RU2796311C1 - Method for predicting the progression of heart failure in patients with obstructive sleep apnea syndrome - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to cardiology, therapy, rehabilitation, and can be used to predict the progression of heart failure in patients with obstructive sleep apnea. DNA is isolated from the buccal epithelium. The polymorphic locus rs3918242 is determined using the real-time polymerase chain reaction method followed by allele typing of the matrix metalloproteinase-9 gene. In the presence of a heterozygous genotype, the risk of progression of heart failure in its carriers is predicted.

EFFECT: method improves the accuracy of disease prognosis by determining the heterozygous genotype of the polymorphic locus rs3918242 of the matrix metalloproteinase-9 gene.

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Description

The invention relates to medicine and can be used in cardiology, therapy, rehabilitation to improve the accuracy of predicting the progression of chronic heart failure in patients with obstructive sleep apnea and, therefore, reduce the risk of high premature mortality in patients with socially significant pathology, taking into account genetic markers.

According to the literature, the prevalence of sleep apnea syndrome (OSAS) in a cohort of patients with CHF reaches 18%, significantly exceeding the general population level [1], while it is known that OSAS significantly aggravates the course of CHF [2, 3]. One of the reasons for the rapid progression of CHF in OSAS is the similarity of the pathogenetic mechanisms of these conditions: hypersympathicotonia, oxidative stress against the background of periodic hypoxia and reoxygenation, chronic subclinical inflammation and their additivity in combination of pathologies [4]. The most sensitive analytical indicators that allow determining the prognosis of the disease at an early stage of CHF progression are laboratory biomarkers [5, 6].

Biomolecules of the family of matrix proteinases are currently considered as one of the most significant inflammatory mediators actively involved in the pathogenesis of cardiovascular diseases [7, 8]. Matrix metalloproteinase 9 (MMP 9) is one of the most active in this respect [9]. Numerous clinical studies with the determination of the level of MMP-9 in the blood of patients suffering from various cardiovascular diseases, as well as laboratory studies on animals, demonstrate the greatest increase in MMP-9 activity against the background of processes associated with hypoxia and reoxygenation [10].

Given the key role of hypoxia-reoxygenation processes in the pathogenesis of OSA, MMP-9 activity has been actively studied in this category of patients in recent years. The literature describes significant positive correlations between the activity of this enzyme and the severity of nocturnal hypoxemia in OSAS [11]. According to a number of studies, MMP-9 activity in patients with OSAS was also associated with an increased risk of cardiovascular complications [12]. Separately, in a number of studies, various genetic polymorphisms responsible for MMP-9 expression were studied [13, 14, 15]. The results of these studies were rather contradictory. Thus, in the work of Chinese researchers, the predominance of the 1562 C/T polymorphism in patients with severe OSA and a high risk of cardiovascular complications was shown [16]. On the contrary, a publication by Turkish authors indicates the predominance of 1626 C/T polymorphism in this cohort of patients [17]. Information about similar studies for the Russian population is not available in available sources.

The literature presents the result of a discussion of the possibility of the influence of matrix metalloproteinase-9 genotypes on the development of OSAS, the essence of which is to determine the MMP-9 gene polymorphism by polymerase chain reaction to confirm the relationship between MMP-9 –15 62C > T and predisposition to the development of the disease itself - OSAS , but it was not possible to prove its existence [18]. The disadvantages of this study is that the MMP-9 gene polymorphism was determined to assess the relationship of polymorphisms of this gene with a predisposition to the development of the disease, but did not provide an opportunity to assess the prognosis of the course of an existing disease and its complications, in particular, the progression of chronic heart failure.

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

The objective of the invention is to improve the accuracy of predicting the progression of chronic heart failure in patients with obstructive sleep apnea syndrome by analyzing the polymorphism of the matrix metalloproteinase-9 (MMP-9) gene.

The problem is solved by isolating DNA from the buccal epithelium using real-time polymerase chain reaction, followed by typing of alleles of the matrix metalloproteinase-9 gene (polymorphic locus rs3918242) in patients with obstructive sleep apnea syndrome. If carriers of the polymorphic locus rs3918242 of the matrix metalloproteinase-9 gene of the heterozygous genotype are detected, a high risk of progression of chronic heart failure is predicted.

New in the proposed method is that the polymorphism of one gene - the MMP-9 gene (polymorphic locus rs3918242) - is determined to predict the progression of chronic heart failure in patients with obstructive sleep apnea syndrome.

The proposed method for predicting the progression of chronic heart failure using genetic risk markers is based on the fact that it is based on the participation of matrix metalloproteinases in the proteolysis of extracellular matrix proteins and, consequently, in the remodeling of the heart and vascular tissue, maintaining it.

architectonics and homeostasis, in angiogenesis, cell proliferation, migration and differentiation, programmed cell death, release of apoptosis ligands, as well as modulation of chemokine and cytokine activity, which potentiates the manifestation and progression of heart failure (HF) and, ultimately, leads to death due to her decompensation.

The data of several studies with the determination of the level of MMP-9 in the blood of patients suffering from various cardiovascular diseases, as well as laboratory studies on animals, demonstrate the greatest increase in MMP-9 activity against the background of processes associated with hypoxia and reoxygenation [19]. Active oxygen radicals generated by macrophages in this case are the main activator of MMP-9 [20]. Given the key role of hypoxia-reoxygenation processes in the pathogenesis of OSAS, MMP-9 activity has been actively studied in this category of patients in recent years [11], while data are provided on the presence of a positive relationship between the expression of this biomarker and the degree of nocturnal hypoxemia in OSAS [12]. According to other studies in patients with OSAS, MMP-9 activity is associated with an increased risk of cardiovascular complications [21]. In animal experiments, associations of MMP-9 with the level of key pro-inflammatory cytokines and the severity of cardiac fibrosis induction were found [22].

Therefore, the determination of the MMP-9 genotype can make a significant contribution to improving the risk stratification of apoptosis and myocardial remodeling, leading to the progression of chronic heart failure and its decompensation.

The technical result of the invention is to improve the accuracy of disease prognosis.

The advantage of the invention is that the method allows:

- assess the personal risk of chronic heart failure progression in patients with hypoxia/reoxygenation due to obstructive sleep apnea syndrome and prescribe appropriate personalized therapy aimed at inhibiting myocardial remodeling processes;

- to determine the priority group of patients with obstructive sleep apnea for dispensary observation and optimization of effective targeted preventive measures aimed at preventing the progression of cardiac dysfunction.

- to reduce the large financial costs of health care associated with expensive treatment of a widespread pathology of the working-age population of the state.

Significant features showed in the claimed combination of new properties that do not explicitly follow from the prior art in this field and are not obvious to a specialist. An identical set of features was not found in the analyzed literature. The present invention can be used in health care.

Based on the foregoing, the invention should be considered as meeting the conditions of patentability “Novelty”, “Inventive step”, “Industrial applicability”.

The invention will become apparent from the following description and the accompanying figure.

In FIG. 1 shows the results of the regression analysis. The calculated values of the odds ratio are shown, reflecting the significance of the influence on the course and prognosis of CHF of the polymorphism of the MMP-9 gene (rs3918242). The ordinate shows the odds ratios, the abscissa shows the A/A, G/A, and G/G genotypes of the MMP-9 gene (rs3918242). According to the analysis, it follows that the presence of the G/A genotype is associated with an increase in the frequency of CHF progression by 5.34 times (OR 5.34 (1.81-23.12), p=0.001).

The method is carried out as follows:

DNA is isolated from buccal epithelial cells using the phenol-chloroform extraction method [23]. Tubes with clinical specimens (buccal epithelium) are centrifuged at 14 thousand rpm, 15 minutes. The pellet is resuspended in 300 µl of solution #1 (100 mM Tris HCl pH = 8.0; 10 mM EDTA, 100 mM NaCl), then 50 µl of solution #2 (10% sodium dodecyl sulfate (SDS)) and 10 µl of proteinase K ( 10 mg/ml), mix well and incubate for 1 hour at 55°C. 200 µl of TE-equilibrated phenol and 200 µl of chloroform are added. Mix vigorously and centrifuge for 10 min at maximum speed (14 t/min). The upper phase is transferred into a clean test tube, without touching the lower and interphase. 400 μl of chloroform is added to it, mixed and centrifuged for 5 min at maximum speed (14 t/min). The upper phase is transferred to a clean test tube. Add 10 µl LPAAG, 40 µl 3M AcNa pH5.4, 800 µl EtOH, mix thoroughly and incubate overnight at –200°C. Centrifuge for 15 min at maximum speed (14 t/min). The supernatant is removed and 400 µl of 75% EtOH is added to the pellet. Incubate 10 min at room temperature. The supernatant is removed, making sure that the precipitate remains in the tube. Dry tubes with open lids in a microtube incubator at 370° C. for 15 min. 100 μl of distilled water is added to the precipitate and heated at 650°C for 10 minutes.

Primers are used to analyze allele variants of genes by real-time allele-specific amplification using SYBR Green I dye to induce fluorescence. One of the primers in the pair is common, the other two differ in the 3'-terminal nucleotide: one of the primers is complementary to the wild-type DNA sequence, the other to the sequence containing a single nucleotide substitution. Each sample is amplified using both pairs of primers. With complete complementarity of the template and primer, the amplification reaction proceeds with greater efficiency than in the case of the presence of an unpaired nucleotide at the 3'-end of the primer. Detection of the results of the polymerase chain reaction is carried out in real time. To do this, the fluorescent dye SYBR Green I is added to the reaction mixture, which is an intercalating dye that fluoresces approximately 200 times more intensely when bound to a double-stranded DNA molecule. The PCR product is a double-stranded DNA fragment. Thus, the intensity of the fluorescent signal is directly proportional to the amount of product formed.

Statistical processing of the study results was carried out using STATISTICA 10.0 and MedCalc 11.5.0.0 programs. The nature of the distribution of signs was assessed using the Kolmogorov-Smirnov criteria with the Lilliefors and Shapiro-Wilk corrections and visually using the construction of histograms. The homogeneity of general variances was assessed using the Levene test. To test statistical hypotheses in the analysis of quantitative indicators, the following were used: the Mann-Whitney test when comparing two independent groups. When analyzing qualitative features, contingency tables were analyzed using Pearson's χ ² test. If there were cells with an expected frequency less than 5, then a two-tailed Fisher's exact test or Yates' correction (for 2×2 tables) was applied.

The strength of associations of the genotypic characteristics of the studied genes with the risk of developing an unfavorable outcome was assessed by the values of the odds ratio (odds ratio, OR) and its 95% confidence interval (95% CI, C.I.). Calculation of the relative risk indicator of adverse course of CHF was carried out on the basis of the calculation of the odds ratio (odds ratio - OR) according to the formula: OR=(a+0.5)(d+0.5)/(b+0.5)(c+ 0.5), where a is the frequency of the genotype in the sample of patients, b is the frequency of the genotype in the control sample, c=(1-a) is the sum of the frequencies of the remaining genotypes in the sample of patients, d=(1-b) is the sum of the frequencies of the remaining genotypes in the control sample. The parameter 0.5 in the presented formula is used when one of the numbers a, b, c, d is zero or less than three. The value OR=1 indicated the absence of associations, with OR>1 there was a positive association of the genotype with the disease (“risk factor”).

We examined 71 male patients with moderate and severe OSAS (with an apnea/hypopnea index (AHI) >15 per hour) at an average age of 47 [38.0; 55.0] years with CHF I-III functional class (according to NYHA) (Table 1).

Table 1 - Characteristics of the examined patients

Parameter Index Age, years 47 [38; 55] Weight, kg 108 [98; 119] Height, cm 178 [174; 181.5] Body mass index, kg / m ² 34 [31.6; 37.9] Apnea/hypopnea index, number/hour 28 [23.0; 34.0] Average night saturation, % 94.4 [93.5; 95.8] Left ventricular ejection fraction, % 60.0 [55.5; 62] Longitudinal size of the left atrium, cm 5.35 [5.0; 6.2] LVMI, g/m ² 111.4 [87.5; 128.7] Chronic heart failure, FC I
Chronic heart failure, FC II
Chronic heart failure, FC III 21 (29.6)
44 (62.0)
6 (8.4) 6-minute walk test, m 411.0 [378.0; 512.0] RVSD, mm Hg 30.0 [19.0; 38.0] Diastolic dysfunction type 1, n (%)
Diastolic dysfunction type 2, n (%) 37 (52.1)
34 (47.9) Notes. LVMI - mass index of the myocardium of the left ventricle, FC - functional class, RVH - systolic pressure in the right ventricle.

To diagnose OSAS, all patients underwent a polysomnographic study of night sleep using the Somnolab2PSG diagnostic system (Weinemann, Germany). The severity of obstructive sleep disorders was assessed by the apnea/hypopnea index (AHI), the study included patients with moderate (14 < AHI < 30 per hour) and severe (AHI ≥ 30 per hour) forms of OSAS. Also, according to the results of the polysomnographic study, the level of average night saturation (SPO ₂ av.), the desaturation index, and the presence of cardiac arrhythmias at night were evaluated.

Echocardiography (EchoCG) was performed for all patients according to the standard protocol using the EPIQ device (Philips Ultrasound, Inc., USA), the following parameters were evaluated: the size of the left and right chambers of the heart, LV EF (according to Simpson), the mass index of the left ventricular myocardium, the thickness of the interventricular septum , wall thickness of the left and right ventricles, systolic pressure in the pulmonary artery (determined by the calculation method according to the degree of tricuspid regurgitation using the continuous wave method).

Physical tolerance was assessed by a 6-minute walk test (TSW) at entry into the study and at 12 months of prospective follow-up.

As a genetic marker, polymorphisms of the matrix metalloproteinase-9 (MMP-9, rs3918242) gene were evaluated using the polymerase chain reaction.

A specially designed clinical card was filled out for each patient. All patients gave their written informed consent to participate in the study. Drug therapy for hypertension and CHF, which patients received during the observation period, was optimal and in line with modern recommendations.

After 12 months of observation, no symptoms and signs of progression of CHF were found in 44 patients (Group 1), in other patients (Group 2, n=32), progression of CHF was registered according to the 6-minute walk test.

Analysis of the frequency of occurrence of polymorphisms of the MMP-9 gene (rs3918242) depending on these groups of patients showed that in patients with an unfavorable course of CHF, the G/A genotype prevailed (Table 2).

Table 2 - The frequency of occurrence of gene polymorphisms depending on the development of progression of CHF according to TSH (n,%)

Gene Genotype Group 1, n=44 Group 2, n=32 χ2 p-value MMP-9 (rs3918242) A/A 16 (36.4) 13 (40.6) 0.93 0.332 G/A 21 (47.7) 11 (34.4) 5.34 0.012 G/G 7 (15.9) 8 (25.0) 1.94 0.114

According to regression analysis data, the presence of the G/A genotype of the MMP-9 gene (rs3918242) was associated with an increase in the risk of CHF progression by 5.34 times (OR 5.34 (1.81-23.12), p=0.001). Therefore, the G/A genotype of the MMP-9 gene (rs3918242) has a high ability to activate transcription and expression of target genes in the myocardium, through which myocardial remodeling and progression of CHF in patients with OSAS are realized.

A method for predicting the progression of CHF in patients suffering from obstructive sleep apnea based on the determination of the MMP-9 gene polymorphism is illustrated by the following clinical examples, indicating that the determination of the G/A of the MMP-9 gene (rs3918242) provides an objective assessment of the risk of developing an unfavorable course of pathology .

Example 1

Patient T., aged 53 (BMI - 33.1 kg/m ² ). He was admitted to the cardiology department on 06/06/2018 with complaints of weakness and shortness of breath during physical exertion (climbing to the 3rd floor, walking at a normal pace for 300-400 m), daytime sleepiness. Objective examination: pulse - 96 beats/min, blood pressure 140/100 mm Hg, respiratory rate - 18 per minute. When conducting a polysomnographic study of nocturnal sleep, a severe form of obstructive sleep apnea syndrome was diagnosed: AHI - 44 per hour. The level of NT-proBNP in the blood is increased - 425 pg/ml (table 3).

Genotyping revealed the G/G genotype of the gene (rs3918242) of the MMP-9 gene.

Clinical diagnosis: Hypertensive disease stage III, Controlled course, target levels of blood pressure <140/90 mm Hg. Obesity 1 tbsp. Risk 4 (very high). CHF 2A, FC III (NYHA). Obstructive sleep apnea syndrome. Severe form (IAH 44 per hour).

Against the background of ongoing drug therapy in accordance with current clinical guidelines, a clinical improvement in the patient's condition was achieved - hemodynamics were stabilized, shortness of breath ceased to bother, edema resolved and exercise tolerance improved. At discharge from the hospital, the following were prescribed: valsartan 320 mg per day, spironolactone 25 mg per day, atorvastatin 40 mg per day. The patient adhered to these recommendations at the outpatient stage. The patient did not receive the recommended hardware CPAP therapy.

Table 3 - The main clinical and instrumental characteristics of patient T.

Indicators Initially After 12 months FC HSN (according to NYHA) II I TSHH (m) 335 435 LV EF (%) 62 62 LP ave. (mm) 60 56 LVMI (g/m ² ) 132.6 138.6 MZHP (mm) 12 12 diastolic dysfunction 1 type 1 type RVPS (mm Hg) thirty 28 NT-proBNP (pg/ml) 425 288 YAG (per hour) 44 35 SPO2 avg. (%) 91 93

Note. Here and in Table 5. FC CHF - functional class of chronic heart failure, TSHH - six-minute walk test, LV EF - left ventricular ejection fraction, LP pr.r. - longitudinal diameter of the left atrium, LP S - left atrial area, LVMI - index masses of the myocardium of the left ventricle; IVS - the thickness of the interventricular septum of the left ventricle; RRV - mean pressure in the right ventricle; EDD - end-diastolic size, AHI - apnea / hypopnea index, SPO ₂ cf. – average night saturation.

After 12 months The patient's condition clinically deteriorated, he did not actively complain. He did not seek medical help. Exercise tolerance improved by 23%. Objectively: the skin is clean, of normal color, moisture. The tongue is moist and clean. BP 125/65 mm Hg, muffled heart sounds, rhythmic 72 beats/min. Respiration is vesicular, carried out in all departments, the respiratory rate is 15 per minute, the abdomen is not enlarged, soft, painless on palpation, peristalsis is auscultated. There are no edema. FC CHF - up to I according to NYHA. According to Echo-KG - positive dynamics, signs of reverse myocardial remodeling were revealed.

It was shown that in a patient with obstructive sleep apnea syndrome, having the G/G genotype of the rs3918242 polymorphism of the MMP-9 gene, there was no progression of chronic heart failure, but, on the contrary, there was a decrease in the severity of CHF.

Example 2

Patient S., 49 years old. (BMI - 40.4 kg / m ² ). He was admitted to the cardiology department on July 19, 2018 with complaints of mixed dyspnea, palpitations during physical exertion: walking at a normal pace for 300-400 m, climbing 3-4 floors, headache in the morning, daytime sleepiness, disturbed sleep. Objective examination: pulse - 84 beats/min, blood pressure - 160/100 mm Hg, respiratory rate 18 per minute, moderate swelling of the feet. When conducting a polysomnographic study of night sleep, a severe obstructive sleep apnea syndrome was diagnosed (AHI - 54.2 per hour). The level of NT-proBNP in the blood is increased - 346 pg/ml (table 4).

Table 4 - Main clinical and instrumental characteristics of patient S.

Indicators Initially After 12 months FC HSN (according to NYHA) II III TSHH (m) 425 288 LV EF (%) 66 48 LP ave. (mm) 58 62 LVMI (g/m ² ) 132.9 138.4 MZHP(mm) 13 13 diastolic dysfunction 1 type type 2 RPV (mm Hg) 38 40 NT-proBNP (pg/ml) 346 428 YAG (per hour) 54.2 58.6 SPO2 avg. (%) 92.5 91

Note: see table 3.

Genotyping revealed the G/A genotype of the MMP-9 gene (rs3918242).

Clinical diagnosis: Stage III hypertension, controlled course, target levels <140/90 mm Hg. Obesity 2 tbsp. Risk 4 (very high). CHF 2A, FC II (NYHA). Obstructive sleep apnea syndrome. Severe form (IAH 54.2 per hour).

Against the background of ongoing drug therapy in accordance with current clinical guidelines, a clinical improvement in the patient's condition was achieved - hemodynamics were stabilized, shortness of breath ceased to bother, edema resolved and exercise tolerance improved. At discharge from the hospital, the following were prescribed: azilsartan 40 mg per day, chlorthalidone 12.5 mg per day, eplerenone 50 mg per day, atorvastatin 40 mg per day. The patient adhered to these recommendations at the outpatient stage. The patient did not receive the recommended hardware CPAP therapy.

After 5 months, the patient was re-admitted to the hospital for emergency reasons with complaints of shortness of breath, irregular heartbeat. ECG registered paroxysmal atrial fibrillation, tachysystolic variant (HR 120 per minute). Against the background of ongoing antiarrhythmic therapy (propafenone 600 mg per day), cardiac arrhythmias were stopped and sinus rhythm was restored. In accordance with the recommendations, dabigatran 300 mg per day and metoprolol succinate 25 mg per day were prescribed. The patient's condition improved, shortness of breath at rest and during normal exertion no longer bothered him, and he was discharged to the outpatient stage.

During the subsequent period of outpatient follow-up, the patient's condition remained stable and he did not seek medical attention. After 12 months from the moment of the first visit, during the control examination, a decrease in exercise tolerance was noted (the distance according to TSH decreased by 32%), body weight increased by 6 kg, pastosity of the feet was occasionally noted. FC CHF increased to FC III according to NYHA. According to Echo-KG, signs of myocardial remodeling were noted in dynamics: a decrease in LV EF, an increase in the size of the left atrium.

Thus, it was demonstrated that a patient with obstructive sleep apnea syndrome, having the G/A genotype of the rs3918242 polymorphism of the MMP-9 gene, developed progression of chronic heart failure.

The proposed method was applied in 71 patients with obstructive sleep apnea syndrome and allows predicting a high risk of progression of chronic heart failure by analyzing the polymorphism of the matrix metalloproteinase-9 gene even before the start of treatment, which allows assessing the personal risk of developing an unfavorable course of the pathology and prescribing appropriate personalized therapy aimed at inhibition of myocardial remodeling processes; to determine a priority group of patients for dispensary observation and optimization of effective targeted preventive measures aimed at preventing the progression of cardiac dysfunction, thus reducing the large financial costs of health care associated with expensive treatment of a widespread pathology of the working population of the state.

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Claims (1)

A method for predicting the progression of heart failure in patients with obstructive sleep apnea syndrome, characterized in that DNA is isolated from the buccal epithelium using the real-time polymerase chain reaction method, followed by typing of alleles of the matrix metalloproteinase-9 gene and determining the gene polymorphism - the polymorphic locus rs3918242 and at the presence of a heterozygous genotype in its carriers predicts the risk of progression of heart failure.

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