RU2802996C1 - Method of treatment of myocardial fibrosis in patients with ischemic heart disease - Google Patents

Abstract

FIELD: medicine; cardiology.

SUBSTANCE: invention can be used to treat myocardial fibrotic changes in patients with coronary heart disease (CHD). The method is as follows: in addition to antifibrotic therapy, Longidaza 3,000 IU is taken intravenously for 5 days, then Longidaza 3,000 IU suppositories are taken rectally, 1 piece 1 time in 3 days after the act of defecation for 6 months, the following trace elements are prescribed: zinc (Zn) 25 mg per day and vitamins: E 200 mg 1 time per day and C 90 mg 1 time per day.

EFFECT: invention provides reduction of myocardial fibrosis formation, promotes reverse myocardial remodeling, which in turn leads to slowing down of HF development, improving the prognosis of patients with coronary artery disease.

1 cl, 2 ex

Description

The invention relates to medicine, specifically to cardiology. Can be used to treat fibrotic changes in the myocardium in patients with coronary heart disease (CHD) by using hyaluronidase (Longidase) in combination with other drugs that have an antifibrotic effect: ACE inhibitors (ACE inhibitors), sartans, mineralocorticoid receptor antagonists, diuretics (torasemide), statins.

The intensity of cardiac remodeling in the above diseases depends on the reactivity of the connective tissue component of the heart - the extracellular matrix (ECM). The ECM is the basis of connective tissue, including a component of liquid connective tissues (blood, lymph), which provides mechanical support for cells, intercellular interactions, transport of chemicals and cell locomotion [1.Pozzi A., Yurchenco P.D., Iozzo R.V. The nature and biology of basement membranes. Matrix Biol 2017; 57-58: 1-11, https://doi.org/10.1016/j.matbio.2016.12.009; 2. Mouw J.K., Ou G., Weaver V.M. Extracellular matrix Markers of the state of the extracellular matrix and methods for their study 144 STM ∫ 2019 ∫ volume 11 ∫ No. 2 Reviews assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol 2014; 15(12): 771-785, https://doi.org/10.1038/nrm3902].

Previously, it was believed that the ECM is a stable structure that changes primarily in accordance with the needs of growth and repair. However, recent studies have shown that the ECM is metabolically active and is constantly being remodeled.

Two processes occur simultaneously in the body: continuous degradation of the ECM under the influence of special enzymes and, in parallel, the synthesis of matrix components with its restructuring. These changes in the ECM affect cells, regulating their proliferation, migration and differentiation.

The main part of cardiac ECM molecules consists of collagens, proteoglycans (PGs), glycosaminoglycans GAGs, glycoproteins (GPs) and matricellular proteins, which have recently been actively studied.

The main functions of the ECM: 1) maintaining the normal structure of cardiomyocytes and blood vessels and preventing them from slipping during contraction; 2) an active functional role as a force transducer during systole, which contributes to the elongation of cardiomyocytes; 3) this is the main factor determining the diastolic stiffness of the myocardium [Lamas GA, Pfeffer MA. Left ventricular remodeling after acute myocardial infarction: clinical course and beneficial effects of angiotensin; converting enzyme inhibition. Am Heart J 1991;4:1194-202. doi:10.1016/0002-8703(91)90682-8].

It is known that in a healthy adult heart, collagens account for 1-2% of the heart volume. Types I and III collagens are the main representatives of collagens in the heart. They are responsible for the strength (stiffness) (type I) and extensibility (elasticity) of the myocardium (type III). Collagen fibers form the structural framework of the myocardium. They are intertwined into a complex three-dimensional network that provides support for cardiomyocytes throughout the entire cardiac cycle and facilitates the transformation of individual cell contractions into a single force vector.

Fibroblasts are responsible for maintaining the ECM. Collagen synthesis by fibroblasts is promoted by profibrogenic growth factors, including transforming growth factor-β1 (TGF-β1), and collagen degradation is carried out by members of the matrix metalloproteinase (MMP) family [. Ivey M J, Tallquist MD. Defining the Cardiac Fibroblast. Circ J. 2016; 80: 2269-2276].

Type I collagen is a three-stranded protein synthesized as a precursor - procollagen. During the formation of the latter, enzymatic cleavage of N- and C-terminal propeptides (PINP and PICP) occurs. The formed type I collagen molecule attaches to the growing collagen fibril, and PICP and PINP remain in the extracellular fluid. The ratio between the amount of collagen accumulating in the IUD and the amount of PICP or PINP entering the systemic circulation is theoretically equal to 1, therefore, the level of propeptides can be used to judge the ability of fibroblasts to synthesize type I collagen in normal conditions and in pathology. [ Savelieva, I. Update on atrial fibrillation: part I / I. Savelieva, Camm J. - Clin Cardiol. - 2008. - 31. - R. 55-62].

MMPs are a family of extracellular zinc-dependent proteolytic enzymes (endopeptidases) that are involved in the degradation of various ECM components. These proteins are expressed by endothelial, smooth muscle cells and fibroblastic cells in almost all tissues and at all stages of ontogenesis. They are secreted into the intercellular space in the form of an inactive proenzyme, then activated by other proteases and function under physiological conditions of tissue restructuring. The MMP family currently includes more than 28 representatives, grouped into 6 subfamilies depending on structure and substrate specificity. Members of the endopeptidase family such as MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-12, MMP-13 and MPR-23 are involved in myocardial remodeling. The proteolytic activity of these enzymes can be regulated at the level of gene transcription, as well as directly by their tissue inhibitors (TIMP) [1. Gasanov, A.G. The role of changes in the extracellular matrix in the occurrence of cardiovascular diseases / A.G. Gasanov, T.V. Bershova // Biomedical chemistry. - 2009. - T. 55, No. 2. - pp. 155-168; 2. Matrix metalloproteinases / O. Zitka [et al.] // Current Medical Chemistry. - 2010. - No. 17. - P. 3751-3768].

Regulation of genes coordinating MMP activity is carried out at the transcription level by the main fibroblast growth factor. Thus, treatment of human myocardial fibroblasts with the main fibroblast growth factor contributed to an increase in the level of collagenase mRNA and their secretion, and their treatment with transforming growth factor (TGF-b) increased the levels of collagen I and TIMP mRNA, and also suppressed the secretion of collagenases [Matrix metalloproteinases / O. Zitka [et al.] // Current Medical Chemistry. - 2010. - No. 17. - P. 3751-3768].

At the same time, other cytokines, including intelekin 1 (IL-1), tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), can potentiate the activity of metalloproteinases and/or reduce collagen synthesis by fibroblasts. Changes in metabolism, age and epigenetic mechanisms have a clear impact on the functions of fibroblasts, which is important to consider when considering ECM metabolism under normal and pathological conditions [Eliseeva T.I., Geppe N.A., Tush E.V., Khaletskaya O.V., Balabolkin I.I., Bulgakova V.A., Kubysheva N.I., Ignatov S.K. Body height of children with bronchial asthma of various severities. Can Respir J 2017; 2017: 8761404, https://doi. org/10.1155/2017/8761404].

Under conditions of ischemia, secondary pressure overload and other pathophysiological disorders, stimulation of fibroblasts and hyperproduction of collagen types I and III occur. These changes are also accompanied by restructuring of the ECM, which leads to fibrosis, changes in the geometry of the heart chambers and is defined by the term “myocardial remodeling.”

“Left ventricular (LV) myocardial remodeling” refers to changes that lead to the restructuring of structures that ensure its normal functioning.

From a clinical point of view, fibrosis is currently the main marker of heart failure, ischemia and progression of coronary artery disease, as well as a decisive factor determining the morphological heterogeneity of the myocardium, increased diastolic dysfunction and the tendency to recurrent arrhythmias.

The term “diffuse myocardial fibrosis” is a pathological process that is accompanied by excessive deposition of collagen in the myocardium due to the predominance of the process of its synthesis over decay.

The term “replacement myocardial fibrosis” is the replacement of dead cardiomyocytes with the formation of scars, as a rule, occurs during myocardial infarction.

The main consequence of both fibrosis is a decrease in ventricular compliance.

The term “diastolic dysfunction of the left ventricle” is a disruption of the functioning of the heart muscle and a decrease in the filling of the left ventricle with blood during diastole (its relaxation).

Thus, “myocardial remodeling” is a reversible process, but provided that the cause of such restructuring can be partially or completely eliminated.

A number of researchers have noted an increase in the concentration of PICP in the blood serum of patients with chronic heart failure (CHF) with predominantly systolic dysfunction. Moreover, the PICP level correlated with LV size, isovolemic relaxation time and wall thickness [Biomarkers of collagen type I metabolism are related to B-type natriuretic peptide, left ventricular size, and diastolic function in heart failure / J. Löfsjögård [et al.] // Cardiovascular Medicine. - 2014. - No. 6. - R. 463-469].

MMPs are known to be involved in the enzymatic breakdown of collagen. They are counteracted by TIMPs, which bind MMPs, forming high-affinity irreversible complexes and thereby slowing down the breakdown of collagen. According to modern concepts, with tissue fibrosis, the level of MMPs decreases, and the level of inhibitors increases. When collagen is destroyed, on the contrary, the content of MMPs increases, and the content of inhibitors decreases [Solomakhina N.I., Belenkov Yu.N. Prognostic value of tissue inhibitor of matrix metalloproteinases "1 (TIMP"1) in patients with CHF // Heart failure. - 2010. - T. 61, No. 5. - P. 281-284].

A number of studies have established the role of imbalance of MMP-9 and TIMP-1 in the outcome of CHF with predominantly impaired systolic function. It was revealed that high values of MMP-9/TIMP-1 determine the clinical outcome of the disease and are a significant predictor of major adverse cardiovascular events in patients with heart failure and systolic dysfunction [. Deardorff, R. Cytokines and matrix metalloproteinases as potential biomarkers in chronic heart failure / R. Deardorff, F.G. Spinale // Biomark Med. - 2009. - 3. - R. 513-523].

A number of authors have studied the concentrations of MMP-2,3,9 and TIMP-1 in patients with decompensated heart failure (HF). As a result of the study, an increase in the level of MMP-2.9 and TIMP- was recorded compared to the control group. However, only MMP-2 values were significantly correlated with New York Heart Association (NYHA) classes. The study found that MMP-2 is an independent predictor of mortality from CHF [Circulating matrix metalloproteinase-2 but not matrix metalloproteinase-3, matrix metalloproteinase-9, or tissue inhibitor of metalloproteinase-1 predicts outcome in patients with congestive heart failure / J. George [et al.] // American Heart Journal. - 2005. - Vol. 150 (3). - R. 484-487].

Thus, metalloproteinases also contribute to the development and progression of heart failure.

In acute myocardial infarction (AMI), patients from the first days showed increased concentrations of the amino-terminal propeptide of type III procollagen (PIIINP - a marker of type III collagen synthesis) in the blood serum [Uusimaa P., Risteli J., Niemelä M., Lumme J. , Ikäheimo M., Jounela A., Peuhkurinen K. Collagen Scar Formation Аfter Acute Myocardial Infarction: Relationships to Infarct Size, Left Ventricular Function, and Coronary Artery Patency // Circulation. 1997. Vol. 96, No. 8. P. 2565-2572].

A number of studies have shown the association of high levels of carboxy-terminal telopeptide of type I collagen (CITP - a marker of type I collagen degradation) with late mortality and other serious clinical events one year after MI [Barthélémy O., Beygui F., Vicaut E., Rouanet S., Van Belle E., Baulac C., Degrandsart A., Dallongeville J., Montalescot G., OPERA Investigators. Relation of High Concentrations of Plasma Carboxy-Terminal Telopeptide of Collagen Type I with Outcome in Acute Myocardial Infarction // Am. J. Cardiol. 2009. Vol. 104, No. 7. P. 904-909].

MMPs initiate collagen degradation by hydrolysis of the peptide bond following the glycine residue at the amino-terminal end of collagen, and the resulting carboxy-terminal telopeptide of type I collagen (CITP) circulates in the blood in an amount proportional to the cleaved CITP from collagen molecules. Thus, CITP can be considered a marker of type I collagen degradation [Lopez B., Gonzalez A., Diez J. Circulating biomarkers of collagen metabolism in cardiac diseases // Circulation. - 2010. - Vol. 121. - P.1645-1654]

In a study by D. Kelly et al. It was shown that the activity of MMPs, in particular MMP-2, in patients with AMI increased from the first hours and persisted up to 4 days. MMP-9 activity was maximum at 12 hours and was closely correlated with the number of leukocytes and neutrophils. Moreover, the degree of increase in MMP-9 correlated with the unfavorable outcome of AMI with ST segment elevation [Pecherina, T.B. / The role of matrix metalloproteinases in assessing the prognosis of patients with ST-segment elevation myocardial infarction during hospital stay / T.B. Pecherina, O.V. Gruzdeva, V.V. Kashtalap, O.L. Barbarash // Cardiology. - 2013. - T. 53, No. 6. - P. 18-24].

In addition, coronary balloon angioplasty resulted in immediate release of MMP-9 into the bloodstream. In addition, it was noted that overexpression of TIMP-1 reduces the likelihood of developing restenosis, and MMP-9, on the contrary, increases [Active matrix metalloproteinase-9 is associated with clinical in-stent restenosis / S. Balta [et al.] // Cardiology. - 2013. - Vol. 7, No. 125(2). - P. 86].

Thus, replacement fibrosis and post-infarction LV remodeling are two simultaneously occurring processes, reflecting the synthesis and degradation of ECM biopolymer molecules in the first case and structural and functional changes in the heart in the second. Cardiac remodeling cannot be considered as a general stereotypical process.

Some authors note overexpression of MMPs (MMP-2, MMP-9) and their tissue inhibitors (TIMP-1, TIMP-2) in patients with mixed type of dyslipidemia. Predictors of increased concentrations of MMP-2 and MMP-9 were high levels of total cholesterol, low-density lipoproteins, and high-sensitivity C-reactive protein [Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in combined dyslipidemia/ G. Derosa [et al.] / / Clin Invest Med. - 2009. - 32 (2). - P. 124-132]. An increase in MMP levels was observed in familial hypercholesterolemia and familial mixed hyperlipidemia. An increase in the level of the MMP-9/TIMP-1 complex in the blood plasma correlated with the degree of damage to the vascular wall. In patients with hypercholesterolemia without clinical manifestations of coronary heart disease (CHD), an increase in the concentration of MMP-9/TIMP-1 is due to an increase in atherogenic lipids. Moreover, the increase in MMP-9/TIMP-1 in the blood occurs in proportion to the severity of coronary artery disease; the highest values were recorded in patients with myocardial infarction [Grigoriadi, N.E. Features of fibrosis indicators in patients with coronary heart disease depending on the degree of stenosis and the number of affected coronary arteries / N.E. Grigoriadi, L.M. Vasilets, A.V. Tuev // Modern problems of science and education. - 2014. - No. 3. - Electronic magazine. - http://www.science-education.ru/ 117-13182].

Increased expression of MMPs was detected in the atherosclerotic plaque itself and, apparently, activation of these enzymes contributes to the development of atherosclerosis, plaque instability and platelet aggregation. The source of the formation of these cytokines in atheroma are macrophages. The thickness of the fibrous capsule is highly dependent on the activity of MMPs, since they are able to degrade extracellular matrix proteins at neutral pH. In particular, the role of MMP-2 in the instability and rupture of atherosclerotic plaque, as well as the progression of atherosclerotic arterial lesions has been established [Potential role of selected biomarkers for predicting the presence and extent of coronary artery disease / M. Griva [et al.] // Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. - 2010. -154. - R. 219-225].

Hyaluronidase (Longidase) has hyaluronidase (enzymatic) activity of prolonged action, chelating, antioxidant, immunomodulatory and moderate anti-inflammatory effects.

Prolonged action is achieved by covalent binding of the enzyme to a physiologically active polymer carrier (azoximer). Longidase exhibits antifibrotic properties, weakens the course of the acute phase of inflammation, regulates (increases or decreases, depending on the initial level) the synthesis of inflammatory mediators (interleukin-1 and TNF-α), increases the humoral immune response and the body's resistance to infection.

The pronounced antifibrotic properties of the drug Longidaza are ensured by the conjugation of hyaluronidase with the carrier, which significantly increases the resistance of the enzyme to denaturing influences and the action of inhibitors: enzymatic activity of the drug Longidaza persists when heated to 37°C for 20 days, while native hyaluronidase loses its activity within 24 hours under the same conditions. In the drug Longidaza the simultaneous local presence of the hyaluronidase enzyme and a carrier is ensured, capable of binding enzyme inhibitors and stimulators of collagen synthesis (iron, copper ions, heparin and others) released during hydrolysis of matrix components. Thanks to these properties, Longidaza not only has the ability to depolymerize the connective tissue matrix in fibrogranulomatous formations, but also suppress the reverse regulatory reaction aimed at the synthesis of connective tissue components.

The specific substrate of testicular hyaluronidase is glycosaminoglycans (hyaluronic acid, chondroitin, chondroitin-4-sulfate, chondroitin-6-sulfate), which form the basis of the connective tissue matrix. As a result of depolymerization (breaking the bond between C ₁ acetylglycosamine and C ₄ glucuronic or induric acids), glycosaminoglycans change their basic properties: viscosity decreases, the ability to bind water and metal ions decreases, the permeability of tissue barriers temporarily increases, fluid movement in the intercellular space is facilitated, and elasticity increases. connective tissue, which manifests itself in reducing tissue swelling, flattening scars, increasing the range of motion of joints, reducing contractures and preventing their formation, reducing adhesions.

Biochemical, immunological, histological and electron microscopic studies have proven that Longidaza does not damage normal connective tissue, but causes destruction of connective tissue altered in composition and structure in the area of fibrosis.

Longidaza does not have mutagenic, embryotoxic, teratogenic or carcinogenic effects. The drug was well tolerated by patients; no local or general allergic reactions were noted.

Longidaza is actively used in the treatment of urological, gynecological, surgical, pulmonological diseases, in the treatment of arterial hypertension, arteriosclerosis, but until now it was unknown that Longidaza can have an effect on fibrotic changes in the myocardium in patients with coronary artery disease.

The objective of the invention is to develop a method for treating fibrotic changes in the cardiovascular system in patients with coronary artery disease.

The technical result is a reduction in the formation of myocardial fibrosis. The method promotes reverse myocardial remodeling, which in turn leads to a slowdown in the development of heart failure and an improved prognosis in patients with coronary artery disease.

A method is claimed for the treatment of fibrotic changes in the cardiovascular system in patients with coronary artery disease, which consists in the fact that in addition to the main antifibrotic therapy, the drug Longidaza 3000 IU is prescribed intravenously for 5 days, then Longidaza 3000 IU suppositories are prescribed rectally, 1 piece 1 time in 3 days after defecation for 6 months, microelements are prescribed - zinc (Zn) 25 mg per day and vitamins: E 200 mg once a day and C 90 mg once a day, vitamin E, vitamin C 90 mg once a day.

Longidaza 3000 IU (manufactured by NPO Petrovax Pharm LLC) is used rectally, 1 piece once every 3 days after defecation for 6 months.

Also added to the therapy are microelements - zinc (Zn) and vitamins E and C.

Stimulation of MMP is carried out by Zn, a coenzyme that activates MMP. When using zinc, an increase in MMP activity is expected.

The suggested dosage is 25 mg per day. This issue has not been described in the studied medical literature. The use of Zn to activate MMP and, as a consequence, reduce collagen synthesis, was proposed for the first time.

Taking vitamin E 200 mg once a day, vitamin C. The suggested dosage is 90 mg once a day.

Hyaluronidase acts on hyaluronic acid, which is the “cement” that binds collagen threads. As a result of this effect, the elasticity of the extracellular matrix increases and the manifestations of fibrosis of the heart and blood vessels are reduced.

Treatment with hyaluronidase leads to the treatment of fibrosis of the whole body and in particular fibrosis of the prostate, which leads to an increase in testosterone synthesis and, as a consequence, a decrease in lipid spectrum indicators (TC, LDL, VLDL, TG), an increase in HDL, a decrease in blood pressure and other risk factors for coronary artery disease.

Hyaluronidase is able to suppress stimulators of collagen synthesis (IL-1 and TNF), thus realizing its pronounced antifibrotic and anti-inflammatory effect.

As a result of the use of hyaluronidase, a decrease in the N-terminal propeptide of type 1 procollagen (PINP) - a marker of type 1 collagen synthesis, an increase in the carboxy-terminal telopeptide of type 1 collagen (CITP) - a marker of the breakdown of type 1 collagen, and a decrease in the level of TNF-α is expected.

In addition to laboratory markers, in terms of assessing the degree of myocardial fibrosis, the ultrasound method has its place. According to echocardiography data while taking Longidase, we have:

- reduction in the deceleration time of peak E of the transmitral diastolic flow from the peak of the flow velocity to the end of the flow (DTe) compared to the original;

- increase in left ventricular isovolumetric relaxation time (IVRT) compared to initial values;

- reduction in the ratio of early and late ventricular filling rates (E/A) at the mitral valve in patients with type 1 left ventricular diastolic dysfunction;

- decrease in the E/e' ratio according to tissue Doppler.

Suggested regimen for using the drug Longidase (hyaluronidase):

- In the hospital:

Intravenous administration of the drug Longidaza 3000 IU (manufactured by NPO Petrovax Pharm LLC) for 5 days.

- After discharge:

Suppositories Longidaza 3000 IU (manufactured by NPO Petrovax Pharm LLC) rectally, 1 piece once every 3 days after defecation for 6 months.

Also added to the therapy are microelements - zinc (Zn) and vitamins E and C.

Stimulation of MMP is carried out by Zn, a coenzyme that activates MMP. When using zinc, an increase in MMP activity is expected.

The suggested dosage is 25 mg per day. This issue has not been described in the studied medical literature. The use of Zn to activate MMP and, as a consequence, reduce collagen synthesis, was proposed for the first time.

Taking vitamin E 200 mg once a day, vitamin C. The suggested dosage is 90 mg once a day.

These vitamins prevent peroxidation of collagen protein and its glycation. Peroxidation and glycation of collagen leads to an increase in collagen stiffness and a decrease in its elasticity.

Several patients with CAD have been successfully treated with hyaluronidase. Below are data obtained from the treatment of two patients.

Clinical examples:

Example 1. Patient K., 55 years old. Suffered from stable angina pectoris I f.k. within 1.5 years. History of hypertension with maximum blood pressure values up to 150/100 mmHg, type 2 diabetes mellitus. He was admitted with complaints of pressing pain in the chest when performing physical activity and accelerating the pace of walking. Over the past 1.5 years, he has been on therapy: Prestarium (Perindopril) 5 mg, bisoprolol 2.5 mg, rosuvastatin (Crestor) 20 mg, cardiomagnyl 75 mg, spironolactone (Veroshpiron) 25 mg, dafagliflozin (Forxiga) 10 mg.

During treatment in the hospital, the patient underwent standard laboratory and instrumental studies.

It was decided to leave antihypertensive and lipid-lowering therapy the same due to the achievement of target values for lipid spectrum and blood pressure indicators.

According to coronary angiography, the patient did not have any significant stenoses of the coronary arteries.

In the hospital, in addition to the main therapy, the patient was prescribed therapy with Longidaza 3000 IU (manufactured by NPO Petrovax Pharm LLC) intravenously for 5 days, Zn preparations 25 mg/day, vitamin E 200 mg/day, vitamin C 90 mg/day orally. Before discharge from the hospital, the patient was given recommendations for taking basic drug therapy: Prestarium (Perindopril) 5 mg, bisoprolol 2.5 mg, rosuvastatin (Crestor) 20 mg, cardiomagnyl 75 mg, spironolactone (Veroshpiron) 25 mg, dafagliflozin (Forxiga) 10 mg, nitroglycerin preparations on demand, and it is also recommended to continue therapy with Zn 25 mg/day, vitamin E 200 mg/day, vitamin C 90 mg/day orally, Longidaza 3000 IU suppositories (manufactured by NPO Petrovax Pharm LLC) rectally, 1 piece 1 once every 3 days after defecation for 6 months.

After 6 months, the patient was assessed for laboratory tests of interest and echocardiographic results.

1) Laboratory research

a) Lipid profile indicators

Index Before treatment After treatment Reference values THC, mmol/l 4.2 4.0 3.0-5.2 TG, mmol/l 1.8 1.75 0.45-1.9 HDL, mmol/l 1.02 1.1 0.9-1.9 LDL, mmol/l 1.45 1.37 0.9-2.8 VLDL, mmol/l 0.89 0.7 0.26-1.04

b) Testosterone level, nmol/l

Before treatment After treatment Reference values 5.07 5.12 5.41 - 19.54

c) ECM indicators

Index Before treatment After treatment Reference values PINP, ng/ml 75 71 10.2 - 86 CITP, ng/ml 0.32 0.4 0 - 0.573 TNF α, pg/ml 6.9 5.3 0 - 8.2

2) Results of echocardiographic study (performed at heart rate 60-70 beats/min)

Index Before treatment After treatment Reference values E/A ratio 0.76 0.82 >1 DTE, m/s 238 234 Up to 230 IVRT, m/s 75 79 76±11 E/e' ratio 10.4 10.2 ≤ 10

As a result of the addition of hyaluronidase to the treatment of coronary artery disease for 6 months, the patient showed a decrease in lipid spectrum indicators, an increase in testosterone levels, a decrease in the N-terminal propeptide of type 1 procollagen (PINP) - a marker of type 1 collagen synthesis, an increase in the carboxy-terminal telopeptide of type 1 collagen (CITP). ) - a marker of type 1 collagen breakdown, a decrease in the level of TNFα - a marker of inflammation, as well as a decrease in diastolic dysfunction of the left ventricular myocardium. The patient also noted a decrease in angina symptoms.

Example 2. Patient A., 61 years old. He suffered from stable angina pectoris II f.k for 2 years. From the anamnesis it is known that he is a long-term hypertensive patient with maximum blood pressure values of up to 160/110 mmHg; a year ago he underwent stenting for hemodynamically significant stenosis of the right coronary artery (RCA); he did not suffer myocardial infarctions. He was admitted to clarify the condition of the coronary arteries and assess the patency of the stent; from complaints he noted periodic sensations of interruptions in the work of the heart. Took therapy: Enalapril 20 mg, Bisoprolol 5 mg, Atorvastatin 80 mg, Cardiomagnyl 75 mg, Clopidogrel (Plavix) 75 mg, Torsemide (Diuver) 5 mg, Pantoprazole (Nolpaza) 20 mg.

During treatment in the hospital, the patient underwent standard laboratory and instrumental studies. According to coronary angiography, no significant stenoses of the coronary arteries were detected, the RCA stent is passable.

In the hospital, in addition to the main therapy, the patient was prescribed therapy with Longidaza 3000 IU (manufactured by NPO Petrovax Pharm LLC) intravenously for 5 days, Zn preparations 25 mg/day, vitamin E 200 mg/day, vitamin C 90 mg/day orally.

Before discharge from the hospital, the patient was given recommendations for taking basic drug therapy: Enalapril 20 mg, Bisoprolol 5 mg, Atorvastatin 80 mg, Cardiomagnyl 75 mg, Torasemide (Diuver) 5 mg, Pantoprazole (Nolpaza) 20 mg, nitroglycerin preparations on demand, and it is also recommended to continue therapy with Zn 25 mg/day, vitamin E 200 mg/day, vitamin C 90 mg/day orally, Longidaza 3000 IU suppositories (manufactured by NPO Petrovax Pharm LLC) rectally, 1 piece 1 time every 3 days after defecation for 6 months.

After 6 months, the patient was assessed for laboratory tests of interest and echocardiographic results.

1) Laboratory research

a) Lipid profile indicators

Index Before treatment After treatment Reference values THC, mmol/l 4.5 4.4 3.0-5.2 TG, mmol/l 1.6 1.57 0.45-1.9 HDL, mmol/l 0.9 0.95 0.9-1.9 LDL, mmol/l 1.5 1.44 0.9-2.8 VLDL, mmol/l 0.91 0.89 0.26-1.04

b) Testosterone level, nmol/l

Before treatment After treatment Reference values 4.6 4.68 5.41 - 19.54

c) ECM indicators

Index Before treatment After treatment Reference values PINP, ng/ml 88.5 87.2 10.2 - 86 CITP, ng/ml 0.26 0.31 0 - 0.573 TNF α, pg/ml 8.3 8.1 0 - 8.2

3) Results of echocardiographic study (performed at heart rate 65-75 beats/min)

Index Before treatment After treatment Reference values E/A ratio 0.68 0.74 >1 DTE, m/s 244 240 Up to 230 IVRT, m/s 72 75 76±11 E/e' ratio 10.8 10.6 ≤ 10

Also, due to complaints of interruptions in heart function, the patient underwent Holter monitoring for 24 hours during his hospital stay and 6 months later during treatment with hyaluronidase.

*Before treatment with hyaluronidase: average daytime heart rate 68 beats/min, min. 55, max 80, at night average 60 beats/min, min. 52 beats/min. Ventricular extrasystoles grade 3 according to Ryan, Single VVCs total 470, 181 during the day, 289 at night, Single supraventricular extrasystoles 10 during the day, 4 at night. No ischemic ECG changes were detected.

*After treatment with hyaluronidase: average daytime heart rate 72 beats/min, min. 56, max 84, at night average 64 beats/min, min. 50 beats/min. Ventricular extrasystoles grade 3 according to Ryan, Single VVCs total 382, 144 during the day, 238 at night, Single supraventricular extrasystoles 12 during the day, 3 at night. No ischemic ECG changes were detected.

As a result of adding hyaluronidase to the treatment of coronary artery disease for 6 months, the patient experienced a decrease in lipid spectrum, an increase in testosterone levels, a decrease in the N-terminal propeptide of type 1 procollagen (PINP) - a marker of type 1 collagen synthesis, an increase in the carboxy-terminal telopeptide of type 1 collagen (CITP). ) - a marker of collagen breakdown, a decrease in the level of TNFα - a marker of inflammation, as well as a decrease in diastolic dysfunction of the left ventricular myocardium according to echocardiography. The patient also noted a decrease in the number of ventricular extrasystoles, which is of no small importance in the prognostic plan of patient management.

In conclusion, it should be noted that currently there is a steady increase in cardiovascular diseases with the subsequent development of heart failure and, in most cases, myocardial fibrosis is the basis for the unfavorable course of these diseases. Within the framework of this concept, verification of fibrosis, study of the rate of its progression, and assessment of the antifibrotic effectiveness of the therapy are of undoubted scientific and practical value.

However, in modern practice, the most realistic therapeutic goal is to slow the progression of fibrosis, rather than regress it [Rockey DC, Bell PD, Hill JA. Fibrosis is a common pathway to organ injury and failure. New England Journal of Medicine. 2015;372:1138-1149]. In particular, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and statins used to treat patients with heart failure have antifibrotic effects. Such therapy can cause “reverse remodeling” of the heart, reduce the frequency of arrhythmic events, in particular ventricular tachycardia and sudden death [Massare J, Berry JM, Luo X, et al. Diminished cardiac fibrosis in heart failure is associated with altered ventricular arrhythmia phenotype. Journal of Cardiovascular Electrophysiology. 2010;21:1031-1037. doi:10.1111/j.1540-8167.2010.01736.x].

Further study of fibrosis biomarkers will significantly increase the ability to predict the development and progression of coronary artery disease, as well as the effectiveness of optimal treatment tactics for managing patients with this pathology.

In the work carried out, we see the positive effect of hyaluronidase, Zn, vit E and C, when added to standard antifibrotic therapy, on markers of myocardial fibrosis and echocardiography data in patients with coronary artery disease.

Thus, there was a decrease in the N-terminal propeptide of type 1 procollagen (PINP) - a marker of type 1 collagen synthesis, an increase in the carboxy-terminal telopeptide of type 1 collagen (CITP) - a marker of type 1 collagen breakdown, a decrease in the level of TNFα, a decrease in diastolic dysfunction of the left ventricular myocardium: a decrease in time slowing down of the peak E of the transmitral diastolic flow from the peak of the flow velocity to the end of the flow (DTe) compared to the initial value, an increase in the left ventricular isovolumetric relaxation time (IVRT) compared to the initial values, a decrease in the ratio of early and late ventricular filling velocities (E/A) by mitral valve in patients with type 1 left ventricular diastolic dysfunction, a decrease in the E/e' ratio according to tissue Doppler.

In addition, while taking the proposed therapy, a decrease in the number of ventricular extrasystoles was noted, which also allows us to indirectly judge the decrease in myocardial fibrosis and the decrease in antiarrhythmic complications in this disease.

Thus, the addition of hyaluronidase, Zn, Vit E and C to standard antifibrotic therapy in patients with IHD leads to a decrease in the formation of myocardial fibrosis, promotes reverse myocardial remodeling, which in turn leads to a slowdown in the development of HF, improving the prognosis of patients with IHD.

Claims (1)

A method for treating fibrotic changes in the myocardium in patients with coronary heart disease, which consists in taking the drug Longidaza 3000 IU intravenously for 5 days, in addition to antifibrotic therapy, then taking Longidaza 3000 IU suppositories rectally, 1 piece 1 time every 3 days after defecation for 6 months, take microelements - zinc (Zn) 25 mg per day and vitamins: E 200 mg once a day and C 90 mg once a day.