Научная статья на тему 'Pulmonary hypertension: modern methods of treatment and ways of their long-term development'

Pulmonary hypertension: modern methods of treatment and ways of their long-term development Текст научной статьи по специальности «Клиническая медицина»

CC BY
54
7
i Надоели баннеры? Вы всегда можете отключить рекламу.
Ключевые слова
pulmonary hypertension / endothelial dysfunction / treatment methods / легочная гипертензия / эндотелиальная дисфункция / методы лечения

Аннотация научной статьи по клинической медицине, автор научной работы — Anna V. Zagrebelnaya, Liliya V. Korokina, Tatyana N. Malorodova, Olesya V. Shcheblykina, Tatyana V. Avtina

Introduction: The purpose of this work is to review the main pathogenetic mechanisms of the development of pulmonary hypertension (PH), as well as modern established methods of treatment of PH and to consider new most relevant and promising possibilities of therapy for this pathology. Materials and Methods: Electronic resources were used as the main sources of information for this work. Research papers that were predominantly selected included reports of clinical and preclinical trials, clinical guidelines, data from various registries, systematic reviews, and meta-analyses. All received data were analyzed and structured. Results and Discussion: In the modern structure of diseases, pulmonary hypertension has a significant place, affecting about 1% of the population. However, each of its main groups has its own characteristics. At the same time, despite the multiplicity of etiological factors, the main pathogenetic link in the development of pulmonary hypertension is endothelial dysfunction. After that, the main established approaches to the treatment of pulmonary hypertension are the following: general recommendations for patients, drugs used as supportive nonspecific therapy, as well as specific conservative and radical methods of treatment. In addition, the main modern directions of scientific research in the field of treatment of pulmonary hypertension are described: stem cells, gene therapy and epigenetic drugs. Conclusion: Despite active research and many different drugs intended for the treatment of pulmonary hypertension, this pathological condition remains an urgent health problem. Thus, the search for new points of application of therapy and fundamentally new methods of treatment of pulmonary hypertension remains relevant to this day.

i Надоели баннеры? Вы всегда можете отключить рекламу.
iНе можете найти то, что вам нужно? Попробуйте сервис подбора литературы.
i Надоели баннеры? Вы всегда можете отключить рекламу.

Лёгочная гипертензия: современные методы лечения и пути их дальнейшего развития

Введение. Целью данной работы является обзор основных патогенетических механизмов развития легочной гипертензии (ЛГ), а также современных зарекомендовавших себя методов лечения ЛГ и рассмотрение новых наиболее актуальных и перспективных возможностей терапии данной патологии. Материалы и методы. В качестве основного источника информации для работы использовались электронные ресурсы. Рассматриваемые научные статьи включали, преимущественно, отчеты о клинических и доклинических испытаниях, клинические рекомендации, данные из различных регистров, систематические обзоры и метаанализы. Все полученные данные были проанализированы и структурированы. Результаты и их обсуждение. В современной структуре заболеваний легочная гипертензия занимает значительное место, поражая около 1% населения. Однако каждая из его основных групп имеет свои особенности. В то же время, несмотря на множественность этиологических факторов, основным патогенетическим звеном в развитии легочной гипертензии является эндотелиальная дисфункция. Основные сложившиеся подходы к лечению легочной гипертензии: общие рекомендации для больных, препараты, применяемые в качестве поддерживающей неспецифической терапии, а также специфические консервативные и радикальные методы лечения. Кроме того, описаны основные современные направления научных исследований в области лечения легочной гипертензии: стволовые клетки, генная терапия и эпигенетические препараты. Заключение. Несмотря на активные исследования и множество различных препаратов, предназначенных для лечения легочной гипертензии, это патологическое состояние остается актуальной проблемой здравоохранения. Таким образом, поиск новых точек приложения терапии и принципиально новых методов лечения легочной гипертензии остается актуальным и по сей день.

Текст научной работы на тему «Pulmonary hypertension: modern methods of treatment and ways of their long-term development»

® Research Results in Pharmacology

3 Review Article

Research Results in Pharmacology 9(2): 37-54 UDC: 615.036.2 DOI 10.18413/rrpharmacology.9.10026

Pulmonary hypertension: modern methods of treatment and ways of their long-term development

Anna V. Zagrebelnaya1, Liliya V. Korokina1, Tatyana N. Malorodova1, Olesya V. Shcheblykina1, Tatyana V. Avtina1, Anton A. Bolgov1, Elena S. Malyutina1, Vladislav I. Simonov1, Vladislav A. Travkin2, Artem A. Dmitriev1, Amonullo A. Aripov1, Dmitry V. Shcheblykin1

1. Belgorod State National Research University, 85 Pobedy St., Belgorod 308015 Russia

2. Gubkinskaya central district hospital, 20 Chaikovskogo St., Gubkin 309186Russia

Corresponding author: Anton A. Bolgov (toxabolgovvMmail.ru)

Academic editor: Tatyana Pokrovskaia ♦ Received 09 February 2023 ♦ Accepted 06 April 2023 ♦ Published 27 May 2023

Citation: Zagrebelnaya AV, Korokina LV, Malorodova TN, Shcheblykina OV, Avtina TV, Bolgov AA, Malyutina ES, Simonov VI, Travkin VA, Dmitriev AA, Aripov AA, Shcheblykin DV (2023) Pulmonary hypertension: modem methods of treatment and ways of their long-term development. Research Results in Pharmacology 9(2): 37-54. https://doi.org/10.18413/ rrpharmacology. 9.10026

Abstract

Introduction: Hie purpose of this work is to review the main pathogenetic mechanisms of the development of pulmonary hypertension (PH), as well as modem established methods of treatment of PH and to consider new most relevant and promising possibilities of therapy for this pathology.

Materials and Methods: Electronic resources were used as the main sources of information for this work. Research papers that were predominantly selected included reports of clinical and preclinical trials, clinical guidelines, data from various registries, systematic reviews, and meta-analyses. All received data were analyzed and structured.

Results and Discussion: In the modem structure of diseases, pulmonary hypertension has a significant place, affecting about 1% of the population. However, each of its main groups has its own characteristics. At the same time, despite the multiplicity of etiological factors, the main pathogenetic link in the development of pulmonary hypertension is endothelial dysfunction. After that, the main established approaches to the treatment of pulmonary hypertension are the following: general recommendations for patients, drugs used as supportive nonspecific therapy, as well as specific conservative and radical methods of treatment. In addition, the main modem directions of scientific research in the field of treatment of pulmonary hypertension are described: stem cells, gene therapy and epigenetic drugs.

Conclusion: Despite active research and many different drugs intended for the treatment of pulmonary hypertension, this pathological condition remains an urgent health problem. Thus, the search for new points of application of therapy and fundamentally new methods of treatment of pulmonary hypertension remains relevant to this day.

Copyright Zagrebelnaya AV et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Graphical abstract:

o

jï'

e>5

9ft

Mwkw

Improvement of the condition caused by PH

Pulmonary hypertension (PH)

is a hemodynamic and pathophysiological condition characterized by an average pressure in the pulmonary artery at rest > 25 mm Hg.

Pharmacotherapy of PH 1. Supportive therapy

• diuretic drugs,

• cardiotonic drugs,

• antiarrhythmic drugs,

• anticoagulants,

• antiplatelet agents 2. Specific therapy

2.1 "Classical" therapy

• selective antagonists of endothelin-1

receptors, • dual antagonists of endothelin-1 receptors,

• selective agonists of prostaglandin 12

receptors,

• prostacyclin analogues, stimulants of soluble guanylate cyclase,

• nitric oxide and its donators, phosphodiesterase inhibitors of type 5, • blockers of slow calcium channels 2.2 "Promising" therapy

• Rho-kinase inhibitors,

• prostaglandin E2,

• selonsertib,

• regenerative cell therapy,

• gene therapy,

• epigenetic drugs

Keywords

pulmonary hypertension, endothelial dysfunction, treatment methods

Introduction

Pulmonary hypertension (PH) has never lost its relevance in the global healthcare environment since its discovery at the end of the IX century. On the contrary, more and more new works and studies reveal the connection of PH with various pathological conditions of the cardiovascular and respiratory systems, as well as many infectious and hereditary diseases (Galie et al. 2016; Rosenkranz et al. 2016; Olschewski et al. 2018). This is suggested by the fact that over the past 20 years the number of publications on this topic has increased by more than 5 times (Fig. 1).

6000

5000

:

:

; 4000

# ^ # ^ ^ # # ^ ^ ^ a? ^

Year

Figure 1. The number of scientific papers on the topic of pulmonary hypertension on the PubMed Internet resource in the period from 2000 to 2022.

The purpose of this work is to review the main pathogenetic mechanisms of the development of PH, as well as modern established methods of treatment of various types of PH and to consider new most relevant and promising possibilities of therapy for this pathology.

Materials and Methods

Electronic resources, such as PubMed, were used as the main sources of information for this work. Research papers that were predominantly selected included reports of clinical and preclinical trials, clinical guidelines, data from various registries, systematic reviews, and metaanalyses. In this case, information from works published no earlier than 2013 was mainly used. However, it is worth noting that in this work there are references to earlier publications, if their information is fundamental and extremely important. Naturally, the main keyword used to search was "pulmonary hypertension". All the data obtained were analyzed and structured.

Results and Discussion

Definition. Epidemiology

PH is a hemodynamic and pathophysiological condition characterized by mean resting pulmonary artery pressure

pressure (RPA) > 25 mm Hg. Etiopathogenetically, PH is divided into 5 main groups: 1) arterial pulmonary hypertension (PAH) and pulmonary veno-occlusive disease; 2) PH which develops due to diseases of the left heart; 3) PH which develops due to diseases of the respiratory system; 4) Chronic thromboembolic pulmonary hypertension (CTEPH); 5) PH with unclear and/or multifactorial mechanisms of development.

Pulmonary arterial hypertension is described as a subset of pathological conditions characterized hemodynamically by precapillary pulmonary hypertension with increased pulmonary vascular resistance (PVR), which is PLA>25 mmHg at normal pulmonary artery wedge pressure (PAWP)<15 mm Hg, and LSS>240 dinxsxcm-5 (Galie et al. 2015, 2016).

However, for the diagnosis of pulmonary arterial hypertension, in addition to meeting these criteria, it is also necessary to exclude other forms of precapillary pulmonary hypertension. This is especially important in diseases of the lungs and left heart with normalized PAWP.

In the modern structure of diseases, PH has a significant place, affecting about 1% of the population. At the same time, in age-related patients (over 65 years old), the incidence rates increase to 10% (Hoeper et al. 2017). However, it is worth noting that the epidemiological indicators of various etiopathogenetic groups differ significantly.

Information on the prevalence and incidence of PAH is currently provided by various national and international registries. According to one of these registries, these rates were 15 and 2.4 cases per 1 million adults, respectively (Humbert et al. 2006). At the same time, in the structure of PAH, its idiopathic form (IPAH) invariably occupies the first place, ranging from 41% to 50%, according to various registries. A smaller proportion is occupied by cases of hereditary PAH (0.4%) associated with congenital heart defects (36%), systemic connective tissue diseases (19.5%), portal hypertension (1.9%), HIV infection (0.4%) and taking drugs and toxins (0.4%) (Benza et al. 2010; Chazova et al. 2019).

Speaking about IPAH, it is also worth noting that the female population is most often affected by this pathology (Badesch et al. 2010; Humbert et al. 2010). The ratio of women to men diagnosed with IPAH ranges from 1.7:1 to 2.3:1, according to various registries (Hoeper et al. 2013).

The most common form in the structure of PH is its form which develops in the pathology of the heart, accounting for from 48% to 80% of the total number of all registered cases of PH (Rosenkranz et al. 2018). PH is formed in many patients with systolic (60%) and diastolic (83%) left ventricular failure, as well as with defects of the mitral valve (with stenosis - in 38% of cases, with insufficiency - 23%) and aortic (29% and 16% with stenosis and insufficiency, respectively) of the valves.

In obstructive pulmonary diseases, PH has a rather heterogeneous prevalence. So, in idiopathic pulmonary fibrosis, PH is determined in 8-15% of patients at the initial stage, in the late stage - in 30-50% and in the final stage - in more than 60% (Raghu et al. 2015). While in chronic obstructive pulmonary disease stage IV, about 90% of patients have signs of PH at rest (Nathan et al. 2019).

Determining the epidemiological indicators of CTEPH is currently a rather difficult task. On the one hand, in itself, a reliable diagnosis of this condition causes certain difficulties. On the other hand, overdiagnosis of CTEPH is quite common in patients with acute pulmonary embolism, while CTEPH, reliably verified during transventional catheterization of the heart, is found on average in 3.4% of patients who have undergone pulmonary embolism (Simonneau et al. 2017).

Etiology and pathogenesis

PAH is a disease that affects the small pulmonary arteries. Proliferation of the intima and middle membrane, thickening of the adventitia with the formation of foci of perivascular inflammation in PAH are the result of a violation of the processes of apoptosis of endotheliocytes and/or angiogenesis, followed by obliteration of the pulmonary vessels (Humbert et al. 2019). Such disorders can be the result of both mutations in various genes (BMPR2, which controls cell proliferation; KCNK3, which is responsible for caveolin-1 and potassium channels, etc.), and epigenetic mechanisms (DNA methylation, histone modifications) (Olschewski et al. 2018). Moreover, the role of a number of drugs and toxins that may be risk factors for the development of PAH has been identified. Such substances include aminorex, dasatinib, metformins, cocaine, etc. (Galie et al. 2016; Simonneau et al. 2019). Complete or partial vascular obstruction resulting from all of these mechanisms leads to a progressive increase in vascular resistance. This increases the right ventricular afterload of the heart and hence leads to right ventricular heart failure.

Despite the heterogeneity of various pathologies of the left heart, as a rule, the development of PH in these cases has the same general mechanism. Systolic and/or diastolic overload of the left ventricle leads to stretching of the left atrium and an increase in pressure in it. Passive transfer of elevated pressure from the left side of the heart to the venous vessels of the lungs leads to damage to the endothelium with a subsequent decrease in the synthesis of nitric oxide (NO) and a decrease in sensitivity to various vasodilators. These changes naturally increase PVR and lead to an increase in mean PAP (Rosenkranz et al. 2016).

The basis of PH in lung pathology is persistent hypoxemia with subsequent vasoconstriction in the pulmonary circulation system and further remodeling of arterial vessels. Rigidity of the pulmonary vessels and damage to their endothelial layer, in turn, leads to an increase in PVR and, as a result, an increase in pressure in the pulmonary artery system (Klinger et al. 2016).

Pathogenetic relationships in CTEPH are complex and currently not well understood. However, even now we can say that the development of this pathology is due not only to the fact of chronic obstruction by thrombotic masses. This is evidenced by the fact that severe hypertension observed in CTEPH can develop in conditions of damage to less than 50% of the arterial bed. On this basis, it can be concluded that in the pathogenesis of CTEPH, disorders of angiogenesis, fibrinolysis and other neurohumoral factors play a significant role (Simonneau et al. 2017).

Summing up, we can say that, despite the multiplicity of the initial causes of the development of PH, its most important link in the pathogenesis is endothelial dysfunction.

Vasoconstriction in this case is due to abnormal function or expression of potassium channels and endothelial dysfunction, which in turn leads to a decrease in the production of vasodilators such as NO and prostacyclin and an increase in the production of vasoconstrictors such as endothelin-1 (Soldatov et al. 2018; Shcheblykin et al. 2022).

Treatment

Treatment of PAH, like any form of PH, can be roughly divided into three main components: general recommendations, maintenance therapy, and specific therapy.

The ESC/ERS Guidelines for the Diagnosis and Management of Pulmonary Hypertension report positive effects of physical activity within symptom limits in patients with PH (Galiè et al. 2015; Galiè et al. 2016). Studies have shown the beneficial effects of exercise on performance, quality of life and cardiac function in patients with PH (de Man et al. 2009; Chan et al. 2013; Ehlken et al. 2016; Grunig et al. 2021). However, it is necessary to focus on the fact that before embarking on a physical rehabilitation program, patients should be selected the optimal pharmacological therapy that ensures a stable clinical condition. (Grünig et al. 2019). In addition, special rehabilitation measures and active physiotherapy are equally helpful in improving physical performance, quality of life and cardiac function in patients with pulmonary hypertension. (Ehlken et al. 2016).

Separately, it should be noted that patients with PH should be strongly recommended regular vaccination against the influenza virus, Streptococcus pneumoniae and the SARS-CoV-2 virus, due to the high mortality rates of patients with PH from various types of pneumonia (Galiè et al. 2016).

Also, an important aspect of working with a patient is the development of adherence to therapy, since PAH therapy often involves taking a large number of drugs with many side effects.

Supportive therapy

As a non-specific therapy in the presence of signs of hypoxemia (with arterial pO2<60 mm Hg), patients with PAH should be given oxygen therapy. Under the influence of oxygen, the degree of hypoxia decreases and, as a result, the vasoconstriction of the vessels of the pulmonary circulation also decreases. Ambulatory oxygenation should be considered if it results in a subjective improvement in the patient's condition (Ulrich et al. 2017, 2109). Nocturnal oxygen therapy should be considered in case of sleep-related hypoxia (Adir et al. 2021). However, there are no randomized clinical trials confirming the beneficial effect of long-term oxygen use. A significant contribution to hypoxemia is often made by concomitant lung pathology, the adequate treatment of which, in combination with oxygen therapy, favorably affects the course of PAH.

In patients with PAH, it is important to monitor iron levels. Iron deficiency is defined as serum ferritin <100 (g/l or serum ferritin 100-299 (xg/l in conjunction with transferrin saturation <20% (McDonagh et al. 2018). In PAH patients, iron deficiency correlates with myocardial dysfunction, worsening of symptoms, and increased risk

of mortality (Van De Bruaen et al. 2011; Sonnweber et al. 2018).

Diuretics are indicated for patients with signs of overhydration. However, data on their effectiveness in PAH are extremely scarce. Loop diuretics are commonly used, often in combination with mineralocorticoid receptor antagonists. It is important to note that, in the case of the appointment of diuretics, patients should also be advised to regularly monitor body weight and consult a doctor in case of weight gain. In the management of patients with PAH, renal function and serum electrolytes should be regularly monitored, and a decrease in intravascular volume should be avoided, as this may cause a further decrease in systolic volume and systemic arterial pressure. Also, we should not forget that fluid retention and edema do not always signal right-sided heart failure, but can also be a side effect of PAH therapy (Stickel et al. 2019).

Data on the use of another group of nonspecific drugs - anticoagulants - are rather contradictory. The largest COMPERA registry analysis to date has shown a potential survival benefit associated with anticoagulants in patients with idiopathic PAH (Olsson et al. 2014), but this finding has not been confirmed by other studies (Preston et al. 2015). Two recent meta-analyses have also shown that the use of anticoagulants may improve survival in patients with idiopathic PAH (Khan et al. 2018; Wang et al. 2020); but they also did not have a reliable methodology. Data obtained from PAH registries (REVEAL, COMPERA) also did not give a clear answer about the effect of indirect anticoagulants on survival in patients with PAH; moreover, their use in patients with PAH was accompanied by an increased risk of mortality due to more frequent bleeding (Ngian et al. 2012; Olsson et al. 2014; Said, 2014; Preston et al. 2015; Roldan et al. 2017). Hypocoagulation is often recorded in patients with congenital heart defects and portopulmonary hypertension due to impaired synthesis/degradation of coagulation factors, as well as due to thrombocytopenia and thrombasthenia. In addition, in patients with cirrhosis of the liver, esophageal varices, hemorrhoidal veins can be the source of bleeding, and in patients with PAH on the background of congenital heart defects, dilated bronchial arteries. Thus, at present, anticoagulants are not recommended for general use in PAH. In general, the appointment of anticoagulants in patients with PAH can be considered only in the presence of documented arterial or venous thrombosis, atrial fibrillation/flutter, right ventricular heart failure (Galiè et al. 2016; Grünig et al. 2018; Goncharova et al. 2019).

Also, to date, there is no reliable evidence of the effectiveness of therapy with inhibitors of platelet aggregation in patients with PAH. Therefore, the routine administration of antiplatelet agents is not recommended as a pathogenetic one, but can be used if there are indications for the treatment of comorbidities.

In patients with PAH, supraventricular arrhythmias are often observed (Rajdev et al. 2012), which is accompanied by a worsening of the clinical condition, the appearance of signs of right ventricular heart failure. The risk of death in the event of cardiac arrhythmia in patients with PH increases by 1.75 times. Restoration of sinus rhythm leads not only to an improvement in the clinical condition, but also leads to a decrease in mortality (Olsson et al. 2013).

Methods for restoring sinus rhythm depend on the nature of rhythm disturbances and the clinical condition of the patient. In most patients with atrial flutter, catheter radiofrequency ablation is performed. After successful rhythm restoration by radiofrequency ablation, no additional antiarrhythmic therapy is usually required, while other methods of sinus rhythm restoration require anti-relapse therapy with amiodarone (Olsson et al. 2013; Grunig et al. 2018). If it is impossible to restore sinus rhythm, rhythm-reducing therapy is prescribed. To control the heart rate in atrial fibrillation, patients with PH are recommended to prescribe digoxin (Galiè et al. 2016; Kirchhof et al. 2016; Grunig et al. 2018).

In patients with decompensated PAH or end-stage PAH, cardiotonic drugs may be prescribed as a symptomatic remedy to improve right ventricular contractility and maintain adequate perfusion pressure (Jentzer and Mathier 2015; Galiè et al. 2016; Condliffe and Kiely 2017).

Specific therapy

In the case of diagnosing PAH, one should start etiopathogenetic schemes for its correction as soon as possible. For this purpose, specific therapy methods have been developed based on the modern understanding of

endothelial dysfunction in pulmonary artery remodeling. The action of targeted therapy is associated with blockade of vasoconstrictor substance receptors and stimulation of major pathways mediated by potent vasodilators such as nitric oxide and prostacyclin (Figure 2) (Korokin et al. 2018).

Drugs from six different substance classes are currently being used to treat PAH in Europe. These drugs can be used singly or in combination. It must be remembered that pulmonary arterial hypertension remains an incurable disease. Thus, the goal of therapy is the localization of the disease, that is, the stabilization of the patient's condition at a satisfactory clinical level without signs of right ventricular failure and, ideally, without progression of the disease. In one randomized trial using initial combination therapy (Galie et al. 2015), this goal was achieved in 40% of patients. The choice of drug depends in part on the severity of pulmonary arterial hypertension, and current guidelines define (Galie et al. 2015, 2016) it as low, moderate, or high risk based on expected mortality within one year. For patients with newly diagnosed "typical" PH and at low or moderate risk, initial or early combination treatment is used, including an endothelin receptor antagonist (ERA) with a phosphodiesterase-5 (PDE-5) inhibitor or a soluble guanylate cyclase (sGC) stimulator.

Figure 2. Pathways of action of various specific drugs on the tone of vascular smooth myocytes in PH. Note: cERAs - selective endothelin-1 receptor antagonists, dERAs - dual endothelin-1 receptor antagonists, ET A - endothelin type A receptor, ET B - endothelin type B receptor, FP - prostaglandin F receptor, TP - thromboxane receptor, CA IP receptors - selective agonists of prostaglandin I2 (prostacyclin) receptors, IP - prostaglandin I2 (prostacyclin) receptor, PGI2 - prostaglandin I2 (prostacyclin), DP 1 - type 2 prostaglandin D2 receptor, EP 1-4 - prostaglandin E2 1-4 receptor type, PG E2 - prostaglandin E2, sGC - soluble guanylate cyclase, NO - nitric oxide, iPDE-5

- phosphodiesterase type 5 inhibitors, PLC - phospholipase C, AC - adenylate cyclase, ATP - adenosine triphosphate, cAMP - cyclic adenosine monophosphate, GTP - guanosine monophosphate , cGMP - cyclic guanosine monophosphate, BMCK - blockers of slow calcium channels), K - effect of vasoconstriction, D - effect of vasodilation. The arrows on the light part of the scheme: "with a crossbar on the tail"

- indicate the main target of the path; "with shading on the body" - a negative impact; "with a transparent tail" - a positive impact he number of scientific papers on the topic of pulmonary hypertension on the PubMed Internet resource in the period from 2000 to 2022.

Blockers of "slow" calcium channels

iНе можете найти то, что вам нужно? Попробуйте сервис подбора литературы.

If patients with idiopathic, hereditary, or drug-induced pulmonary arterial hypertension test positive for vasoreactivity during right heart catheterization (decrease in mean PAP from more than 10 mm Hg to a level not exceeding 40 mm Hg. without reducing cardiac output), calcium antagonists, individually titrated to high doses, should be given first (Galie et al. 2015; Simonneau et al. 2019). The choice of CCB may be influenced by increased heart rate or the presence of concomitant arterial hypertension: in the first case, diltiazem can be prescribed, in the second - amlodipine or nifedipine. Verapamil is not recommended for use in patients with PAH due to the presence of a negative inotropic effect. CCB therapy begins with a minimum dosage, gradually increasing the dosage to the maximum tolerated, given the possibility of developing systemic hypotension and edematous syndrome. In the most favorable case, this leads to the normalization of pulmonary hemodynamics. For patients with PAH who meet the criteria for a positive vasodilating response and are treated with calcium antagonists, every 3-4 months, fully reassess their condition and the effectiveness of ongoing therapy. In the absence of an adequate response in the form of a decrease in the functional class in combination with a pronounced improvement in hemodynamics (close to normal), additional therapy should be prescribed. However, this treatment regimen is suitable for less than 5% of the total number of patients with PAH (Galie et al. 2015; Galie et al. 2016). The practice of using calcium antagonists without a preliminary test for vasoreactivity is outdated.

For vasoreactivity-negative patients and those at high risk, combination therapy is recommended, including targeted drugs for specific PH therapy (Barst et al. 1996).

Endothelin-1 antagonists

Endothelin-1 (ET-1) is a peptide of endothelial origin that has two receptor subtypes, designated endothelin A (ETRA) and endothelin B (ETB), located on smooth muscle cells of the pulmonary arteries. ET-1 is a potent pulmonary vasoconstrictor and stimulates arterial smooth muscle cell mitosis, thereby promoting pulmonary vascular remodeling. Pulmonary and plasma levels of ET-1 are elevated in human PAH and in experimental animal models of PAH.

Binding of endothelin-1 to endothelin A and B receptors on pulmonary artery smooth muscle cells promotes cell proliferation and vasoconstriction (Clozel et al. 2013). Endothelin B receptors are predominantly expressed on pulmonary endothelial cells, promoting vasodilation through accelerated production of prostacyclin and nitric oxide and excretion of endothelin-1 (Clozel et al. 2013). However, selective blockade of only endothelin A receptors and non-selective blockade of both types of receptors have shown similar efficacy in PAH (Clozel et al. 2013). At the same time, it must be remembered that endothelial receptor antagonists are teratogenic and should not be used during pregnancy (Xing et al. 2017).

Currently, the following drugs from the group of endothelin-1 antagonists are used for the treatment of PAH:

Ambrisentan is an oral ERA drug that preferentially blocks endothelin A receptors. It has been shown to be effective in patients with PAH with respect to symptoms,

exercise, hemodynamics, and time to clinical deterioration (Galie et al. 2008). However, subsequent studies have shown that the use of this drug is associated with an increase in the incidence of peripheral edema, while an increase in the frequency of liver dysfunction was not observed (Galie et al. 2015).

Bosentan is an oral, non-selective ET antagonist that improves exercise performance, hemodynamics, and time to clinical deterioration in patients with PAH. When using this drug, it must be taken into account that in 10% of patients treated with bosentan, there is a reversible dose-dependent increase in hepatic transaminases (Humbert et al. 2007). It follows that in such patients, monthly monitoring of liver function should be carried out (Humbert et al. 2007). Moreover, due to pharmacokinetic interactions, bosentan may reduce the effectiveness of hormonal contraceptives, as well as reduce the levels of warfarin, sildenafil and tadalafil in serum (van Giersbergen et al. 2006; Wrishko et al. 2008).

Macitentan is an oral, non-selective ERA that improves physical performance in PAH patients and prevents disease progression (Pulido et al. 2013). Despite the absence of hepatotoxicity, 4.3% of patients experienced a decrease in Hb levels to <80 g/l, during therapy with 10 mg macitentan (Pulido et al. 2013).

PDE-5 inhibitors

Phosphodiesterases (PDEs) are a complex family of intracellular enzymes isolated in the early 1970s from rat brain by polyacrylamide gel electrophoresis, which hydrolyze 3', 5'-cyclic nucleotide monophosphates into the corresponding 5'-monophosphates (Francis et al. 2001), i.e. cause degradation of (adenosine monophosphate) cAMP and guanosine monophosphate (cGMP). Thus, PDEs balance the work of effector enzymes - adenylcyclase and guanylcyclase, which catalyze the formation of cAMP and cGMP from ATP and GTP, respectively. This is the basis for the most important role of PDEs in maintaining intracellular homeostasis and their influence on cellular functions.

From the point of view of the chemical structure and functional features, it is customary to distinguish 11 types (families, isoenzymes) of PDEs (Jeon et al. 2005) involved in the implementation of various functional reactions of the body.

PDE-5 is overexpressed in PH patients (Nagendran et al. 2007), and sildenafil, as the first PDE-5 inhibitor, significantly improves pulmonary vasorelaxation (Rubin et al. 2011). It acts on the NO-dependent pathway of pulmonary vasodilation by inhibiting phosphodiesterase type 5 (cGMP-dependent). An increase in the level of intracellular cGMP, a secondary messenger of endogenous nitric oxide, stimulates vasodilation in the pulmonary vessels by relaxing the smooth muscle cells of the vascular wall and inhibits their proliferation due to the activation of cGMP-dependent peptidkinases and potassium channels (Martynyuk et al. 2015). Thus, cGMP is considered as a unique target molecule in PH. PDE-5 is also abundantly expressed in platelets, and its inhibition reduces platelet aggregation. Insufficient NO-cGMP signal leads to pulmonary thrombosis and platelet activation, which is a common clinical manifestation of PH (Dunkern et al. 2005; Gudmundsdottir et al. 2005). Treatment with sildenafil has been shown to increase the

sensitivity of platelets to NO, which prevents platelet aggregation (Mullershausen et al. 2004). It is worth noting that sildenafil, tadalafil, and vardenafil increase pulmonary vasorelaxation in a dose- and time-dependent manner, with vardenafil having a maximum effect after 40-45 minutes, sildenafil after 60 minutes, and tadalafil after 75-90 minutes. The results of clinical trials SUPER-1 (double-blind study) and SUPER-2 (open study) in patients with PH showed a positive effect of treatment with sildenafil. Hemodynamic parameters, which include total mean pulmonary artery pressure, pulmonary vascular resistance, and 6-minute walk test results, were significantly improved. In addition, one-year survival was 96% in patients with IPAH, which is 7l% higher than expected survival. The REPLACE trial to replace riociguat, a soluble guanylate cyclase stimulator, with sildenafil was positive and supported the hypothesis of PDE-5 inhibition as a treatment option in patients with PH with an intermediate risk of mortality within 1 year (Tsareva and Avdeev 2013; Koklin and Danilenko 2019; Hoeper et al. 2021; Liu et al. 2023). Sildenafil and tadalafil are FDA approved for the treatment of PAH and are used to reduce mortality either as monotherapy or in combination with prostacyclin analogues or endothelin-1 receptor blockers.

Although none of the studies directly compared vardenafil, tadalafil, and sildenafil, a positive effect of PDE-5 inhibitors was seen in all three of the above drugs. However, the effect size seemed larger for sildenafil compared to vardenafil and tadalafil, possibly due to the large number of studies that included the drug sildenafil. In the Russian Federation, only one IFDE-5 drug, sildenafil, is registered for the treatment of PAH.

cGMP production stimulator - Riociguat

Riociguat, as a sGC stimulator, unlike PDE-5 inhibitors that slow down the degradation of cGMP, enhance its production by directly stimulating the enzyme, both in the presence and in the absence of endogenous NO (Schermuly et al. 2011).

Riociguat has a dual mechanism of action: it sensitizes sGCs to endogenous NO by stabilizing their binding, and also directly enhances cGMP production by directly stimulating the enzyme, both in the presence and absence of endogenous NO, which is significantly reduced in PAH patients. Due to these effects, riociguat restores the metabolic pathway "NO - sGC - cGMP" and causes an increase in the production of cGMP, which plays an important role in the regulation of vascular tone, proliferation processes, fibrosis and inflammation (Ghofrani et al. 2016).

The study demonstrated that patients with PAH treated with riociguat up to 2.5 mg intravenously showed favorable results in terms of physical performance, hemodynamics, and time to clinical deterioration (Ghofrani et al. 2013). Riociguat has a good safety spectrum, as the frequency of the most serious adverse events, such as syncope, did not fundamentally differ from the placebo group at the maximum dosage. Before starting therapy, the patient must give up cigarettes, since the concentration of riociguat in the blood decreases significantly against the background of smoking. Riociguat has a teratogenic effect and its use in pregnant women is contraindicated.

Prostacyclin analogues

Prostacyclin (prostaglandin I2) is a potent pulmonary vasodilator that acts via the cAMP pathway. It has been shown that in PAH, the production of prostacyclin in endothelial cells is significantly reduced, which in turn leads to vosoconstriction, proliferation of smooth myocytes and platelet aggregation, which can lead to both the development and aggravation of this pathological condition. Three prostacyclin analogs are currently available: epoprostenol, iloprost, and treprostinil.

The first synthetic drug, epoprostenol, has shown significant efficacy as a therapeutic agent in improving hemodynamic parameters, exercise performance, and mortality. However, it is not without its shortcomings. Its short half-life requires continuous intravenous infusion through a central venous catheter, which requires central line placement and potentially poses a risk of central line infection. The initial preparations were required to be stored in the refrigerator or on ice; however, newer drugs have a more stable half-life of 24 hours (Kallen et al. 2008; Sitbon et al. 2014; Sitbon and Vonk Noordegraaf 2017).

Iloprost is a chemically stable prostacyclin analogue that is most commonly used by inhalation. In the Russian Federation, only iloprost is registered from this group, which is used on average 6-9 times a day using an ultrasonic nebulizer at a dose equivalent to the content of 2.5-5 ^g of the drug at the level of the alveoli, as part of specific combined therapy. The efficacy of inhaled iloprost was evaluated in the AIR-1 short-term RCT in patients with PAH and inoperable forms of CTEPH with FC III-IV (NYHA). During therapy with iloprost, there was a significant improvement in hemodynamic parameters, an increase in exercise tolerance and a decrease in PAH FC. However, long-term iloprost monotherapy did not result in improved survival and morbidity (Opitz et al. 2005). Therefore, at present, iloprost is used only as part of a specific combination therapy in addition to oral drugs (Hoeper et al. 2006; McLaughlinet al. 2006; Zheng et al. 2014). Side effects include headaches, hot flashes, and jaw pain. In addition, in patients with broncho-obstructive syndrome, against the background of inhaled iloprost, the reactivity of the upper respiratory tract may increase and cough may appear. Iloprost has a pronounced antiplatelet effect, so its use in patients with bleeding is contraindicated.

Treprostinil is a tricyclic benzidine thermostable analog of epoprostenol. Chemical stability allows you to prescribe the drug intravenously and subcutaneously. The effects of treprostinil were studied in randomized clinical trials and were characterized by improvement in physical abilities, hemodynamics and symptoms.

Prostacyclin (IP) receptor agonists

Selexipag is a long-acting oral selective non-prostanoid prostacyclin receptor (IP) agonist indicated for the treatment of symptomatic pulmonary arterial hypertension (PAH) in adults. It was designed to overcome the pain associated with standard prostanoid therapy, presenting fewer side effects and comparable hemodynamic benefits.

Stimulation of IP receptors by selexipag leads to vasodilation, as well as antiproliferative and antifibrotic effects.

The active substance prevents remodeling of the heart and lungs in rats with pulmonary PAH and causes a proportional decrease in pulmonary and peripheral pressure, showing that peripheral vasodilation reflects pharmacodynamic efficacy in relation to pulmonary vessels.

Selexipag is metabolized by the cytochrome P450 system (CYP 2C9 and 3A4), which can lead to the formation of a toxic intermediate and can also cause drug interactions, especially with cyclosporine A.

Selexipag has been shown to be effective in improving the combined morbidity-mortality outcome in adult patients with PAH (primarily idiopathic connective tissue disease secondary to corrected congenital heart disease) WHO FC II and III as monotherapy or as an adjunct to an endothelin receptor agonist or a phosphodiesterase 5 inhibitor (Panagiotidou et al. 2021).

In clinical practice, selexipag is mainly used when patients have an inadequate response to initial oral combination therapy with an endothelin receptor agonist and a PDE-5 inhibitor. Selexipag is not equivalent to parenteral prostacyclin and is not intended to replace its use in high-risk patients (Genecand et al. 2021).

Other specific therapies

Response to specific therapy is usually assessed after 4-12 weeks and then at intervals of 3 to 6 months. Further correction of the treatment regimen should be purely individual. If the main therapeutic goal has not been achieved - the patient has not moved into the low-risk category, after the initial treatment, the next step is a double or triple combination treatment. Combination therapy is an attractive approach due to the possibility of simultaneous influence on several pathways of PAH pathogenesis, which leads to a decrease in PVR, prevention of further remodeling of the pulmonary arteries and, as a result, to an increase in the time until the course of PAH worsens, and a decrease in the incidence of complications, including fatal ones.

If the response to treatment is still inadequate, evaluation for lung transplantation should be started immediately, as decompensation can occur quickly and without warning in such patients. Although the majority of patients with pulmonary arterial hypertension currently do not require transplantation, this measure is indispensable for those whose pathology has proven resistant to conservative methods of treatment. Combined heart and lung transplantation is only necessary in exceptional cases, as right heart function almost always returns to normal after lung transplantation (Crovetto et al. 2016). In recent years, the results of lung transplantation have shown significant progress, and now experienced centers report a one-year survival > 90% (Tudorache et al. 2015).

As an operative, but less radical method of treatment, fluoroscopically guided denervation of the pulmonary artery (PADN) can be used. This procedure is aimed at correcting the sympathetic regulation of pulmonary vascular tone in PAH. In single-center clinical studies, this method has been associated with a reduction in PAP and an improvement in right ventricular function (Chen et al. 2013). However, the adaptation of PADN to routine clinical practice has so far been limited by the lack of multicentre clinical trials in PAH, the lack of unique expertise required for successful ablation, and uncertainty

about its efficacy compared to placebo or drug therapy in PAH.

Right atrial pacing has been used to alleviate right ventricular failure in patients after myocardial infarction. In PAH, chronotropic insufficiency is associated with impaired cardiac output. Recent clinical data from patients with PAH (Khural et al. 2021) have shown that right atrial pacing significantly reduced end-diastolic pressure and right ventricular volume and increased cardiac output to normal levels. However, this and similar methods still need deeper study and additional tests.

The management of patients with "atypical" PAH is less standardized. Treatment of most of these patients, as a rule, begins with monotherapy with PDE-5 inhibitors (Opitz et al. 2016). Further adjustment of the treatment regimen depends on the response and individual circumstances; due to the lack of complete data for this type of pathology, at the moment there are no general recommendations for the management of such patients. Due to age and the presence of comorbidities, most patients with "atypical" PAH are usually not candidates for lung transplantation.

Promising areas of research in the field of PH therapy

Departing from standardized in most countries targeted drugs for the treatment of PAH, it is worth noting that in recent years many new specific drugs and methods for its therapy have been discovered. Recent studies have shown that the Rho-kinase inhibitor fasudil improves the acute hemodynamics of congenital heart disease with severe pulmonary hypertension in a dose-dependent manner (Ruan et al. 2019). In addition, studies have shown that silibinin, an inhibitor of CXCR4, can attenuate PAH and reduce phases of pulmonary arterial pressure, however, this was not effective in the advanced stages of the disease (Zhang et al. 2019). Moreover, silibinin can delay pulmonary artery occlusion and pulmonary vascular remodeling by inhibiting the CXCR4/SDF-1 axis (Zhang et al. 2019). At the same time, the efficacy, durability, safety, and long-term clinical impact of these specific drugs in patients with PAH need further evaluation.

Prostanoids are a promising group of drugs for the treatment of PAH, since they have not only vasodilating, but also antiplatelet and antiproliferative effects. Currently, prostacyclins remain the mainstay of PAH treatment. However, there is another mechanism of vasoconstriction of the vessels of the pulmonary circulation, it is associated with inhibition of the formation of prostaglandins (primarily prostaglandin E2), which normally have a vasodilating effect (Ostroumova et al. 2022). The prostacyclin (IP) receptor, prostaglandin E3 (EP3) receptor and prostaglandin E4 (EP4) receptor are the main pulmonary artery receptor subtypes in both rat and human pulmonary arteries. Patients with PH have decreased levels of circulating PGI2 and PGE2. PGE 2 is a potent vasodilator, although it may have a vasoconstrictive effect in some cases. In many vascular preparations, including mouse aortic annulus, rabbit ductus arteriosus, human pulmonary vein, PGE2 directly relaxes tissues precompressed with KCl or norepinephrine with nearly two orders of magnitude greater efficiency than PGI 2 (IP) or PGD receptor activation. 2 (DP) (Ostroumova et al. 2022).

The biological action of PGE2 is mediated by G protein-coupled E-prostanoid receptors, EP1, EP2, EP3

and EP4. These four EP receptor subtypes are associated with different signaling pathways. In general, EP1/EP3 receptors have a vasoconstrictive and prohypertensive effect, while EP2/EP4 receptors have a vasodilating and antihypertensive effect (Sugimoto et al. 2007). In connection with the above, the development of drugs for EP3 antagonists and EP4 agonists can become a new promising direction in the treatment of PH. Also, in patients with PAH, there is often a violation of bronchodilation, which is mediated specifically by the EP 4 receptor. Respiratory function is one of the key parameters in patients with PH, drugs that cause bronchorelaxation and reduce hypoxia can be of great benefit to patients with PH.

Nitric oxide (NO) is the most important vasodilator of endothelial origin and numerous studies have found that its concentrations are reduced in patients with PH (Sausbier et al. 2000). Recent studies show that NO donor drugs such as diethylamine-NO, sodium nitroprusside, monoorganic nitrite can be very effective in patients with PH due to its natural vasodilating properties (Mondejar-Parreno et al. 2019; Hurtsen et al. 2020).

The action of most of the above drugs is based on the restoration of endothelial function through the restoration of the balance of vasostrictors and vasodilators. However, due to the fact that the pathogenesis of PAH and many other forms of PH is endothelial dysfunction, which is manifested by oxidase (or oxidative) stress, antioxidant drugs may become a promising direction in the treatment of PH (Simonneau et al. 2019).

For example, recent studies have shown that alginate oligoside (AO) acts as an antioxidant and antiinflammatory agent in PAH by inhibiting monocrotaline-induced pulmonary vascular remodeling. AO also reduces the expression of malondialdenide and pro-inflammatory cytokines, while increasing the expression of antiinflammatory cytokines (Feng et al. 2020). Sulforaphane reduces pulmonary vascular remodeling, inflammation and fibrosis (Kang et al. 2020). Oral melatonin given to mother sheep late in pregnancy improved lambs' pulmonary vascular function, stimulated antioxidant activity, and reduced reactive oxygen species and nitrotyrosine, a marker of oxidative stress in small pulmonary vessels (Astorga et al. 2018; Gonzalez-Candia et al. 2019; ). Oral administration of seloncertib resulted in a dose-dependent decrease in pulmonary artery pressure and right ventricular hypertrophy in a model of PAH (Boucherat et al. 2018; Budas et al. 2018).

In addition, multiple studies have led to the emergence of other equally promising therapeutic approaches in the field of PAH. Thus, recent scientific work has shown that regenerative cell therapy, gene therapy, and epigenetic drugs can offer a new perspective in the treatment of PAH (Baliga et al. 2011; Loisel et al. 2018). ).

It has been shown that damage and dysfunction of the endothelium in PAH conditions cause disruption of apoptosis processes in endotheliocytes and stimulate the formation of obliterating plexiform lesions (Sakao et al. 2009). Cell alteration and subsequent endothelial dysfunction may, in turn, cause loss of the distal, most functional pulmonary vessels. Stem cell therapy aims to repair endothelial damage and dysfunction while at the same time repairing the distal pulmonary vasculature (Weiss et al. 2011). As the main types of stem cells used

in therapy, the following are distinguished: endothelial progenitor cells (EPC); mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs) (Weiss et al. 2011).

EPCs were first derived from mononuclear cells in 1997, after which their rapid study began (Yoder 2012). This discovery showed that angiogenesis can occur postembryogenesis from a population of cells other than angioblasts (Foster et al. 2014).

In preclinical studies, EPC administration has demonstrated the ability of these cells to engraft in the distal pulmonary arterioles and to significantly slow down or completely prevent disease progression in rat models of PH. When administered 3 days after injection of monocrotaline to rats, ECP significantly reduced the pressure in the right ventricle of the heart. This study was the first to present the possibilities of not only therapeutic but also prophylactic use of EPA. It should also be noted that rats treated with EPC transduced with human endothelial nitric oxide synthase (eNOS) showed a significant change in PAP in the monocrotaline-induced PH model. In addition, ECP delivery successfully prevented the onset of PAH in athymic rats (Zhao et al. 2005).

Recent studies have shown the possible efficacy of cell therapy based on the enhancement of BMPR2 signaling, the activation of which suppresses the rapid expansion of blood vessel smooth muscle tissue, which contributes to the life support of pulmonary arterial endothelial cells and the prevention of arterial damage (Harper et al. 2019). To do this, the researchers used EPCs transduced with adenovirus vectors and carrying the luciferase reporter gene and GFP (AdTrackLuc) or BMPR2 (AdCMVBMPR2myc) obtained from the bone marrow of rat femurs. Using the monocrotaline-induced PAH model, rats were injected into the tail vein after the onset of signs of PH. The authors found that injections of these cells significantly increased BMPR2 expression and signaling in the lungs by the end of the first day after injection. Overall, this study has shown the therapeutic efficacy of enhancing BMPR2 signaling, which may be of great importance for future translational studies.

In 2007, a pilot randomized control trial was conducted in 31 patients with idiopathic PAH after successful trials in laboratory animals to evaluate the safety and efficacy of ECP therapy in humans. Patients treated with ECP in addition to conventional therapy showed significant improvement in 6-minute walk test, mean PAP, PVR, and cardiac output at 12 weeks, while no side effects were identified (Wang et al. 2007). A small pilot study was also conducted in children with IPAH and showed improvement in hemodynamic parameters, exercise tolerance and quality of life after 12 weeks (Zhu et al. 2008). It is worth noting that in order to reliably confirm such efficacy and safety, additional, more extensive studies with long-term follow-up are needed before they are included in the main structure of the treatment of PH.

In 2015, the aim of the Pulmonary Hypertension and Angiogenic Cell Therapy (PHACeT) study was to investigate the tolerability of cultured eNOS-transfected EPCs in PAH patients who had failed other methods (Granton et al. 2015). Patients received 3 doses of eNOS-transfected EPCs (eNOS-transfected EPCs) injected into the right atrium for several consecutive days. The results showed that such therapy is well

tolerated and improves hemodynamics in the short term.

MSCs have been widely studied in recent years and successfully used to treat various diseases (Lalu et al.

2012). The source of these cells is usually adipose tissue and Wharton's jelly. MSCs have pronounced regenerative properties and play a significant role in tissue repair and angiogenesis. It has been shown that, when introduced into tissues, they migrate to the sites of damage, differentiate, and contribute to their recovery (Suen et al.

2013).

Recent studies report several benefits of using MSCs as a stem cell transplant. Firstly, they are quite easily cultivated and are immunologically compatible since the main histocompatibility complex is absent in their structure. Secondly, they have demonstrated anti-inflammatory, pro-angiogenic, and anti-apoptotic properties, which makes the use of MSCs promising (Foster et al. 2014). In a rat model of pulmonary hypertension, intravenous administration of MSCs after PH induction with monocrotaline reduced right ventricular systolic pressure, medial thickening, and suppressed pulmonary collagen synthesis along with anti-inflammatory and anti-apoptotic markers (de Mendonca et al. 2017). Moreover, MSCs simultaneously reduced right heart hypertrophy and normalized right ventricular ejection fraction in a monocrotaline-induced PAH model in rats (Umar et al. 2009).

iPSCs are adult somatic cells that, through genetic reprogramming (through the transduction of certain transcription factors), have acquired the characteristics of embryonic stem cells. The results of a 2016 study of the therapeutic potential of iPSCs in rats with monocrotaline-induced PH showed that rats with PH treated with iPSCs had a marked improvement in hemodynamic parameters (Huang et al. 2016). Histological examination additionally confirmed the favorable effect of iPSCs on the degree of remodeling of small-caliber pulmonary arteries. Thus, in rats treated with iPSCs, a significant decrease in hypertrophy of the media was observed. In addition, immunohistochemical analysis showed that the use of this kind of stem cells significantly suppressed inflammation in the lungs of rats with monocrotaline-induced PH (Huang et al. 2016). However, it is important to emphasize that iPSC regimens still require further optimization and further study before clinical use.

Various genetic defects can potentiate the occurrence of PH through various mechanisms, such as resistance to apoptosis or impaired calcium metabolism (Lee and Young 2013). It follows that the development of efficient harmless gene delivery systems is a promising approach to the treatment of PAH. A large number of experimental studies have demonstrated that the delivery of targeted drugs that can influence the degree of gene expression can be used both for the treatment and prevention of the onset of the disease (Reynolds 2011).

Of the many mechanisms of delivery of gene agents in the case of PAH, endotracheal administration by aerosol has the greatest promise, acting on endothelial and smooth muscle cells of the pulmonary arteries, as well as on connective tissue cells. This method remains non-invasive and prevents the degradation of nucleic acids by reducing endonuclease activity (Katz et al. 2019). In addition, direct delivery through the respiratory tract causes little to no systemic side effects and allows the agents not to undergo primary metabolism in the liver.

Genetic studies have identified more than 450 heterozygous germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene (Fessel et al. 2011). Reduced BMPR2 expression has also been reported in rodent models of monocrotaline-induced pulmonary hypertension. Moreover, the association of mutations in this gene or its low expression with the progression of PH has been identified in several scientific papers (Austin and Loyd 2014).

In 2013, a study identified the compound FK506 (tacrolimus). This compound activates BMPR2-mediated signaling and regulation of endothelial-specific genes. This compound reversed severe hypertension in a rat model of monocrotaline-induced PH, as well as in a conditional deletion of BMPR2 mouse model, as evidenced by reductions in right ventricular systolic pressure, pAp, medial hypertrophy, and neointimal formation (Spiekerkoetter et al. 2013). This efficacy stimulated further work in the direction of studying the safety of using FC506 in patients with PAH, which showed rather conflicting results (Spiekerkoetter et al. 2015).

Another approach to therapy associated with BMPR2 is associated with the restoration of signaling of this gene based on the direct effect of BMP9, its ligand, on target cells (Long et al. 2015). A 2015 study showed that BMP9 endothelial pretreatment prevents endothelial cell apoptosis. This study also demonstrated that daily intraperitoneal administration of BMP9 reversed PAH in a mouse model carrying a heterozygous knockdown of the R899X mutation of human BMPR-II (Long et al. 2015).

Another study showed that targeted delivery of an adenoviral vector containing the BMPR2 gene is effective as a therapy for hypoxic pulmonary hypertension in experimental rodent models (Reynolds et al. 2007). The authors found that delivery of the BMPR2 gene significantly reduces the degree of morphological changes, as well as pressure in the right ventricle and pulmonary artery (Reynolds et al. 2007). However, the adenoviral vector itself is a limiting factor for both research and clinical use. In particular, numerous studies have shown that the use of such vectors is associated with an inflammatory response (Lee et al. 2017).

In recent years, more and more different genes have been identified that are involved in the etiology or pathogenesis of PH. Along with their identification, work is slowly beginning to explore the potential use of such genes as new etiopathogenetic treatments (Table 1).

Over the years, more and more studies have shown that epigenetic factors play a significant role in the etiopathogenesis of PAH (Cheng et al. 2019; Bisserier et al. 2020). Epigenetics is defined as an inherited change in gene expression without changing the DNA sequence (Weinhold 2006). Such changes are partly mediated by specific epigenetic modifications (epigenetic marks) and are represented by processes such as methylation, acetylation, or phosphorylation of DNA/histone proteins. Such changes can affect the degree of chromatin condensation, transcription processes, and the intensity of gene expression (Weinhold 2006). For example, several studies have reported hypermethylation of the BMPR2 promoter gene in blood mononuclear cells in patients with hereditary PAH using genomic bisulfite sequencing (Liu et al. 2017).

Table 1. Research work on the topic of gene therapy correction of PH

An investigational method for the correction of pulmonary hypertension Experimental model Effects Source

1. Gene: Tagln Delivery method: lentoviral vector Method of administration: intratrachelal Hypoxic pulmonary hypertension in rats Decreased right ventricular systolic pressure and vascular remodeling Zhang et al. 20l4

2. Gene: Gal-3 Delivery method: lentoviral vector Method of administration: intratrachelal Monocrotaline-induced pulmonary hypertension in rats Decrease in systolic pressure in the right ventricle, decrease in right ventricular hypertrophy Li et al. 20l9

3. Gene: Twistl Delivery method: lentoviral vector Method of administration: Delivery of cells from fibrin gel Hypoxic pulmonary hypertension in mice Prevention hypoxia-induced endothelial-mesenchymal transition Mammoto et al.2020

4. Gene: CD40 Delivery method: lentoviral vector Route of administration: intravenous Monocrotaline-induced pulmonary hypertension in rats Decrease in mean pulmonary arterial pressure, decrease in right ventricular systolic pressure, decrease in right ventricular hypertrophy YanYun et al. 20l5

5. Gene: HIF-la Delivery method: lentoviral vector Route of administration: intratracheal Hypoxic pulmonary hypertension in rats Decrease in systolic pressure in the right ventricle, decrease in right ventricular hypertrophy Li et al. 20l6

6. Gene: Tphl Delivery method: adenovirus vector Route of administration: intravenous Hypoxic pulmonary hypertension in rats Decrease in systolic pressure in the right ventricle, decrease in right ventricular hypertrophy, decrease in the degree of remodeling of the vessels of the pulmonary circulation Morecroft et al. 20l2

7. Gene: CGRP (AdRSVCGRP) Delivery method: adenovirus vector Route of administration: intratracheal Hypoxic pulmonary hypertension in mice Decreased pulmonary arterial pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary vascular remodeling Bivalacqua et al. 2002

8. Endothelial NO synthase gene (AdCMVceNOS) Delivery method: adenovirus vector Route of administration: intratracheal Hypoxic pulmonary hypertension in rats Restoration of NO production in the vessels and a decrease in the formation of neointima, a decrease in the remodeling of the vessels of the pulmonary circulation, decreased pulmonary arterial pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy Janssens et al. l996

9. Gene: Kvl.5 KCNA5 Delivery method: adenovirus vector Route of administration: intratracheal Hypoxic pulmonary hypertension in rats Decrease in systolic pressure in the right ventricle, decrease in right ventricular hypertrophy Pozeg et al. 2003

10. Gene: Forkhead box O (FoxOl) Delivery method: adenovirus vector Route of administration: orotracheal Monocrotaline-induced pulmonary hypertension, hypoxic pulmonary hypertension, hypoxia + SU5416-induced pulmonary hypertension in rats Decreased pulmonary arterial pressure, pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary vascular remodeling Savai et al. 20l4

ll. Gene: VEGF (VEGF l65 human) Delivery method: adenovirus vector Route of administration: intratracheal Hypoxic pulmonary hypertension in rats Increased activity of endothelial nitric oxide synthase in the lung tissue, restoration of endothelium-dependent vasodilation, decreased systolic pressure in the right ventricle, decreased right ventricular hypertrophy Partovian et al. 2000

l2. Gene: Angiostatin (Ad.K3) Delivery method: adenovirus vector Route of administration: intratracheal Hypoxic pulmonary hypertension in mice Aggravation of the development of PH Enhance remodeling Increased pressure in the right ventricle Pascaud et al. 2003

l3. Gene: BMPR2 Delivery method: adenovirus vector Route of administration: intravenous Hypoxic pulmonary hypertension in rats Decrease in mean pulmonary arterial pressure, decrease in right ventricular systolic pressure, decrease in right ventricular hypertrophy Reynolds et al. 2007

l4. Gene: sTIE2 Delivery method: adeno-associated viral vector Route of administration: into the pulmonary artery Monocrotalin-induced pulmonary hypertension in rats; pulmonary hypertension by increasing the expression of angiopoietin 1 in the smooth muscles of the pulmonary vessels; hypoxic pulmonary hypertension in rats Lack of proliferation of smooth muscle cells in the arterioles of the lungs, the absence of occlusion of small pulmonary vessels in monocrotaline and angiopoietin 1-induced pulmonary hypertension Kido et al. 2005

l5. Gene: human PGIS (hPGIS) Delivery method: adeno-associated viral vector Route of administration: intramuscular Hypoxic pulmonary hypertension in mice Monocrotaline-induced pulmonary hypertension in rats Decrease in systolic pressure in the right ventricle, decrease in RV hypertrophy Decreased vascular remodeling of ICC Kawakami et al. 2007

l6. Human gene: SERCA2a Delivery method: adeno-associated virus serotype l (AAVl) Route of administration: intratracheal Rats with monocrotaline-induced pulmonary arterial hypertension Reduced pulmonary artery pressure, decreased vascular remodeling, right ventricular hypertrophy, and fibrosis Hadri et al. 20l3

l7. Human gene: SERCA2a Delivery method: adeno-associated virus serotype l (AAVl) Route of administration: intratracheal Yorkshire pigs with partial pulmonary vein bandage Decrease in pulmonary artery remodeling with concomitant improvements in pulmonary hemodynamics and right ventricular function Aguero et al. 20l6

l8. Human prostacyclin synthase gene Route of administration/delivery: transfection into the liver Rats with monocrotaline-induced pulmonary hypertension Improvement in the condition caused by pulmonary hypertension and higher survival Suhara et al. 2002

l9. Human prostacyclin synthase cDNA (hPGIS) Delivery method: luminal adeno-associated virus serotype 9 Route of administration: into the lungs Rats with monocrotaline-induced pulmonary arterial hypertension Significant reduction in PAH severity, prevention of cardiac and pulmonary vascular remodeling Gubrij et al. 20l4

20. SERCA2a gene Delivery method: aerosolized AAVl.S2a Administration method: intratracheal Rats with monocrotaline-induced pulmonary arterial hypertension Decreased myocardial remodeling and susceptibility to ventricular tachycardia in palpitations Strauss et al. 20l9

2l. SERCA2a gene Delivery method: aerosolized AAVl.S2a Administration method: intratracheal Lung tissue from patients with idiopathic PAH. Rats with monocrotaline-induced PAH Weakening of remodeling and resistance of pulmonary vessels and, inhibition of remodeling of the right ventricle of the heart and a significant restoration of its function Bisserier et al. 202l

22. Class I HDAC inhibitor MS-275 (intraabdominal infection) and miR-34a agomiR (tail vein infection) Rats with monocrotaline-induced pulmonary arterial hypertension Reduces pulmonary artery remodeling and worsening of PAH Li et al. 202l

This led to a decrease in BMPR2 expression, which, in turn, could stimulate cell proliferation and provoke the development of PAH. In 2010, researchers found that levels of mitochondrial superoxide dismutase 2 (SOD2) were significantly reduced in FHR rats, in which PAH forms spontaneously (Archer et al. 2010). Since there were no changes in the sequence of the DNA chain, bisulfite sequencing of pulmonary vascular myocytes obtained from such rats was performed and revealed hypermethylation of CpG islands in the SOD2 promoter region. Inhibition of DNA methyltransferases by 5-aza-2'-deoxycytidine restored SOD2 expression, suppressed cell proliferation and resistance to apoptosis in rat pulmonary artery myocytes (Archer et al. 2010). Taken together, this study suggested that DNA methylation-specific targeted therapy may be a promising option for PAH inhibition.

Histone deacetylase (HDAC) is a class of enzymes that remove the acetyl group from histone proteins, affecting chromatin compaction and availability of transcription factors in DNA (Seto, Yoshida, 2014). This changes the mechanism of transcription and is usually associated with its suppression. Preliminary studies have shown that HDAC types 1 and 5 are elevated in patients with PAH and experimental PH models in laboratory animals (Zhao et al. 2012). In a rat model of monocrotaline-induced PH caused by pulmonary artery

References

■ Adir Y, Humbert M, Chaouat A (2021) Sleep-related breathing disorders and pulmonary hypertension. The European Respiratory Journal 57(1): 2002258. https://doi.org/10.1183/13993003.02258-2020 [PubMed]

■ Aguero J, Ishikawa K, Hadri L, Santos-Gallego CG, Fish KM, Kohlbrenner E, Hammoudi N, Kho C, Lee A, Ibáñez B, García-Alvarez A, Zsebo K, Maron BA, Plataki M, Fuster V, Leopold JA, Hajjar RJ (2016) Intratracheal gene delivery of SERCA2a ameliorates chronic post-capillary pulmonary hypertension: A large animal model. Journal of the American College of Cardiology 67(17): 2032-2046. https://doi.org/10.1016Zj.jacc.2016.02.049 [PubMed]

■ Alison MR, Poulsom R, Forbes S, Wright NA (2002) An introduction to stem cells. The Journal of Pathology 197(4): 419423. https://doi.org/10.1002/path.1187 [PubMed]

■ Archer SL. Marsboom G Kim GH. Zhang HJ. Toth PT. Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN, Cipriani N, Rehman J (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121(24): 2661-2671. https://doi.org/ 10.1161/CIRCULATI0NAHA.109.916098 [PubMed] [PMC] Astorga CR, González-Candia A, Candia AA, Figueroa EG, Cañas D, Ebensperger G, Reyes RV, Llanos AJ, Herrera EA (2018) Melatonin decreases pulmonary vascular remodeling and oxygen sensitivity in pulmonary hypertensive newborn lambs. Frontiers in Physiology 9: 185. https://doi.org/10.3389/fphys.2018.00185 [PubMed]

iНе можете найти то, что вам нужно? Попробуйте сервис подбора литературы.

Austin ED, Loyd JE (2014) The genetics of pulmonary arterial hypertension. Circulation Research 115(1): 189-202. https://doi.org/ 0.1161/CIRCRESAHA.115.303404 [PubMed] [PMC]

■ Badesch DB. Raskob GE. Elliott CG. Krichman AM. Farber HW. Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD (2010) Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 137(2): 376-387. https://doi.org/10.1378/chest.09-1140 [PubMed]

Baliga RS, MacAllister RJ, Hobbs AJ (2011) New perspectives for the treatment of pulmonary hypertension. British Journal of Pharmacology 163(1): 125-140. https://doi.org/10.1111/ j.1476-5381.2010.01164.x [PubMed] [PMC]

ligation, HDAC (valporic acid) inhibitors have been shown to be beneficial, significantly reducing the rate of right ventricular remodeling (Cho et al. 2010). Similarly, compound MC1568 (selective HDAC class IIa inhibitor) inhibited monocrotaline-induced PH (Kim et al. 2015). Overall, these independent studies have further supported the therapeutic potential of using HDAC inhibitors to reduce histone acetylation.

Conclusion

Currently, there are multiple and multidirectional methods of treatment and correction of PH. However, despite the abundance of works devoted to the study of this pathology, pulmonary hypertension of any etiology remains, as a rule, an incurable condition that significantly reduces both the quality and life expectancy. In this regard, the search for new mechanisms of therapeutic effects, and at the same time new more effective treatment strategies, remains an important issue for public health and the scientific community.

Conflict of Interest

The authors declare no conflict of interests.

■ Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW, Primary Pulmonary Hypertension Study Group (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The New England Journal of Medicine 334(5): 296-301. https:// doi.org/10.1056/NEJM199602013340504 [PubMed]

■ Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD (2010) Predicting survival in pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL). Circulation 122(2): 164-172. https://doi.org/10.1161/ circulationaha.109.898122 [PubMed]

■ Bisserier M, Janostiak R, Lezoualc'h F, Hadri L (2020) Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease. Vascular Biology 2(1): R17-R34. https://doi.org/10.1530/vb-19-0030 [PubMed] [PMC]

■ Bisserier M, Katz MG, Bueno-Beti C, Brojakowska A, Zhang S, Gubara S, Kohlbrenner E, Fazal S, Fargnoli A, Dorfmuller P, Humbert M, Hata A, Goukassian DA, Sassi Y, Hadri L (2021) Combination therapy with STAT3 inhibitor enhances SERCA2a-induced BMPR2 expression and inhibits pulmonary arterial hypertension. International Journal of Molecular Sciences 22(17): 9105. https://doi.org/10.3390/ijms22179105 [PubMed]

■ Bivalacqua TJ, Hyman AL, Kadowitz PJ, Paolocci N, Kass DA, Champion H C (2002) Role of calcitonin gene-related peptide (CGRP) in chronic hypoxia-induced pulmonary hypertension in the mouse: Influence of gene transfer in vivo. Regulatory Peptides 108: 129-133. https://doi.org/10.1016/s0167-0115(02)00100-3 [PubMed]

■ Boucherat O, Provencher S, Bonnet S (2018) Therapeutic value of ASK1 inhibition in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 197(3): 284286. https://doi.org/10.1164/rccm.201708-1767ED [PubMed]

■ Budas GR, Boehm M, Kojonazarov B, Viswanathan G, Tian X, Veeroju S, Novoyatleva T, Grimminger F, Hinojosa-Kirschenbaum F, Ghofrani HA (2018) ASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension. American

Journal of Respiratory and Critical Care Medicine 197(3): 373385. https://doi.org/l0.ll64/rccm.20l703-0502OC [PubMed] Chan L, Chin LMK, Kennedy M, Woolstenhulme JG, Nathan SD, Weinstein AA, Connors G, Weir NA, Drinkard B, Lamberti J, Keyser RE, (2013) Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension. Chest 143(2): 333-343. https://doi.org/ l0.l378/chest.l2-0993 [PubMed] [PMC]

Chazova IE, Arkhipova OA, Martynyuk TV (2019) Pulmonary arterial hypertension in Russia: six-year observation analysis of the National Registry. Therapeutic Archive 91(1): 24-31. https:// doi.org/10.26442/00403660.2019.01.000024 [PubMed] Chen SL, Zhang FF, Xu J, Xie DJ, Zhou L, Nguyen T, Stone GW (2013) Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension). Journal of the American College of Cardiology 62(12): 1092-1100. https://doi.org/l0.l0l6/ j.jacc.2013.05.075 [PubMed]

Cheng X, Wang Y, Du L (2019) Epigenetic modulation in the initiation and progression of pulmonary hypertension. Hypertension 74(4): 733-739. https://doi.org/l0.ll6l/

HYPERTENSIONAHA.119.13458 [PubMed] Cho YK, Eom GH, Kee HJ, Kim HS, Choi WY, Nam KI, Ma JS, Kook H (2010) Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats. Circulation Journal 74(4): 760-770. https://doi.org/l0.l253/ circj.cj-09-0580 [PubMed]

Clozel M, Maresta A, Humbert M (2013) Endothelin receptor antagonists. Handbook of Experimental Pharmacology 218: 199227. https://doi.org/l0.l007/978-3-642-38664-0_9 [PubMed] Condliffe R, Kiely DG (2017) Critical care management of pulmonary hypertension. BJA Education 17(7): 228-234. https:// doi.org/l0.l093/bjaed/mkw074

Crovetto DM, Charterina SA, Lopez-Guarch CJ, Vilalta MP, Núñez MP, Gafas AP, Subías PE (2016) Multidetector computed tomography shows reverse cardiac remodeling after double lung transplantation for pulmonary hypertension. Radiologia 58(4): 277282. https://doi.org/l0.l0l6/j.rx.20l6.04.005 [PubMed] de Man FS, Handoko ML, Groepenhoff H, van 't Hul AJ, Abbink J, Koppers RJ, Grotjohan HP, Twisk JWR, Bogaard H-J, Boonstra A, Postmus PE, Westerhof N, van der Laarse W J, Vonk-Noordegraaf A (2009) Effects of exercise training in patients with idiopathic pulmonary arterial hypertension. The European Respiratory Journal 34(3): 669-675. https://doi.org/l0.ll83/0903l936.00027909 [PubMed]

de Mendonca L, Felix NS, Blanco NG, Da Silva JS, Ferreira TP, Abreu SC, Cruz FF, Rocha N, Silva PM, Martins V, Capelozzi VL, Zapata-Sudo G, Rocco PRM, Silva PL (2017) Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension. Stem Cell Research & Therapy 8(1): 220. https://doi.org/l0.ll86/sl3287-0l7-0669-0 [PubMed] [PMC]

Dunkern TR, Hatzelmann A (2005) The effect of sildenafil on human platelet secretory function is controlled by a complex interplay between phosphodiesterases 2, 3 and 5. Cellular Signalling 17(3): 33 1-339. https://doi.org/l0.l0l6/ j.cellsig.2004.07.007 [PubMed]

Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal R, Uiker S, Halank M, Olsson K, Seeger W, Gall H, Rosenkranz S, Wilkens H, Mertens D, Seyfarth HJ, Opitz C, Ulrich S, Egenlauf B, Grünig E (2016) Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. European Heart Journal 37(1): 35-44. https:// doi.org/l0.l093/eurheartj/ehv337 [PubMed] [PMC] Feng, W, Hu, Y, An N, Feng Z, Liu J, Mou J, Hu T, Guan H, Zhang D, Mao Y (2020) Alginate oligosaccharide alleviates monocrotaline-induced pulmonary hypertension via anti-oxidant and anti-inflammation pathways in rats. International Heart Journal 61(1): 160-168. https://doi.org/l0.l536/ihj.l9-096 [PubMed] Fessel JP, Loyd JE, Austin ED (2011) The genetics of pulmonary arterial hypertension in the post-BMPR2 era. Pulmonary Circulation 1(3): 305319. https://doi.org/l0.4l03/2045-8932.87293 [PubMed] [PMC]

Foster WS, Suen CM, Stewart DJ (20l4) Regenerative cell and tissue-based therapies for pulmonary arterial hypertension. Canadian Journal of Cardiology 30(ll): l350-l360. https://doi.org/l0.l0l6/ j.cjca.20l4.08.022 [PubMed]

Foster WS, Suen CM, Stewart DJ (20l4) Regenerative cell and tissue-based therapies for pulmonary arterial hypertension. Canadian Journal of Cardiology 30(ll): l350-l360. https://doi.org/l0.l0l6/ j.cjca.20l4.08.022 [PubMed]

Foudi N, Kotelevets L, Louedec L, Leséche G, Henin D, Chastre E, Norel X (2008) Vasorelaxation induced by prostaglandin E2 in human pulmonary vein: role of the EP4 receptor subtype. British Journal of Pharmacology l54: l63l-l639. https://doi.org/l0.l038/ bjp.2008.2l4 [PubMed] [PMC]

Francis SH, Turko IV, Corbin JD (200l) Cyclic nucleotide phosphodiesterases: relating structure and function. Progress in Nucleic acid Research and Molecular Biology 65: l—52. https:// doi.org/l0.l0l6/s0079-6603(00)6500l-8 [PubMed] Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JV, Grünig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ, AMBITION Investigators (20l5) Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. The New England Journal of Medicine 373(9): 834844. https://doi.org/l0.l056/nejmoal4l3687 [PubMed] Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, ESC Scientific Document Group (20l6) 20l5 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European Heart Journal 37(l): 67-ll9. https://doi.org/l0.l093/eurheartj/ehv3l7 [PubMed] Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M (20l5) 20l5 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). The European Respiratory Journal 46(4): 903-975. https://doi.org/ l0.ll83/l3993003.0l032-20l5 [PubMed]

Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ, Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group (2008) Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study l and 2. Circulation ll7(23): 30l0-30l9. https:// doi.org/l0.l l6l/CIRCULATIONAHA.l07.7425l0 [PubMed] Genecand L, Wacker J, Beghetti M, Lador F (202l) Selexipag for the treatment of pulmonary arterial hypertension. Expert Review of Respiratory Medicine l5(5): 583-595. https://doi.org/ l0.l080/l7476348.202l.l866990 [PubMed]

Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ, PATENT-l Study Group (20l3) Riociguat for the treatment of pulmonary arterial hypertension The New England journal of medicine 369(4): 330-340. https://doi.org/l0.l056/ NEJMoal209655 [PubMed]

Ghofrani HA, Humbert M, Langleben D, Schermuly R, Stasch JP, Wilkins MR, Klinger JR (20l6) Riociguat: Mode of action and clinical development in pulmonary hypertension. Chest l5l(2): 468-480. https://doi.org/l0.l0l6Zj.chest20l6.05.024 [PubMed] Goncharova NS, Simakova MA, Moiseeva OM (20l9) Antithrombotic therapy in patients with pulmonary arterial hypertension. Arterial Hypertension 25(l): 25-33. https://doi.org/l0.l8705/l607-4l9X-20l9-25-l-25-33

Gonzalez-Candia A, Veliz M, Carrasco-Pozo C, Castillo RL, Cárdenas JC, Ebensperger G, Reyes RV, Llanos AJ, Herrera EA (2019) Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in pulmonary hypertensive newborn sheep. Redox Biology 22: 101128. https://doi.org/10.1016/j.redox.2019.101128 [PubMed] [PMC]

Granton J, Langleben D, Kutryk MB, Camack N, Galipeau J, Courtman DW, Stewart DJ (2015) Endothelial NO-synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension: The PHACeT trial. Circulation Research 117(7): 645654. https://doi.org/10.1161/CIRCRESAHA.114.305951 [PubMed]

■ Grünig E, Benjamin N, Krüger U, Kaemmerer H, Harutyunova S, Olsson, KM, Klose H (2018) General measures and supportive therapy for pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018. International Journal of Cardiology 272S: 30-36. https://doi.org/ 10.1016/j.ijcard.2018.08.085 [PubMed]

■ Grünig E, Eichstaedt C, Barbera JA, Benjamin N, Blanco I, Bossone

E, Cittadini A, Coghlan G, Corris P, D'Alto M, D'Andrea A, Delcroix M, de Man F, Gaine S, Ghio S, Gibbs S, Gumbiene L, Howard LS, Johnson M, Jureviciené E, Peacock AJ (2019) ERS statement on exercise training and rehabilitation in patients with severe chronic pulmonary hypertension. The European Respiratory Journal 53(2): 1800332. https://doi.org/10.1183/13993003.00332-2018 [PubMed] Grunig E, MacKenzie A, Peacock AJ, Eichstaedt CA, Benjamin N, Nechwatal R, Ulrich S, Saxer S, Bussotti M, Sommaruga M, Ghio S, Gumbiene L, Paleviciuté E, Jureviciené E, Cittadini A, Stanziola AA, Marra AM, Kovacs G, Olschewski H, Barbera A, Johnson M (2021) Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial. European Heart Journal 42(23): 2284-2295. https:// doi.org/10.1093/eurheartj/ehaa696 [PubMed]

■ Gubrij IB. Martin SR. Pangle AK. Kurten R. Johnson LG (2014) Attenuation of monocrotaline-induced pulmonary hypertension by luminal adeno-associated virus serotype 9 gene transfer of prostacyclin synthase. Human Gene Therapy 25(6): 498-505. https:// doi.org/10.1089/hum.2013.187 [PubMed]

■ Gudmundsdóttir IJ, McRobbie SJ, Robinson SD, Newby DE, Megson IL (2005) Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation. Biochemical and Biophysical Research Communications 337(1): 382-385 https:// doi.org/10.1016/j.bbrc.2005.09.060 [PubMed]

Hadri L, Kratlian RG, Benard L, Maron BA, Dorfmüller P, Ladage D, Guignabert C, Ishikawa K, Aguero J, Ibanez B, Turnbull IC, Kohlbrenner E, Liang L, Zsebo K, Humbert M, Hulot JS, Kawase Y, Hajjar RJ, Leopold JA (2013) Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension. Circulation 128(5): 512-523. https://doi.org/10.1161/ CIRCULATIONAHA.113.001585 [PubMed]

■ Harper RL, Maiolo S, Ward RJ, Seyfang J, Cockshell MP, Bonder CS, Reynolds PN (2019) BMPR2-expressing bone marrow-derived endothelial-like progenitor cells alleviate pulmonary arterial hypertension in vivo. Respirology: official journal of the Asian Pacific Society of Respirology 24(11): 1095-1103. https://doi.org/ 10.1111/resp.13552 [PubMed]

■ Hoeper MM. Al-Hiti H. Benza RL. Chang SA. Corris PA. Gibbs JSR, Grünig E, Jansa P, Klinger JR, Langleben D, McLaughlin VV, Meyer GMB, Ota-Arakaki J, Peacock AJ, Pulido T, Rosenkranz S, Dario Vizza C, Vonk-Noordegraaf A, White JR, Chang M, Kleinjung

F, Meier C, Paraschin K, Ardeschir Ghofrani H, Simonneau G (2021) Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. The Lancet. Respiratory Medicine 9(6): 573-584. https://doi.org/10.1016/s2213-2600(20)30532-4 [PubMed] Hoeper MM, Ghofrani HA, Grunig E, Klose H, Olschewski H, Rosenkranz S (2017) Pulmonary Hypertension. Deutsches Ärzteblatt International 114(5): 73-84. https://doi.org/10.323 8/ arztebl.2017.0073 [PubMed] [PMC]

Hoeper MM, Huscher D, Ghofrani HA, Delcroix M, Distler O, Schweiger C, Grunig E, Staehler G, Rosenkranz S, Halank M, Held M, Grohe C, Lange TJ, Behr J, Klose H, Wilkens H, Filusch A, Germann M, Ewert R, Seyfarth HJ, Olsson KM, Opitz CF, Gaine SP, Vizza CD, VonkNoordegraaf A, Kaemmerer H, Gibbs JS, Pittrow D (2013) Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. International

Journal of Cardiology 168(2): 871-880. https://doi.org/10.1016/ j.ijcard.2012.10.026 [PubMed]

■ Hoeper MM, Leuchte H, Halank M, Wilkens H, Meyer FJ, Seyfarth HJ, Wensel R, Ripken F, Bremer H, Kluge S, Hoeffken G, Behr J (2006) Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. The European Respiratory Journal 28(4): 691-694. https://doi.org/ 10.1183/09031936.06.00057906 [PubMed]

■ Huang WC. Ke MW. Cheng CC. Chiou SH. Wann SR. Shu CW. Chiou KR, Tseng CJ, Pan HW, Mar GY, Liu CP (2016) Therapeutic benefits of induced pluripotent stem cells in monocrotaline-induced pulmonary arterial hypertension. PLoS One 11(2): e0142476. https:// doi.org/10.1371/journal.pone.0142476 [PubMed] [PMC]

■ Humbert M, Guignabert C, Bonnet S, Dorfmuller P, Klinger JR, Nicolls MR, Olschewski AJ, Pullamsetti SS, Schermuly RT, Stenmark KR, Rabinovitch M (2019) Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. The European Respiratory Journal 53(1): 1801887. https://doi.org/ 10.1183/13993003.01887-2018 [PudMed] [PMC]

Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM (2007) Results of European post-marketing surveillance of bosentan in pulmonary hypertension. The European Respiratory Journal 30(2): 338-344. https://doi.org/10.1183/09031936.00138706 [PubMed]

■ Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G (2006) Pulmonary arterial hypertension in France: results from a national registry. American Journal of Respiratory and Critical Care Medicine 173(9): 1023-1030. https://doi.org/10.1164/ rccm.200510-1668oc [PubMed]

Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jais X, Montani D, Souza R, Simonneau G (2010) Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122(2): 156-163. https://doi.org/ 10.1161/circulationaha.109.911818 [PubMed]

■ Hurtsén AS. Nilsson IZ. Dogan EM. Nilsson KF (2020) A comparative study of inhaled nitric oxide and an intravenously administered nitric oxide donor in acute pulmonary hypertension. Drug Design, Development and Therapy 14: 635-645. https:// doi.org/10.2147/DDDT.S237477 [PubMed] [PMC]

■ Janssens SP. Bloch KD. Nong Z. Gerard RD. Zoldhelyi P. Collen D (1996) Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats The Journal of Clinical Investigation 98: 317-324. https://doi.org/10.1172/jci118795 [PMC] [PubMed]

■ Jentzer JC, Mathier MA (2015) Pulmonary hypertension in the intensive care unit. Journal of Intensive Care Medicine 31(6): 369385. https://doi.org/10.1177/0885066615583652 [PubMed]

■ Jeon Y, Heo Y, Kim C, Hyun YL, Lee TG, Ro S, Cho JM (2005) Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. Cellular and molecular life sciences: CMLS 62(11): 1198-1220. https://doi.org/10.1007/s00018-005-4533-5 [PubMed]

■ Kallen AJ, Lederman E, Balaji A, Trevino I, Petersen EE, Shoulson R, Saiman L, Horn EM, Gomberg-Maitland M, Barst RJ, Srinivasan A (2008) Bloodstream infections in patients given treatment with intravenous prostanoids. Infection Control and Hospital Epidemiology 29(4): 342-349. https://doi.org/10.1086/529552 [PubMed]

■ Kang Y Zhang G Huang EC. Huang J. Cai J. Cai L. Wang S. Keller BB (2020) Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension. American journal of physiology. Heart and circulatory physiology 318(1): H853-H866. https://doi.org/10.1152/ ajpheart.00321 [PubMed]

■ Katz MG. Fargnoli AS. Gubara SM. Fish K. Weber T. Bridges CR. Hajjar RJ, Ishikawa K (2019) Targeted gene delivery through the respiratory system: Rationale for intratracheal gene transfer. Journal of Cardiovascular Development and Disease 6(1): 8. https://doi.org/ 10.3390/jcdd6010008 [PubMed] [PMC]

Kawakami T, Kanazawa H, Satoh T, Ieda M, Ieda Y, Kimura K, Mochizuki H, Shimada T, Yokoyama C, Ogawa S, (2007) AAV-PGIS

gene transfer improves hypoxia-induced pulmonary hypertension in mice. Biochemical and Biophysical Research Communications 363: 656-66l. https://doi.org/l0.l0l6/j.bbrc.2007.09.039 [PubMed] Khan MS, Usman MS, Siddiqi TJ, Khan SU, Murad MH, Mookadam F, Figueredo VM, Krasuski RA, Benza RL, Rich JD

(2018) Is anticoagulation beneficial in pulmonary arterial hypertension? Circulation. Cardiovascular Quality and Outcomes ll(9): e004757. https://doi.org/l0.ll6l/CIRCOUTCOMES.ll8.004757 [PubMed] [PMC] Khural JS, Houston BA, Leary PJ, Mathai SC, Kolb TM, Damico R, Hassoun PM, Kass DA, Hsu S, Tedford RJ (202l)

Right atrial pacing to improve acute hemodynamics in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 203(4): 508-5ll. https://doi.org/l0.ll64/ rccm.202006-2278le [PubMed] [PMC]

Kido M, DuL, Sullivan CC, Deutsch R, Jamieson SW, (2005) Thistlethwaite P.A. Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents. The Journal of Thoracic and Cardiovascular surgery l29: 268-276. https://doi.org/ l0.l0l6/j.jtcvs.2004.09.0l3 [PubMed]

Kim J, Hwangbo C, Hu X, Kang Y, Papangeli I, Mehrotra D, Park H, Ju H, McLean DL, Comhair SA, Erzurum SC, Chun HJ (20l5) Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation l3l(2): l90-l99. https://doi.org/l0.ll6l/ CIRCULATIONAHA.114.013339 [PubMed] [PMC] Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P; ESC Scientièc Document Group (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. European Journal of Cardio-Thoracic Surgery 50(5): e1-e88. https://doi.org/10.1093/ejcts/ezw313 [PubMed]

Klinger JR (2016) Group III pulmonary hypertension: pulmonary hypertension associated with lung disease: Epidemiology, pathophysiology, and treatments. Cardiology Clinics 34(3): 413433. https://doi.org/10.1016/j.ccl.2016.04.003 [PudMed] Koklin IS, Danilenko LM (2019) Combined use of arginase II inhibitors and tadalafil for the correction of monocrotaline pulmonary hypertension. Research Results in Pharmacology 5(3): 79-85. https://doi.org/10.3897/rrpharmacology. 5.39522 Korokin M, Zhernakova NI, Korokina L, Pokopejko O (2018) Principles of pharmacological correction of pulmonary arterial hypertension. Research Results in Pharmacology 4(2): 59-76. https://doi.org/10.3897/rrpharmacology.4.27732 Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ, Canadian Critical Care Trials G (2012) Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One 7(10): e47559. https://doi.org/10.1371/ journal.pone.0047559 [PubMed] [PMC]

Lee CS, Bishop ES, Zhang R, Yu X, Farina EM, Yan S, Zhao C, Zheng Z, Shu Y, Wu X, Lei J, Li Y, Zhang W, Yang C, Wu K, Wu Y, Ho S, Athiviraham A, Lee MJ, Wolf JM, Reid RR, He TC (2017) Adenovirus-mediated gene delivery: Potential applications for gene and cell-based therapies in the new era of personalized medicine. Genes & Diseases 4(2): 43-63. https://doi.org/10.1016/ j.gendis.2017.04.001 [PubMed] [PMC]

Lee TI, Young RA (2013) Transcriptional regulation and its misregulation in disease. Cell 152(6): 1237-1251. https://doi.org/ 10.1016/j.cell.2013.02.014 [PubMed] [PMC] Li F, Wang D, Wang H, Chen L, Sun X, Wan Y (2021) Inhibition of HDACl alleviates monocrotaline-induced pulmonary arterial remodeling through up-regulation of miR-34a. Respiratory Research 22(1): 239. https://doi.org/10.1186/s12931-021-01832-7 [PubMed]

Li T, Zha L, Luo H, Li S, Zhao L, He J, Li X, Qi Q, Liu Y, Yu Z

(2019) Galectin-3 mediates endothelial-to-mesenchymal transition in pulmonary. Arterial Hypertension Aging and Disease 10: 731745. https://doi.org/10.14336/ad.2018.1001 [PMC] [PubMed]

Li Y, Shi B, Huang L, Wang X, Yu X, Guo B, Ren W (20l6) Suppression of the expression of hypoxia-inducible factor-lalpha by RNA interference alleviates hypoxia-induced pulmonary hypertension in adult rats. International Journal of Molecular Medicine 38: 1786-1794. https://doi.org/10.3892/ijmm.2016.2773

Liu D, Yan Y, Chen JW, Yuan P, Wang XJ, Jiang R, Wang L, Zhao QH, Wu WH, S imonneau G, Qu JM, Jing ZC (2017) Hypermethylation of BMPR2 promoter occurs in patients with heritable pulmonary arterial hypertension and inhibits BMPR2 expression. American Journal of Respiratory and Critical Care Medicine 196(7): 925-928. https://doi.org/10.1164/ rccm.201611-2273LE [PubMed]

Liu YY, Qu YY, Wang S, Luo CJ, Qiu HL, Li HT, Yuan P, Wang L, Li JL, Jiang R, Zhang R (2023) Efficacy and safety of riociguat replacing PDE-5is for patients with pulmonary arterial hypertension: A systematic review and meta-analysis. Frontiers in Pharmacology 14: 1052546. https://doi.org/10.3389/fphar.2023.1052546 [PubMed] [PMC]

Loisel F, Provost B, Haddad F, Guihaire J, Amsallem M, Vrtovec B, Fadel E, Uzan G, Mercier O (2018) Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy? Pulmonary Circulation 8(2): 2045893218755979. https://doi.org/10.1177/2045893218755979 [PubMed] [PMC]

Long L, Ormiston ML, Yang X, Southwood M, Graf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore SD, Drake KM, Aldred MA, Yu PB, Upton PD, Morrell NW (2015) Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nature Medicine 21(7): 777-785. https://doi.org/10.1038/nm.3877 [PubMed] [PMC] Mammoto A, Hendee K, Muyleart M, Mammoto T (2020) Endothelial Twistl-PDGFB signaling mediates hypoxia-induced proliferation and migration of alphaSMA-positive cells. Scientific Reports 10: 7563 https://doi.org/10.1038/s41598-020-64298-5 [PMC] [PubMed]

Martynyuk TV, Dadacheva ZH, Paramonov VM, Arkhipova OA, Nakonechnikov SN, Chazova IY (2015) Application of phosphodiesterase type 5 inhibitors sildenafil in patients with pulmonary hypertension. Eurasian Heart Journal 2: 42-49. https:// doi.org/10.38109/2225-1685-2015-2-42-49

McDonagh T, Damy T, Doehner W, Lam CSP, Sindone A, van der Meer P, Cohen-Solal A, Kindermann I, Manito N, Pfister O, Pohjantähti-Maaroos H, Taylor J, Comin-Colet J (2018) Screening, diagnosis and treatment of iron deficiency in chronic heart failure: putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice. European Journal of Heart Failure 20(12): 1664-1672. https://doi.org/10.1002/ejhf.1305 [PubMed] [PMC]

McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ (2006) Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 174(11): 1257-1263. https://doi.org/10.1164/ rccm.200603-358OC [PubMed]

Mondéjar-Parreno G, Moral-Sanz J, Barreira B, de la Cruz A, Gonzalez T, Callejo M, Esquivel-Ruiz S, Morales-Cano D, Moreno L, Valenzuela C, Perez-Vizcaino F, Cogolludo A (2019) Activation of Kv7 channels as a novel mechanism for NO/cGMP-induced pulmonary vasodilation. British Journal of Pharmacology 176(13): 2131-2145. https://doi.org/10.1111/bph.14662 [PMC] Morecroft I, White K, Caruso P, Nilsen M, Loughlin L, Alba R, Reynolds P N, Danilov S.M, Baker A H, Maclean M R (2012) Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tphl attenuates hypoxia-induced pulmonary hypertension. Molecular Therapy 20: 1516-1528. https://doi.org/ 10.1038/mt.2012.70 [PMC] [PubMed]

Mullershausen F, Russwurm M, Friebe A, Koesling D (2004) Inhibition of phosphodiesterase type 5 by the activator of nitric oxide-sensitive guanylyl cyclase BAY 41-2272. Circulation 109(14): 1711-1713. https://doi.org/10.1161/01.cir.0000126286.47618.bd [PubMed]

Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED (2007) Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116(3): 238-248. https://doi.org/10.1161/ circulationaha.106.655266 [PubMed]

Nathan SD, Barbera JA, Gaine SP, Harari S, Martinez FJ, Olschewski H, Olsson KM, Peacock AJ, Pepke-Zaba J, Provencher S, Weissmann N, Seeger W (2019) Pulmonary hypertension in chronic lung disease and hypoxia. The European Respiratory Journal

Ngian GS, Stevens W, Prior D, Gabbay E, Roddy J, Tran A et al.

(2012) Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study. Arthritis Research & Therapy 14(5): R213. https://doi.org/10.1186/ar4051 [PubMed] [PMC]

Olschewski A, Berghausen EM, Eichstaedt CA, Fleischmann BK, Grunig E, Grunig G, Hansmann G, Harbaum L, Hennigs JK, Jonigk D, Kuebler WM, Kwapiszewska G, Pullamsetti SS, Stacher E, Weissmann N, Wenzel D, Schermuly RT (2018) Pathobiology, pathology and genetics of pulmonary hypertension: Update from the Cologne Consensus Conference 2018. International Journal of Cardiology 272S: 4-10. https://doi.org/10.1016/j.ijcard.2018.09.070 [PudMed]

Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, Grünig E, Staehler G, Rosenkranz S, Halank M, Held M, Lange TJ, Behr J, Klose H, Claussen M, Ewert R, Opitz CF, Vizza CD, Scelsi L, Vonk-Noordegraaf A, Hoeper MM (2014) Anticoagulation and survival in pulmonary arterial hypertension: results from the comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA). Circulation 129(1): 57-65. https://doi.org/10.1161/circulationaha.113.004526 [PubMed]

■ Olsson KM, Nickel NP, Tongers J, Hoeper MM (2013) Atrial flutter and fibrillation in patients with pulmonary hypertension. International Journal of Cardiology 167: 2300-2305. https://doi.org/ 10.1016/j.ijcard.2012.06.024 [PubMed]

■ Opitz C, Hoeper MM, Gibbs JSR, Kaemmerer H, Pepke-Zaba J, Coghlan JG, Scelsi L, D'Alto M, Olsson KM, Ulrich S, Scholtz W, Schulz U, Grünig E, Vizza CD, Staehler G, Bruch L, Huscher D, Pittrow D, Rosenkranz S (2016) Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. Journal of the American College of Cardiology 68(4): 368-378. https://doi.org/10.1016/jjacc.2016.05.047 [PubMed]

■ Opitz CF. Wensel R. Winkler J. Halank M. Bruch L. Kleber FX. Hoffken G, Anker SD, Negassa A, Felix SB, Hetzer R, Ewert R (2005) Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. European Heart Journal 26(18): 1895-1902. https://doi.org/10.1093/ eurheartj/ehi283 [PubMed]

Ostroumova OD, Listratov AI, Kochetkov AI, Bliznyuk SA, Komarova AG, Sychev DA (2022) Drug-induced pulmonary artery hypertension. Good Clinical Practice [Kachestvennaya Klinicheskaya Praktika] 1: 53-63. https://doi.org/10.37489/2588-0519-2022-1-53-63 Panagiotidou E, Boutou A, Pitsiou G (2021) An evaluation of selexipag for the treatment of pulmonary hypertension. Expert Opinion on Pharmacotherapy 22(1): 29-36 https://doi.org/ 10.1080/14656566.2020.1812579 [PubMed]

Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier I M, Lemarchand P, Eddahibi S (2000) Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. American Journal of Respiratory Cell and Molecular Biology 23: 762-771. https:// doi.org/10.1165/ajrcmb.23.6.4106 [PubMed] Pascaud MA, Griscelli F, Raoul W, Marcos E, Opolon P, Raffestin B, Perricaudet M, Adnot S, Eddahibi S (2003) Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice. American Journal of Respiratory Cell and Molecular Biology 29: 449-457. https://doi.org/10.1165/rcmb.2002-0120oc [PubMed]

■ Pozeg ZI. Michelakis ED. McMurtry MS. Thebaud B. Wu XC. Dyck JR, Hashimoto K, Wang S, Moudgil R, Harry G (2003) In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107: 20372044. https://doi.org/10.1161/01.cir.0000062688.76508.b3 [PubMed]

■ Preston IR. Roberts KE. Miller DP. Sen GP. Selej M. Benton WW. Hill NS, Farber HW (2015) Effect of warfarin treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation 132(25): 2403-2411. https://doi.org/10.1161/ CIRCULATIONAHA.115.018435 [PubMed] [PMC]

■ Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Brun FOL, Mehta S, Mittelholzer CM, Perchenet L, Sastry BKS, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G, SERAPHIN Investigators

(2013) Macitentan and morbidity and mortality in pulmonary arterial hypertension. The New England Journal of Medicine

369(9): 809-818. https://doi.org/10.1056/nejmoa1213917 [PubMed]

■ Raghu G Nathan SD. Behr J. Brown KK. Egan JJ. Kawut SM. Flaherty KR, Martinez FJ, Wells AU, Shao L, Zhou H, Henig N, Szwarcberg J, Gillies H, Montgomery AB, O'Riordan TG (2015) Pulmonary hypertension in idiopathic pulmonary fibrosis with mild to moderate restriction. European Respiratory Review 46(5): 13701377. https://doi.org/10.1183/16000617.0044-2019 [PudMed] [PMC]

Rajdev A, Garan H, Biviano A (2012) Arrhythmias in pulmonary arterial hypertension. Progress in Cardiovascular Diseases 55(2): 180-186. https://doi.org/10.1016Zj.pcad.2012.06.002 [PubMed] [PMC]

■ Reynolds AM. Xia W. Holmes MD. Hodge SJ. Danilov S. Curiel DT, Morrell NW, Reynolds PN (2007) Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. American Journal of Physiology. Lung Cellular and Molecular Physiology 292(5): L1182-1192. https://doi.org/10.1152/ ajplung.00020.2006 [PubMed]

■ Reynolds PN (2011) Gene therapy for pulmonary hypertension: prospects and challenges. Expert Opinion on Biological Therapy 11(2): 133-143. https://doi.org/10.1517/14712598.2011.542139 [PubMed] Roldan T, Rios JJ, Villamanan E, Waxman AB (2017) Complications associated with the use of oral anticoagulation in patients with pulmonary arterial hypertension from two referral centers. Pulmonary Circulation 7(3): 692-701. https://doi.org/ 10.1177/2045893217721903 [PubMed] [PMC]

Rosenkranz S, Gibbs JS, Wachter R, De Marco T, Vonk-Noordegraaf A, Vachiery JL (2016) Left ventricular heart failure and pulmonary hypertension. European Heart Journal 37(12): 942-954. https:// doi.org/10.1093/eurheartj/ehv512 [PudMed] [pMC] Rosenkranz S, Lang IM, Blindt R, Bonderman D, Bruch L, Diller GP, Felgendreher R, Gerges C, Hohenforst-Schmidt W, Holt S, Jung C, Kindermann I, Kramer T, Kubler WM, Mitrovic V, Riedel A, Rieth A, Schmeisser A, Wachter R, Weil J, Opitz CF (2018) Pulmonary hypertension associated with left heart disease: Updated Recommendations of the Cologne Consensus Conference 2018. International Journal of Cardiology 272S: 53-62. https://doi.org/ 10.1016/j.ijcard.2018.08.080 [PubMed]

■ Ruan H. Zhang Y. Liu R. Yang X (2019) The acute effects of 30 mg vs 60 mg of intravenous Fasudil on patients with congenital heart defects and severe pulmonary arterial hypertension. Congenit Heart Disaese 14(4): 645-650. https://doi.org/10.1111/chd.12764 [PubMed]

iНе можете найти то, что вам нужно? Попробуйте сервис подбора литературы.

Rubin LJ, Badesch DB, Fleming TR, Galiè N, Simonneau G, Ghofrani HA, Oakes M, Layton G, Serdarevic-Pehar M, McLaughlin MV, Barst RJ (2011) Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 140(5): 1274-1283. https://doi.org/10.1378/ chest.10-0969 [PubMed]

■ Said K (2014) Anticoagulation in pulmonary arterial hypertension: Contemporary data from COMPERA registry. Global Cardiology Science & Practice 2: 48-52. https://doi.org/10.5339/gcsp.2014.25 [PubMed] [PMC]

■ Sakao S. Tatsumi K. Voelkel NF (2009) Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Respiratory Research 10(1): 95. https:// doi.org/10.1186/1465-9921-10-95 [PubMed] [PMC]

Sausbier M, Schubert R, Voigt V, Hirneiss C, Pfeifer A, Korth M, Kleppisch T, Ruth P, Hofmann F (2000). Mechanisms of NO/cGMP-dependent vasorelaxation. Circulation Research 87(9): 825 -830. https://doi.org/10.1161/01.RES.87.9.825 Savai R, Al-Tamari HM, Sedding D, Kojonazarov B, Muecke C, Teske R, Capecchi MR, Weissmann N, Grimminger F, Seeger W (2014) Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. Nature Medicine 20: 1289-1300. https://doi.org/10.1038/nm.3695 [PubMed]

Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA (2011) Riociguat for the treatment of pulmonary hypertension. Expert Opinion on Investigational Drugs 20(4): 567576. https://doi.org/10.1517/13543784.2011.565048 [PubMed]

■ Seto E, Yoshida M (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harbor Perspectives in Biology 6(4): a018713. https://doi.org/10.1101/cshperspect.a018713 [PubMed] [PMC]

■ Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV,

Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV (2022) Endothelial dysfunction: developmental mechanisms and therapeutic strategies. Research Results in Pharmacology 8(4): 115-139. https://doi.org/10.3897/rrpharmacology. 8.80376 Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. The European Respiratory Journal 53(1): 1801913. https://doi.org/10.1183/13993003.01913-2018 [PudMed] [PMC] Simonneau G, Torbicki A, Dorfmuller P, Kim N (2017) The pathophysiology of chronic thromboembolic pulmonary hypertension European Respiratory Review 26(143): 160112. https://doi.org/10.1183/16000617.0112-2016 [PudMed] [PMC] Sitbon O, Delcroix M, Bergot E, Boonstra A, Escribano, Subias P, Galie N, Pfister T, Lemarie JC, Simonneau G (2014) EPITOME-2, An open-label study evaluating a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension. American Heart Journal 167(2): 210-217. https://doi.org/10.1016/ j.ahj.2013.08.007 [PubMed]

Sitbon O, Vonk Noordegraaf A (2017) Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. European Respiratory Review 26(143): 160055. https://doi.org/ 10.1183/16000617.0055-2016 [PubMed] [PMC] Soldatov VO, Malorodova, TN, Balamutova TI, Ksenofontov AO, Dovgan AP, Urozhevskaya ZS (2018). Endothelial dysfunction: comparative evaluation of ultrasound dopplerography, laser dopplerflowmetry and direct monitoring of arterial pressure for conducting pharmacological tests in rats. Research Results in Pharmacology 4(1): 73-80. https://doi.org/10.3 897/ rrpharmacology.4.25529

Sonnweber T, Nairz M, Theurl I, Petzer V, Tymoszuk P, Haschka D, Rieger E, Kaessmann B, Deri M, Watzinger K, Steringer-Mascherbauer R, Tancevski I, Weiss G, Löffler-Ragg J (2018) The crucial impact of iron deficiency definition for the course of precapillary pulmonary hypertension. PloS One 13(8): e0203396. https://doi.org/10.1371/journal.pone.0203396 [PubMed] [PMC] Spiekerkoetter E, Sung YK, Sudheendra D, Bill M, Aldred MA, van de Veerdonk MC, Vonk Noordegraaf A, Long-Boyle J, Dash R, Yang PC, Lawrie A, Swift AJ, Rabinovitch M, Zamanian RT (2015) Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine 192(2): 254-257. https://doi.org/10.1164/ rccm.201411-2061LE [PubMed] [PMC]

Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, Haghighat L, de Jesus Perez V, Wang L, Reddy S, Zhao M, Bernstein D, Solow-Cordero DE, Beachy PA, Wandless TJ, Ten Dijke P, Rabinovitch M (2013) FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. Journal of Clinical Investigation 123(8): 3600-3613. https://doi.org/10.1172/JCI65592 [PubMed] [PMC]

Stickel S, Gin-Sing W, Wagenaar M, Gibbs JSR (2019) The practical management of fluid retention in adults with right heart failure due to pulmonary arterial hypertension. European Heart Journal Supplements 21(Suppl K): K46-K53. https://doi.org/ 10.1093/eurheartj/suz207 [PubMed] [PMC]

Strauss B, Sassi Y, Bueno-Beti C, Ilkan Z, Raad N, Cacheux M, Bisserier M, Turnbull IC, Kohlbrenner E, Hajjar RJ, Hadri L, Akar FG (2019) Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension. Journal of Molecular and Cellular Cardiology 127: 20-30. https://doi.org/10.1016/ j.yjmcc.2018.11.017 [PubMed]

Suen CM, Mei SH, Kugathasan L, Stewart DJ (2013) Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases. Comprehensive Physiology 3(4): 1749-1779. https://doi.org/10.1002/cphy.c120034 [PubMed]

Sugimoto Y, Narumiya S 2007 Prostaglandin E receptors. The Journal of Biological Chemistry 282(16): 11613-11617. https:// doi.org/10.1074/jbc.R600038200 [PubMed]

Suhara H, Sawa Y, Fukushima N, Kagisaki K, Yokoyama C, Tanabe T, Ohtake S, Matsuda H (2002) Gene transfer of human prostacyclin synthase into the liver is effective for the treatment of pulmonary hypertension in rats. The Journal of Thoracic and Cardiovascular Surgery 123(5): 855-861. https://doi.org/10.1067/ mtc.2002.118687 [PubMed]

Tsareva NA, Avdeev SN (2013) Phosphodiesterase-5 inhibitor in the treatment of pulmonary arterial hypertension. Medical Council 5-6: 78-82. https://doi.org/10.21518/2079-701X-2013-5-6-78-82 Tudorache I, Sommer W, Kuhn C, Wiesner O, Hadem J, Fühner T, Ius F, Avsar M, Schwerk N, Böthig D, Gottlieb J, Welte T, Bara C, Haverich A, Hoeper MM, Warnecke G (2015) Lung transplantation for severe pulmonary hypertension-awake extracorporeal membrane oxygenation for postoperative left ventricular remodeling. Transplantation 99(2): 451-458. https://doi.org/10.1097/tp.0000000000000348 [PubMed]

Ulrich S, Hasler ED, Saxer S, Furian M, Müller-Mottet S, Keusch S, Bloch KE (2017) Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial. European Heart Journal 38(15): 1159-1168. https://doi.org/10.1093/ eurheartj/ehx099 [PubMed]

Ulrich S, Saxer S, Hasler ED, Schwarz EI, Schneider SR, Furian M, Bader PR, Lichtblau M, Bloch KE (2019) Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial. The European Respiratory Journal 54(2): 1900276. https://doi.org/ 10.1183/13993003.002762019 [PubMed]

Umar S, de Visser YP, Steendijk P, Schutte CI, Laghmani el H, Wagenaar GT, Bax WH, Mantikou E, Pijnappels DA, Atsma DE, Schalij MJ, van der Wall EE, van der Laarse A (2009) Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension. American Journal of Physiology 297(5): H1606-H1616. https://doi.org/ 10.1152/ajpheart.00590.2009 [PubMed]

Van De Bruaen A, Delcroix M, Pasquet A, De Backer J, De Pauw M, Naeije R, Vachiéry JL, Paelinck B, Morissens M, Budts W (2011) Iron deficiency is associated with adverse outcome in Eisenmenger patients. European Heart Journal 32(22): 2790-2799. https://doi.org/ 10.1093/eurheartj/ehr130 [PubMed]

van Giersbergen PL, Halabi A, Dingemanse J (2006) Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. International Journal of Clinical Pharmacology and Therapeutics 44(3): 113-118. https://doi.org/10.5414/cpp44113 [PubMed]

Wang P, Hu L, Yin Y, Yan D, Zheng H, Zhang J, Li Y (2020) Can anticoagulants improve the survival rate for patients with idiopathic pulmonary arterial hypertension? A systematic review and meta-analysis. Thrombosis Research 196: 251-256. https://doi.org/ 10.1016/j.thromres.2020.08.024 [PubMed]

Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM, Zhu JH, Chen JZ (2007) Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. Journal of the American College of Cardiology 49(14): 1566-1571. https://doi.org/ 10.1016/j.jacc.2006.12.037 [PubMed]

Weinhold B (2006) Epigenetics: the science of change. Environmental Health Perspectives 114(3): A160-167. https://doi.org/10.1289/ ehp.114-a160 [PubMed] [PMC]

Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S, Rojas M, Stripp B, Warburton D, Prockop DJ (2011) Stem cells and cell therapies in lung biology and lung diseases. Proceedings of the American Thoracic Society 8(3): 223272. https://doi.org/10.1513/pats.201012-071DW [PubMed] [PMC] Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI (2008) Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. Journal of Clinical Pharmacology 48(5): 610-618. https://doi.org/10.1177/0091270008315315 [PubMed]

Xing J, Cao Y, Yu Y, Li H, Song Z, Yu H (2017) In vitro micropatterned human pluripotent stem cell test (^P-hPST) for morphometric-based teratogen screening. Scientific Reports 7(1): 8491. https://doi.org/10.1038/s41598-017-09178-1 [PubMed] [PMC] YanYun P, Wang S, Yang J, Chen B, Sun Z, Ye L, Zhu J, Wang X (2015) Interruption of CD40 pathway improves efficacy of transplanted endothelial progenitor cells in monocrotaline induced pulmonary arterial hypertension. Cellular Physiology and Biochemistry 36: 683-696. https://doi.org/10.1159/000430130 [PubMed]

Yoder MC (2012) Human endothelial progenitor cells. Cold Spring Harbor perspectives in medicine 2(7): a006692.

https://doi.org/10.1101/cshperspect.a006692 [PubMed] [PMC]

■ Zhang R. Shi L. Zhou L. Zhang. Wu X. Shao F. Ma G. Ying K (2014) Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension American journal of physiology. Lung Cellular and Molecular Physiology 306: L574-L583. https://doi.org/ 10.1152/ajplung.00327.2013 [PubMed]

■ Zhang T, Kawaguchi N, Yoshihara K, Hayama E, Furutani Y, Kawaguchi K, Tanaka T, Nakanishi T (2019) Silibinin efficacy in a rat model of pulmonary arterial hypertension using monocrotaline and chronic hypoxia. Respiratory Research 20(1): 79. https://doi.org/ 10.1186/s12931-019-1041-y [PubMed] [PMC]'

■ Zhao L, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, Wang D, Li M, McKinsey TA, Stenmark KR, Wilkins MR (2012) Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation 126(4): 455-467. https://doi.org/10.1161/

Author Contributions

Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ (2005) Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circulation Research 96(4): 442-450. https:// dol.org/10.1161/01.RES.0000157672.70560.7b [PubMed]

■ Zheng Y Yang T. Chen G. Hu E. Gu Q. Xiong С (2014) Prostanoid therapy for pulmonary arterial hypertension: a meta-analysis of survival outcomes. European Journal of Clinical Pharmacology 70(1): 13-21. https://dol.org/10.1007/s00228-013-1583-8 [PubMed]

■ Zhu JH. Wang XX. Zhang FR. Shang YP. Tao QM. Zhu JH. Chen JZ (2008) Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: open-label pilot study. Pediatric Transplantation 12(6): 650-655. https://doi.org/10.1111/j.1399-3046.2007.00863.x [PubMed]

■ Anna V. Zagrebelnaya, postgraduate student, Department of Pharmacology and Clinical Pharmacology, e-mail: Zagrebelnaya@bsu.edu.ru, ORCID ID https://orcid.org/0009-0002-5647-6000. The author was engaged in literature analysis and paper writing.

■ Liliya V. Korokina, PhD in Medical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, e-mail: korokina@bsu.edu.ru, ORCID ID https://orcid.org/0000-0002-4115-1564. The author was engaged in developing the concept and conducting the literature analysis.

■ Tatyana N. Malorodova, PhD in Medical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, e-mail: malorodova_tn@mail.ru, ORCID ID https://orcid.org/0000-0002-4186-2577. The author made a contribution to collection, analysis and interpretation of the data for the paper.

■ Olesya V. Shcheblykina, PhD in Medical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, e-mail: sheolvi31@gmail.com, ORCID ID https://orcid.org/0000-0003-0346-9835. The author was engaged in developing the concept and conducting the literature analysis.

■ Tatyana V. Avtina, PhD in Pharmaceutical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, e-mail: tatyanavtina@yandex.ru; ORCID ID https://orcid.org/0000-0003-0509-5996. The author made a contribution to collection, analysis and interpretation of the data for the paper.

■ Anton A. Bolgov, post-graduate student, Department of Pathology; e-mail: toxabolgovv@mail.ru, ORCID ID https://orcid.org/0000-0001-9708-8181. The author made a contribution to collection, analysis and interpretation of the data for the paper.

■ Elena S. Malyutina, PhD in Medical Sciences, Associate Professor of the Department of Pathology, e-mail: malyutina@bsu.edu.ru, ORCID ID https://orcid.org/0009-0008-5626-2460. The author made a contribution to collection, analysis and interpretation of the data for the paper.

■ Vladislav I. Simonov, medical student, e-mail: simonovvladislav@bsu.edu.ru. The author was engaged in structuring the article and arranging the references.

■ Vladislav A. Travkin, surgeon, e-mail: vladislavtravkin91@yandex.ru. The author was engaged in structuring the article and arranging the reference.

■ Artem A. Dmitriev, medical student, e-mail: artemdmitriev200313@gmail.com, ORCID ID https://orcid.org/ 0000-0001-5844-4737. The author was engaged in structuring the article and arranging the references.

■ Amonullo A. Aripov, medical student, e-mail: 1506754@bsu.edu.ru, ORCID ID https://orcid.org/ 0009-0006-3811-1322. The author was engaged in structuring the article and arranging the references.

■ Dmitry V. Shcheblykin, post-graduate student, Department of Pharmacology and Clinical Pharmacology; e-mail: dmitryshch1@gmail.com, ORCID ID https://orcid.org/0000-0002-2420-2243. The author was engaged in literature

analysis.

i Надоели баннеры? Вы всегда можете отключить рекламу.