epidemiological studies of recent years have shown that pathology of the cardiovascular system dominates the structure of morbidity, disability and mortality in women. The share of cardiovascular diseases among the causes of death of women (46%) exceeded their share among the causes of death of men (40%) (Report of the American Heart Association "Cardiovascular diseases in women", 1998). The turning point in the incidence of cardiovascular disease in women is the onset of premenopause.

The change in the incidence of cardiovascular pathology is due to a number of adverse changes in the body of women developing under conditions of hormonal imbalance of the late fertile period. Such pathological changes include an increase in blood pressure, a change in metabolism in the myocardium and connective tissue of blood vessels. This explains the close attention to the problem of premenopause in women and the accompanying pathological processes.

Since menopause is characterized by a sharp decrease in estrogen levels, it can be assumed that the increase in blood pressure in the late fertile period may be to some extent due to the initial decrease in estradiol production. In recent decades, experimental data have been obtained on the effect of female sex hormones on indicators involved in the regulation of blood pressure (Karachentsev AN, Kuznetsova IV, 2003; Sader MA, Celermajer DS, 2000, Dubey RK, 2003) . It has been proven that estradiol and progesterone reduce the total peripheral resistance of arterioles using endothelium-dependent and endothelium-independent mechanisms of action on vascular tone (Dubey R.K., 2003; Mueck A., Seeger N., 2004). Low estrogen and progesterone levels can, along with other factors, lead to endothelial dysfunction and contribute to the development of hypertension or worsen the course of the disease in the late reproductive period, as well as be one of the key consequences of the appearance of painless myocardial ischemia.

The publication Tereshchenko S.N. was chosen as the closest analogue. Gene polymorphism of angiotensin converting enzyme, angiotensin II, NO synthetase, estrogen receptors and gender differences in their effect on the development of cardiovascular pathology. - Cardiology. 2009.4 p. 58-62. According to this publication, genetic factors determine the resistance or predisposition to the development of cardiovascular disease (CVD). A promising method in identifying risk and in predicting CVD outcomes is the study of candidate genes. Endogenous estrogens have an inhibitory effect on RAAS, reducing the expression of ACE mRNA, block the induction of oncogenes by angiotensin 2 and inhibit myocardial hypertrophy. Estrogens can directly regulate the level of nitric oxide (via the nuclear element SP1, which increases the transcription of NO synthetase) or indirectly block the activity of the promoter of the tumor necrosis factor α-factor, which increases the duration of its presence in the blood and the activity of NO synthetase. Polymorphism of not only the estrogen receptor gene, but also the ACE, angiotensin II, and NO synthetase genes can have different consequences. There are interconnections of polymorphic variants with the risk, prognosis and course of CVD. Polymorphism of the gene of NO synthetase type 3 (endothelial) is involved in the synthesis of NO by endothelium and, therefore, in the regulation of vascular tone, blood flow and blood pressure (BP). NO is also important in the pathogenesis of coronary heart disease (CHD), because inhibits the proliferation of smooth muscle cells, has a protective effect on platelet aggregation, inhibits the adhesion of leukocytes to the endothelium. All this suggests the presence of a connection between the polymorphism of this gene with AH and IHD. Currently, there are only a few works devoted to the sex-specific effect of the polymorphism of this gene. However, it was found that variants of the NO synthetase gene affect diastolic blood pressure and contribute to the risk of hypertension, and higher in women.

The authors found that the presence of a variant of the ACE gene DD is associated with an increased risk of developing vascular diseases. The presence of homozygotes (DD genotype) corresponds to an increase in the risk of developing coronary heart disease by 1.2 times on average in 30 studies, MI by 1.3 times.

The results of the study of the polymorphism of the angiotensin II receptor gene type 1 (AT II P1) are very contradictory. In the closest analogue, the effect of this polymorphism on the development of LV myocardial hypertrophy is noted. It was shown that a significantly large mass of the left ventricular myocardium and the thickness of the interventricular septum in individuals with the CC AT II P1 genotype. In a number of works this is not confirmed. The incidence of myocardial infarction was significantly higher in individuals with the DD genotype of the ACE gene and CC of the AT II P1 gene. A high risk of early development of CHD in individuals with a combination of these genotypes has been shown. The association of MI with the SS genotype in the European population was confirmed.

Gene polymorphism of estrogen receptors. Women carriers of the ESR1 gene have twice the cardiovascular risk. The study showed that two variants of the estrogen receptor gene (ESR1) double the risk of myocardial infarction and CHD in postmenopausal women.

The influence of SS genotype carriage in young and middle-aged women on the thickness of the intima of the coronary arteries was revealed. Autopsy material of coronary vessels was studied in 115 women from 15 to 49 years old. In the group with the SS genotype, the intima thickness was significantly greater than in the groups with TT and CT genotypes, regardless of age and BMI.

Estrogens are known to have a direct and indirect effect on cardiomyocytes. Scientists have studied the relationship between the polymorphism of the ESR 1 gene in individuals with breast cancer. In carriers of the SS genotype, hypertrophy of the interventricular septum developed by 17% and 20% of LVMH, earlier strokes were noted than in carriers of heterozygotes.

It is important that this relationship was not dependent on dyslipidemia, hypertension, diabetes, BMI, namely, gene polymorphism.

The disadvantages of the closest analogue are as follows: studies were conducted in the population as a whole, without gender differences. Women included in the study were in menopause and postmenopausal periods. In our study, cardiovascular complications - painless ischemia, in particular, are detected in young women not only with estrogen deficiency, but also the main thing is polymorphism, i.e. mutations of certain genes.

The objective of the invention is to develop a method for the diagnosis of painless myocardial ischemia in women with estrogen deficiency with hypertension in the late fertile period, depending on intergenic interactions.

The technical result - it is possible to prevent the development of complications of the cardiovascular system in subsequent periods of a woman's life - the period of menopause and postmenopause due to timely diagnosis of the risk of developing painless ischemia at the prehospital stage. In addition, it is possible to develop recommendations aimed at improving the quality of examination of patients, improve the methodology of diagnosis, treatment and dynamic monitoring.

The specified technical result is achieved by the fact that a method for diagnosing the development of painless myocardial ischemia in young women with estrogen deficiency with arterial hypertension in the late fertile period, which consists in conducting an echocardiographic, laboratory examination, the obtained results are processed and make up the decisive rule

,

,

 where a is the left ventricular myocardial mass index (LVMI) according to echocardiography,

       b - the ratio A / E (units) according to echocardiography,

      C is the level of estradiol in blood serum, (PCG / ml),

with Z <0 and the presence of gene polymorphism, painless myocardial ischemia is diagnosed, with Z> 0 and in the absence of gene polymorphism it is diagnosed that there is no painless myocardial ischemia.

In order to identify predictors of the occurrence of BBIM episodes in women with estrogen deficiency with hypertension with various intergenic interactions (gene polymorphism NOS3 - 786, ESR1 - 397, AGTR1 1166), echocardiographic parameters were used to construct a regression model. Previously, using a correlation analysis, we tried to identify which echocardiography parameters, in our opinion, reflecting the structural-geometric state of the left ventricle, systolic and diastolic function, are the most dependent on the occurrence of BBIM in the groups of patients studied.

As shown by the multiple correlation analysis, in women with estrogen deficiency with hypertension with various intergenic interactions (gene polymorphism NOS3 - 786, ESR1 - 397, AGTR1 1166), the most significant correlation was observed between the occurrence of BBIM episodes and LVMI (r = 0.66; p < 0.001), with a ratio of integral A / integral E (r = 0.47; p <0.001), with estradiol level (r = -0.58, p <0.001). Further, by adding step-by-step the studied parameters in decreasing order of their predictor ability to influence the appearance of BBIM, a model was obtained for the patients included in the study. To evaluate the constructed model, sensitivity and specificity indicators were calculated.

The regression equation for patients with estrogen deficiency with hypertension with various intergenic interactions included in the study, and the indicators of sensitivity and specificity are presented below:

,

,

where a is the left ventricular myocardial mass index (LVMI) (g / m ² ) according to echocardiography;

      b - the ratio of the integrals A to E (units) according to the data of echocardiography;

      c - the level of estradiol in blood serum, (PCG / ml).

At Z <0, the risk of episodes of BBIM can be reliably predicted (p <0.001).

Sensitivity 97.6%, specificity 93.6%.

The reference value of estradiol level was obtained for the risk of developing BBIM episodes in women with estrogen deficiency with hypertension and various intergenic interactions 0.25 ± 0.02 pg / ml with LVMI 130.7 ± 3.4 g / m ² , integral A / integral E 0 , 88 ± 0.2.

An association of the genotype of endothelial synthetase nitric oxide NOS3 - 786 SS, estrogen receptor ESR1 - 397 SS, type 1 angiotensin II receptor AGTR1 1166 SS with a high risk of developing painless myocardial ischemia was revealed.

The testing of this regression equation was carried out on a control sample of 54 women with estrogen deficiency with hypertension with various intergenic interactions, the average age of 43.4 ± 7.5 years, different from the initial sample used to build the model. The sensitivity and specificity of the method have been confirmed. Thus, apparently, this model can be used in patients with hypertension with estradiol deficiency with various intergenic interactions between the ages of 35 and 50 years for the possible prevention of the development of CCC complications in subsequent periods of a woman’s life - the period of menopause and postmenopause due to timely risk diagnosis development of BBIM at the prehospital stage.

It can be assumed that in women with esradiol deficiency with hypertension with the genotype of endothelial synthetase nitric oxide NOS3 - 786 CC, estrogen receptors ESR1 - 397 CC, angiotensin type II receptor AGTR1 1166 CC, the occurrence of BBIM episodes may be due not only to the degree of development of GDV , features of the structural and functional state of the left ventricle during its remodeling by the severity of disorders of systolic and, especially, diastolic functions, but also by the presence of hypoestrogenemia, gene polymorphism.

Examples of applying the regression equation in clinical practice.

1. Patient B., 46 years old, the duration of hypertension is 5 years, on an outpatient basis, blood pressure is 138/89 mm Hg. There is a violation of the rhythm and nature of menstruation, the level of estradiol is 0.29 pkg / ml. The genotype of endothelial synthetase of nitric oxide NOS3 - 786 TC, estrogen receptor ESR1 - 397 CT, type 1 angiotensin II receptor AGTR1 1166 AC were revealed. She complained of an increase in blood pressure, which is accompanied by a headache in the temporal areas. When conducting an echocardiography examination according to a standard method, the left ventricular myocardial mass index (LVMI, g / m ² ) = 105.754; the ratio of the integrals A and E (unit) = 0.91.

The use of the above equation for a patient with estrogen deficiency with hypertension indicated that painless myocardial ischemia should not be detected. At the next stage, in order to check the equation for identifying episodes of painless myocardial ischemia, ECG holter monitoring was performed. No episodes of painless myocardial ischemia were detected.

2. Patient I., 49 years old, the duration of hypertension is 5.5 years, on admission the level of blood pressure is 141/94 mm Hg. There is a violation of the rhythm and nature of menstruation, the level of estradiol is 0.21 pkg / ml. The genotype of endothelial synthetase of nitric oxide NOS3 - 786 SS, estrogen receptor ESR1 - 397 SS, and receptor type 1 angiotensin II AGTR1 1166 SS were revealed. She complained of frequent headache in the occipital region, dizziness, tachycardia, cardialgia, associated with psycho-emotional stress at work, poor sleep. When conducting echocardiography examination according to a standard method, the left ventricular myocardial mass index (LVMI, g / m ² ) = 138.87; the ratio of the integrals A and E (unit) = 0.98.

The use of the above equation for a patient with estrogen deficiency with hypertension with gene polymorphism suggested the presence of episodes of painless myocardial ischemia.

In order to check the equation for detecting painless myocardial ischemia in this case, ECG holter monitoring was performed according to the generally accepted method on an outpatient basis for 24 hours against the background of complete drug withdrawal. BBIM was determined in accordance with diary entries about the absence of pain. There were 5 episodes of BBIM during the day; total duration of episodes of painless ischemia (11 min); ST segment offset depth (2.7 mm).

Claims (1)

A method for diagnosing the development of painless myocardial ischemia in young women with estrogen deficiency with arterial hypertension in the late fertile period, which consists in conducting an echocardiographic, laboratory examination, the obtained results are processed and constitute a decisive rule
Z = -0.025a-0.0215b + 34.309c-5.515, where:
a - left ventricular myocardial mass index (LVMI) according to echocardiography,
b - the ratio A / E (units) according to echocardiography,
C is the level of estradiol in blood serum, (PCG / ml),
with Z <0 and the presence of gene polymorphism, painless myocardial ischemia is diagnosed, with Z> 0 and in the absence of gene polymorphism it is diagnosed that there is no painless myocardial ischemia.