Pulmonary hypertension, including chronic thromboembolic pulmonary hypertension: clinical guidelines

List of Abbreviations

ERA – endothelin receptor antagonists (ATX Antihypertensive agents for pulmonary arterial hypertension)

Prostacyclin analogues – prostanoids (ATX Antithrombotic agents excluding heparin)

IP receptor agonists – prostacyclin receptor agonists (ATX Antithrombotic agents excluding heparin)

Vasopressors – vasopressors (ATX adrenergic and dopaminergic agents)

VLEL – vital and essential drugs

CT – clinical trial

CP – clinical guidelines

ICD-10 – International Classification of Diseases, 10th Revision

INN – International Nonproprietary Name

WG – working group

RF – Russian Federation

LCE – level of confidence of evidence

GRS – grade of recommendation strength

CCB – calcium channel blockers

WHO – World Health Organization

CHD – congenital heart disease

DPAP – diastolic pulmonary artery pressure

PCWP – pulmonary capillary wedge pressure

PAP / mPAP – pulmonary artery pressure / mean pulmonary artery pressure

ILD – interstitial lung disease

IPAH – idiopathic pulmonary arterial hypertension

PDE-5i – phosphodiesterase type 5 inhibitors (ATX Drugs for erectile dysfunction)

CT – computed tomography

PA – pulmonary artery

PAH – pulmonary arterial hypertension

PAH-specific drugs – ERAs, PA analogues, IP receptor agonists, PDE-5i, sGC stimulators

PVOD – pulmonary veno-occlusive disease

PH – pulmonary hypertension

LA / LV – left atrium / left ventricle

PCH – pulmonary capillary hemangiomatosis

PVR – pulmonary vascular resistance

PCC – pulmonary circulation

MRI – magnetic resonance imaging

HPAH – heritable pulmonary arterial hypertension

IVC – inferior vena cava

RV – right ventricle

PoPH – portopulmonary hypertension

DOACs – direct oral anticoagulants (ATC: Direct thrombin inhibitors, Direct factor Xa inhibitors)

RA – right atrium

PC – prostacyclin

sGC – soluble guanylyl cyclase

RCT – randomized controlled trial

SV – stroke volume

mPAP / e-mPAP – mean pulmonary arterial pressure / estimated mean pulmonary arterial pressure

CTD – connective tissue disease

sGC stimulator – soluble guanylyl cyclase stimulator (ATC: Antihypertensive agents for pulmonary arterial hypertension)

CI – cardiac index

HF – heart failure

HFrEF – heart failure with reduced ejection fraction

HFpEF – heart failure with preserved ejection fraction

SSc – systemic sclerosis

TV – tricuspid valve

6MWT – six-minute walk test

PE – pulmonary embolism

PFT – pulmonary function testing, study of unforced respiratory volumes and flows

FC – functional class

COPD – chronic obstructive pulmonary disease

CTEPH – chronic thromboembolic pulmonary hypertension

CTED – chronic thromboembolic disease

cGMP – cyclic guanosine monophosphate, RHC – right heart catheterization

ECG – electrocardiogram

ECMO – extracorporeal membrane oxygenation

ET-1 – endothelin-1

EchoCG – echocardiography

BMPR-II (bone morphogenetic protein receptor type II) – bone morphogenetic protein receptor type II

DLCO – diffusing capacity of the lungs for carbon monoxide, pulmonary diffusing capacity testing

NO – nitric oxide

NT-proBNP – N-terminal pro-brain natriuretic peptide

NYHA – New York Heart Association

PaCO2 – partial pressure of carbon dioxide in arterial blood

PaO2 – partial pressure of oxygen in arterial blood

PETCO2 – partial pressure of end-tidal carbon dioxide

Qp/Qs – pulmonary-to-systemic blood flow ratio

SvO2 – mixed venous oxygen saturation

TAPSE – tricuspid annular plane systolic excursion

VE/VCO2 – ventilatory equivalent for carbon dioxide

VO2peak – peak oxygen uptake

Terms and Definitions

Evidence-based medicine – the conscientious, explicit, and judicious use of current best evidence (clinical research results) in making decisions about the care and treatment of individual patients [1].

Disease – a disorder of bodily function, working capacity, and the ability to adapt to changing environmental and internal conditions, arising from the impact of pathogenic factors, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms [2].

Instrumental diagnostics – diagnostics utilizing various devices, apparatuses, and instruments to examine a patient.

Outcome – any possible result arising from the exposure to a causal factor, prophylactic or therapeutic intervention, or any established changes in health status occurring as a consequence of an intervention [3].

Clinical trial – any investigation conducted in human subjects intended to discover or verify the clinical and/or pharmacological effects of investigational products, and/or to identify any adverse reactions to investigational products, and/or to study absorption, distribution, metabolism, and excretion with the object of ascertaining their safety and/or efficacy. The terms "clinical trial" and "clinical study" are synonymous [4].

Conflict of interest – a situation in which a medical or pharmaceutical worker, in the exercise of their professional activities, has a personal interest in obtaining material gain or other advantage, either personally or through a representative, which influences or may influence the proper performance of their professional duties due to a contradiction between the personal interest of the medical or pharmaceutical worker and the interests of the patient [2].

Laboratory diagnostics – a set of methods aimed at analyzing test material using various specialized equipment.

Pulmonary hypertension – a pathophysiological condition characterized by an elevation in pulmonary arterial pressure, associated with the development of right ventricular heart failure and premature patient mortality.

Medicinal products – pharmacological agents in the form of dosage forms used for the prevention, diagnosis, and treatment of diseases, rehabilitation, and the preservation, prevention, or termination of pregnancy [5].

Medical worker – an individual who has medical or other education, works in a medical organization whose job (official) duties include the performance of medical activities, or an individual who is an individual entrepreneur directly engaged in medical activities [2].

Medical intervention – a set of medical examinations and/or procedures and artificial termination of pregnancy (abortion) performed by a medical professional or other healthcare worker authorized to practice medicine, affecting a person's physical or mental state and aimed at prevention, diagnosis, treatment, rehabilitation, or research [2].

Lifestyle modification – measures aimed at normalizing weight, diet, and physical activity with the goal of reducing cardiovascular risk.

Patient – an individual who receives medical care or applies for medical care regardless of the presence or absence of a disease and their health status [2].

Sequential combination PAH-specific therapy – the sequential administration of two or more different classes of specific drugs for the treatment of pulmonary hypertension [6].

Working group for the development/updating of clinical guidelines – a team of specialists working together and in coordination to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

Syndrome – a stable set of multiple symptoms sharing a common pathogenesis [7].

Condition – alterations in the body arising from the impact of pathogenic and/or physiological factors that require medical care [2].

Initial combination PAH-specific therapy – the simultaneous administration of two or more different classes of specific drugs for the treatment of pulmonary hypertension [6].

Thesis-recommendation – a statement reflecting the procedure and correctness of performing a particular medical intervention with proven efficacy and safety.

Level of evidence (LoE) – the degree of confidence that the estimated effect of a medical intervention is true [8].

Level of recommendations (LoR) – the degree of certainty in the validity of an intervention's effect and that following the recommendations will do more good than harm in a specific clinical situation [8].

Goal of pharmacotherapy – stable achievement of low mortality risk [9, 10].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Pulmonary hypertension (PH) – a hemodynamic and pathophysiological condition characterized by an increase in mean pulmonary arterial pressure (mPAP) >20 mmHg at rest, measured via right heart catheterization (RHC) [11, 12].

Normal pulmonary arterial pressure at rest: mean PAP (mPAP) ≤20 mmHg [13].

Pulmonary capillary wedge pressure (PCWP) indirectly reflects left atrial pressure and left ventricular (LV) end-diastolic pressure.

Pulmonary vascular resistance (PVR) – a calculated parameter reflecting the severity of pulmonary arterial bed involvement, defined as the transpulmonary gradient (mPAP – PCWP) divided by cardiac output (CO), measured in Wood units [to convert to dyn·s·cm⁻⁵, multiply the value in Wood units by 80] [13–15].

Pre-capillary pulmonary hypertension – a hemodynamic PH subtype defined by mPAP >20 mmHg, PCWP ≤15 mmHg, and PVR >2 Wood units [12].

Post-capillary pulmonary hypertension – a hemodynamic PH subtype defined by mPAP >20 mmHg and PCWP >15 mmHg [12].

Combined post-/pre-capillary pulmonary hypertension – a hemodynamic PH subtype defined by mPAP >20 mmHg, PCWP >15 mmHg, and PVR >2 Wood units [12].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Group I. PAH is driven by structural changes in the pulmonary arteries/arterioles due to intimal hyperplasia, medial and adventitial hypertrophy and hyperplasia, with perivascular inflammatory infiltrates and fibrosis [41, 42]. The apoptosis-resistant endothelial cell phenotype characteristic of PAH promotes plexogenic arteriopathy, leading to subtotal vascular lumen obliteration, elevated PVR, and ultimately right ventricular (RV) overload. The acquisition of an oncogene-like, proliferative phenotype by vascular wall cells is linked to impaired mitochondrial respiration and increased energy dependence on aerobic glycolysis, resulting in pathological activation of transcription factors [6, 15].

A key pathogenetic mechanism of PAH is endothelial dysfunction with overexpression of vasoconstrictive (endothelin-1 [ET-1], thromboxane A2, serotonin) and reduced synthesis of vasodilatory (nitric oxide [NO], prostacyclin) substances, creating prothrombotic conditions, alongside vascular wall inflammation due to loss of endothelial anti-adhesive properties and autoimmune abnormalities.

The development and progression of PAH are mediated by the interaction of genetic, epigenetic factors (DNA methylation, histone modifications, and microRNAs) and environmental factors. In familial PAH, 75% of cases harbor mutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), which belongs to the TGF-beta superfamily and regulates cell proliferation; mutations are found in 25% of idiopathic PAH (sporadic) cases [18]. In patients with a family history of PAH or hereditary hemorrhagic telangiectasia, mutations are identified in genes encoding activin receptor-like kinase 1 (ALK-1), endoglin, and TGF-beta superfamily proteins (BMPR1B, SMAD9). Whole-genome sequencing in PAH patients has revealed rarer mutations in genes encoding caveolin-1 and potassium channels (KCNK3) [6, 15, 16]. RV functional status is the primary determinant of PH prognosis, which directly depends on the severity of pulmonary vascular and myocardial damage.

Group II. Diseases of the left heart causing increased mPAP are extremely heterogeneous. The main mechanism of post-capillary PH development is the passive transmission of elevated filling pressure from the left heart chambers to the pulmonary venous bed. Left atrial enlargement can serve as an early marker of LV systolic or diastolic dysfunction. The similarity in histological patterns indicates common pathogenetic mechanisms between combined post-/pre-capillary PH and PAH. Elevated venous pressure in the pulmonary circulation leads to endothelial injury, accompanied by increased ET-1 secretion, decreased NO production, and reduced sensitivity to the vasodilating effects of natriuretic peptides [31].

Group III. Pulmonary vasocontriction in response to hypoxemia, followed by arterial and arteriolar remodeling, is a key link in the pathogenesis of PH in lung disease. This is supported by a correlation between mPAP, partial pressure of oxygen, and DLCO [35, 36]. The paradoxical response of the pulmonary vasculature to hypoxemia may be genetically determined. A link has been established between the development of PH in patients with lung disease and the presence of the LL polymorphism in the 5-HTT serotonin transporter gene. Additionally, overexpression of ET-1, tumor necrosis factor-alpha, transforming growth factor-beta, vascular endothelial growth factor, and elevated C-reactive protein levels confirm shared pathogenetic mechanisms of PH development in pulmonary pathology and in PAH patients. Additional risk factors for PH include metabolic syndrome, insulin resistance, and associated oxidative stress leading to endothelial dysfunction.

Group IV. In the pathogenesis of CTEPH, apart from chronic obstruction of elastic pulmonary arteries by thrombotic masses, distal pulmonary vasculopathy plays a significant role. The development of the disease is associated with impaired fibrinolysis and angiogenesis, early fibrotic changes, and secondary vasculopathy, partly due to the pathological impact of newly formed aortopulmonary collaterals [43].

1.3 Epidemiology of the Disease or Condition

PH is a global public health problem affecting approximately 1% of the world's population, and up to 10% in age groups over 65 due to the high prevalence of heart and lung diseases [20]. Incidence and prevalence vary significantly across clinical PH groups, with left-sided heart disease and pulmonary pathology being the leading causes. Regardless of the underlying disease type, the development and progression of PH are associated with worsening symptoms and increased mortality [21].

Group I. PAH is classified as a rare disease; therefore, primary data on population incidence and prevalence are derived from national and international registries. In economically developed countries, the incidence and prevalence of PAH are 6 and 48–55 cases per million adults, respectively [12].

In most registries, IPAH is the most prevalent form in Group I (up to 50%), followed by connective tissue disease-associated PAH (CTD-PAH), congenital heart disease (CHD), and portopulmonary hypertension [6, 12]. According to the Russian registry, among 740 newly diagnosed PAH patients, 40.9% had confirmed IPAH, while the most frequent causes of associated forms were simple systemic-to-pulmonary shunts (36.6%) and CTD (19.3%).

In Russian patients, PAH was diagnosed at the age of 45.2 ± 14.9 years [17]. In the US National Institutes of Health (NIH) registry, the mean age of IPAH patients at diagnosis was 35 ± 15 years, with a female-to-male ratio of 1.7:1 [22]. Currently, HPAH is believed to manifest at a younger age, affecting females twice as often as males [12, 23].

Over the past three decades, the "profile" of IPAH patients has shifted toward an increasing proportion of elderly patients with comorbid cardiovascular conditions, such as hypertension (27–42%), obesity (30–38%), type 2 diabetes mellitus (14%), and coronary artery disease (10–12%) [15]. The mean age of patients in the French and US (REVEAL) registries was 52 ± 15 years and 53 ± 15 years, respectively [24, 25]. In the COMPERA registry, the proportion of IPAH patients older than 65 years exceeded 64%, with a female-to-male ratio of 2.3:1 [26]. Drugs and toxins known to induce PAH are classified as definite or possible based on proposals from the 6th World Symposium on PH (Table 13, Appendix B1) [11, 27–30]. A definite association is established based on epidemic data, epidemiological studies, or large multicenter case series. A possible association is indicated by case series where PAH develops during exposure to drugs/toxins or agents with similar properties and mechanisms of action [12].

Group II. PH due to left heart disease is one of the most common forms of the condition (accounting for up to 80% of all PH patients) [6, 15, 31]. The 2013 Global Burden of Disease study estimated 61.7 million cases of heart failure (HF) worldwide, which is twice its prevalence in 1990 [32]. In Europe and the USA, more than 80% of HF patients are aged ≥65 years. Post-capillary PH—whether isolated or combined post-/pre-capillary—is a frequent complication, predominantly seen in HFpEF, affecting at least 50% of patients [33].

The prevalence of PH increases with the severity of left-sided valvular heart disease. Pulmonary arterial pressure is elevated in 60–70% of patients with severe myocarditis [33] and in 50% of patients with aortic stenosis [34].

Group III. PH is identified in severe obstructive and parenchymal lung diseases: mPAP elevated to 35–40 mmHg is observed in 1–5% of patients with progressive chronic obstructive pulmonary disease (COPD) and chronic respiratory failure, as well as in candidates for lung transplantation [35, 36]. In idiopathic pulmonary fibrosis, an mPAP ≥25 mmHg was recorded in 8–15% of patients in the early stage, 30–50% during disease progression, and 60% in the terminal stage [36].

Hypoxia is a public health concern for 120 million people living at altitudes above 2,500 meters, who are at risk of developing PH and chronic mountain sickness. The study of high-altitude PH must be addressed using updated methodologies in large-scale population-based studies [37].

Group IV. The detection rate of chronic thromboembolic pulmonary hypertension (CTEPH) has increased in recent years due to heightened physician awareness and active screening in patients with persistent dyspnea following pulmonary embolism (PE) in the presence of risk factors. According to registries, the incidence and prevalence of CTEPH are 2–6 and 26–38 cases per million adults, respectively [12, 38, 39]. Patients with chronic thromboembolic disease (CTED) without PH account for only a small fraction of referrals to CTEPH centers [12].

Group V. Epidemiological data on PH associated with hematologic, metabolic, and other disorders are lacking, which is attributable to multifactorial pathogenesis and the development of both pre- and post-capillary types of PH [20]. Data from adult sarcoidosis registries have demonstrated that PH is frequently associated with increased morbidity and mortality [40].

1.4 Features of Coding the Disease or Condition

Other forms of cardiopulmonary failure (I.27):

I27.0 – Primary pulmonary hypertension

I27.2 – Other secondary pulmonary hypertension

I27.8 – Other specified forms of pulmonary heart disease

1.5 Classification of the disease or condition

PH is typically a syndrome associated with various cardiovascular and respiratory diseases, and very rarely presents as an independent disease, as in the case of idiopathic (IPAH) or hereditary pulmonary arterial hypertension (HPAH).

The clinical classification of PH comprises five groups categorized by shared pathophysiological mechanisms, clinical and hemodynamic characteristics, and treatment approaches (Table 1) [11, 16].

Table 1. Clinical Classification

Notes: * Among patients with HPAH and drug-/toxin-induced PAH, similar to IPAH, subgroups with negative and positive vasoreactivity testing are distinguished [12].

In accordance with the provisions of the 6th World Symposium on PH and the 2022 ESC/ERS guidelines, the following modifications have been made to the clinical classification:

1. In group I (PAH), among patients with IPAH, HPAH, and drug/toxin-induced PAH, subgroups with negative and positive vasoreactivity tests are distinguished [12]. In the presence of vasoreactivity reserve, patients with these forms of PAH have a unique phenotype with a favorable disease course when treated with calcium channel blockers (CCBs) at the maximum tolerated doses (Section 3.2.2.1).

According to the Russian registry, the most common cause of associated PAH is congenital heart disease (CHD) — simple systemic-to-pulmonary shunts (36.6%) (Section 4.1) [17]. PAH with involvement of pulmonary veins and capillaries (pulmonary veno-occlusive disease (PVOD) / pulmonary capillary hemangiomatosis (PCH)), which is characterized by an unfavorable prognosis and associated with the risk of pulmonary edema when PAH-specific therapy is prescribed, is included in group I according to the consensus of experts of the 6th World Symposium on PH [11, 15]. This is because involvement of the pulmonary veins/capillaries in the pathological process can also be observed in diseases associated with the development of PAH, notably systemic sclerosis (SSc). The clinical and hemodynamic picture of PVOD/PCH in most cases corresponds to PAH, and histological examination reveals pronounced remodeling of pulmonary arterioles alongside changes in veins/capillaries [11]. PVOD/PCH should be suspected in the presence of occupational exposure to organic solvents (trichloroethylene, etc.); decreased diffusing capacity of the lungs for carbon monoxide (DLCO <50% of predicted); marked hypoxemia; thickening of septal lines, centrilobular ground-glass opacities in the lung parenchyma, and enlargement of mediastinal lymph nodes according to chest computed tomography (CT) [11, 15, 18].

1. In group III, obstructive sleep apnea syndrome is excluded as a cause of PH due to the lack of a proven causal relationship; hypoventilation and hypoxia without lung pathology (high-altitude PH) are indicated in the structure of this group [12].

2. In group IV, as before, CTEPH and other diseases associated with pulmonary artery obstruction are distinguished.

3. In group V, the form of PH due to pulmonary thrombotic microangiopathy resulting from tumor cell embolism has been added [12]. In complex CHD, there are hemodynamic disturbances in the pulmonary circulation in the form of pre- and/or post-capillary PH (including PH in CHD with univentricular hemodynamics and segmental PH in individual lung segments due to aortopulmonary collaterals), which allowed Russian experts to retain the subgroup of complex CHD in group V, despite changes in the 2022 ESC/ERS guidelines [11, 15].

Table 2. Hemodynamic classification

In 2018, experts at the 6th World Congress on PH changed the previously accepted diagnostic criterion for PH (mPAP ≥25 mmHg) to mPAP >20 mmHg, and the new criteria for pre-capillary PH became mPAP >20 mmHg, PAWP ≤15 mmHg, and PVR >3 Wood units [18]. In the 2022 ESC/ERS guidelines, the threshold values for PVR were lowered to 2 Wood units taking into account the upper limit of normal values for this parameter [12, 13] (Table 2). At the same time, it should be emphasized that the evidence base regarding the efficacy/safety of PAH-specific drugs was obtained in randomized controlled trials (RCTs) that included PAH patients (group I) with mPAP ≥25 mmHg, PAWP ≤15 mmHg, and PVR >3 Wood units [12]. Dynamic monitoring is required for patients with mPAP of 21–24 mmHg and PVR of 2.1 to 2.9 Wood units.

PVR depends on body surface area and age; in elderly individuals, even in the absence of cardiovascular pathology, higher values are typically observed [14]. The PVR value must be taken into account to exclude an increase in PAP due to increased pulmonary blood flow or elevated intrathoracic pressure [12]. Although the upper limit of normal PAWP is considered to be 12 mmHg, the PH guidelines and the European Society of Cardiology consensus on heart failure (HF) propose a higher threshold for diagnosing HF with preserved ejection fraction (HFpEF) (PAWP ≥15 mmHg) [6, 12, 19]. RCTs investigating PAH-specific therapy used a PAWP threshold of ≤15 mmHg. While retaining this PAWP value as a criterion for pre-capillary PH, it is important to bear in mind that this threshold is arbitrary, requiring consideration of the patient's phenotype, risk factors, and echocardiography (EchoCG) data, including left atrial (LA) volume, when establishing pre- and post-capillary PH [12].

Pre-capillary PH is observed in patients with PAH (group I), lung pathology and/or hypoxemia (group III), pulmonary artery obstruction (group IV), and certain subtypes of group V. Post-capillary PH is observed in left heart pathology (group II) and may occur in group V PH or isolated pulmonary veno-occlusive/capillary disease (PVOD/PCH).

Post-capillary PH is defined by an elevated mPAP >20 mmHg and PAWP >15 mmHg. The PVR value is used to identify patients with a significant pre-capillary component — combined post-/pre-capillary PH (>2 Wood units). Previously, to characterize pulmonary artery/arteriole involvement in post-capillary PH, in addition to PVR, it was recommended to evaluate the diastolic pulmonary gradient as the difference between diastolic PAP (dPAP) and PAWP [15, 16, 18]. According to the 2022 ESC/ERS guidelines, assessing PVR alone is sufficient to determine the pre-capillary component [12]. Isolated post-capillary PH is established at a PVR ≤2 Wood units.

When mPAP >20 mmHg is elevated in combination with low PVR (≤2 Wood units) and PAWP ≤15 mmHg, patients have accelerated pulmonary blood flow and, as a rule, despite the presence of PH, the latter does not meet the criteria for pre- or post-capillary PH. This hemodynamic state can be described by the term "unclassifiable PH" [12]. Such patients may have CHD, liver disease, lung pathology, or hyperthyroidism as the cause of elevated mPAP, which requires thorough diagnosis and appropriate treatment (in particular, surgical correction of CHD).

To assess the functional status of PH patients, the functional classification recommended by the World Health Organization (WHO) in 1998 is used

along with the New York Heart Association (NYHA) classification for HF patients (Table 3) [6, 12, 15, 16]. Assessment of the NYHA/WHO functional class (FC) is used for routine evaluation of patient status at all stages of medical care, determining prognosis, and evaluating treatment efficacy.

Table 3. Functional classification (WHO)

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criterion for diagnosing PH is an elevated mPAP >20 mmHg at rest during RHC [12].

The goal of a comprehensive examination is to establish the diagnosis of PH, determine the clinical group, hemodynamic type, and functional status in all PH patients, as well as the mortality risk profile in all PAH patients [6, 12, 15, 16, 44, 45].

The stages of PH diagnosis are:

— Screening, including taking medical history, assessing PAH risk factors, and determining the probability of PH using transthoracic EchoCG.

— Exclusion of the most common causes of PH: left heart diseases (group II), lung pathology (group III), and CTEPH (group IV).

— Verification of the diagnosis of PAH, CTEPH, severe PH via RHC, and determination of the nosological form of PH.

— Assessment of the patient's FC (WHO).

— Mortality risk stratification in all PAH patients [6, 10, 12, 15, 16].

Given the lack of pathognomonic symptoms of PH and the high prevalence of this pathology in various diseases, the diagnosis of PH requires a multidisciplinary approach and strict adherence to a diagnostic algorithm, excluding the most common causes of PH development and identifying rarer forms. According to the Russian registry, the median time from symptom onset to confirmation of the diagnosis of IPAH in patients with PAH is 52.8 months [17], and in patients with CTEPH, 14 months [44].

2.1 Complaints and Anamnesis

RSC IC (LoE C, GoR 5)

Comment. The symptoms of PH vary significantly depending on the cause of PH, associated conditions, and comorbid pathology. In the early stages, PH symptoms occur during physical exertion and are mainly associated with RV dysfunction [6, 49]. At disease onset, patients complain of dyspnea, which progresses as the disease courses; fatigue, weakness, and dizziness. In later stages, syncopal episodes and/or symptoms of right ventricular HF appear: leg edema, hepatomegaly, ascites, and jugular venous pulsation [12, 15, 44]. Patients with a long-standing history of PAH may experience anginal-type chest pain. Causes of myocardial ischemia may include relative coronary insufficiency due to low cardiac output and increased RV wall stress; hypoxemia; and compression of the left coronary artery by an aneurysmally dilated pulmonary artery (PA). In Eisenmenger syndrome, pulmonary hemorrhages are recorded in 43% of cases and are a cause of mortality in 8% of patients [45, 48]. The source of bleeding in 90% of cases is altered bronchial arteries, most commonly detected in patients with PAH associated with congenital heart disease (CHD). In patients without CHD, hemoptysis occurs in 1.5–6% of cases [6, 15]. Significant dilation of the PA can cause dissection or rupture, clinically accompanied by cardiac tamponade.

2.2 Physical Examination

RSC IC (LoE C, GoR 5)

Comment. Physical examination may reveal a potential cause of PH. Telangiectasias, fingertip ulcerations, and sclerodactyly are characteristic of SSc; inspiratory crackles may indicate interstitial lung disease (ILD); spider angiomas, testicular atrophy, and palmar erythema suggest liver disease [6, 47-49]. The presence of clubbing ("drumstick fingers" / "watch glass" nails) may suggest cyanotic CHD, ILD, or liver pathology [12, 15, 48]. Pulse oximetry is performed during patient examination: in IPAH patients, oxygen saturation levels are within the normal range; if desaturation is detected at rest and during exertion, pulmonary pathology or CHD with veno-arterial shunting should be suspected. The presence of differential cyanosis (normal skin color of the upper half of the body with signs of central cyanosis of the lower half of the body, clubbing and watch glass nails only on the toes) indicates the presence of Eisenmenger syndrome secondary to a patent ductus arteriosus. With the development of right ventricular HF in patients, engorgement and pulsation of the jugular veins, hepatomegaly, peripheral edema, and ascites are noted.

Upon therapeutic auscultation of the lungs in patients with severe dyspnea in postcapillary PH, fine crackles in the lower lung fields combined with an orthopneic position are heard. The auscultatory pattern in the lungs may be unchanged in patients with PAH [16, 49]. During therapeutic auscultation of the heart, an accentuated second sound over the PA is heard—one of the key physical signs of PH. In some cases, a systolic murmur of tricuspid regurgitation is determined, and with PA dilation and the development of relative pulmonary valve insufficiency, a Graham Steell diastolic murmur is detected. In patients with Eisenmenger syndrome in the presence of a large defect, the shunt murmur may not be heard due to the absence or minimal pressure gradient across the defect in severe PH [15, 45, 48].

2.3 Laboratory Diagnostics

• All patients with PH are recommended to undergo a complete blood count (CBC) with assessment of hemoglobin and hematocrit levels, erythrocyte, leukocyte, and platelet counts, and erythrocyte sedimentation rate as part of the initial examination, upon admission to the hospital, and during follow-up every 6–12 months [6, 12, 15, 16, 44, 48].

RSC I C (LoE C, GoR 5)

Comment. The complete blood count (CBC) should evaluate hemoglobin and hematocrit levels, and the presence of microcytosis. Secondary erythrocytosis is frequently observed in patients with PH associated with CHD and pulmonary pathology [47, 48].

• All patients with PH are recommended to undergo a general general-medical biochemical blood test (assessment of potassium, sodium, glucose, creatinine, total protein, urea, uric acid, total bilirubin, free and conjugated bilirubin levels in the blood, and determination of aspartate aminotransferase and alanine aminotransferase activity in the blood) as part of the initial examination, upon admission to the hospital, and during follow-up every 3–6 months [6, 12, 15, 16, 44, 48].

RSC I C (LoE C, GoR 5)

Comment. Liver function tests may be elevated during decompensation of right ventricular HF and/or during therapy with endothelin receptor antagonists (ATX Antihypertensive agents for the treatment of pulmonary arterial hypertension) (ERAs). Uric acid levels can be a marker of HF severity, but may also increase during diuretic therapy.

RSC I C (LoE C, GoR 5)

Comment. Iron deficiency state is observed in almost half of patients with Eisenmenger syndrome and IPAH [6, 15, 48].

• All PAH patients receiving ERA therapy (ambrisentan**, bosentan**, macitentan**) are recommended to undergo monthly blood aspartate aminotransferase and alanine aminotransferase activity testing to evaluate treatment safety [6, 12].

ESC IC (Level of Evidence 5, Grade of Recommendation C)

Comment. Liver function tests may become elevated during ERA therapy [16, 47, 49, 50].

• All PAH patients receiving ERA therapy (ambrisentan**, bosentan**, macitentan**) are recommended to undergo a monthly blood total hemoglobin test to evaluate treatment safety [6, 15, 16].

ESC IC (LoE C, SoR 5)

Comment. Blood total hemoglobin testing is a mandatory test during ERA therapy, which is complicated by a decrease in hemoglobin levels in up to 15% of cases [6, 12, 49, 50].

• All patients with PH are recommended to undergo a coagulogram (exploratory hemostasis assay) (activated partial thromboplastin time, blood or plasma prothrombin (thromboplastin) time, blood D-dimer concentration, blood fibrinogen level, blood antithrombin III activity), and measurement of the international normalized ratio (INR) as part of the initial assessment, upon hospital admission, and subsequently every 6–12 months to diagnose hemostatic disorders and assess bleeding risk [15, 16, 44, 47].

RSC I C (LoE C, GoR 5)

ESC / RSC IC (LoE A, LoR 2)

Comment. Thyroid disorders are common in patients with PH. Thyroid pathology can complicate the diagnosis and treatment of PH patients or worsen the course of the disease [49, 51].

RSC I C (LoE C, GoR 5)

ESC IC (LoE 5, LoR C)

Comment. An elevated titer of antinuclear antibodies at a low level (1:80) is quite common in patients with PH. The diagnostic titer for antinuclear antibodies by indirect immunofluorescence is considered to be ≥ 1:160, at which point the antinuclear antibody profile should be assessed for the differential diagnosis of systemic sclerosis or overlap syndrome, which most frequently manifest with PH [6,16,47,49].

RSC IC (LoE 5, GoR C)

Comment. BNP and NT-proBNP remain the only routine biomarkers effectively used in clinical practice to assess the prognosis of PAH patients and evaluate treatment outcomes [279].

• In all PH patients with moderate-to-severe anemia, as well as when bleeding is suspected, it is recommended to determine ABO blood groups, Rh factor (D antigen), C, c, E, e, Cw, K, k phenotypes, and screen for anti-erythrocyte antibodies upon hospital admission to address the issue of transfusing type-specific packed red blood cells [15, 16, 48].

RSC I C (LoE C, GoR 5)

• In all patients with PH, it is recommended to test for hepatitis B surface antigen (HBsAg) in the blood, antibodies to hepatitis C virus (HCV) in the blood, antibodies to Treponema pallidum in the blood, and IgM and IgG antibodies to human immunodeficiency virus HIV-1 and HIV-2 in the blood as part of the initial evaluation and upon hospital admission [15, 16, 48].

RSC I C (LoE C, GoR 5)

Comment. In case of clinically significant abnormalities in liver function tests, serological testing for viral hepatitis is necessary to rule out portopulmonary hypertension. Testing for IgM and IgG antibodies to human immunodeficiency virus HIV-1 and HIV-2 in the blood is required to exclude the association of PH with HIV infection [6, 16, 48].

2.4 Instrumental Diagnostics

Electrocardiography

RSC IC (LoE A, GoR 2)

Comment. Typical ECG signs of PH include: right axis deviation, P pulmonale, signs of right ventricular hypertrophy and overload, right bundle branch block, and QTc interval prolongation [6, 47, 53]. Increased R-wave amplitude and R/S ratio in the right precordial leads as ECG signs of right ventricular hypertrophy have insufficient sensitivity (55%) and specificity (70%) for screening purposes, whereas right ventricular overload is a more sensitive sign [54]. QRS complex widening and QTc interval prolongation indicate disease severity and are associated with a poor prognosis in PH [55]. Supraventricular arrhythmias occur more frequently in advanced stages of the disease, leading to decompensation of heart failure [6, 56]. Atrial flutter or fibrillation is recorded in 25% of PAH patients during 5 years of follow-up, significantly worsening the patient's prognosis if sinus rhythm cannot be restored [6, 12, 15]. A normal ECG does not rule out the presence of PH; however, the combination of a normal ECG with normal biomarker levels (BNP/NT-proBNP) in patients with suspected PH or risk factors for PH (e.g., following acute pulmonary embolism) indicates a low probability of the disease [12, 57].

Chest radiography

RSC IC (LoE A, GoR 2)

Comment. Targeted chest X-ray reveals signs characteristic of pulmonary pathology (Group III) or congestion in left-sided heart disease (Group II), as well as specific signs of a number of rare diseases [45, 49]. In 90% of patients with idiopathic PAH at the time of diagnosis, pathological changes are detected in the form of pulmonary artery trunk dilatation (2nd arch along the left heart border), attenuation of the pulmonary vascular pattern, and enlargement of the right heart chambers [16, 18, 47]. The severity of PH may not correlate with the extent of radiological changes.

Comprehensive pulmonary function testing and arterial blood gas analysis

ESC IC (LoE C, SoR 5)

ESC IC (LoE C, SoR 5)

Comment. Assessment of pulmonary function (spirometry — evaluation of unprovoked respiratory volumes and flows, see List of Abbreviations) is necessary to detect pulmonary pathology and assess its severity. COPD as a cause of hypoxic PH is diagnosed in the presence of irreversible broncho-obstructive changes, often combined with an increased residual lung volume on body plethysmography and a possible decrease in DLCO. Analysis of arterial blood gas composition in COPD patients typically shows a decreased arterial partial pressure of oxygen (PaO2) with normal or increased arterial partial pressure of carbon dioxide (PaCO2) [36, 47]. The severity of emphysema and/or interstitial lung disease is assessed using chest computed tomography (CT). The combination of emphysema and pulmonary fibrosis can lead to a pseudo-normal spirometry pattern, while DLCO remains reduced, which requires a comprehensive evaluation of both pulmonary function results and imaging data to avoid diagnostic errors [58]. In PAH patients, mild to moderate reduction in lung volumes associated with disease severity is observed; DLCO is reduced due to ventilation-perfusion mismatch [15, 57]. A low DLCO level, especially in combination with decreased lung volumes, may indicate the association of PAH with systemic sclerosis and also requires differential diagnosis with interstitial lung disease (Group III) and pulmonary veno-occlusive disease [16, 18]. Extremely low DLCO in PAH patients, defined as < 45% of predicted, is associated with a poor prognosis [12]. Analysis of arterial blood gas composition in PAH patients shows that resting PaO2 remains within the normal range or is slightly decreased, while PaCO2 is decreased due to alveolar hyperventilation [49].

Echocardiography

ESC IC (LoE C, SoR 5)

Comment. Echocardiography is the single most informative non-invasive diagnostic method for screening patients with suspected PH. Regardless of etiology, PH leads to right ventricular pressure overload and dysfunction. TTE provides information on the morphology of the right and left heart chambers, right and left ventricular function, valve status, and allows non-invasive estimation of certain hemodynamic parameters (pulmonary artery pressure, right atrial pressure, right ventricular stroke volume, cardiac output). TTE is also a valuable tool for identifying the cause of suspected or confirmed PH, such as left-sided heart disease or congenital heart disease. However, TTE cannot be used to verify the diagnosis of PH, which requires right heart catheterization (RHC). In patients with an established diagnosis of PH, TTE is indicated to assess prognosis (in PAH) and monitor patients undergoing therapy [15, 16, 44, 48, 59].

Considering the heterogeneous nature of PH and the specific geometry of the RV, it is clear why there is no single echocardiographic parameter that could reliably indicate both the presence of PH and the etiology of the disease. Therefore, a comprehensive echocardiographic examination is required, the methodological aspects of which are detailed in relevant guidelines and publications [60-64]. The most informative echocardiographic parameters for the diagnosis of PH are the peak tricuspid regurgitation (TR) velocity (Vtr) and its derivatives (the peak systolic pressure gradient across the tricuspid valve (TV) and the estimated systolic PAP (eSPAP) [65, 66]. Given the inaccuracy of non-invasive RA pressure estimation using echocardiography [67] and the increased measurement error when using variables derived from TR velocity [68, 69], these guidelines, like the ESC guidelines [12], use the peak TR velocity (Vtr) as the key parameter for assessing echocardiographic probability of PH. A probabilistic approach to echocardiographic diagnosis of PH is recommended only when examining treatment-naive patients (prior to diagnosis confirmation). The probability of PH in a patient is assessed as low, intermediate, or high, depending on the peak TR velocity (determined by continuous-wave Doppler ultrasound) and the presence of additional echocardiographic signs involving the heart chambers, PA, as well as the inferior vena cava (IVC) and right atrium (RA) (Tables 4 and 5).

Table 4. Determination of pulmonary hypertension probability based on echocardiography data

Note: * additional signs from at least 2 different categories (ventricles / PA / IVC and RA) must be present

Table 5. Additional echocardiographic signs increasing the probability level of pulmonary hypertension in addition to tricuspid regurgitation velocity measurement

In case of a low probability of PH, a search for other causes explaining the patient's symptoms or clinical follow-up is recommended (if such causes are not established); for intermediate and high probability, referral to a PH specialist (Fig. 1. Appendix B1).

It is important to evaluate the obtained echocardiographic results in a clinical context. In addition to echocardiographic parameters, the probability level of PH is increased by the presence of PAH risk factors (CTD, especially SSc; portal hypertension; HIV infection; family history of PAH) and CTEPH (history of PE; presence of indwelling right-sided intravascular devices; inflammatory bowel disease; essential thrombocythemia; history of splenectomy; high-dose thyroid hormone replacement therapy; presence of malignant neoplasms), which requires a more thorough approach to the examination and follow-up of these categories of patients [12]. Despite recent criticism regarding the non-invasive estimation of PAP using echocardiography, the estimated SPAP (eSPAP) has remained an integral part of the standard echocardiographic protocol for decades [60, 70].

Echocardiographic estimation of SPAP is based on determining the peak tricuspid regurgitation velocity (Vtr) and using the simplified Bernoulli equation combined with RA pressure assessment. The simplified Bernoulli equation calculates the systolic pressure gradient between the RV and RA: $PsGPtv = 4 \times Vtr ²$; where PsGPtv is the peak systolic pressure gradient across the TV (= systolic pressure gradient between the RV and RA). RA pressure (RAP) can be estimated by measuring the IVC diameter and its respiratory variation: an IVC diameter $\le 2.1$ cm with $>50\%$ collapse on forced inspiration indicates a normal RAP of 3 mmHg (range 0–5 mmHg), whereas an IVC diameter $>2.1$ cm with $<50\%$ collapse on forced inspiration or $<20\%$ collapse on a sniff indicates a high RAP of 15 mmHg (range 10–20 mmHg). When the IVC diameter and its inspiratory collapse do not fall within these specified ranges, an intermediate value of 8 mmHg (range 5–10 mmHg) may be used. In the absence of RV outflow tract obstruction (RV outflow tract stenosis, pulmonary stenosis, including supravalvular), right ventricular systolic pressure is assumed to be equal to pulmonary artery systolic pressure. In this case, the formula for calculating SPAP is as follows: eSPAP = PsGPtv + RAP. The upper limit of normal for eSPAP ranges from 35 to 40 mmHg [60].

A large single-center study [71] with high echocardiography expertise in a cohort of 1,695 patients (72% of whom had various forms of PH) revealed a good correlation between echocardiographic eSPAP and RHC-derived SPAP. This study also determined a threshold eSPAP value of 36 mmHg, which corresponded to a mPAP of 25 mmHg by RHC, with good performance characteristics for a non-invasive diagnostic test (sensitivity 87%; specificity 79%; positive predictive value (91%) and negative predictive value (70%); diagnostic accuracy 85% for detecting PH. According to a meta-analysis of 27 studies [72] comparing eSPAP and RHC-derived SPAP, the overall sensitivity and specificity of Doppler echocardiography in diagnosing PH were 85% and 74%, respectively, with a positive likelihood ratio of 3.2. For a threshold eSPAP value $\ge 35$ mmHg (4 out of 27 studies were included in the subanalysis), sensitivity increased to 92%, and specificity was 65%.

Thus, normal eSPAP is <36 mmHg. When determining eSPAP, one should keep in mind both the possibility of underestimation (small or excessively large tricuspid regurgitation volume, misalignment of the ultrasound beam with the regurgitation jet direction, etc.) and overestimation (with high cardiac output in patients with liver disease or sickle cell anemia; incorrect peak velocity measurement from the tricuspid regurgitation velocity spectrum) [12].

In patients with a previously established diagnosis of PH, the echocardiography protocol should record the presence of PH signs indicating the eSPAP value, which is sufficient for primary healthcare. Expert echocardiography protocols may indicate additional calculated PAP values: mPAP calculated from both TR and PR flows, diastolic PAP (dPAP), as well as PCWP calculated using the Nagueh formula [74]. The aforementioned diagnostic algorithm for detecting PH using echocardiography is, unfortunately, not always applicable to patients with CHD [48, 75]. An important component of the echocardiographic examination is the assessment of RV myocardial contractile function, which determines the prognosis of patients with PH. RV contractility is assessed using a number of parameters: TAPSE – tricuspid annular plane systolic excursion (mm); RV fractional area change (FAC, %); peak systolic velocity of the tricuspid annulus using pulsed tissue Doppler imaging (TAPSV or $S'$, cm/s); RV free wall longitudinal strain (%, speckle-tracking technology); and potentially the ejection fraction (RVEF, %) using 3D echocardiography. Of diagnostic and prognostic significance is the RV-pulmonary arterial coupling (RV-PA coupling), which characterizes the physiological adaptation of RV function to changes in increasing load within the pulmonary circulation vascular bed (to ejection resistance, i.e., afterload) and is the most reliable marker of myocardial contractility. In routine echocardiography, RV-PA coupling is recommended to be assessed using a non-invasive surrogate of this parameter – the TAPSE/eSPAP ratio ($N > 0.55$) [12].

Echocardiographic parameters also make a significant contribution to risk stratification in patients with PAH (Table 22, Appendix B1) and differential diagnosis of group II PH. PH due to left heart disease is indicated by signs of left atrial enlargement, left ventricular systolic/diastolic dysfunction, left ventricular myocardial hypertrophy, etc. (Table 15, Appendix B1). During dynamic follow-up of PAH patients receiving PAH-specific therapy, attention should be paid not so much to changes in mean pulmonary arterial pressure (mPAP, which usually decreases insignificantly) as to signs of reverse remodeling of the right heart (decreased RA and RV dimensions, reduced severity of tricuspid regurgitation, and decreased LV eccentricity index), improved RV myocardial contractility, and increased cardiac output (CO), which will indicate the efficacy of the therapy [59, 76]. In addition, it should be kept in mind that a decrease in systolic PAP in PAH patients can occur not only as a result of a decrease in pulmonary vascular resistance (PVR) during successful therapy, but also due to a decrease in CO resulting from impaired RV contractility. In this regard, the dynamics of systolic PAP in patients must be evaluated solely in conjunction with data on RV contractility and CO.

ESC IIaC (LoE C, GoR 5)

Comment. Detection of congenital heart disease (CHD) is one of the important tasks in the differential diagnostic algorithm for a patient with PH, especially when sinus venosus atrial septal defect and/or partial anomalous pulmonary venous drainage is suspected. The most frequent causes of precapillary PH remain septal defects, patent ductus arteriosus, anomalous pulmonary venous drainage, and other, including complex, CHDs. Thus, echocardiography and, if necessary, cardiac CT and magnetic resonance imaging (MRI) of the heart and great vessels are used to detect and determine the type of CHD in patients with PH.

Perfusion lung scintigraphy

ESC IIC (LoE C, GoR 5)

Comment. Planar ventilation-perfusion lung scintigraphy is a screening method that allows the thromboembolic origin of PH to be ruled out. The absence of perfusion defects with normal ventilation allows CTEPH to be ruled out with a sensitivity of 90–100% vs. 51% in the case of computed tomography pulmonary angiography (CTPA), and a specificity of 94–100% [78].

RSC IIaC (LoE C, GoR 5)

Comment. In our country, ventilation-perfusion lung scintigraphy can be performed exclusively in a number of federal centers; therefore, planar perfusion lung scintigraphy is performed in most cases. To rule out pulmonary pathology, targeted chest X-ray or computed tomography of the chest organs can be used. A number of studies have demonstrated that single-photon emission computed tomography combined with chest computed tomography surpasses planar lung scintigraphy in sensitivity for ruling out thromboembolic involvement of the pulmonary vascular bed [44, 52, 77]. Recently, a new technology—three-dimensional magnetic resonance perfusion mapping—has shown comparable sensitivity to perfusion scintigraphy in CTEPH screening [80].

The absence of perfusion defects with normal ventilation allowed CTEPH to be ruled out with a sensitivity of 90–100% vs. 51% in the case of computed tomography pulmonary angiography, and a specificity of 94–100%, according to a 2007 study [78].

More recent studies (2017–2020) comparing ventilation-perfusion scintigraphy with computed tomography pulmonary angiography and perfusion lung CT performed in dual-energy CT (DECT) mode have shown high sensitivity (97%) and specificity of CT in the diagnosis of CTEPH [81, 82]. Similar results when comparing perfusion CT with ventilation-perfusion scintigraphy were obtained in the PASEP study, where the sensitivity of CT was 81.3% and 78.9% [82].

If ventilation-perfusion scintigraphy is unavailable, it can be replaced by perfusion CT combined with computed tomography pulmonary angiography or perfusion MRI (if the medical institution has experience in conducting such studies) to confirm or rule out the diagnosis of CTEPH in patients with PH of unclear etiology.

Computed tomography of the chest organs and computed tomography pulmonary angiography

ESC IIaC (LoE C, GoR 5)

Comment. CT can provide important information for patients with dyspnea and suspected/confirmed PH. CT signs indicating the presence of PH include an increased pulmonary artery (PA) diameter, a PA-to-aorta ratio >0.9, and right heart enlargement [84]. The combination of three parameters (PA diameter ≥30 mm, RV anterior wall thickness ≥6 mm, and RV:LV ratio ≥1) allows PH to be diagnosed with high probability [85]. Chest computed tomography makes it possible to identify the cause of PH in the presence of signs of parenchymal lung disease or changes characteristic of pulmonary veno-occlusive disease (PVOD), which include centrilobular ground-glass opacities (which can also be detected in PAH), interlobular septal thickening, and lymphadenopathy [84].

ESC IC (LoE C, GoR 5)

Comment. CT angiography of the pulmonary vessels is used to detect direct or indirect signs of CTEPH. Direct signs include filling defects in the form of intravascular strands, small mural structures such as membranes, webs, or bands. Indirect signs include decreased contrast of the distal pulmonary vascular bed, inhomogeneous contrast enhancement of the lung parenchyma in the form of mosaic perfusion, enlargement of bronchial arteries, and the presence of intersystem collaterals. Diagnostic accuracy is improved by using modern wide-detector scanners, adhering to the standards of computed tomography pulmonary angiography with the preferred two-phase study: pulmonary phase (during the first passage of the contrast agent through the right heart) and arterial phase, which makes it possible not only to assess the state of the pulmonary vessels, but also to identify additional findings, such as the presence of thrombotic masses in the right heart chambers. The accuracy of result interpretation depends on the investigator's experience; therefore, the ability to remotely evaluate CT images in expert centers plays an important role [86, 87]. In patients with a clinical presentation of acute pulmonary embolism (PE), computed tomography pulmonary angiography can help detect signs of CTEPH, including those listed above, as well as RV hypertrophy as a consequence of chronic PH [88, 89]. Detection of CTEPH signs in these cases is important as it may influence the management strategy for patients with suspected acute PE. Pericardial effusion and contrast reflux into the hepatic veins are predictors of poor prognosis in PH patients [38, 44].

Computed tomography pulmonary angiography helps determine the operability of CTEPH patients by assessing the localization and extent of thrombotic lesions: the presence of occlusions of the main or lobar PA branches or predominantly distal PA bed involvement [90–92]. Chest computed tomography is an important tool for the timely diagnosis of such a formidable complication of balloon pulmonary angioplasty (BPA) as reperfusion pulmonary edema [93].

Subtraction computed tomography pulmonary angiography provides additional information in the form of iodine maps, which reflect pulmonary tissue perfusion, increasing the diagnostic accuracy of CTEPH [90–92]. These methods are increasingly used in scientific research, but the diagnostic value of iodine maps in evaluating PH patients has not yet been established.

[6, 15, 16, 38, 48].

ESC IC (LoE C, GoR 5)

Comment. Computed tomography pulmonary angiography can also be used to detect other cardiovascular anomalies, including intracardiac shunts, anomalous pulmonary venous drainage, patent ductus arteriosus, and pulmonary arteriovenous malformations [16, 47, 48].

Magnetic resonance imaging of the heart and great vessels

ESC IC (RR S, ELD 5)

Comment. Cardiac and great vessel magnetic resonance imaging (MRI) provides an accurate and reproducible assessment of atrial and ventricular size, morphology, and function [94-100]. Special pulse sequences and additional image processing also allow for the evaluation of LV and RV strain parameters. This method does not involve ionizing radiation, which is important when examining children and young adults. Special pulse sequences and additional image processing allow the assessment of LV and RV myocardial deformation parameters. Cardiac and great vessel MRI can determine blood flow volume in the pulmonary artery, aorta, and venae cavae, enabling the calculation of RV stroke volume, the magnitude of intracardiac shunting, and retrograde flow volume. The ability to perform contrast-enhanced magnetic resonance angiography (single region) of the pulmonary arteries, evaluate pulmonary perfusion and myocardial viability using late gadolinium enhancement, allows comprehensive information about the heart and lungs to be obtained in a single examination. In patients with suspected congenital heart disease, cardiac MRI can be a useful modality when echocardiography and CT results are ambiguous. Contrast-enhanced magnetic resonance angiography (single region) holds promise for studying the vascular bed in patients with suspected CTEPH, particularly in pregnant women with suspected chronic thrombosis, young patients, or those with contraindications to iodine-containing compounds (125I).

Abdominal ultrasound

ESC IC (LoE C, GoR 5)

Comment. Abdominal ultrasound should be part of the comprehensive diagnostic evaluation of patients with newly diagnosed PH, particularly when liver disease is suspected. The primary objective is to detect liver pathology and/or portal hypertension or portacaval shunting (Abernethy malformation). With the progression of PH, patients may develop secondary hepatic and renal dysfunction [101, 102]. When ultrasound results are inconclusive, abdominal MRI, contrast-enhanced abdominal MRI, abdominal CT, or contrast-enhanced bolus abdominal CT are used.

ESC IIIC (LoE C, GoR 53)

6-minute walk test

• In all patients with PH, it is recommended to perform the 6-minute walk test to assess physical performance as part of the initial evaluation, upon hospital admission, and during follow-up every 6–12 months [6, 15, 16, 44, 48, 99].

ESC IC (LoE C, GoR 5)

Comment. The 6-minute walk test (6MWT) is the simplest method for assessing patients' physical performance, supplemented by the Borg dyspnea scale and pulse oximetry at rest and at the end of the test [15, 16, 49]. The 6MWT distance served as the primary endpoint in most randomized controlled trials investigating the efficacy of PAH-specific therapy [6, 12, 103]. However, a meta-analysis of 22 randomized controlled trials did not reveal a significant correlation between the improvement in 6MWT distance and long-term patient prognosis, including all-cause mortality, need for hospitalization due to PH worsening, or lung/heart-lung transplantation [104].

Cardiopulmonary exercise testing (Ergospirometry)

ESC IIaC (LoE C, GoR 5)

Comment. Cardiopulmonary exercise testing is an essential tool for assessing the pathophysiological mechanisms leading to reduced exercise tolerance [105-107]. Quantitative assessment of oxygen consumption during CPET remains an integrative parameter reflecting the functional state and compensatory reserves of the cardiovascular, pulmonary, and muscular systems. PAH patients exhibit a typical pattern characterized by a low end-tidal carbon dioxide partial pressure (PETCO2), a high ventilatory equivalent for carbon dioxide (VE/VCO2), a low oxygen pulse (VO2/HR), and low peak oxygen consumption (VO2peak) [105, 106]. It is believed that a normal VO2peak value allows the diagnosis of PAH to be excluded [107]. Detecting a PAH-like pattern in patients with COPD or left heart disease indicates pulmonary vascular disease [108].

Transvenous cardiac catheterization

ESC IC (LoE C, GoR 5)

ESC IC (LoE C, GoR 4)

Comment. RHC makes it possible to verify the diagnosis, assess patient severity, and determine disease prognosis, serving as the "gold standard" for PH diagnosis [49, 52]. Due to the complexity of the procedure and potential patient risks associated with it, RHC must be performed in expert centers [109]. Although RHC is an invasive procedure, the risk of serious complications when performed in expert centers is quite low (procedure-related mortality is 0.055%). The presence of a mass, thrombus, any implanted devices in the right heart chambers, acute infection, or unexplained fever are contraindications to RHC. The risk-benefit ratio must be evaluated individually prior to each procedure. The most dangerous complication of RHC is pulmonary artery perforation.

The interpretation of RHC results must be carried out in the context of the clinical picture and data obtained from other diagnostic studies, particularly echocardiography. Invasive diagnostics is performed to confirm the diagnosis of PAH, assess the severity of hemodynamic impairment, and conduct a vasoreactivity test in patients with IPAH, HPAH, or drug/toxin-induced PAH to resolve the choice of disease-modifying therapy and evaluate its efficacy [12, 110].

ESC IC (LoE C, GoR 5)

Comment. RHC is performed in the supine position with continuous monitoring of basic physiological parameters. The external pressure transducer must be zeroed with the patient in the supine position at the midthoracic line level, which is calculated as half the distance between the anterior chest wall and the bed surface and corresponds to the left atrial level in most patients [111]. Among the available venous access options, the antecubital approach appears to be the safest [112].

For a comprehensive hemodynamic assessment, the following parameters must be measured: mean RAP, PAP (systolic, diastolic, mean), PAWP, cardiac output (CO) (assessed by thermodilution or the Fick method in the presence of systemic-to-pulmonary shunts), cardiac index (CI), stroke volume, pulmonary and systemic vascular resistance, arterial and mixed venous oxygen saturation, as well as superior vena cava oxygen saturation to rule out systemic-to-pulmonary shunts (Table 6). CI must be measured by thermodilution or the direct/indirect Fick method [12, 113, 114].

Table 6. Hemodynamic parameters obtained during RHC [12]

The following formulas are used for calculated parameters:

1. Pulmonary vascular resistance (PVR): (mPAP - PAWP) / CO

2. Total pulmonary resistance: mPAP / CO

3. Pulmonary artery compliance: SV / (sPAP - dPAP) [12].

The thermodilution method is the most widely used in clinical practice due to its simplicity and rapid execution; however, it often demonstrates significant error in PH patients with low CO, severe tricuspid regurgitation, pulmonary valve regurgitation, or intracardiac shunts in congenital heart disease (CHD). Errors in CO measurement in these cases are due to conditions where the blood temperature recorded by the sensor returns to baseline faster, mimicking a high CO. Nevertheless, thermodilution currently remains the main method for measuring CO. The direct Fick method requires direct measurement of oxygen consumption, which is rarely available in routine practice. The indirect Fick method uses the predicted oxygen consumption calculated by software based on the patient's height and weight. This approach is acceptable, but the reliability of the method is somewhat reduced in this case [113–115].

All measurements, including PAWP, should be performed at the end of normal expiration (without breath-holding maneuvers). The greatest technical complexity and value during right heart catheterization (RHC) is the determination of PAWP, which reflects the pressure in the post-capillary pulmonary bed. Normal PAWP ranges from 6 to 12 mm Hg. A PAWP level >15 mm Hg is considered a threshold value indicating left heart disease of various etiologies with elevated pulmonary venous pressure. To measure central hemodynamic parameters, and PAWP in particular, a multipurpose Swan-Ganz catheter with a balloon-tipped end is used. The balloon allows the catheter to be advanced with the blood flow into the PA until it wedges in the small branches of the vascular bed, after which post-capillary pressure is recorded via the distal port of the catheter [115]. In patients with significant changes in intrathoracic pressure during the respiratory cycle (e.g., in COPD, obesity, or during exercise testing), it is advisable to average the data over at least three to four respiratory cycles.

ESC IIaC (LoE C, GoR 5)

Comment. PAWP measurement results are affected by intrathoracic pressure fluctuations during the respiratory cycle, which can be especially pronounced in patients with concomitant lung diseases or inadequate positioning of the Swan-Ganz catheter in marked PA dilatation. Therefore, if there is uncertainty regarding measurement accuracy, retrograde left heart catheterization with left ventricular end-diastolic pressure measurement or a fluid challenge test should be considered [49, 116, 117].

ESC IC (LoE C, GoR 5)

Comment. During RHC, blood samples must be drawn from the arterial bed (from a peripheral artery or left heart chambers), the right atrium, and mixed venous blood (from the PA) with blood gas analysis while breathing ambient air and without oxygen inhalation. If anomalous pulmonary venous drainage is suspected, additional blood samples for oximetry should be drawn from the superior and inferior vena cava. SvO2 > 75% increases the likelihood of a left-to-right shunt and CHD in the patient [118, 119].

ESC IC (LoE C, GoR 5)

ESC IIbC (Level of Evidence C, Level of Certainty 5)

ESC IIaC (LoE C, GoR IIa)

Vasoreactivity testing during transvenous cardiac catheterization

ESC IC (LoE C, GoR 4)

ESC IC (LoE C, GoR 4)

Comment. Criteria for a positive vasoreactivity test are achieved in no more than 10% of IPAH patients [120]. According to the Russian registry, the proportion of IPAH patients with a positive vasoreactivity test was 18% [17]. If the vasoreactivity test is negative or cannot be performed, CCB therapy is not indicated.

ESC IC (LoE C, GoR 5)

• When performing a vasoreactivity test in patients with idiopathic, heritable PAH, drug- or toxin-induced PAH, it is recommended to use inhaled nitric oxide or #iloprost [12, 15, 16, 336, 337].

ESC IC (LoE C, GoR 5)

Comment. Inhaled NO or inhaled iloprost is recommended as a vasodilator during the vasoreactivity test [120, 121].

• Performing a vasoreactivity test during RHC is not recommended in patients with associated forms of PAH (except for the group with idiopathic, heritable PAH, drug- or toxin-induced PAH), as well as in PH of other etiologies [6, 12, 15, 16, 122].

ESC IIIC (LoE C, GoR III)

• When conducting a vasoreactivity test in patients with idiopathic, heritable PAH, drug- or toxin-induced PAH, it is not recommended to use calcium channel blockers and oxygen [6, 12, 15, 16].

ESC IIIC (Level of Evidence C, Level of Certainty 5)

Fluid challenge test during right heart catheterization

• When evaluating patients with pre-capillary pulmonary hypertension and suspected post-capillary component, a fluid challenge test should be considered on an individual basis [6, 12, 116].

ESC IIbC (Level of Evidence C, Level of Certainty 5)

Comment. The fluid challenge test allows the diagnosis of left ventricular diastolic dysfunction in patients with PAWP <15 mm Hg in the presence of objective data indicating left heart disease. In patients with left heart disease, PAWP may drop below 15 mm Hg while on diuretics. To perform differential diagnosis between PAH and PH due to LV diastolic dysfunction, a fluid challenge test is used by rapidly administering (5–10 minutes) 500 mL of 0.9% sodium chloride solution** with repeated PAWP measurement. An increase in PAWP >18 mm Hg indicates HFpEF [116]. However, there is currently no compelling evidence confirming the safety and diagnostic value of this approach, which limits its routine use.

Selective pulmonary angiography

ESC IIaC (LoE C, GoR 5)

Comment. Selective pulmonary angiography (pulmonary angiography) during RHC is a mandatory step in the invasive examination to determine the lesion type and decide on further patient management. Selective pulmonary angiography should be performed sequentially in the anteroposterior and lateral projections in digital subtraction mode, which allows for assessing the presence of reduced peripheral perfusion zones, as well as the extent and type of lesion (proximal or distal) [15, 16, 38, 123]. Selective pulmonary angiography is necessary to visualize pulmonary arteriovenous malformations and certain congenital heart diseases (patent ductus arteriosus, anomalous pulmonary venous drainage) to discuss the possibility of surgical treatment [45, 48, 124].

Coronary angiography

ESC IIaB (CEN C, LOR 5)

Polysomnography and cardiorespiratory monitoring

RSC IIaB (Reliability of Evidence C, Level of Evidence 5)

Comment. The prevalence of nocturnal hypoxemia and sleep-disordered breathing among PAH patients reaches 89%, which emphasizes the importance of diagnosing and correcting these conditions [49, 125]. In patients with obesity hypoventilation syndrome (Pickwickian syndrome) and a combination of COPD with obstructive sleep apnea syndrome, PH is common (Group III) and is typically associated with RV dysfunction and a poor prognosis. In this patient subgroup, positive airway pressure therapy is effective, allowing in some cases to almost normalize pulmonary circulation hemodynamics [125, 126].

2.5 Other Procedures

2.5.1 Genetic testing

• In patients with IPAH, HPAH, PAH associated with appetite suppressant intake [anorectogens], as well as in asymptomatic first-degree relatives of PAH patients with identified mutations, gene identification via polymerase chain reaction [genetic testing] should be considered on an individual basis [6, 12, 15].

RSC IIaB (Reliability of Evidence C, Level of Evidence 5)

Comment. Given the low availability for PAH patients in our country, genetic testing is considered as an additional diagnostic method. As part of genetic counseling, gene identification via polymerase chain reaction is performed—screening for BMPR2, ACVRL1, ENG mutations and rarer mutations (KCNK3, CAV1) [41, 42]. Patients with sporadic or familial forms of PVOD/PCH should be screened for EIF2AK4 mutations. Detecting a biallelic EIF2AK4 mutation makes it possible to confirm the diagnosis of PVOD/PCH without histological examination [93].

Due to the potential impact of test results on the patient's psychological state, counseling is conducted by a multidisciplinary team including a PH specialist, medical geneticist, and medical psychologist. All patients with sporadic (IPAH) and familial forms of PAH, as well as PAH associated with appetite suppressant intake [anorectics], must be informed about the possibility of an inherited disease and the increased risk of PAH development in family members if a mutation is carried [6, 12, 41]. If gene identification via polymerase chain reaction [genetic testing] is not feasible, family members must be informed about the early signs and symptoms of PAH for timely diagnosis [15].

2.5.2 Diagnostic algorithm

The evaluation algorithm for patients with dyspnea and other symptoms/signs suggesting PH includes an initial assessment at the primary care level to select patients for specialized diagnostic workup at an expert center (Figure 1 (Appendix B)). Russian experts adapted the diagnostic algorithm of the 2022 ESC/ERS guidelines taking into account the specifics of clinical practice in our country. Patients with a high risk of PAH (CTD, CHD, portal hypertension, HIV infection) or CTEPH (prior PE, presence of risk factors), combined with a intermediate/high probability of PH on Echocardiography, should be immediately referred to an expert center [16, 17].

To improve the early diagnosis of PAH and CTEPH as diseases with an extremely unfavorable prognosis, a comprehensive approach is applied: (1) screening in asymptomatic high-risk groups, including patients with SSc (prevalence: 5–19%), BMPR2 mutation carriers (14–42%), close relatives of patients with HPAH, and patients undergoing evaluation before liver transplantation (2–9%) [12]; (2) early detection in symptomatic patients within risk groups: portal hypertension [127], HIV infection (0.5%) [128], CTD without SSc where low PAH prevalence rates are noted, which justifies the absence of a need for screening in asymptomatic patients [129].

Systemic sclerosis

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. Risk factors for PAH in SSc include: (1) clinical and demographic factors (dyspnea, skin dryness, Raynaud's phenomenon, digital ulcers, older age, male sex); (2) examination findings (elevated antinuclear antibody titer, mild interstitial lung disease (ILD), decreased DLCO, increased forced vital capacity (FVC) to DLCO ratio, or blood N-terminal pro-brain natriuretic peptide (NT-proBNP) level testing [130, 131].

• In adult patients with a systemic sclerosis duration > 3 years, with FVC ≥40% and DLCO <60%, the DETECT algorithm is recommended to detect asymptomatic PAH [132].

ESC IB (CQR A, LOR 2)

• In patients with SSc, the risk of PAH should be evaluated based on an analysis of dyspnea severity, echocardiography data, pulmonary function testing (spirometry), and blood N-terminal pro-brain natriuretic peptide (NT-proBNP) level testing [130, 131].

ESC IIaB (LoE C, GoE 5)

Comment. Several screening algorithms have been developed using a combination of clinical signs, echocardiography data, pulmonary function testing, and blood N-terminal pro-brain natriuretic peptide (NT-proBNP) level testing to select SSc patients requiring RHC [132]. Screening programs make it possible to detect PAH at early stages of the disease with less pronounced hemodynamic disorders and achieve better patient survival [133, 134]. The use of a model including clinical symptoms, DLCO, and NT-proBNP level allows the identification of patients with an extremely low probability of PAH who do not require further examination [12].

• In patients with mixed connective tissue disease, annual assessment of the risk of developing PAH should be considered [12].

ESC IIaC (Level of Evidence C, Grade of Recommendation 5)

PAH risk groups

ESC IB (LoE C, GoR 5)

Comment. Among mutations associated with the development of PAH, screening experience is generally limited to BMPR2 mutation carriers with a lifetime risk of developing PAH of 20%, with higher penetrance in female carriers (42%) compared to males (14%) [135]. Asymptomatic relatives with identified PAH-causing mutations are most commonly offered annual echocardiography for screening purposes [25, 26]. The screening algorithm includes ECG, blood N-terminal pro-brain natriuretic peptide (NT-proBNP) level testing, pulmonary diffusing capacity testing, echocardiography, cardiopulmonary exercise testing (CPET), and, if necessary, RHC [136].

ESC IB (Level of Evidence C, Grade of Recommendation 5)

• In patients referred for liver transplantation, echocardiography is recommended for PH screening [16, 17].

ESC IC (Level of Evidence C, Grade of Recommendation 4)

• In patients with symptoms of PH in the presence of CTD, portal hypertension, or HIV infection, echocardiography, blood N-terminal pro-brain natriuretic peptide (NT-proBNP) level testing, pulmonary function testing, and/or cardiopulmonary exercise testing should be considered for PAH screening [12].

ESC IIaB (Level of Evidence C, Quality of Evidence 5)

Comment. Screening is performed to identify asymptomatic individuals at risk for PAH. Tools used for PH screening include ECG and echocardiography [12]. In CTD without SSc, the FVC/DLCO ratio and cardiopulmonary exercise testing data may be used [12, 129]. Among laboratory tests, blood N-terminal pro-brain natriuretic peptide (NT-proBNP) level testing should be used [12].

Chronic thromboembolic pulmonary hypertension

• Patients with persistent or newly onset dyspnea, or worsening exercise tolerance after a history of PE, are recommended to undergo further diagnostic evaluation to rule out chronic thromboembolic disease or chronic thromboembolic pulmonary hypertension [12, 16, 123].

ESC IC (LoE C, GoR 5)

Comment. Approaches to early detection of CTEPH after acute PE are based on identifying patients at high risk of developing the disease [38]. Further diagnostic evaluation is advisable in asymptomatic patients with CTEPH risk factors 3–6 months after PE [44, 123].

ESC IC (LoE C, GoR 5)

Comment. In patients with persistent or newly onset dyspnea after PE, EchoCG is used to assess PH probability and ventilation/perfusion lung scintigraphy is used to detect persistent perfusion defects. When CTEPH is suspected, EchoCG is the first-line method for symptomatic patients [52, 125]. Persistent perfusion defects after acute PE remain in almost 50% of patients, but their clinical significance remains unclear [12, 38, 136]. Symptomatic patients with confirmed thrombotic pulmonary artery obstruction are diagnosed with CTEPH or chronic thromboembolic disease in the absence of PH [85].

Evidence is emerging regarding the potential use of computed tomography pulmonary angiography, lung MRI, and chest MRI. Leiden criteria can be used to rule out CTEPH in order to justify further evaluation [38, 137]. Cardiopulmonary exercise testing allows for the detection of characteristic signs of exercise capacity limitation. For early detection of CTEPH, evaluating symptomatic patients 3–6 months after acute PE is optimal, which coincides with the routine assessment after the initiation of anticoagulant therapy, although earlier evaluation may also be considered in patients with clinical deterioration [38]. Symptomatic patients with PH after acute PE should undergo comprehensive screening programs, although to date the optimal strategy remains uncertain, requiring international multicenter studies.

[12].

Algorithm

Step 1 (Suspicion). Patients with suspected PH are consulted by general practitioners, general physicians, cardiologists, pulmonologists, and rheumatologists. The initial evaluation includes taking a medical (including family) history, a thorough physical examination (including peripheral blood pressure measurement, heart rate, and pulse oximetry), resting ECG, targeted chest radiography, unforced spirometry, comprehensive abdominal ultrasound, and laboratory tests.

PH may be detected incidentally during transthoracic EchoCG performed for other indications. As a primary screening tool, EchoCG helps determine the probability of PH. Patients with risk factors for PAH or CTEPH and low PH probability are indicated for outpatient follow-up at their place of residence with periodic EchoCG. In patients without significant PAH/CTEPH risk factors and with intermediate or high PH probability, evaluation should be continued locally. Patients with PAH risk factors and intermediate or high PH probability should be immediately referred to an expert center for further evaluation, including based on a telemedicine consultation conclusion from an expert center specialist.

Step 2 (Detection). The second stage includes conventional evaluation of the lungs and heart. EchoCG and cardiopulmonary exercise testing allow for the diagnosis of left heart disease, mitral/aortic valve pathology (Group II). Targeted chest radiography, diffusing capacity testing, unforced spirometry, and contrast-enhanced chest computed tomography reveal lung diseases (Group III). For CTEPH screening, perfusion lung scintigraphy and ventilation lung scintigraphy are performed. Patients with perfusion defects in the absence of ventilation abnormalities and/or lung parenchyma changes on chest CT should be directly referred to an expert center for further evaluation regarding CTEPH and operability assessment [38].

Step 3 (Verification). Patients should be referred to an expert center for further evaluation in the following situations: (1) intermediate/high probability of PH; (2) history of PAH or PE risk factors. During patient monitoring, signs of clinical deterioration associated with worse outcomes and requiring urgent intervention should be identified—rapid progression of symptoms (WHO FC III/IV), clinical signs of RV dysfunction, syncope, signs of low cardiac output, severe arrhythmias, and hemodynamic instability or deterioration (hypotension, tachycardia).

During comprehensive evaluation at the expert center, differential diagnosis is performed to determine the clinical group of PH, as well as invasive evaluation to determine the hemodynamic profile of PH and, if necessary, a vasoreactivity test during right heart catheterization [15, 16, 18]. The PH expert center analyzes the results of previously performed studies, and key studies should be repeated if necessary.

Patients with precapillary PH undergo additional evaluation to verify Group I (PAH) and Group V (other rare conditions). In complex clinical situations and when assessing operability in patients with congenital heart disease and CTEPH, a multidisciplinary team conference including radiologists and cardiovascular surgeons must be held [44, 48].

2.5.3 Assessment of disease severity and prognosis

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. Based on a comprehensive evaluation using a multifactorial stratification model, all PAH patients should be assigned a risk status of low, intermediate, or high corresponding to an estimated 1-year mortality of <5%, 5–20%, and >20%, respectively (Table 22. Appendix G1) [12]. Data from modern registries have shown that observed 1-year mortality rates in the intermediate- and high-risk groups exceed those previously predicted [138, 139]. Low-risk criteria include WHO FC I or II with a 6-minute walk distance >440 m, right atrial pressure <8 mm Hg, and cardiac index ≥2.5 L/min/m² [10]. The intermediate-risk group is represented by WHO FC III patients with moderately reduced physical activity and signs of RV dysfunction without clinical manifestations of right ventricular heart failure. High mortality risk should be predicted in WHO FC III–IV patients with progressive PAH, manifestations of right ventricular heart failure, and secondary dysfunction of other organs. It is known that parameters may belong to different risk categories, which determines the choice of treatment strategy.

The 2022 ESC/ERS guidelines implement a repeat risk stratification approach in patients receiving PAH-specific therapy, taking into account the fact that 60–70% of patients remain at intermediate risk [12]. Identifying cohorts of intermediate-low and intermediate-high mortality risk patients allows international clinical practice to consider approaches to escalating specific therapy. In Russian practice, parenteral prostacyclin analogues have not yet been approved, which precludes the use of the proposed risk stratification algorithm to optimize therapy.

Clinical evaluation provides important information for determining PAH severity in diagnosed patients. During follow-up, the presence of syncope, hemoptysis, chest pain, and signs of right ventricular heart failure should be considered. Physical examination includes measuring peripheral blood pressure, heart rate, presence of cyanosis and jugular venous distention, edema, ascites, and pleural effusion. WHO functional class remains one of the most important predictors of survival in PAH patients both at diagnosis and during follow-up; its worsening requires further evaluation to identify the cause(s) of clinical deterioration [15, 16, 140, 141].

Although the 6MWT is the most accessible method for assessing physical performance in patients, data from 22 clinical studies reveal no reliable correlation between increased 6MWD and long-term patient prognosis, including all-cause mortality, hospitalizations for clinical deterioration of PAH, lung transplantation, or heart-lung transplantation [103]. At the same time, threshold values of 6MWD have been established that indicate the worst and best 1-year survival in patients with PAH: <165 m and >440 m, respectively [142]. Several studies have shown that serial assessment of heart rate and peripheral oxygen saturation via pulse oximetry during the test can improve the prognostic value of the method [142-144].

Quantitative assessment of oxygen consumption during cardiopulmonary exercise testing (CPET) remains the most accurate integrative parameter reflecting the functional state and compensatory reserves of the cardiovascular, pulmonary, and muscular systems, and can be used to assess PAH severity and prognosis [105-107]. CPET can be performed exclusively in expert centers, which limits its widespread use in routine practice.

Cardiac imaging plays an important role in the follow-up of patients with PAH. A number of echocardiographic and MRI parameters with prognostic significance allow for dynamic monitoring of RV function (Table 16. Appendix B1). For risk stratification in the cardiac MRI protocol, the following parameters indicating low, intermediate, and high mortality risk should be used: RV ejection fraction >54%; 37–54%; <37%, respectively; stroke index >40 mL/m2; 26–40 mL/m2; <26 mL/m2, respectively; RV end-systolic volume index <42 mL/m2; 42–54 mL/m2; >54 mL/m2, respectively [12]. Unlike echocardiography, cardiac and great vessel MRI data can only be evaluated in expert centers, which limits the widespread use of the method in routine practice.

The strongest prognostic significance in patients with PAH is held by hemodynamic parameters: right atrial pressure (RAP), cardiac index (CI), and SvO₂ [6, 12, 141, 142]. RAP provides an indirect indication of the severity of RV dysfunction. The CI value depends on stroke volume and reflects the amount of oxygenated blood returning from the lungs to the left chambers of the heart. Mean pulmonary arterial pressure (mPAP) is not included in the list of prognostically significant hemodynamic parameters because its decrease can be a consequence of RV dysfunction. Clinical improvement in a patient with PAH very rarely leads to normalization or reduction of mPAP. Exceptions include patients with a positive vasoreactive test receiving calcium channel blocker therapy [120]. Among biomarkers, the most important is the measurement of blood N-terminal pro-brain natriuretic peptide (NT-proBNP), the level of which correlates with hemodynamic parameters and structural-functional changes of the RV in patients with PAH [6, 12, 15, 16].

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. A non-invasive risk assessment method based on three criteria—WHO FC I–II, 6MWD >440 m, and NT-proBNP <300 ng/L / BNP <50 ng/L—is used to identify PAH patients who achieve and maintain a very low-risk status [140, 145]. The number of low-risk criteria accurately predicted event-free survival and identified a cohort of patients with low risk of all-cause mortality according to the French registry and treatment-naïve patients in the COMPERA registry. Patients with newly diagnosed PAH who met all three low-risk criteria showed the most favorable long-term prognosis. During follow-up, additional cardiac imaging and hemodynamic parameters should be evaluated if risk refinement is necessary.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The modern management strategy for patients with PAH should distinguish between general recommendations, supportive therapy, and targeted therapy [6, 12, 15, 16]. While supportive therapy drugs do not affect survival in patients with PAH, pathogenetic drugs help increase patient life expectancy, reduce the need for hospitalization, and prolong the time to clinical deterioration and transplantation [24-26, 47].

• The initiation of PAH-specific therapy is recommended for patients with PAH with mPAP ≥25 mm Hg and PVR ≥3 Wood units, in accordance with the evidence base for drug use [12, 15, 16].

RRC IA (Reliability of Evidence Level C, Consistency of Evidence Level 5)

Comment. According to current criteria, the diagnosis of PAH is established at mPAP >20 mm Hg and PVR >2 Wood units [12]. However, the efficacy of drugs approved for PAH treatment has currently been proven exclusively in patients with mPAP ≥25 mm Hg and PVR ≥3 Wood units. Patients at high risk for developing PAH, such as those with systemic sclerosis (SSc) or first-degree relatives of patients with heritable PAH (HPAH), should be referred to a PH expert center for evaluation aimed at early PH diagnosis and selection of optimal treatment tactics. Patients with mPAP of 21–24 mm Hg and PVR of 2.1 to 2.9 Wood units who present with PH symptoms should undergo regular follow-up including echocardiography and 6MWT; the decision to perform right heart catheterization is made on an individual basis.

• As a therapeutic goal for patients with PAH, it is recommended to achieve and maintain a low-risk profile through ongoing targeted therapy.

[12, 15, 16].

ESC IB (Level of Evidence C, Grade of Recommendation 5)

• In patients with PAH of established etiology and concomitant diseases, treatment optimization should be considered on an individual basis, taking into account that achieving a low-risk profile is not always possible [12].

ESC IIaB (LoE C, GoE 5)

3.1. General recommendations

Upon establishing the diagnosis of PAH and during patient follow-up, discussions should cover individual daily physical activity regimens, family planning, contraception and postmenopausal hormone replacement therapy, preparation for elective surgical interventions, prevention of infectious diseases, psychosocial support, travel, medication adherence, and the need for follow-up by specialists at a PH expert center [6, 12, 49, 125]. Approximately 35% of patients with PAH develop anxiety states, panic attacks, and depression, which are closely interrelated with the severity of PAH symptoms and physical limitations [15, 154]. Patients with PAH and their families should be advised to seek psychological support and actively participate in patient organizations, which can positively influence adaptation through constructive collaboration between the patient and the physician [6, 15].

Physical activity and rehabilitation

ESC IA (Reliability of Evidence Level C, Consistency of Evidence Level 5)

Comment. In recent years, clinical studies have demonstrated the efficacy of physical rehabilitation programs—including aerobic exercise, strength training, respiratory gymnastics, and yoga elements—on the physical performance of PAH patients, with a reliable increase in 6MWD, peak VO₂, and quality of life parameters [150-152]. Participation in training programs should be offered to stable patients receiving PAH-specific therapy at expert centers with experience in managing this patient population [6, 12, 15]. As a rule, physical rehabilitation programs are conducted in a hospital setting, which ensures safety. The best results in clinical studies were achieved with training programs lasting two hours a day, five times a week, combining endurance aerobic exercises on a stationary cycle or treadmill, low-weight strength training, and respiratory muscle exercises [150]. A prospective RCT demonstrated improved hemodynamic parameters in patients with PAH and inoperable chronic thromboembolic pulmonary hypertension (CTEPH), manifesting as a significant increase in CI, and a reduction in mPAP and PVR compared to the control group [152].

In our country, physical rehabilitation protocols for patients with PAH are currently under development.

• Patients with PAH are not recommended to engage in excessive physical activity that provokes severe dyspnea, dizziness, syncope, chest pain, or fatigue [6, 15, 16, 47, 48].

ESC IIIC (CGR C, LOR 5)

Comment. Participation in training programs is contraindicated for PAH patients presenting with chest pain, palpitations, exertional presyncope and syncope, symptoms of right ventricular HF, or recent hospitalization or evaluation for clinical worsening [151].

Elective surgical interventions

RSC IC (LoE C, GoR 5)

• For elective surgical procedures, regional anesthesia, including epidural anesthesia, should be preferred in PAH patients to prevent complications [6, 15, 16].

ESC IIaC (LoE C, GoR 5)

• When planning any surgical procedure in PAH patients, performing it in a PH expert center may be considered to minimize perioperative risks [12, 330].

RSC IIbC (LoE C, GoR 5)

Comment. Surgical procedures in PAH patients are associated with an increased risk of right ventricular HF and mortality related to disease severity [6, 12, 152]. In a prospective international registry including 114 PAH patients undergoing non-cardiac and non-obstetric procedures, perioperative mortality was 2% and 15% for elective and emergency procedures, respectively [153]. The highest risks and challenges in perioperative management are observed in patients with newly diagnosed PH at the time of surgery. Whenever possible, elective surgery should be postponed and the patient referred to an expert center for a thorough evaluation including RHC and, if necessary, a vasoreactivity test, followed by optimization of PAH-specific therapy [6, 15]. The patient's hemodynamic and functional status should be assessed, and the scope of surgery, anesthesia management, and the potential use of nitric oxide, iloprost, and extracorporeal membrane oxygenation (ECMO) should be discussed in detail. All evaluations and optimization of PAH therapy should ideally be completed no later than two weeks prior to the scheduled surgery [152]. When planning surgery, the patient should be informed about potential perioperative risks associated with the nature of the surgery and anesthesia, a possible worsening of the PAH course, and the risk of mortality.

• In PAH patients, it is recommended to consider a mini-laparotomy approach to prevent complications [15, 154].

RSC IIbC (LoE C, GoR 4)

Comment. In PAH patients, the creation of pneumoperitoneum or diaphragmatic compression can impair pulmonary ventilation and significantly increase RV afterload due to pulmonary hypertensive crisis [152, 154].

Infection prevention

• For PAH patients, it is recommended to consider vaccination against influenza virus, pneumococcal infection, and SARS-CoV-2 to prevent disease progression triggered by intercurrent infection [6, 12, 15, 16].

ESC IIaC (LoE C, GoR 5)

Comment. In PAH patients, pneumonia accounted for 7% of deaths [6]. Despite the lack of RCTs, vaccination against influenza, pneumococcus, and SARS-CoV-2 should be administered [6, 12]. The exceptions are patients with CTD and HIV infection, in whom the decision regarding vaccination should be made taking into account the activity of the underlying disease and ongoing immunosuppressive therapy.

Treatment adherence

Factors influencing medication adherence in PH patients include demographic characteristics, cognitive impairment, comorbidities, psychological status, polypharmacy, adverse drug effects, health literacy, and understanding of treatment goals [15, 155, 156]. Patients should be informed about the goals of therapy, the mechanism of action of the main drug classes, treatment options, potential side effects, the consequences of non-adherence, and the necessity of reporting any changes in their medication regimen to their attending physician. Physician-related factors include experience, knowledge of guidelines, and a multidisciplinary approach; healthcare system-related factors include working conditions, drug availability, and treatment costs [12, 156].

Travel

• Oxygen therapy during air travel is recommended to be considered in patients with WHO functional class III–IV PH who have an arterial oxygen tension <8 kPa (60 mm Hg) at rest or a blood oxygen saturation <92% by pulse oximetry while breathing ambient air, for the prevention of complications [6, 12, 15, 16].

ESC IIaC (LoE C, GoR 5)

Comment. It has been shown that short-term (less than 24 hours) normobaric hypoxemia is generally well tolerated clinically by stable PAH patients without baseline hypoxemia at sea level [125, 157]. Patients who use oxygen are advised to use oxygen supplementation during air travel if PaO₂ < 8 kPa (<60 mm Hg) or SaO₂ < 92% (at rest breathing ambient air) [6, 12]. Since the effects of moderate to prolonged (hours to days) hypoxemia in PAH are not sufficiently studied, patients should be advised to avoid staying at altitudes above 1,500 m without supplemental oxygen [125]. An oxygen flow rate of 2 L/min increases the oxygen concentration in the inhaled air to sea-level values. Patients with a need for long-term oxygen therapy may require higher oxygen flow rates during air travel [12, 158]. Patients should travel with written documentation of their PAH diagnosis, current therapy, and contact information for the nearest PH center [6, 12, 15].

3.2. Pharmacological treatment

Pharmacotherapy in PH patients includes supportive therapy (oral anticoagulants [ATC antithrombotic agents], diuretics, cardiac glycosides, oxygen therapy) and PAH-specific drugs: CCBs, endothelin receptor antagonists (ATC antihypertensives for pulmonary arterial hypertension, ERAs), phosphodiesterase type 5 inhibitors (ATC drugs used in erectile dysfunction, PDE5is), soluble guanylate cyclase stimulators (ATC antihypertensives for pulmonary arterial hypertension, sGC stimulators), prostacyclin analogues—prostanoids (ATC antiplatelet agents excluding heparin), IP receptor agonists (ATC antiplatelet agents excluding heparin) [6, 12, 15, 16].

3.2.1. Supportive therapy

The effect of supportive PAH therapy on patient survival has not been studied in RCTs. However, routine practice has demonstrated the efficacy of oxygen therapy in comorbid pulmonary conditions or intercurrent diseases, as well as the effect of diuretics on symptoms of right ventricular HF [6, 31, 49, 125].

• In patients with IPAH, APAH, and PAH, the prescription of oral anticoagulants (ATC antithrombotic agents) may be considered for the prevention of thrombotic complications [6, 12, 161, 59, 159–162].

ESC IIbC (LoE B, GoR 2)

Comment. The rationale for prescribing anticoagulant therapy in PAH is the detection of in situ organized thrombi in small pulmonary arteries in histopathological lung samples from IPAH patients [49, 159]. In congenital heart disease-associated PAH (PAH-CHD), thrombosis of aneurysms of the pulmonary trunk and branches is observed [45, 118, 160]. Coagulation and fibrinolytic abnormalities, indicating a procoagulant state, have been described in PAH patients [6, 47].

There are no RCT data evaluating anticoagulant therapy in PAH. Two meta-analyses have shown that the use of anticoagulants may improve survival in patients with IPAH [161, 162]. According to the Russian registry, anticoagulant therapy is prescribed to 61.5% of PAH patients, including warfarin** (51.6%), low molecular weight heparins (ATC heparin group) (5.9%), and direct oral anticoagulants (ATC direct thrombin inhibitors, direct factor Xa inhibitors) (4.2%) [51].

• In patients with connective tissue disease-associated PAH, the prescription of antithrombotic agents may be considered on an individual basis in the presence of a prothrombotic tendency [6, 15, 16, 133].

ESC/RSC IIbC (LoE C, GoR 4)

Comment. Registry and meta-analysis data have shown that the administration of oral anticoagulants in systemic sclerosis-associated PAH is associated with an increased risk of bleeding [12, 47, 129].

ESC IIIC (Level of Evidence C, Level of Certainty 5)

Comment. Hypocoagulation due to impaired synthesis/degradation of clotting factors and thrombocytopenia is frequently detected in patients with portopulmonary hypertension [47, 49]. In patients with liver cirrhosis, bleeding sources may include esophageal varices and hemorrhoids. The efficacy and safety of coadministering antithrombotic agents and systemic antiviral drugs are poorly studied in patients with HIV infection [15].

ESC IIIC (LoE C, GoR 3)

Comment. Randomized controlled trials (RCTs) on the use of antithrombotic agents in patients with CHD-PAH are lacking. Anticoagulant therapy is associated with an increased risk of bleeding: patients with CHD exhibit impaired synthesis/degradation of clotting factors and thrombocytopenia. In patients with CHD, dilated bronchial arteries can be a source of bleeding. The administration of antithrombotic agents did not significantly affect the survival of patients with Eisenmenger syndrome [48, 165]. The administration of antithrombotic agents may be considered in the presence of arterial/venous thrombosis, atrial fibrillation/flutter, or right ventricular HF [6, 160, 161].

RSC IIIC (LoE C, GoR 5)

RSC IIIC (LoE C, GoR 5)

• Patients with PH are recommended therapy with loop diuretics in case of fluid retention or clinical manifestations of edema syndrome [6, 12, 15, 16].

ESC IC (LoE C, GoR 5)

Comment. Right ventricular HF is associated with fluid retention, decreased renal blood flow, and activation of the renin-angiotensin-aldosterone system [19, 49]. RCTs on the use of diuretics in PAH patients are lacking, but clinical experience demonstrates a clear improvement in symptoms when loop diuretics are administered to patients with congestive HF. It is advisable to combine loop diuretics (furosemide**, torasemide) with aldosterone antagonists (spironolactone**, eplerenone), and in cases of severe congestion, with carbonic anhydrase inhibitors (acetazolamide**) [16, 159, 163]. Patients receiving diuretic therapy should regularly undergo body weight measurement and urine output determination, blood pressure measurement, blood creatinine level testing, blood sodium level testing, blood potassium level testing, and blood chloride level testing. In conditions of severe systemic hypotension and anasarca, intravenous infusion of furosemide** under the control of blood pressure, central venous pressure, and hourly diuresis is advisable. If indicated, the administration of vasopressors under hemodynamic monitoring in an intensive care unit may be discussed.

ESC IC (LoE CA, GoR 5)

Comment. Oxygen therapy helps to reduce PVR, increase CI, and improve exercise tolerance in patients with PAH, although reliable data on a positive effect on the course of the disease are lacking. Most PAH patients in the absence of a patent foramen ovale, except for cases of CHD and pulmonary-systemic shunts, have mild arterial hypoxemia at rest. In patients with Eisenmenger syndrome, long-term oxygen therapy does not affect the natural course of PAH. Hypoxemia may be caused by concomitant pulmonary pathology, the treatment of which in combination with oxygen therapy favorably affects the course and exercise tolerance in PAH patients. The prescription of oxygen therapy may be considered to improve symptoms and reduce desaturation during exercise [6, 12, 159]. Nighttime oxygen therapy should be performed in patients with nocturnal desaturation ≤ 90% [125].

ESC IB (LoE C, GoR 5)

Comment. The efficacy of digoxin** in patients with PAH has been demonstrated in open-label, non-randomized studies. Its prescription allows for slowing the ventricular rate in PAH patients with tachy-form atrial fibrillation [12, 49].

ESC IIIC (Level of Evidence C, Level of Certainty 5)

Comment. Currently, there is no convincing evidence regarding the benefit and safety of the above-mentioned drug classes in patients with PAH. Prescription is considered in accordance with indications in the presence of concomitant pathology, taking into account the potential decrease in CO due to hypotension and bradycardia.

ESC IC (LoE C, GoR 5)

• In the absence of anemia, it is recommended to consider iron deficiency correction in patients with PAH [12].

ESC IIaC (LoE C, GoR 5)

Comment. In patients with PAH, iron deficiency is associated with impaired myocardial function, an increased risk of clinical worsening, and mortality regardless of the severity of anemia [12, 15]. Iron deficiency is established at a serum ferritin level <100 µg/L or 100–299 µg/L with transferrin saturation <20%. Iron deficiency states are detected in 43% of patients with IPAH, 46% of patients with CTD-associated PAH, and 56% of patients with Eisenmenger syndrome [12, 165]. Regular monitoring of iron status (serum iron level testing, blood ferritin level testing, transferrin iron saturation testing) is recommended in all PAH patients. RCTs comparing the efficacy of oral and intravenous iron preparations in patients with PAH are lacking. The efficacy of iron-containing preparations (ATC B03A) may be reduced in patients with PAH [166, 167].

• To prevent clinical deterioration in patients with PAH who develop atrial fibrillation, a rhythm control strategy with external electrical cardioversion (defibrillation) followed by amiodarone** administration should be considered [12, 15].

RSC IIaC (LOC C, LOE 5)

Comment. Supraventricular tachyarrhythmias and atrial fibrillation predominate in patients with PAH [6]. The development of atrial fibrillation/flutter leads to clinical deterioration, the development and decompensation of right ventricular HF, and is associated with an increased risk of mortality. Restoration of sinus rhythm helps to improve the clinical state, reduce NT-proBNP levels, and improve survival in patients with PAH [12]. Methods of sinus rhythm restoration depend on the nature of rhythm disturbances and the clinical condition of the patient. In patients with atrial flutter, radiofrequency ablation of arrhythmogenic zones of the cavotricuspid isthmus or modification of the atrioventricular junction in paroxysmal reciprocating AV nodal tachycardia should be considered. In patients with atrial fibrillation in PH, pulmonary vein radiofrequency ablation is not performed. In unstable hemodynamics, overdrive pacing, electrical and pharmacological cardioversion are performed. Following successful radiofrequency ablation of arrhythmogenic zones, patients generally do not require antiarrhythmic therapy; when other methods of sinus rhythm restoration are chosen, amiodarone** is prescribed [159.a.i.159, 168]. If sinus rhythm restoration is impossible, rate-control therapy is used.

3.2.2. Specific therapy

Modern PAH-specific therapy includes CCBs for the treatment of patients with IPAH, HPAH, drug-/toxin-induced PAH in the presence of a positive vasoreactivity test; in case of a negative vasoreactivity test or in patients with other forms of PAH, five classes of pathogenetic drugs that have proven efficacy and safety are used – ERA, phosphodiesterase type 5 inhibitors (PDE5i), sGC stimulators, prostacyclin (PC) analogues (prostanoids) (ATC, Antiplatelet agents other than heparin), PC receptor agonists [12, 15, 16].

ESC IC (LoE C, SoR 5)

Comment. CCB therapy has demonstrated efficacy in a small subgroup of PAH patients – IPAH, HPAH, and drug-associated PAH with a positive vasoreactivity test in the absence of right ventricular heart failure [120]. The choice of CCB depends on the baseline heart rate: in case of a tendency to sinus tachycardia, #diltiazem 240–360 mg should be prescribed; with a normal heart rate, #amlodipine 10–15 mg or #nifedipine 120–240 mg [16]. CCB therapy is initiated at the minimum dosage with gradual titration to the maximum dose under the control of blood pressure and tolerability (Table 12. Appendix A3). If administration of high doses of CCBs is not feasible, the immediate addition of other PAH-specific drugs should be considered [16].

ESC IIIC (CGR C, LOR 5)

ESC IIIC (C-V, LoE 5)

ESC IIIC (C-V, LoE 5)

ESC IC (C-V, LoE 5)

• In patients with a positive vasoreactivity test receiving CCBs who do not achieve near-normal hemodynamic parameters (mPAP <30 mmHg and PVR <4 Wood units) according to RHC and retain WHO FC III-IV, the continuation of CCB treatment in combination with an ERA, sGC stimulator, PDE5i, prostacyclin, or prostacyclin receptor agonist (ATC: antiplatelet agents except heparin) (PRA) should be considered [12, 15, 16].

ESC IIaC (LoE C, GoR 5)

Comment. 3–4 months after initiating CCB therapy, patients with a positive vasoreactivity test should achieve the aforementioned hemodynamic parameters according to RHC while maintaining WHO FC I-II [12]. Patients with long-term efficacy of CCBs are extremely rare and require careful monitoring for timely escalation of therapy by adding other PAH-specific medications [16].

Endothelin-1 (ET-1) is an endothelium-derived peptide that causes vasoconstriction and proliferation of vascular smooth muscle cells, as well as activation of extracellular matrix protein synthesis by fibroblasts upon binding to type A receptors (ETA) [169]. The effect of ET-1 on type B receptors (ETB) of endothelial cells stimulates vasodilation by enhancing pulmonary clearance and increasing the production of NO and PGI2. Currently, it has been proven that the clinical efficacy of ERAs with selective blockade of ETA receptors or non-selective blockade of both receptor types is comparable, and differences are determined by the pharmacokinetic profiles of the drugs [6, 15, 16, 170]. In the Russian Federation, three ERAs are approved for the treatment of PAH: the selective ETA receptor antagonist ambrisentan**, and the non-selective ERAs bosentan** and macitentan** (Table A3.1 (Appendix A3) [15].

RKO IB (C-V, LoE 5)

RSC IB (LoE B, GoR 2)

Comment. Before initiating treatment and during follow-up, it is recommended to perform monthly blood tests for aspartate aminotransferase and alanine aminotransferase activity due to the risk of hepatotoxicity, as well as a complete blood count due to the likelihood of decreased hemoglobin levels.

RKO IB (C-V, LoE 5)

Comment. ERAs are teratogenic and contraindicated during pregnancy [6, 15]. When prescribing bosentan**, dual contraception is required due to pharmacokinetic drug interactions with systemic hormonal contraceptives [12, 16].

Ambrisentan** is a non-sulfonamide, selective ETA receptor antagonist that has demonstrated efficacy in PAH patients regarding symptoms, exercise capacity, hemodynamic parameters, and time to clinical worsening in two placebo-controlled RCTs, ARIES-1 and ARIES-2 [49, 170]. The RCTs confirmed the efficacy of the drug in patients with IPAH, HPAH, and CTD-associated PAH with WHO FC II-III. When ambrisentan** was prescribed at daily doses of 5 and 10 mg, an increased incidence of peripheral edema was observed with a low probability of elevated liver transaminases (0.8–3%) [12, 169, 170].

ESC IA (C-V, LoE 5) for patients with WHO FC II-III

ESC IIbC (C-V, LoE 5) for patients with WHO FC IV

Bosentan** is a non-selective ERA blocking endothelin type A and B receptors, which has been shown to improve exercise tolerance, WHO FC, hemodynamic parameters, and time to clinical worsening in six RCTs (Study-351, BREATHE-1, BREATHE-2, BREATHE-5, EARLY, COMPASS-2) in patients with IPAH, CTD-associated PAH, and Eisenmenger syndrome [6, 16, 171]. In adults, bosentan** is prescribed at a dose of 62.5 mg twice daily, followed by an increase to 125 mg twice daily after 4 weeks upon reviewing laboratory test results. A dose-dependent increase in transaminase activity may be observed in 10% of patients (reversible after dose reduction or treatment cessation), which requires careful monthly monitoring of liver function tests – blood AST and ALT activity [172]. Inhibition of bile salt transport is considered the most likely mechanism for the elevation of liver enzymes [174]. Hemoglobin levels may decrease and peripheral edema may develop during bosentan** therapy [172].

A wide range of pharmacokinetic interactions between bosentan** and drugs metabolized in the liver via the CYP3A4 and CYP2C9 cytochrome systems should be considered. Bosentan** therapy decreases the efficacy of systemic hormonal contraceptives, necessitating dual methods of contraception, as well as warfarin**. Co-administration of bosentan** and sildenafil leads to a 50% decrease in the concentration of the latter and a 50% increase in the concentration of bosentan**, which increases the risk of hepatotoxicity [172].

ESC IA (C-V, LoE 5) for patients with WHO FC II-III

ESC IIbC (C-V, LoE 5) for patients with WHO FC IV

RSC I C (LoE C, GoR 5)

Macitentan** is a non-selective ERA with high tissue specificity that improves exercise capacity and reduces the risk of morbidity/mortality in PAH patients as assessed by a combined endpoint comprising time to the first event of PAH progression (clinical worsening, atrial septostomy, lung transplantation, need for parenteral prostacyclin analogues, or all-cause mortality) based on the results of a long-term multicenter double-blind placebo-controlled RCT SERAPHIN [50]. In PAH patients, a significant reduction in PVR and an increase in CI were revealed, and the efficacy of macitentan** therapy was proven regardless of prior PAH-specific therapy with PDE5 inhibitors or inhaled prostanoids.

Macitentan** has a favorable safety profile: the incidence of transaminase elevations >3-fold and the development of peripheral edema did not differ between treatment groups, indicating a lack of hepatotoxicity. Anemia was significantly more frequent with macitentan** compared to placebo: a hemoglobin decrease to ≤8 g/dL was observed in 4.3% of patients receiving macitentan** at a daily dose of 10 mg [50]. Macitentan** is the only drug whose efficacy and safety have been studied in patients with portopulmonary hypertension in the PORTICO RCT [127]. No significant drug-drug interactions were noted for macitentan**, including when co-administered with sildenafil [6, 12, 15].

ESC/RSC IB (LoE C, GoR 5) for patients in WHO FC II–III

ESC/RSC IIbC (LoE C, GoR 5) for patients in WHO FC IV

The NO-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway plays a proven role in the pathogenesis of PAH: the effects of nitric oxide are mediated by the activation of sGC and increased synthesis of cGMP, which regulates vascular smooth muscle cell relaxation, endothelial permeability, proliferation and inflammation processes, and platelet aggregation [49, 125]. In the pulmonary vasculature of patients with PAH, the level of phosphodiesterase type 5—an enzyme that neutralizes the effects of cGMP as a secondary messenger of NO—is significantly elevated.

Sildenafil is the first PDE5i approved for the treatment of patients with PAH [15, 16]. In 4 RCTs in patients with PAH, the drug demonstrated a positive effect on exercise tolerance, WHO FC, and hemodynamic parameters [6, 12, 173]. The drug is prescribed at a dose of 20 mg three times daily. Most side effects of sildenafil are mild to moderate in severity and are mainly associated with vasodilation (headache, facial flushing, epistaxis) [173, 174]. In terms of drug-drug interactions, the risk of a multiple-fold increase in sildenafil concentration during highly active antiretroviral therapy should be taken into account. In patients receiving protease inhibitors, a significant increase in PDE5i concentrations has been reported, requiring lower dosing with careful monitoring of potential side effects, including hypotension [175]. However, in routine practice, sildenafil dosage adjustment in patients with PAH-HIV is generally not required. Concomitant use of sildenafil, molsidomine, organic nitrates, and riociguat** is contraindicated due to the risk of hypotension and syncope [6, 12, 174].

ESC IA (C-V, LoE 5) for patients with WHO FC II-III

ESC IIbC (C-V, LoE 5) for patients with WHO FC IV

Tadalafil is an oral PDE5i for once-daily administration (half-life of 17.5 hours) [5]. In the PHIRST RCT involving 406 patients with PAH receiving tadalafil at doses up to 40 mg daily (53% were on baseline bosentan therapy), positive treatment effects were shown on exercise tolerance, symptom severity, hemodynamic parameters, and time to clinical worsening [12, 16, 331, 335].

The adverse event profile is comparable to that of sildenafil. However, the SITAR study in 35 patients with PAH showed that switching from sildenafil to tadalafil was accompanied by greater patient satisfaction with treatment quality. This makes such a substitution worth considering in patients with prominent side effects from sildenafil [332]. The recommended dose is 20–40 mg once daily [12, 16]. Tadalafil should be prescribed at low doses with careful monitoring of potential side effects, including hypotension.

ESC IB (LoE C, GoR 5) for patients in WHO FC II–III

ESC IIbC (LoE C, GoR 5) for patients in WHO FC IV

Riociguat**, the first sGC stimulator, has a dual mechanism of action:

it sensitizes sGC to endogenous NO by stabilizing their binding, and also directly stimulates the enzyme through a different binding site, independently of NO [176]. Unlike PDE5i, which prevent cGMP degradation, sGC stimulators increase its production under conditions of impaired redox status of sGC [174, 177, 178]. The 12-week double-blind placebo-controlled PATENT-1 RCT demonstrated the efficacy of riociguat** in patients with PAH (n=443) (44% and 6% on ERA or prostacyclin analogue therapy, respectively) when administered at a dose up to 2.5 mg 3 times daily, resulting in improved clinical symptoms, exercise tolerance, hemodynamic parameters, WHO FC, and increased time to clinical worsening [177]. According to the open-label 2-year PATENT-2 study, the 2-year survival rate of patients with PAH on riociguat** therapy was 93%, with 79% of patients experiencing no clinical worsening. After two years, 83% of patients continued to receive riociguat** as monotherapy [178]. Riociguat** has a favorable safety profile; its adverse effect profile is similar to that of PDE5i [49].

Titration of riociguat** starting from a dose of 1 mg three times daily is carried out every two weeks by 0.5 mg 3 times daily, monitoring tolerability and sitting resting systolic blood pressure (≥95 mm Hg) up to a maximum daily dose of 7.5 mg. Patients should be informed of the need to quit smoking, given the substantial decrease in blood riociguat** concentration [177]. Riociguat** is contraindicated during pregnancy due to its teratogenic effect [15, 16].

ESC IB (LoE B, GoR 2) for patients in WHO FC II–III

ESC IIbC (C-V, LoE 5) for patients with WHO FC IV

ESC IIIB (LoE C, GoR 5)

One of the pathophysiological targets for pharmacological intervention in PAH is impaired synthesis of prostacyclin (PGI2), a potent vasodilator with cytoprotective, antiproliferative, anti-inflammatory, and antiplatelet effects [179]. Its action is mediated through the activation of prostacyclin receptors (IP) by increasing cyclic adenosine monophosphate production. In clinical practice, synthetic analogues of prostacyclin—prostanoids—are used to correct prostacyclin deficiency.

Iloprost is the only stable aerosolized prostacyclin analogue registered in the Russian Federation, administered 6–9 times daily using a mesh nebulizer at a dose equivalent to 2.5–5 mcg of the drug at the alveolar level. The efficacy of inhaled iloprost was evaluated in the 12-week AIR-1 RCT in treatment-naive patients with PAH and inoperable forms of CTEPH WHO FC III–IV (NYHA) [180]. Iloprost therapy showed a significant improvement in exercise tolerance, WHO FC, hemodynamic parameters, and clinical events compared to the placebo group. However, long-term iloprost monotherapy did not lead to improved survival and morbidity [181]. Iloprost is preferably used as part of combination PAH-specific therapy [15].

The most common side effects of iloprost include headache, facial flushing, systemic vasodilation, or non-selective effects on prostacyclin receptors (jaw pain, diarrhea) [180, 182]. Cough may occur during iloprost administration due to increased upper airway hyperreactivity, especially in patients with bronchobstructive syndrome. Iloprost has a pronounced antiplatelet effect, therefore its use in patients with active bleeding is contraindicated.

ESC IB (LoE C, GoR 5) for patients in WHO FC III

ESC IIbC (C-V, LoE 5) for patients with WHO FC IV

Selexipag** is the first oral selective non-prostanoid IP receptor agonist. The large-scale Phase 3 GRIPHON RCT, which included 1156 patients with PAH, demonstrated that specific therapy including selexipag** resulted in a 40% increase in time to the first morbidity/mortality event [183]. The efficacy of selexipag** has been proven in IPAH, HPAH, CTD-PAH, and PAH associated with repaired simple congenital heart disease when administered in combination with PDE5i and/or ERAs or as monotherapy, regardless of patient age and PAH etiology [12].

Selexipag** therapy starts at a dose of 200 mcg twice daily, with weekly titration of the single dose by 200 mcg to the maximum tolerated dose of 1600 mcg twice daily. In the GRIPHON RCT, 42.9% of patients received high doses (1200–1600 mcg twice daily), 31.2% received medium doses, and 23.2% received low doses (200–400 mcg twice daily). The most common side effects were headache, diarrhea, nausea, and jaw pain. Adverse events associated with selexipag** administration occurred in 14.3% of cases compared to 7.1% in the placebo group, which in some cases led to the discontinuation of further participation in the GRIPHON study (p <0.001) [12].

ESC IB (LoE C, GoR 5) for WHO FC II–III patients

ESC IIbC (C-V, LoE 5) for patients with WHO FC IV

High-dose CCBs are the optimal choice of initial therapy for patients with IPAH/HPAH/APAH who have a positive vasoreactivity test (Figure 2, Appendix B1, Section 3.2.2.1) [6, 12, 15, 16]. An important task is careful dynamic monitoring of patients after 3–4 months for timely correction of therapy if optimal treatment results are not achieved (Section 3.2.2.1). Once treatment goals are met, subsequent follow-up visits should be considered individually every 3–12 months [16].

Considering the range of approved PAH-specific drugs and the specifics of drug supply in the regions of the Russian Federation, it appears advisable to use an initial combination therapy strategy in patients with intermediate-risk PAH. In low-risk PAH patients, after initiating monotherapy, treatment results should be closely monitored to allow timely escalation via an early sequential therapy regimen no later than 3–4 months after treatment initiation.

• In patients with IPAH, HPAH, PAH induced by drugs, PAH associated with CTD, or residual PAH after correction of simple low-risk systemic-pulmonary shunts without cardiopulmonary comorbidity, initial monotherapy is recommended with an ERA, PDE5i, riociguat**, or selexipag** [6,12,15,16].

ESC IC (LoE C, GoR 5)

Comment. The strategy of initial monotherapy, including ERAs, PDE5is, riociguat**, or selexipag**, may be considered in patients with PAH (IPAH/HPAH, APAH) with a negative vasoreactivity test, as well as in residual PAH after correction of simple systemic-to-pulmonary shunts, or low-risk CTD-PAH (Table A3.7, Section 3.2.2.2–3.2.2.6) [6, 15, 16]. According to modern registries, the proportion of low-risk patients at the time of PAH diagnosis ranges from 12.3% to 23% [138–140]. According to the French registry, when evaluating cumulative survival in low-risk PAH patients receiving initial monotherapy versus initial dual combination therapy, no reliable differences were identified [184].

• In patients with IPAH/HPAH/APAH, CTD-PAH, or residual PAH after correction of simple systemic-to-pulmonary shunts without cardiopulmonary comorbidity receiving low-risk initial monotherapy, the decision to escalate therapy should be considered 3–4 months after treatment initiation [12, 15, 16].

ESC IIaC (LoE C, GoR 5)

Comment. When choosing the initial treatment strategy for patients with IPAH/HPAH/APAH and CTD-PAH, the 2022 ESC/ERS guidelines propose stratification into two cohorts for the first time based on the presence or absence of cardiopulmonary comorbidity [12]. In 2018, this approach was proposed by the Cologne Consensus experts: among patients with these forms of PAH, a classic phenotype of precapillary PH without comorbidity is distinguished, alongside a phenotype with left heart disease and associated conditions (>3 risk factors for left heart disease: diabetes mellitus, obesity, arterial hypertension, atrial fibrillation) or pulmonary pathology (presence of hypoxemia, significant smoking history, risk factors for lung disease, FEV1 <60%, FVC <70%, DLCO <45%) [9, 188]. For PAH patients with comorbid conditions, typically in an older age group regardless of mortality risk, it is proposed to use monotherapy followed by an efficacy assessment and an individual decision regarding sequential combination therapy (Figure 2, Appendix B1) [12].

• In patients with IPAH, HPAH, APAH, CTD-PAH, or residual PAH after correction of simple systemic-to-pulmonary shunts with cardiopulmonary comorbidity, initial monotherapy with PDE5is or ERAs should be considered [12].

ESC IIaC (LoE C, GoR 5)

Comment. Initiation of upfront combination PAH-specific therapy in older patients with IPAH/HPAH, APAH, and CTD-PAH in the presence of cardiopulmonary comorbidity has not shown the results observed in younger classic PAH patients [189]. It should be noted that significant comorbid pathology, including heart and lung diseases, has traditionally been an exclusion criterion for patient participation in all RCTs evaluating the efficacy/safety of PAH-specific therapy [6, 189, 190]. According to the COMPERA registry, 35.8% of IPAH patients had left heart disease and 51.6% had lung disease [139]. Compared to patients without cardiopulmonary comorbidity, patients with left heart or lung disease show a poorer response to PAH-specific therapy, a lower probability of achieving low-risk status, and a higher risk of treatment discontinuation due to ineffectiveness or poor tolerability, as well as higher mortality [12].

• In patients with IPAH, HPAH, APAH, CTD-PAH, or residual PAH after correction of simple systemic-to-pulmonary shunts with cardiopulmonary comorbidity who remain at intermediate/high risk on PDE5i or ERA monotherapy, the addition of further PAH medications may be considered on an individual basis [12].

ESC IIbC (Level of Evidence C, Grade of Recommendation 5)

Comment. Considering the pronounced heterogeneity of the patient population initially stratified into the low-risk group and the possibility of PAH progression, careful monitoring of patients should be ensured every 6–12 months for timely treatment adjustment [15, 185]. According to a meta-analysis of foreign registries, mortality in PAH patients with baseline WHO FC I–II reached 22% after three years of follow-up [186].

Upfront monotherapy is the preferred strategy in patients with HIV-associated PAH, portopulmonary PAH, and Eisenmenger syndrome, given the lack of data on the effect of upfront combination therapy on survival and PAH progression (Section 4.1) [9, 12]. The monotherapy strategy may also be justified by safety criteria: in patients with suspected or high probability of PVOD/PCH, as well as in the presence of potential contraindications, such as severe liver disease [15]. When prescribing initial combination PAH-specific therapy, organizational, legal, and other formalities that create difficulties in drug supply across regions of the Russian Federation must be taken into account [187].

• In patients with HIV-associated PAH, initial monotherapy should be considered, followed, if necessary, by sequential combination therapy, taking into account concomitant diseases and drug-drug interactions [12, 15, 16].

ESC IIaC (LoE C, GoR 3)

• In patients with portopulmonary hypertension, initial monotherapy should be considered, followed, if necessary, by sequential combination therapy, taking into account liver pathology and indications for liver transplantation [12, 15, 16].

ESC IIaC (LoE C, GoR 5)

• In patients with Eisenmenger syndrome, bosentan** is recommended to improve exercise tolerance [191].

ESC IB (Level of Evidence B, Grade of Recommendation 2)

• In adults with congenital heart disease, including Eisenmenger syndrome, the use of other ERAs, PDE5is, riociguat**, iloprost, or selexipag** should be considered [12, 15, 16].

ESC IIaC (LoE C, GoR 3)

• In adult patients with Eisenmenger syndrome, considering sequential combination therapy should be recommended if treatment goals are not achieved [12, 16, 48].

ESC IIaC (LoE C, GoR 5)

Co-administration of PAH-specific drugs acting on multiple disease pathways results in synergistic effects. The efficacy of combination therapy is determined taking into account potential drug-drug interactions and the risk of adverse effects [15, 16, 187, 335].

• In intermediate-risk patients with IPAH/HPAH/APAH, residual PAH after correction of simple systemic-to-pulmonary shunts, or CTD-PAH without cardiopulmonary comorbidity, initial combination therapy with an ERA combined with a PDE5i or riociguat** is recommended [15, 16, 187, 333, 334].

RSC IIaC (LoE C, GoR 5)

• For patients with IPAH, APAH, drug-induced PAH, residual PAH after correction of simple systemic-to-pulmonary shunts, or connective tissue disease-associated PAH (CTD-PAH) at intermediate risk without cardiopulmonary comorbidities, initial combination therapy with riociguat** or a PDE-5i combined with an ERA is recommended [187, 192].

RSC IIbC (LoE C, GoR 5)

• For patients with IPAH, APAH, drug-induced PAH, residual PAH after correction of simple systemic-to-pulmonary shunts, or CTD-PAH at intermediate risk without cardiopulmonary comorbidities, initial combination therapy with selexipag** or iloprost combined with an ERA is recommended [187, 192].

RSC IIbC (Level of Evidence C, Grade of Recommendation 5)

• For patients with IPAH, APAH, drug-induced PAH, residual PAH after correction of simple systemic-to-pulmonary shunts, or CTD-PAH at high risk (>20% per year) without cardiopulmonary comorbidities, initial combination PAH-specific therapy with a PDE-5i/riociguat**, an ERA, and inhaled iloprost is recommended [12, 15, 16, 48].

ESC IIbC (Level of Evidence C, Grade of Recommendation 5)

• For patients with IPAH, APAH, drug-induced PAH, residual PAH after correction of simple systemic-to-pulmonary shunts, or CTD-PAH at high risk without cardiopulmonary comorbidities, initial combination PAH-specific therapy with a PDE-5i/riociguat**, an ERA, and selexipag** is recommended [12, 15, 16, 48].

ESC IIbC (Level of Evidence C, Grade of Recommendation 4)

Most RCTs were conducted using a sequential combination therapy regimen, which reflects the concept of escalating PAH-specific therapy when low mortality risk criteria are not met [49, 125, 187].

ESC IIC (LoE C, GoR 5)

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. In the SERAPHIN RCT, 63.7% of patients with PAH received background specific therapy, predominantly PDE-5i, and 5.4% received prostacyclin analogues. With sequential combination therapy including macitentan**, the risk of adverse events (hospitalization, death, worsening of PAH, transplantation/atrial septostomy) was reduced by 38% (p=0.009) [50].

• In patients with IPAH, APAH, or drug/toxin-induced PAH who achieve an intermediate risk status on PDE-5i and/or ERA therapy, the addition of selexipag** is recommended to reduce morbidity/mortality risk [12, 183, 193].

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. In the GRIPHON RCT, the risk of adverse events was reduced by 37% in the group of patients receiving selexipag** in addition to PDE-5i and ERA therapy (n=179) compared with the group receiving dual combination therapy (n=197) [183]. The risk of adverse events over a 30-month follow-up period in the GRIPHON RCT decreased by 63% in WHO FC II patients receiving sequential triple therapy (n=55) compared with dual PAH-specific therapy (n=60). The greatest reduction in adverse event risk was observed when selexipag** was prescribed as the second or third drug in relation to PDE-5i and/or ERAs in low-risk patients and within the first 6 months after diagnosis establishment [193, 194].

ESC IB (Level of Evidence B, Grade of Recommendation 2)

• To improve exercise tolerance, it is recommended to consider adding inhaled iloprost to bosentan** [6, 15, 16, 195, 196].

ESC IIaB (Level of Evidence B, Grade of Recommendation 2)

• To improve exercise tolerance, it is recommended to consider adding inhaled iloprost to ambrisentan** or macitentan** [6, 15, 16].

ESC IIbC (Level of Evidence C, Grade of Recommendation 5)

• To improve exercise tolerance, it is recommended to consider adding ambrisentan** to a PDE-5i or riociguat** [197, 198].

ESC IIbC (C-GPR, 4 LoE)

• To improve exercise tolerance, it is recommended to consider adding macitentan** to riociguat** [187, 199].

ESC IIbC (Level of Evidence C, Grade of Recommendation 5)

• To improve exercise tolerance, it is recommended to consider adding tadalafil to bosentan** [12, 335].

RSC IIaC (Level of Evidence C, Grade of Recommendation 5)

• The addition of bosentan** to sildenafil is not recommended for reducing morbidity/mortality risk [12, 15].

ESC IIIB (LoE C, GoR 5)

• The addition of riociguat** to sildenafil/tadalafil is not recommended due to the risk of adverse events [12, 15].

ESC IIIB (LoE C, GoR 5)

• In patients with PAH receiving a PDE-5i combined with an ERA who remain at intermediate risk, switching from the PDE-5i to riociguat should be considered [9, 16, 201, 335].

ESC IIaB (Level of Evidence B, Grade of Recommendation 3)

Comment. The prospective RESPITE study demonstrated for the first time the efficacy of a switching strategy in WHO FC III PAH patients with or without concomitant ERA therapy who had an inadequate clinical response to sildenafil therapy, switching to riociguat** [202]. Replacing high-dose PDE-5i with riociguat** was accompanied by an improvement in 6MWD, functional class, NT-proBNP, PVR, and cardiac index (CI). In a prospective study of IPAH patients, switching from a PDE-5i to riociguat** contributed to improvements in functional class, 6MWD, RV systolic function, and RV-pulmonary arterial coupling by reducing the effective stiffness of the pulmonary circulation [203]. In the REPLACE RCT, evaluating the strategy of switching from a PDE-5i to riociguat** compared with continuing a PDE-5i in intermediate-risk PAH patients, clinical improvement (primary endpoint defined as achieving at least two of three parameters: an increase in 6MWD ≥10% / ≥30 m, achieving WHO FC I/II, and a decrease in NT-proBNP ≥30% from baseline in the absence of clinical worsening) was achieved in 41% of patients in the riociguat** group compared with 20% in the PDE-5i group [204].

• In patients with PAH who remain at high risk despite triple therapy including a PDE-5i or riociguat**, an ERA, and selexipag**, it is advisable to consider replacing selexipag** with inhaled iloprost [12, 16, 335].

ESC IIaC (Level of Evidence C, Grade of Recommendation 5)

• Switching from one drug to another within the same class of PAH-specific therapy or to a drug of another class may be considered if a clinically significant adverse effect develops and therapy cannot be continued [12, 15, 335].

RSC IIbC (LoE C, LoR 4)

Comment. According to a meta-analysis of 9 prospective cohort studies involving 408 PAH patients, switching from bosentan** or ambrisentan** to macitentan** improved 6MWD, functional class, and the safety profile without a significant effect on NT-proBNP levels, hemodynamics, or echocardiographic parameters [205, 206]. Due to the lack of multicenter RCTs investigating the effect of switching ERAs on the clinical course of PAH, switching is advisable only if adverse drug effects or unfavorable drug-drug interactions develop.

3.3. Surgical treatment

3.3.1. Atrial septostomy

RSCC IIaC (LoE B, LoD 2)

Comment. The general principle of atrial septostomy is the creation and long-term maintenance of an interatrial communication with a veno-arterial shunt volume that ensures decompression of the right heart chambers (with a reduction in clinical manifestations of right ventricular failure) while increasing left heart preload (with an increase in cardiac output and systemic oxygen delivery) without severe hypoxemia [12, 207–211]. A meta-analysis of 16 observational studies in 204 patients who underwent atrial septostomy demonstrated a decrease in right atrial pressure (p<0.001) and an increase in cardiac index (p<0.001), along with a decrease in arterial oxygen saturation (p<0.001) [211]. Atrial septostomy should be performed only in expert centers with sufficient experience in such interventions [207–211]. The procedure is contraindicated when right atrial pressure exceeds 20 mm Hg and resting $ ext{SaO}_2$₂ is less than 90% [207, 208, 211].

RSC IIIC (Level of Evidence B, Grade of Recommendation 2)

3.3.2. Lung or heart-lung transplantation

ESC IIaC (LoE C, GoR 5)

ESC IIbC (Level of Evidence C, Level of Certainty 5)

Comment. Intermediate- or high-risk PAH patients with clinical worsening receiving the maximum possible PAH-targeted therapy need timely consultation with a thoracic (transplant) surgeon for placement on the lung or heart-lung transplantation waiting list [12]. Over the past decade, the median survival of PAH patients has significantly improved after lung transplantation, from 4.1 years in 1990–1997 to 6.1 years in 2005–2012, and after heart-lung transplantation from 1.9 (1982–1991) to 5.6 years (2002–2012) [212]. Bilateral lung transplantation is performed more frequently. However, survival after single or double lung transplantation is approximately the same. According to the International Society for Heart and Lung Transplantation registry, in Eisenmenger syndrome due to simple shunts, isolated lung transplantation with simultaneous correction of congenital heart disease (CHD) may be the method of choice. For ventricular septal defects, better outcomes are observed with heart-lung transplantation [6, 212].

3.4. Intensive care

Symptoms of severe right ventricular (RV) HF combined with systemic hypotension are an indication for treatment in the intensive care unit. RV HF in patients with PAH is primarily a consequence of RV systolic dysfunction against the background of chronic pressure overload, which leads to an increase in RV end-diastolic pressure, right atrial pressure, and systemic venous congestion. Elevated central venous pressure, in turn, causes internal organ dysfunction (congestive hepatomegaly, nephropathy, etc.). A patient with decompensated PAH requires a comprehensive workup to rule out potential triggers of clinical deterioration (intercurrent infection, comorbid conditions, anemia, rhythm/conduction disorders, acute PE, side effects of drug therapy) [6, 15, 213].

• In PH patients with a heart rate >110 bpm, hypotension (systolic BP <90 mm Hg), oliguria, and elevated lactate levels, it is recommended to consider admission to the intensive care unit [6, 213, 214].

ESC IIaC (LoE C, GoR 5)

RRCS IIaC (LoE C, GoR 5)

RRCS IIaC (LoE C, GoR 5)

RRCS IIaC (LoE C, GoR 5)

RRCS IIbB (LoE C, GoR 5)

ESC IC (LoE C, LoE 5) for patients in WHO FC IV

ESC IIbB (LoE C, SoE 5)

Comment. In the management of RV heart failure, a key objective is to maintain mean systemic arterial pressure >60 mm Hg. In patients with severe HF, tracheal intubation, double-lumen bronchial intubation, and invasive mechanical ventilation should be avoided whenever possible due to the high risk of further hemodynamic deterioration and death [12].

RRCS IIbB (LoE C, GoR 5)

RRCS IIbB (LoE C, GoR 5)

RRCS IIIC (LoE C, GoR 5)

The algorithm for choosing the optimal treatment strategy for patients with PAH is presented in Figure 2 in Appendix B.

3.5 Specific subgroups of pulmonary arterial hypertension

3.5.1 Pulmonary arterial hypertension associated with congenital heart disease

PH associated with CHD is included in four of the five main PH groups identified in the clinical classification [11, 48]:

• PAH associated with CHD (Eisenmenger syndrome, CHD with left-to-right shunt, small/incidental defects, and post-CHD correction);

• PH associated with left heart disease (congenital/acquired cardiovascular pathology with post-capillary PH);

• PH associated with pulmonary artery obstruction (other obstruction – congenital PA stenosis);

• PH of unknown and/or multifactorial origin (complex CHD – anomalies with univentricular hemodynamics, segmental PH, etc.).

A complete list of congenital heart defects leading to PH development is provided in the 2021 Eurasian Guidelines for the Diagnosis and Treatment of Adult CHD-Associated Pulmonary Hypertension [48].

In the Russian Federation, PAH associated with CHD ranks among the top positions in prevalence among all forms of PAH (ranking first in several regions). The diagnosis of PH associated with CHD has specific features [48, 113, 118, 122, 124, 215–217, 222, 223].

Management of CHD with PH includes surgical correction (for operable patients) and medical therapy (for inoperable patients and in cases of residual PH persistence after surgery) [12, 45, 48, 118, 119, 217, 218–221]. General measures and supportive therapy in PH associated with CHD are identical to the approaches used for PAH. Special attention may be warranted for erythrocytosis (phlebotomy is not recommended), iron deficiency correction, and prevention of air embolism during venous access [12, 45, 48, 119].

Therapy with PAH-targeted drugs—ERAs, prostacyclin analogues, prostacyclin receptor agonists, PDE-5 inhibitors, soluble guanylate cyclase stimulators (see List of Abbreviations)—is indicated for patients with pre-capillary forms of PH: PAH associated with CHD and pre-capillary PH in complex CHD [12, 119, 218, 220, 221]. Evidence is accumulating regarding the so-called "treat-and-repair approach" (surgical correction following a course of PAH-targeted therapy), but the evidence base for this approach is currently insufficient [219].

An analysis of 59 clinical studies (14 of them RCTs) on the therapy with PAH-targeted drugs approved in the Russian Federation (see List of Abbreviations) shows that bosentan** has the most robust evidence base (especially in Eisenmenger syndrome – the BREATHE-5 RCT [220]), although other drugs (ambrisentan**, macitentan**, sildenafil, inhaled iloprost, riociguat**, and selexipag**) also have an evidence base in "simple" and "complex" CHD with pre-capillary PH [218, 221]. At the same time, the indications "PAH associated with CHD and Eisenmenger syndrome" or "PAH associated with corrected simple CHD" are designated for three (bosentan**, macitentan**, and selexipag**) of the eight specific pulmonary vasodilators registered in the Russian Federation [221].

RRCS IC (LoE C, GoR 5)

RRCS IC (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

RSC IIIC (LoE C, GoR 5)

Comment. Assessment of vasoreactivity in adult patients with PAH-CHD is not indicated due to the lack of generally accepted criteria indicating CHD operability, as well as the extremely rare response to CCB therapy in patients with "small/coincidental defects" and following CHD correction [12, 48, 122, 217]. CCB therapy is contraindicated in patients with Eisenmenger syndrome, as it may promote an increase in right-to-left blood shunting and thus exacerbate hypoxemia [6]. Due to the aforementioned circumstances (extremely low probability of a positive result, inappropriateness of prescribing CCBs), performing a vasoreactivity test in patients with Eisenmenger syndrome is not indicated.

RRCS IC (LoE C, GoR 5)

RSC IIaC (LoE C, GoR 5)

Comment. Indications for radical surgical/endovascular correction with a PVR index of 4–8 Wood units × m² and for certain types of palliative endovascular procedures (embolization of pulmonary collateral arteries in hemoptysis, stenting of the left main coronary artery in myocardial ischemia, etc.) are discussed in detail in the 2021 Eurasian Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension Associated with Congenital Heart Disease in Adults [48].

RSC IIIC (LoE C, GoR 5)

ESC IIbC (LoE B, GoR 3)

ESC IIIC (LoE C, GoR 5)

Comment. In the presence of clinical symptoms of hyperviscosity in patients with a hematocrit > 65%, attention should first be paid to adequate hydration [12].

RSC I C (LoE C, GoR 5)

ESC I-IIa-IIb – B-C (LoE C, GoR 5)

[12, 48, 220, 221].

ESC IB (LoE B, GoR 2)

ESC IIaC (C-GPR, 5 LoE)

ESC IIaC (LoE B, GoR 2)

3.5.2 Pulmonary arterial hypertension associated with systemic connective tissue diseases

Systemic sclerosis is an autoimmune systemic connective tissue disease of unknown etiology, in which pulmonary involvement in the form of PAH or interstitial lung disease is the main cause of premature death [224–226]. The overall prevalence of PAH among patients with systemic sclerosis is 6.4% (95% CI 5–8.3%), and the overall incidence is 18.2 cases per 1,000 person-years (95% CI 12–27.4), according to a meta-analysis [226].

The prevalence in other systemic connective tissue diseases is less studied due to their considerable rarity; more than 70% of all patients with PAH associated with rheumatic diseases are patients with systemic sclerosis [227, 228].

RKO IB (C-V, LoE 5)

Comment. The etiology of PH in patients with systemic connective tissue diseases is heterogeneous and includes: PAH; PH due to lung disease and/or hypoxemia; post-capillary PH due to left heart disease (systolic/diastolic dysfunction); pulmonary vascular occlusive disease; chronic thromboembolic pulmonary hypertension in patients with antiphospholipid syndrome or after pulmonary embolism [229].

RSC IB (CQR B, LVE 3)

Comment. Evidence of the clinical value of early PAH detection in systemic sclerosis was obtained from screening programs, which demonstrated less pronounced hemodynamic impairment and better survival in identified patients [129, 130, 225]. Several screening algorithms have been developed using a combination of clinical features, immunological markers, echocardiography, pulmonary function tests (spirometry, diffusing capacity of the lungs for carbon monoxide), and blood N-terminal pro-brain natriuretic peptide (NT-proBNP) levels to select systemic sclerosis patients for right heart catheterization (DETECT) [132] and the Australian Scleroderma Interest Group (ASIG) [229]. It should be emphasized that PAH screening does not apply to systemic sclerosis patients with interstitial lung disease and/or left heart disease. The detection of Group 3 and Group 2 PH during follow-up in these patients indicates the progression of interstitial lung disease and/or left heart disease, worsens the prognosis, and primarily requires optimization of therapy for interstitial lung disease and/or left heart disease, since routine administration of PAH-specific drugs in these patients may lead to clinical deterioration [129, 229, 231].

The PAH-associated phenotype of systemic sclerosis includes anamnestic data (duration of Raynaud's phenomenon for more than 12 years prior to the first signs of PAH), clinical features (telangiectasias, limited skin involvement or its absence), and laboratory parameters (hyperuricemia, presence of anti-centromere antibodies, absence of anti-topoisomerase-I antibodies) associated with the development of PAH in patients with systemic sclerosis [232].

RRC IA (Reliability of Evidence Level C, Consistency of Evidence Level 5)

RRC IA (Reliability of Evidence Level C, Consistency of Evidence Level 5)

RSC IB (LoE B, GoR 2)

Comment. In patients with CTD, uric acid has been identified as a marker of microvascular damage, demonstrating a good correlation with serum creatinine levels and hemodynamic parameters [233]. Hyperuricemia is a common phenomenon in tissue hypoxia: elevated levels of uric acid, a byproduct of purine oxidation, increase when oxidative metabolism is impaired and are found in patients with PAH of various etiologies with a proven correlation with NYHA functional class, mortality, and 6MWD [234]. PAH-specific therapy significantly reduces peripheral blood uric acid levels [235].

ESC IC (LoE C, GoR 5)

Comments. Considering the multifactorial nature of mPAP elevation in patients with SSc and their low survival rates, additional factors are being sought for the early detection of PAH. To address the need for RHC, algorithms for the early diagnosis of SSc-associated PAH have been proposed: the PHAROS study suggests evaluating unforced spirometry data and carbon monoxide diffusing capacity: FVC/DLCO ratio ≥ 1.6; DLCO < 55%; estimated RV pressure > 35 mmHg [12, 236]. In the DETECT study for patients with limited SSc for at least 3 years, diagnosis was based on the FVC/DLCO ratio, presence of telangiectasias, anticentromere antibodies, NT-proBNP and uric acid levels, taking into account data such as right axis deviation on ECG, right atrial area, and tricuspid regurgitation velocity by echocardiography [132]. The negative predictive value of this algorithm was 96%. Given the financial costs and inaccessibility of some instrumental methods (such as carbon monoxide diffusing capacity [DLCO]) associated with the need for annual screening, identifying the risk groups outlined in the guidelines appears most appropriate. An isolated decrease in DLCO is observed in both PAH and early ILD; it has been shown that the prognostic value of this method is inferior to its diagnostic value [237].

ESC IIIC (CCE C, LoE 5)

Comments. Among patients with CTD-PAH, a positive vasoreactivity test is observed in less than 1% of cases; therefore, vasoreactivity assessment during RHC is not performed in this category of patients, and consequently, CCBs are not used to treat PAH [129]. In most cases, CCBs are used solely as therapy for Raynaud's syndrome.

ESC IC (LoE C, GoR 5)

Comments. Patients with CTD participated in RCTs involving all classes of PAH-specific drugs. The administration of PAH-specific therapy in SSc patients increased 3-year survival from 45% to 56% [129, 238]. However, the number of patients with CTD-PAH participating in RCTs is disproportionately smaller compared to the number of patients with IPAH. RCTs evaluating PAH-specific therapy exclusively in the CTD-PAH cohort are currently lacking. This is of definite significance, since older patients with CTD often have musculoskeletal problems and comorbidities, which limits the performance and interpretation of exercise tests [6, 49, 103]. Patients with CTD-PAH showed a smaller increase in 6MWD compared to patients with IPAH. In this regard, the results of recent long-term RCTs SERAPHIN and GRIPHON [50, 183], evaluating a morbidity/mortality combined endpoint, are of particular interest in the CTD-PAH cohort. The heterogeneity of the CTD-PAH patient population in RCTs should be kept in mind. Disease course, lung and heart involvement, PVOD development, concomitant therapy, and complications can vary significantly among patients with systemic lupus erythematosus, SSc, and other CTDs. In most RCTs, pulmonary pathology was excluded based on pulmonary function testing, whereas chest computed tomography is required to detect pulmonary fibrosis/emphysema. In addition, left heart disease is common in patients with CTD, which significantly worsens the prognosis of PH in CTD [239, 240].

ESC IIIA (LoE C, GoR 5)

ESC IIIB (CCE B, LoE 3)

ESC/RSC IC (CCE C, LoE 5)

Comments. No RCTs have compared the efficacy of PAH-specific monotherapy in patients with CTD-PAH. Drug selection decisions should be based on the risk of drug-drug interactions, presence of liver disease (primary biliary cholangitis), and renal impairment. The use of initial combination and sequential PAH-specific therapy in CTD-PAH has demonstrated positive effects, similar to patients with IPAH, in reducing the risk of adverse events [12, 129].

3.5.3 Portopulmonary hypertension

Portopulmonary hypertension (PoPH), as a precapillary form of PH, is observed in 2–6% of patients with portal hypertension in the presence or absence of liver disease, and should be differentiated from hepatopulmonary syndrome. The latter develops in liver disease, congenital portosystemic shunts, and is accompanied by pulmonary vascular dilatation in response to hypoxemia with normal PVR [49, 127]. Hepatopulmonary syndrome may precede or develop concurrently with PoPH [101, 244].

ESC IC (LoE C, GoR 5)

Comments. Transthoracic echocardiography is the method of choice for suspected PH and is recommended as a screening tool in patients awaiting liver transplantation [12].

ESC IB (CCE B, LoE 3)

ESC IC (CCE B, LoE 3)

• In patients with portopulmonary hypertension, it is recommended to apply the PAH treatment algorithm, taking into account the severity of liver disease [6, 12, 15, 16].

ESC IIC (LoE C, GoR 5)

[12, 127].

ESC IIIC (CCE C, LoE 5)

• In patients with portopulmonary hypertension, initial PAH-specific monotherapy is recommended, with subsequent escalation to sequential combination therapy if necessary, taking into account the underlying disease and indications for liver transplantation [12, 127].

ESC IIaC (CCE C, LoE 5)

Comments. Patients with PoPH were not included in RCTs evaluating the efficacy/safety of PAH-specific therapy, which must be considered when prescribing drugs approved for PAH treatment. In patients with PoPH and moderate/severe hepatic impairment, the use of hepatotoxic drugs, particularly ERA, should be avoided [251, 252]. In the placebo-controlled PORTICO RCT involving patients with PoPH (56% with alcoholic liver cirrhosis, 41% with chronic hepatitis C), macitentan** therapy significantly reduced PVR and mPAP and increased CI by week 12 without significant changes in functional class and with no cases of clinically significant transaminase elevation [246].

PDE5 inhibitors are traditionally used in patients with PoPH. In an uncontrolled study of patients with PoPH undergoing RHC, a decrease in PVR and mPAP was observed after 3 years of treatment, and one out of 11 patients successfully underwent liver transplantation [245, 247]. Data on the use of inhaled prostanoids are limited to isolated clinical cases. The presence of thrombocytopenia and a high risk of hemorrhagic complications necessitate caution when using this group of drugs.

In the PATENT-1 RCT, 11 patients with PoPH received riociguat** 2.5 mg 3 times daily; however, no efficacy/safety analysis of the treatment was performed in this subgroup [177]. Data on the use of the IP receptor agonist selexipag** in patients with PoPH are currently lacking.

ESC IIaC (Level of Evidence C, Grade of Recommendation 5)

Comments. Liver transplantation should be considered on an individual basis in patients with PoPH upon achieving normal or near-normal PVR values [12, 127, 245].

ESC IIIC (LoE B, LoR 3)

Comment. The development of PAH is associated with a high mortality risk in patients after liver transplantation due to severe hepatic pathology: with mPAP ≥50 mm Hg, 100% perioperative mortality was observed, and with mPAP 35–50 mm Hg and PVR >3 Wood units, 50% [12, 15]. The International Liver Transplantation Society proposed hemodynamic criteria as absolute contraindications to liver transplantation, which require further validation: mPAP ≥35 mm Hg and PVR >5 Wood units in patients receiving PAH-specific therapy [247]. Following successful transplantation, the decision to de-escalate or discontinue therapy is made on an individual basis [12].

ESC IIIC (CCE C, LoE 5)

Comment. Patients with PoPH have a high bleeding risk due to impaired synthesis of clotting factors and uncontrolled hypocoagulation during anticoagulant therapy, as well as the presence of esophageal varices and hemorrhoids [15, 49, 127]. Anticoagulant therapy may be discussed in the presence of vital indications, such as acute PE [12].

3.5.4 Human Immunodeficiency Virus (HIV)-Associated Pulmonary Arterial Hypertension

The use of highly active antiretroviral therapy and advances in the management of opportunistic infections have contributed to increased life expectancy in patients with HIV [12, 128, 248]. Among cardiovascular complications, PAH develops in only 0.5% of HIV-infected patients and is an independent risk factor for mortality. The use of PAH-specific therapy has improved clinical outcomes, achieving a 3-year survival rate of 72–84% [6, 49]. The pathogenesis of HIV-PAH requires further study: the virus is not detected in lung inflammatory infiltrates, indicating the role of inflammatory and growth factors as triggers of pulmonary vascular disease in susceptible HIV patients [249]. In HIV-PAH, no correlation has been found between the severity of hemodynamic impairment and the stage of the underlying disease or the severity of immunodeficiency; additional PAH risk factors may be identified, such as liver disease (chronic viral hepatitis B or C) or drug/toxin exposure [12, 250].

ESC IIIC (CGR C, LOR 5)

Comment. Due to its low prevalence in HIV infection, echocardiographic screening is considered irrational in asymptomatic patients. Echocardiography should be performed in patients with unexplained dyspnea to detect HIV-related cardiovascular complications such as myocarditis, cardiomyopathy, and PAH [6, 12]. The diagnostic algorithm for HIV-PAH complies with standard guidelines; RHC is mandatory to confirm the precapillary PH phenotype [6, 12].

ESC ILA (CoE C, LoE 5)

Comment. In current guidelines, highly active antiretroviral therapy is recommended for all HIV patients regardless of CD4+ cell count and viral load [12, 128]. The use of highly active antiretroviral therapy does not prevent the development of PAH and does not affect hemodynamic parameters. An analysis of 509 cases of HIV-PAH from 1987 to 2009 showed higher survival in patients receiving antiretroviral therapy (55% vs. 22%, p <0.01), in patients receiving PAH-specific therapy alone (76% vs. 32%), and with the combination of antiretroviral and PAH-specific therapy (69% vs. 38%, p <0.01) [249].

ESC IIaC (LoE C, GoR 5)

Comment. Patients with HIV-PAH were not included in most RCTs. CCBs are not prescribed to this category of patients due to the lack of vasoreactivity [6, 12]. Conclusive evidence supporting the superiority of any particular class of PAH-specific drugs in patients with HIV-PAH has not been obtained. The rationale for combination therapy is based on registry data from patients with IPAH [9, 24, 26]. The risk of new conditions and diseases that can significantly alter both the course of HIV and PAH and the ongoing therapy must be taken into account, considering drug-drug interactions. The development of COPD in HIV-PAH may contribute to hypoxemia [128].

The use of the non-selective ERA bosentan** in a prospective open-label BREATHE-4 study in 16 patients with HIV-PAH at 16 weeks led to improved WHO functional class and 6MWD, increased cardiac index, and decreased mPAP with good drug tolerance [250]. Due to potential interactions with antiretroviral drugs, careful laboratory monitoring is required when prescribing bosentan** [12]. Isolated patients with HIV-PAH were included in the ARIES-1/2, GRIPHON, and SERAPHIN RCTs [15, 50, 170, 183]. PDE5is are most frequently used to treat patients with HIV-PAH, leading to improved functional class and decreased mPAP. Although co-administration with protease inhibitors has been shown to increase blood concentrations of sildenafil, adverse events and systemic hypotension are not described in routine clinical practice [175]. For HIV-PAH, data on the use of the sGC stimulator riociguat** and combination therapy are currently lacking. PAH-specific monotherapy should be prescribed against the background of systemic antiviral drugs; subsequently, individual decisions regarding combination therapy are recommended under safety profile monitoring for HIV-PAH patients who do not achieve low-risk status [12].

ESC IIIC (Level of Evidence C, Level of Certainty 5)

Comment. In the combination therapy of HIV-PAH, antithrombotic agents are generally not used due to the high risk of bleeding associated with thrombocytopenia and comorbidities, as well as drug-drug interactions [6, 49]. In the presence of life-threatening clinical situations (acute PE) or a high risk of thrombotic events, anticoagulant therapy may be discussed on an individual basis.

3.5.5 Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis

PVOD and PCH are rare forms of PH characterized by remodeling of pulmonary venules [6, 12, 93]. Diagnosis can often only be confirmed at autopsy. Genome-wide genetic screening of 13 families with PVOD revealed biallelic mutations in the EIF2AK4 gene, establishing an autosomal recessive inheritance pattern. In one case, PCH was proven, allowing PVOD and PCH to be considered as two clinical-pathological variants of PAH involving pulmonary venules/capillaries [6]. Alongside genetic predisposition, risk factors for PVOD/PCH include the use of alkylating agents, organic solvents, and possibly radiation therapy [15, 27]. In CTD and HIV infection, a morphological type of PVOD/PCH can be observed, leading to complications of PAH-specific therapy in such patients [25, 93].

• Patients with suspected PVOD/PCH are recommended to be urgently referred to a PH expert center for diagnosis verification [6, 12, 15, 16].

ESC IC (LoE C, SoR 5)

Comment. Diagnosis of PVOD/PCH utilizes a combination of clinical and radiological data, assessment of unforced lung volumes and flows, pulmonary diffusing capacity testing, and genetic testing to confirm PAH with involvement of pulmonary venules/capillaries [93]. Chest radiography can reveal Kerley lines, mediastinal lymphadenopathy, and interstitial infiltration in addition to other signs of PH [49]. Chest CT is the primary non-invasive diagnostic method for PVOD, revealing the characteristic triad of findings: centrilobular ground-glass opacities, interlobular septal thickening, and mediastinal lymphadenopathy [6, 12, 93].

PVOD/PCHOD may be accompanied by alveolar hemorrhage, which is why a high percentage of siderophages is often present in bronchoalveolar lavage [47]. Patients with PVOD are characterized by a sharp decrease (<50%) in DLCO in the absence of significant disorders of respiratory mechanics and lung volumes [125]. Histological examination remains the gold standard to confirm the diagnosis of PVOD/PCHOD, but performing lung biopsy is not recommended due to the high risk of complications [6, 12]. Detection of a biallelic EIF2AK4 gene mutation in patients with familial forms makes it possible to confirm the diagnosis of PVOD/PCHOD without performing a biopsy. Despite the localization of the pathological process in the pulmonary venules and capillaries, PCWP in patients is often below 15 mmHg. Performing a vasoreactivity test when PVOD is suspected is not recommended due to the risk of pulmonary edema. When prescribing long-term PAH-specific therapy, the high probability of developing pulmonary edema should be taken into consideration [15].

• For patients with PVOD/PCHOD, it is recommended to consider prescribing PAH-specific therapy on an individual basis under the supervision of clinical symptoms and gas exchange parameters, taking into high consideration the high risk of pulmonary edema [6, 12, 15, 16].

ESC IIbC (LoE C, GoR 5)

ESC IC (LOC C, LOE 5)

3.6 Pulmonary hypertension associated with left heart disease (Group II)

Left heart disease is one of the most frequent causes of PH: group II accounts for 65–80% of all cases of elevated mPAP. The post-capillary PH hemodynamic type is associated with high mortality [6, 12, 20]. This form of PH is observed in left ventricular function disorders – HFpEF and HFrEF, mitral and aortic valve diseases, congenital/acquired cardiovascular diseases [33, 34, 251, 252].

Data on the prevalence of PH vary depending on the detection method (echocardiography or RHC) and left heart pathology: in patients with HFrEF and HFpEF, it is 40–72% and 36–83%, respectively [33, 34, 116]. Combined post- and pre-capillary PH occurs in 12–38% of cases [6, 15]. In patients with valvular heart disease, PH is detected in 65% of patients with aortic stenosis according to echocardiography and in almost all patients with mitral stenosis, as well as in the majority of patients with significant mitral regurgitation [20, 33, 34, 253]. The mortality risk increases as PVR rises: in patients with HFrEF, HFpEF, and valvular pathology, PVR >5 Wood units indicates the presence of a pronounced pre-capillary component and has an unfavorable prognostic value, which should be taken into account in patients who have undergone surgical valve correction, heart transplantation, or left ventricular assist device implantation, as well as when referring patients to expert PH centers [31, 112, 254].

In the pathophysiology of PH due to left heart disease, mechanisms such as a passive increase in left ventricular filling pressure and retrograde pressure transmission to the pulmonary circulation vasculature; endothelial dysfunction as a cause of pulmonary artery vasoconstriction and pulmonary vascular remodeling of both venules and/or arterioles; right ventricular dilatation/dysfunction with the development of relative tricuspid regurgitation; and impaired pulmonary artery-right ventricle coupling are distinguished [255, 256].

Group II PH can develop according to two scenarios: with predominant left heart involvement ("left ventricular phenotype") or remodeling of both the left and right sides of the heart ("right ventricular phenotype"). The latter is associated with high mortality. When performing RHC, it should be kept in mind that loop diuretics can decrease PCWP. The most challenging task is differential diagnosis between PH associated with HFpEF and PAH (Table 17 (Appendix B1).

In patients with left heart disease, PH may be caused by other etiologies – CTEPH or PAH, concomitant pulmonary diseases (COPD, obstructive sleep apnea, etc.). Patients with PH associated with HFpEF may have a low DLCO value, which is an independent predictor of prognosis [116, 252].

• Before evaluation for suspected severe PH in all patients with left heart disease, it is recommended to optimize the treatment of the underlying condition [18, 19, 257].

ESC IC (Level of Evidence A, Grade of Recommendation 1)

Comment. RHC should be performed in expert centers after achieving a stable condition through treatment optimization. Diuretics remain the cornerstone of medical therapy in the presence of fluid retention in patients with left heart disease [12, 15, 33, 34, 258].

ESC IC (LoE C, GoR 5)

Comment. In patients with group II PH, clinical symptoms and physical examination findings may be determined by both the underlying disease and elevated mPAP. The presence of pulmonary venous congestion indicates possible left ventricular dysfunction (see Section 5.1.1). Elevated BNP/NT-proBNP is observed in both left- and right-sided heart failure [31, 33]. Echocardiography allows for differential diagnosis, determination of the PH hemodynamic variant, and assessment of right ventricular dysfunction [60–64]. Diagnostic information will be supplemented by ECG, imaging modalities, and cardiopulmonary exercise testing [12, 112]. Patients with an unclear diagnosis and a predominant pre-capillary component (PVR >5 Wood units) should be referred to expert centers for individualized decision-making.

ESC IC (LoE C, GoR 5)

Comment. Invasive hemodynamic assessment should be performed in expert centers in patients in a clinically stable condition resulting from optimized therapy. Indications for RHC in patients with group II PH include: suspected PAH or CTEPH; suspected severe PH with a pronounced pre-capillary component in HFpEF; evaluation prior to heart transplantation [12, 31]. Hemodynamic parameters (mPAP, PVR, pulmonary artery compliance, transpulmonary and diastolic pressure gradients) in patients with PH due to left heart disease have been shown to be associated with clinical outcomes [12, 31, 116, 257]. The most informative of these is PVR [116]. In patients with a high probability of combined post- and pre-capillary PH with normal resting PCWP, a fluid challenge test should be considered within an expert center [259].

• In patients with PH due to left heart disease with combined post- and pre-capillary PH and borderline PCWP (13–15 mmHg), it is recommended to consider additional fluid challenge testing to rule out a post-capillary component [116, 259].

ESC IIbC (Level of Evidence B, Certainty of Evidence 3)

ESC IC (LoE C, GoR 5)

ESC IIIA (LoE C, LoR 5)

Comment. Patients with PH due to left heart disease are not indicated for PAH-specific therapy. Its efficacy has been evaluated in small, short-term studies and RCTs, which generally showed no reduction in morbidity or improvement in clinical outcomes, while a number of patients experienced fluid retention and an increased rate of hospitalizations due to worsening chronic heart failure [116, 257, 28]. However, the administration of PAH-specific drugs may be discussed in patients with combined post- and pre-capillary PH with a pronounced pre-capillary component in the setting of clinical trials under the supervision of specialists from an expert PH center.

ESC IC (LoE C, GoR 5)

ESC I C (LoE C, GoR 4)

3.7 Pulmonary hypertension associated with lung diseases and/or hypoxemia (Group III)

PH is frequently observed in patients with COPD and/or emphysema, ILD, combined pulmonary fibrosis and emphysema, and obesity-hypoventilation syndrome [35, 36, 125]. In patients with sleep-related breathing disorders, PH is rare in the absence of concomitant pathology – COPD or daytime hypoventilation [12]. It is believed that at altitudes >2500 m, hypoxia-induced PH develops in 0.5% of the population, which is associated with geographical and genetic factors [36, 37, 157, 158].

In patients with lung disease, PH is classified based on hemodynamic assessment as non-severe or severe. Previously, severe PH was defined as mPAP >35 mm Hg or mPAP ≥25 mm Hg combined with CI <2.5 L/min/m² [6, 15]. Currently, PVR >5 WU has been shown to be the optimal threshold for predicting adverse outcomes in patients with PH in both COPD and ILD [260]. Non-severe PH is prevalent in the early stages of COPD and ILD by spirometric criteria, whereas severe PH occurs in 1–5% of patients with COPD and 32 to 85% <10% of patients with advanced stages of ILD [261–263]. This wide range in prevalence reflects different disease stages, with PH being more frequent at later stages. It should be noted that even non-severe PH in lung diseases negatively affects patient symptoms and survival and is associated with an increased hospitalization rate [264–266]. The development of severe PH is generally independent of respiratory function parameters and is typically accompanied by hypoxemia and/or hypercapnia and a significant decrease in DLCO [267].

In patients with lung diseases, CTEPH or PAH should be excluded [125]. Comorbid cardiac conditions are also common in patients with lung diseases and may contribute to the development of PH. Various PH phenotypes are distinguished in patients with lung disease, including the pulmonary vascular phenotype, which is characterized by better preservation of spirometric parameters, low DLCO, and hypoxemia [35, 125, 268, 269].

ESC/RSC IC (LOE C, GOR 5)

ESC/RSC IC (LOE C, GOR 5)

• When PH is suspected in patients with lung disease, it is recommended to perform echocardiography combined with acid-base balance and blood gas analysis, assessment of unforced respiratory volumes and flows, diffusing capacity of the lungs for carbon monoxide (DLCO), and chest CT [6, 12, 15].

ESC IC (LOE C, GOR 5)

Comment. When PH due to pulmonary pathology and/or hypoxemia is suspected, the following should be considered: presence of risk factors for PAH or CTEPH; clinical signs and disease course features (e.g., rapid deterioration after a stable multi-year course, oxygen requirement); PFTs, including DLCO and arterial blood gas analysis; NT-proBNP levels; ECG, echocardiography, imaging data using CT pulmonary angiography or lung scintigraphy, and, in selected cases, MRI to assess the need for RHC. Cardiopulmonary exercise testing (CPET) is necessary to assess respiratory or heart failure in patients with lung diseases [125], although data on its clinical utility for identifying patients with PH in lung diseases are limited.

ESC IC (LoE C, SoR 5)

Comment. Indications for RHC in PH due to lung diseases include evaluating the feasibility of surgical treatment (when considering lung transplantation and lung volume reduction surgery), suspected PAH or CTEPH, and cases where additional information will aid in disease phenotyping and treatment selection [12, 269, 270]. Invasive evaluation is preferably performed at expert PH centers once a clinically stable state is achieved through optimization of treatment for the underlying lung disease.

ESC IC (Level of Evidence C, Grade of Recommendation 4)

ESC IC (LOE C, GOR 2)

Comment. Therapeutic approaches for group III PH are based on optimizing the treatment of the underlying lung disease, including oxygen therapy and non-invasive positive pressure ventilation when indicated, as well as participation in pulmonary rehabilitation programs [125]. There are limited and contradictory data regarding the use of drugs approved for the treatment of non-severe PH, with potential adverse effects on hemodynamics, exercise tolerance, gas exchange, and outcomes in this category of patients [6, 12].

• The prescription of PAH-specific drugs is not recommended for patients with non-severe PH associated with lung diseases [6, 12, 15, 16].

ESC / RSC IIIC (LOE C, GOR 5)

Comment. Studies on the use of drugs approved for PAH treatment in PH associated with COPD or emphysema have shown conflicting results and are mostly limited by small sample sizes, short duration, and insufficient hemodynamic characterization of PH [6, 12, 125]. Due to the lack of large RCTs, there is currently insufficient evidence to recommend PAH-approved drugs for patients with PH associated with COPD. COPD patients with suspected or confirmed severe PH should be referred to PH centers for individualized decision-making. Phase 2 and 3 studies evaluating ERA or sildenafil in patients with PH associated with ILD yielded negative results [6, 15]. The results of several RCTs involving patients with PH associated with COPD were also negative [12]. However, there is currently robust evidence on the benefits of sildenafil in patients with ILD [270], demonstrating improved survival, pulmonary function tests, and increased exercise tolerance in patients receiving this therapy.

ESC/RSC IC (LOE C, GOR 5)

ESC/RSC IIaC (LOE C, GOR 4)

ESC / RSC IIIB (LOE B, GOR 2)

Comment. When prescribing ambrisentan** to patients with ILD with/without PH, unfavorable safety signals related to an increased risk of clinical worsening were observed [271].

ESC/RSC IIIB (LOE B, GOR 2)

Comment. The use of riociguat** was associated with an increased risk of clinical worsening events, including mortality risk, in patients with PH associated with idiopathic interstitial pneumonias [272].

3.8 Pulmonary hypertension associated with pulmonary artery obstructions (Group IV)

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by post-thromboembolic obstructive remodeling of pulmonary artery branches combined with secondary distal pulmonary vascular disease of the lesser circulation, leading to pre-capillary PH [6, 12, 38, 44]. In the absence of precise epidemiological data, the incidence of CTEPH is estimated to be 5–15 cases per million population per year [12, 21, 38, 123]. The frequency of CTEPH is 0.1–9.1% during the first two years after an episode of symptomatic PE [57, 89]. In the differential diagnosis of CTEPH, other causes of pulmonary artery obstruction (pulmonary artery sarcoma, tumor cell embolism, parasitic (echinococcal) cysts, foreign body emboli, congenital or acquired pulmonary artery stenoses) should be excluded.

The diagnosis of CTEPH is based on the evaluation of a patient presenting with dyspnoea and/or reduced exercise tolerance, performed at least three months after therapeutic anticoagulation therapy, when pre-capillary PH criteria are met (mPAP >20 mm Hg, PAWP <15 mm Hg, and PVR >2 WU) combined with imaging evidence of post-thromboembolic pulmonary artery lesions via CT pulmonary angiography and/or selective pulmonary angiography (pulmonary angiography) and/or the presence of perfusion defects on lung perfusion scintigraphy in the absence of ventilation defects [12]. In the presence of post-thromboembolic pulmonary artery lesions on imaging in patients without pre-capillary PH, chronic thromboembolic disease (CTED) is diagnosed [38, 125].

CTEPH is a rare late complication of PE, while the impact of most classical risk factors for venous thromboembolism on the development of CTEPH has not been confirmed. An association with the development of CTEPH has been demonstrated for such prothrombotic conditions as antiphospholipid syndrome, polycythemia vera, splenectomy, homozygous carriage of the coagulation factor V gene polymorphic variant, high-dose hormone replacement therapy for hypothyroidism, presence of intracardiac devices, inflammatory bowel disease, and active cancer. These conditions, along with a history of recurrent venous thrombosis, involvement of large pulmonary artery branches during acute PE with signs of right ventricular overload, should be considered risk factors for the development of CTEPH [12, 43, 273].

Clinical symptoms of CTEPH are nonspecific; a quarter of patients have no history of a PE episode, and dyspnea develops gradually, which hinders timely diagnosis of the disease [274]. For early diagnosis of CTEPH, it should be taken into account that acute PE may develop against the background of pre-existing CTEPH in the patient. This can be indicated by such signs as an estimated sPAP > 60 mm Hg according to echocardiography and signs of CTEPH on CT [44, 88].

Persistence of complaints of decreased exercise tolerance and dyspnea three months after anticoagulant therapy following a PE episode, especially in the presence of CTEPH risk factors, requires performing an echocardiography and assessing the probability of PH in the patient [275]. If the probability of PH according to echocardiography is low and the symptomatic patient has CTEPH risk factors, it is advisable to perform cardiopulmonary exercise testing for differential diagnosis of dyspnea and selection of patients for further examination, including RHC [101, 276-279].

Chest CT with intravenous bolus contrast enhancement is an important tool for differential diagnosis and assessment of operability in a patient with CTEPH [81, 82, 88, 281, 282]. Alternative perfusion imaging methods, such as perfusion map generation using dual-energy CT or MRI, have diagnostic potential but limited availability, which hampers their multicenter validation. RHC combined with selective pulmonary angiography (pulmonary angiography) is performed in an expert center and is a mandatory diagnostic method to verify the diagnosis of CTEPH, assess patient operability, and determine the treatment strategy [283-285].

The algorithm for examining a patient with suspected CTEPH/CTED is presented in Figure 4 (Appendix B1).

In the treatment of CTEPH patients, a multimodal approach is used, opting for surgical treatment in all technically operable patients; inoperable patients are prescribed specific therapy approved for the treatment of PAH patients: given the precapillary nature of PH with the presence of distal pulmonary vasculopathy in CTEPH, the use of PAH-specific therapy is justified [38, 44, 52, 283]. If technically feasible, patients undergo sessions of balloon pulmonary angioplasty [285-287].

ESC IC (RR S, ELD 5)

ESC IC (RR S, ELD 5)

Comment. Pulmonary endarterectomy (PEA) is considered the mainstay of treatment for CTEPH, with mortality rates in major European centers of ≤3.5% [38, 273, 283, 284]. Three-year survival of patients after PEA is 90% [38, 52, 273]. The decision on patient operability is made by a multidisciplinary team (cardiologist/pulmonologist specializing in PH, radiologist, cardiovascular surgeon, and endovascular surgeon) at a PH expert center with sufficient experience in surgical and endovascular treatment, prescribing and evaluating the efficacy of PAH-specific therapy in this category of patients [6, 12, 38]. A patient is declared inoperable if the decision is made by at least two independent expert centers. Criteria for patient selection for surgical treatment include the accessibility of thrombi in the main, lobar, or segmental pulmonary arteries. Patient age is not a contraindication to surgical treatment, nor is the magnitude of PVR and the presence of RV dysfunction.

ESC IC (LoE C, GoR 5)

Comment. Unlike surgical embolectomy for acute PE, CTEPH patients undergo bilateral endarterectomy of the pulmonary artery branches under deep hypothermia and circulatory arrest [284, 288-291]. Postoperative reperfusion pulmonary edema may require venoarterial ECMO [38, 44, 292].

In many CTEPH patients, combined treatment approaches are used — a combination of PEA, endovascular and medical treatment, while the choice of methods and their sequence is determined by the anatomical variant of pulmonary artery lesions, the severity of pulmonary circulation hemodynamic disorders, and the comorbidity profile [52, 273, 293-296]. In case of refusal of surgery in a potentially operable patient with a proximal pulmonary artery lesion (main and lobar pulmonary arteries), five-year survival is significantly reduced to 53% compared to 83% in patients after PEA [297]. Some experience has been accumulated indicating the efficacy of PEA in patients with CTED in terms of improving exercise tolerance, while the decision on the need for surgical treatment should be made with a careful risk/benefit analysis [12, 38, 44, 273].

• Patients with CTEPH 3–6 months after pulmonary endarterectomy are recommended to undergo a comprehensive examination, including right heart catheterization [6, 38, 123, 273].

ESC IC (RR S, ELD 5)

Comment. The efficacy of PEA should be evaluated 3–6 months after surgical treatment by assessing pulmonary circulation hemodynamics. Residual PH after PEA develops in 25–36% of patients. Based on data from a small number of observational studies and RCTs evaluating the efficacy of PAH-specific therapy, the criteria for residual PH after PEA should be considered: mPAP > 25 mm Hg, PAWP < 15 mm Hg, and PVR > 4 Wood units [294-296, 298, 299]. According to Russian experts, it is advisable to use the adopted criteria for precapillary PH as criteria for residual PH after PEA: mPAP > 25 mm Hg, PAWP < 15 mm Hg, and PVR > 3 Wood units.

Further follow-up of patients should be carried out annually with non-invasive risk stratification [300-302].

ESC IC (RR S, ELD 5)

RCS IIIC (LoE C, GoR 5)

Comment. Patients with CTEPH are indicated for lifelong anticoagulant therapy. Given the lack of RCT data comparing the efficacy of vitamin K antagonists (VKAs) and DOACs, priority in prescription should be given to VKAs (provided optimal patient adherence to therapy and the possibility of monitoring the international normalized ratio (INR) with target values of 2.5–3.5. This expert opinion is supported by data from several observational studies indicating a higher frequency of recurrent thrombosis when using DOACs compared to VKAs in patients with CTEPH [38, 303, 304]. In patients with CTED, the decision on long-term anticoagulant therapy is made individually after additional examination and assessment of the risk of recurrent venous thrombosis [38, 275].

ESC IC (LoE C GoR 5)

Comment. CTEPH patients with confirmed antiphospholipid syndrome are prescribed VKA anticoagulant therapy, since there is a risk of recurrent venous thromboembolism when using DOACs [305, 306].

• The prescription of PAH-specific therapy is recommended for patients with inoperable/residual CTEPH with mPAP ≥25 mm Hg and PVR ≥3 Wood units in accordance with the evidence base for drug use [12, 44].

RRC IA (Reliability of Evidence Level C, Consistency of Evidence Level 5)

Comment. The efficacy of drugs approved for the treatment of PAH in patients with inoperable/residual CTEPH has currently been proven exclusively in patients with mean PAP ≥ 25 mm Hg and PVR ≥ 3 Wood units [44, 52].

ESC IB (LoE B, GoR 2)

Comment. According to the results of the CHEST-1 trial, riociguat** therapy for 16 weeks in inoperable patients with CTEPH (in whom PEA was not feasible) or in patients with residual PH after PEA (n=261) resulted in an improvement in 6MWD and hemodynamic parameters, including a decrease in PVR [297].

ESC IIbB (Level of Evidence B, Grade of Recommendation 2)

ESC IIbC (LoE B, GoR 2)

Comment. ERA, PDE-5i, and prostacyclin analogues have not proven efficacy in RCTs in patients with CTEPH; therefore, they can be used off-label for the treatment of inoperable patients or patients with residual PH after PEA, including as part of combination therapy [188, 309, 310]. Based on the results of RCTs, the Eurasian guidelines for the treatment of CTEPH recommend the following additional targeted drugs approved for the treatment of PAH:

— inhaled #iloprost 10 mcg every 3–4 hours via the ventilator circuit, up to 8 inhalations per day for 3–4 days, followed by the initiation of oral targeted therapy if residual PH persists, as a 2nd-line drug;

— #macitentan** 10 mg once daily or sildenafil 60 mg/day as 3rd-line drugs;

— the administration of combination therapy including riociguat** or a PDE-5i in combination with an ERA or inhaled iloprost is considered in inoperable patients when BPA is not feasible [44, 306, 308].

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. Staged BPA in inoperable patients with CTEPH when PEA is not feasible, and in patients with residual PH after PEA, has demonstrated high efficacy by improving hemodynamic parameters (reducing PVR by 49–66%), RV function, and patients' physical performance [285–287, 310–316]. The decision regarding the need for BPA is made within a multidisciplinary approach; BPA should be performed by an experienced cardiovascular surgeon/interventional radiologist specialized in X-ray endovascular diagnostics and treatment at expert centers with experience in managing CTEPH patients.

• When performing endovascular treatment in patients with inoperable/residual PH after pulmonary endarterectomy, it is recommended to perform staged interventions on a limited number of pulmonary artery branches to reduce the risk of complications [12, 15, 16, 38].

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. The most frequent complications of BPA are vessel perforation and severe reperfusion pulmonary injury [317–319]. The number of BPA sessions required to achieve a positive hemodynamic result depends on the anatomical variant of pulmonary artery involvement and the experience of the interventional radiologist [320].

ESC IIaC (Level of Evidence C, Grade of Recommendation 5)

Comment. To reduce the frequency and severity of reperfusion lung injury, according to expert opinion based on the results of the RACE trial, it is advisable to use riociguat** before BPA sessions when PVR > 4 Wood units.

[298, 311].

ESC IIbC (LoE C, GoR 4)

ESC IIaC (Level of Evidence C, Grade of Recommendation 5)

Comment. The decision to perform PEA or BPA in patients with CTEVD is made at an expert PH center with a thorough risk-benefit assessment [38, 128, 273].

ESC IIbC (LoE C, GoR 5)

Comment. In foreign practice, it is believed that the use of PAH-targeted therapy may delay surgical treatment [321]; however, according to the Russian registry, almost 80% of patients are in functional class III–IV, with manifestations of severe CHF (44.1%) [274]. This indicates that prescribing PAH-targeted therapy to technically operable CTEPH patients for 2–3 months as part of preoperative preparation to improve functional and hemodynamic status should be considered.

The treatment algorithm for CTEPH is presented in Figure 4 (Appendix B1).

3.9 Management considerations for women of childbearing potential with pulmonary hypertension

• Pregnancy is not recommended for female patients with pulmonary hypertension [6, 12, 15, 16, 44, 47, 48].

ESC IIIB (LoE C, GoR 5)

Comment. PH is associated with a high rate of maternal and perinatal mortality [15, 16]. Patients with PAH and CTEPH belong to WHO risk group IV for maternal mortality, in which pregnancy is contraindicated [322]. During pregnancy, significant adaptive changes occur in the woman's body: physiological hypervolemia and an increased heart rate lead to a significant (30% to 50%) increase in cardiac output; the tidal volume of the lungs increases by 30–40% by the end of gestation, and the respiratory rate increases by 10%. These changes can lead to PH decompensation [6, 326, 323].

ESC IC (RR S, ELD 5)

3.9.1 Contraception methods

ESC IIIC (CGR C, LOR 5)

RSC IC (LoE C, GoR 5)

Comment. Contraceptive methods are discussed individually, taking into account comorbid conditions. Given WHO maternal mortality risk group IV in PAH and CTEPH, it is recommended to use contraceptive methods with a failure rate <1% (male/female sterilization [324], etonogestrel-releasing implant, intrauterine devices [322]. Systemic hormonal contraceptives, injections, transdermal patches, vaginal rings, and diaphragms) are not recommended as a sole method, as they are ineffective in 6–12% of cases [325]. Medroxyprogesterone** and etonogestrel are preferred as they are effective and devoid of many side effects of synthetic estrogens (Section 3.2.2.2). The intrauterine therapeutic system is a modern and highly effective tool, though the risk of vasovagal reactions and infectious complications during system insertion should be considered. Barrier methods are safe for patients, but do not provide a reliable guarantee against pregnancy [6, 47]. The use of systemic hormonal contraceptives may be discussed in patients taking antithrombotic agents [15, 16].

• As an effective method of emergency contraception, it is recommended to use levonorgestrel after unprotected intercourse [324, 325].

RSC IC (LoE C, GoR 5)

Comment. Levonorgestrel is prescribed at a dose of 1.5 mg once within 72 hours after unprotected intercourse (failure rate 1.1%).

3.9.2 Pregnancy management in patients with pulmonary hypertension

Managing the diagnosis and treatment of pulmonary hypertension (PH) during pregnancy presents significant difficulties related to limited diagnostic capabilities and the choice of pharmacotherapy. Currently, there are no uniform, harmonized approaches globally to the management of pregnant women with PH due to ethical considerations regarding large randomized, placebo-controlled multicenter clinical trials; therefore, all available recommendations generally carry a level of evidence C, based on expert opinion and the experience of individual centers.

ESC IC (LoE C, GoR 5)

Comment. According to the modified WHO risk stratification classification for cardiovascular complications, pregnant women with PH belong to risk category IV, in which pregnancy is contraindicated [15, 323]. A patient with PAH should be offered either pregnancy termination or early delivery (depending on the gestational age). Medical abortion should be performed up to 22 weeks of gestation in a specialized center [322]. The optimal gestational age for termination is 10±3 weeks [15, 324, 328]. Termination at later stages carries risks of complications comparable to those of early delivery at 32–34 weeks of gestation. Medical and surgical methods of pregnancy termination are equally effective and comparable in the incidence of serious complications. However, according to literature data, surgical procedures are performed more frequently (2.1 vs. 0.6%) [329]. Medical abortion is advisable to consider up to 9 weeks of gestation using low doses of #misoprostol (100 mcg) [323].

• In the event of refusal to terminate the pregnancy / undergo early delivery, it is recommended that the patient's pregnancy be managed by a multidisciplinary team with regular monitoring and delivery in specialized level III perinatal centers [15, 323].

ESC IC (LoE C, GoR 5)

Comment. In case of refusal of pregnancy termination/early delivery, the patient is managed as a pregnancy at high risk of cardiovascular complications, including fatal ones, with the participation of a multidisciplinary team consisting of a cardiologist, obstetrician-gynecologist, anesthesiologist-resuscitologist, pediatrician, and a PH specialist [15, 322, 323]. Examination of the pregnant woman by a cardiologist (echocardiography, 6-minute walk test, blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) assay, and pulse oximetry) is performed every 2–4 weeks, and weekly if necessary (in the third trimester of pregnancy in case of pregnancy prolongation) [324]. If signs of clinical deterioration of PAH appear at any stage of pregnancy, hospitalization of the patient in a specialized center is indicated [322, 323].

ESC IC (LoE C, GoR 5)

ESC IIbC (Level of Evidence C, Level of Certainty 5)

ESC IC (LE C, LoE 5)

ESC IIbC (Level of Evidence C, Grade of Recommendation 5)

Comment. Preference is given to low-radiation-dose CT (0.01–0.66 mGy) [323].

ESC IIaC (LE C, LoE 5)

ESC IIaC (LE C, LoE 5)

Comment. The scope of PAH-specific therapy (monotherapy or combination therapy) is determined based on mortality risk stratification [10]. PDE-5 inhibitor sildenafil at a starting dose of 20 mg 3 times/day is often used as a first-line drug. The administration of inhaled iloprost during pregnancy and after delivery is indicated for patients with WHO FC III-IV. In the subgroup of patients with a positive vasoreactivity test, CCB therapy must be initiated [6, 15, 49, 322].

ESC IIIC (LE C, LoE 5)

ESC IC (LE C, LoE 5)

ESC IC (LE C, LoE 5)

• In pregnant women with PAH who did not receive anticoagulant therapy before pregnancy, it is possible to consider prescribing low-molecular-weight heparins (ATC heparin group) in prophylactic doses throughout the entire pregnancy [6, 15, 323, 329].

ESC IIbC (LE C, LoE 4)

ESC IIIC (Level of Evidence C, Level of Certainty 5)

ESC IIaC (CCE C, LoE 5)

Comment. Lactation is a metabolically demanding process; in the postpartum period, patients with PAH/CTEPH require early optimization of specific therapy with drugs excreted in breast milk. Lactation is suppressed using standard doses of cabergoline (0.25 mg every 12 h for 2 days) or bromocriptine** (2.5 mg on the day of delivery, then 2.5 mg twice daily for 14 days) [15, 323].

ESC IC (LoE C, GoR 5)

Comment. Key issues relate to the timing and mode of delivery, and the postpartum management plan (need for mechanical circulatory support, stay in the intensive care unit). Vaginal delivery is the preferred mode of delivery, given the lower risks of hemorrhagic, infectious, and thromboembolic complications, as well as less pronounced hemodynamic changes compared to Cesarean section. It is considered that patients with WHO FC III-IV PAH/CTEPH can be delivered operatively with monitoring of central hemodynamics and blood gas composition [6, 15, 322, 324]. In many specialized centers, it is recommended to perform early delivery at 34–36 weeks of gestation, with the minimum recommended gestational age for delivery being 32 weeks, and the maximum (provided the pregnancy is proceeding normally and the patient is hemodynamically stable) being 37–38 weeks [328, 329].

• In the postpartum period, it is recommended to use nitric oxide or inhaled iloprost** [15, 323].

RSC IC (LoE C, GoR 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

See Section 3.1 General Recommendations, Physical Activity and Rehabilitation.

5. Prevention and Dispensary Observation

ESC IC (LoE C, GoR 5)

Comment. Assessment of clinical status in every patient is essential for evaluating disease severity / risk stratification and should be performed by a physician at every visit. A sequential evaluation is required for the dynamics of the patient's symptoms (severity of dyspnea, presence of syncope, chest pain, peripheral edema, presence/character of cardiac arrhythmias), changes in exercise tolerance, and adherence to the recommended therapy. Patients with PAH in WHO FC III–IV should be advised to keep a blood pressure, heart rate, and weight log for review at follow-up visits. Physical examination includes assessing signs of right ventricular HF and peripheral blood oxygen saturation via pulse oximetry. The interview and physical examination result in the determination of the WHO FC, which, despite its subjective nature, has a high predictive value [15, 146]. An increase in FC is a key indicator of disease progression and warrants investigating the causes of clinical deterioration [12].

ESC IC (RR S, ELD 5)

Comment. The 6MWD in meters is recorded as an absolute value and used for risk stratification, with the change in distance between visits being evaluated. However, its prognostic value remains debated: according to the REVEAL registry, a decrease in 6MWD by more than 15% was associated with an unfavorable prognosis [147]. When performing the 6MWT, the severity of dyspnea should additionally be assessed using the Borg scale (Table 23, Appendix G), along with monitoring the dynamics of peripheral blood oxygen saturation, blood pressure, and heart rate during exertion [103, 148].

ESC IC (LoE C, GoR 5)

Comment. Echocardiography remains an accessible and safe tool for the follow-up of PH patients (Section 2.4) [6, 12, 15, 16]. Prognostic parameters for PAH patients continue to include right atrial (RA) area and the presence of pericardial effusion; left ventricular (LV) eccentricity index, right-to-left ventricular diameter ratio, and RV contractile function should also be taken into account. When echocardiography is inconclusive, cardiac MRI is recommended for PAH patients to precisely assess stroke volume (SV) and cardiac output (CO) [12]. The most informative prognostic indicators are reduced RV ejection fraction, LV end-diastolic index, and LV end-systolic index [12, 94, 95].

ESC IC (LoE C, GoR 5)

• Performing RHC should be considered in PAH patients 3–6 months after adjusting PAH-specific therapy or upon clinical deterioration [6, 15, 16].

ESC IIaC (LoE C, GoR 5)

• Performing RHC is recommended to be considered in stable PAH patients every 6–12 months [12].

ESC IIbC (Level of Evidence C, Level of Certainty 5)

Comment. Currently, there is a lack of evidence supporting the routine performance of RHC to achieve better outcomes in PAH patients. However, there is expert consensus on the necessity of performing RHC when revising PAH-specific therapy or discussing atrial septostomy and/or lung transplantation waitlist placement. The indications for RHC during the routine follow-up of stable patients remain a matter of debate. Approaches vary across expert centers, ranging from regular invasive hemodynamic assessment to a predominantly non-invasive monitoring strategy.

• Cardiopulmonary exercise testing (CPET) should be considered 3–6 months after adjusting PAH-specific therapy [6, 10, 15, 16].

ESC IIaC (LoE C, GoR 5)

• Cardiopulmonary exercise testing (CPET) may be considered every 6–12 months in stable PAH patients or upon clinical deterioration [12].

ESC IIbC (LoE C, GoR 5)

Comment. Integral indicators of pulmonary gas exchange efficiency, such as peak oxygen uptake and ventilatory equivalent for carbon dioxide, possess the highest prognostic value [15, 16, 105]. VO₂peak <11.4 mL/min/kg and VE/VCO2 >45 are associated with low survival in PAH patients [148].

ESC IC (LoE C, GoR 5)

Comment. BNP/NT-proBNP levels correlate with the severity of RV myocardial dysfunction and provide prognostic information both at diagnosis and during follow-up [12]. BNP/NT-proBNP concentrations exhibit high variability; therefore, results should be interpreted in the clinical context. Although BNP correlates more closely with pulmonary circulation hemodynamics and is less dependent on renal function, NT-proBNP appears to be a stronger prognostic marker [149].

ESC IC (RR S, ELD 5)

Comment. During follow-up visits of stable PAH patients, acid-base balance and blood gas analysis may be replaced by pulse oximetry assessment [12].

RSC IC (LoE C, GoR 5)

The follow-up examination algorithm is presented in Table A3.5 (Appendix A3).

6. Organization of Medical Care

6.1. Indications for elective hospitalization:

• Verification of the etiology and hemodynamic type of PH;

• Performing a vasoreactivity test (in patients with newly diagnosed IPAH, HPAH, or drug/toxin-induced PAH);

• Determining indications for the initial PAH-specific therapy strategy;

• Determining indications for lung or heart-lung transplantation;

• Pregnancy and childbirth;

• Extracardiac surgical interventions;

• Ineffective outpatient PAH-specific therapy.

6.2. Indications for emergency hospitalization:

• PAH complications requiring intensive care: decompensated right ventricular HF with systemic hypotension and/or oliguria;

• Acute pulmonary embolism;

• Pulmonary hemorrhage;

• Hemodynamically significant arrhythmias/conduction disorders;

• Recurrent syncopal states

6.3 Indications for patient discharge from the hospital:

− Hemodynamic stability without inotropic support;

− Transition to oral diuretics.

6.4 Other organizational technologies

When evaluating the performance of a medical organization providing care to PH patients, it is advisable to analyze the following indicators:

• percentage of patients who underwent an adequate evaluation according to the level of the medical organization;

• percentage of patients who underwent RHC at an expert center prior to the initiation of PAH-specific therapy;

• percentage of patients with newly diagnosed IPAH/HPAH/drug- or toxin-induced PAH who underwent a vasoreactivity test prior to prescribing specific therapy at an expert center;

• percentage of PAH patients whose PAH-specific therapy strategy was chosen in accordance with risk stratification;

• percentage of patients who underwent extracardiac surgical interventions in an expert center setting;

• percentage of PAH patients managed in outpatient settings by a cardiologist or PH specialist;

• percentage of patients provided with PAH-specific therapy within one month after verification of the diagnosis of PAH/CTEPH;

• percentage of patients for whom indications for lung or heart-lung transplantation were determined in a timely manner;

• percentage of patients with CTEPH referred to an expert center to determine indications for PEA, BPA, or medical therapy.

7. Additional Information

Goals of treatment for PH patients:

• achieving low-risk criteria (<1% or <5% 1-year mortality for PAH patients depending on thresholds);

• correction of all modifiable risk factors (prevention of intercurrent infections, prevention of pregnancy, optimal management of comorbidities, etc.);

• delaying progression and/or reducing the frequency of hospitalizations related to PAH/CTEPH through regular monitoring and timely adjustment of specific and supportive therapy.

Criteria for Evaluating the Quality of Medical Care

• presence of a detailed clinical diagnosis of the PH form in accordance with ICD-10, indicating the functional class (WHO);

• compliance with the examination standard according to the level of the medical institution (Table 21, Appendix B1);

• verification of the diagnosis or determination of referral routing to an expert center;

• risk stratification for mortality;

• justification for the choice of PAH-specific therapy strategy;

• justification for surgical treatment in PAH/CTEPH patients;

• presence of recommendations for outpatient patient management.

• timely referral of pregnant women with PH to an expert center;

• referral of a patient with PAH/CTEPH to an expert center for extracardiac surgery.

PH Expert Center Criteria

• Availability of a multidisciplinary team of specialists (cardiologist, pulmonologist, radiologist, anesthesiologist-resuscitologist, cardiovascular surgeon, endovascular diagnostics and treatment specialist, rheumatologist, medical psychologist); individual specialists (e.g., pulmonologist, rheumatologist, medical psychologist, obstetrician-gynecologist, etc.) may be involved in the multidisciplinary team from other institutions! [6, 15, 16, 44].

ESC IC (CARR C, LE 5)

• Capability for prompt redirection to specialized departments (rheumatology), performance of pulmonary endarterectomy, surgical correction of congenital heart disease, lung or heart-lung transplantation [6, 15, 16, 44].

ESC IA (CARR C, LE 5)

• Follow-up of at least 50 patients with a verified diagnosis of PAH/CTEPH and at least two newly diagnosed cases of PAH/CTEPH monthly [6, 15, 16, 44].

ESC IIaC (CARR C, LE 5)

• Performance of at least 20 vasoreactivity tests per year in patients with IPAH, HPAH, and drug/toxin-associated PAH [6, 15, 16].

ESC IIaC (LoE C, GoR 5)

• Conducting phase II and III clinical trials in patients with PH [6, 12, 15, 16].

ESC IIaC (CARR B, LE 2)

Quality evaluation criteria for primary health care delivered to adults with pulmonary hypertension (ICD-10 codes: I27.0, I27.2, I27.8)

Quality evaluation criteria for specialized medical care delivered to adults with pulmonary hypertension (ICD-10 codes: I27.0, I27.2, I27.8)

References

Appendix A1. Working Group Composition

1. Avdeev Sergey Nikolaevich (Moscow). Russian Respiratory Society

2. Barbarash Olga Leonidovna (Kemerovo). Russian Society of Cardiology

3. Valieva Zarina Soltanovna (Moscow). Russian Society of Cardiology / Russian Medical Society for Arterial Hypertension

4. Volkov Alexander Vitalievich (Moscow). Association of Rheumatologists of Russia

5. Veselova Tatyana Nikolaevna (Moscow). Russian Society of Roentgenologists and Radiologists

6. Galyavich Albert Sarvarovich (Kazan). Russian Society of Cardiology

7. Goncharova Natalia Sergeevna (Saint Petersburg). Russian Society of Cardiology

8. Gorbachevsky Sergey Valerievich (Moscow). Association of Cardiovascular Surgeons of Russia

9. Gramovich Vladimir Vladimirovich (Moscow). Russian Society of Cardiology / European Association of Cardiovascular Imaging / Eurasian Association of Cardiology

10. Danilov Nikolay Mikhailovich (Moscow). Russian Society of Cardiology / Russian Medical Society for Arterial Hypertension

11. Klimenko Alesya Alexandrovna (Moscow). Association of Rheumatologists of Russia

12. Martynyuk Tamila Vitalievna (Moscow). Russian Society of Cardiology / Eurasian Association of Cardiology

13. Moiseeva Olga Mikhailovna (Saint Petersburg). Russian Society of Cardiology

14. Ryzhkova Daria Viktorovna (Saint Petersburg). Russian Society of Nuclear Medicine

15. Simakova Maria Alexandrovna (Saint Petersburg). Russian Society of Cardiology

16. Sinitsyn Valentin Evgenievich (Moscow). Russian Society of Roentgenologists and Radiologists

17. Stukalova Olga Vladimirovna (Moscow). Russian Society of Roentgenologists and Radiologists

18. Chazova Irina Evgenievna (Moscow). Russian Society of Cardiology / Eurasian Association of Cardiology

19. Chernogrivov Igor Evgenievich (Moscow). Association of Cardiovascular Surgeons of Russia

20. Shmalts Anton Alekseevich (Moscow). Association of Cardiovascular Surgeons of Russia

21. Tsareva Natalia Anatolievna (Moscow). Russian Respiratory Society

The members of the working group confirmed no financial support / conflict of interest. If a conflict of interest was reported, the working group member(s) was (were) excluded from the discussion of sections related to the area of conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Cardiologist

2. Pulmonologist

3. Rheumatologist

4. Anesthesiologist-resuscitologist

5. Cardiovascular Surgeon

6. Radiologist

7. General Practitioner (Family Doctor)

Since the RSC is part of the European Society of Cardiology (ESC) and RSC members are also members of the ESC, all European guidelines are formulated with the participation of Russian experts who are co-authors of the guidelines. Thus, existing ESC guidelines reflect the consensus of leading Russian and European cardiologists.

Therefore, the formulation of national guidelines was carried out on the basis of ESC guidelines, taking into account national specifics, features of examination, treatment, and the availability of certain medical care. For this reason, during the development of Russian clinical practice guidelines by the RSC, international classes of recommendation were used to assess the necessity of performing the recommendation statement and the levels of confidence of data for these classes (Tables A2.1 and A2.2).

In cases where the European guidelines lacked classes and levels of evidence, but in the opinion of RSC experts these statements were extremely necessary for implementation or, conversely, absolutely not recommended for use, the RSC experts, based on the rules for forming recommendation classes according to the ESC guidelines, assigned the classes and levels themselves. In such situations, the ESC designation is replaced with RSC – classes and levels assigned by RSC experts.

In addition, a new system of scales for Levels of Evidence (LE) and Grades of Recommendation (GR) for therapeutic, rehabilitative, preventive interventions and diagnostic interventions (Tables A2.3, A2.4, and A2.5) introduced in 2018 by the Center for Expertise and Quality of Medical Care of the Russian Ministry of Health was added. Thus, the text of clinical practice guidelines developed by RSC experts simultaneously uses two scales (Tables A2.1–A2.5).

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months

Table A2.1. Classes of recommendations according to the European Society of Cardiology (ESC) guidelines.

Table A2.2. Levels of evidence according to the European Society of Cardiology (ESC) guidelines.

Table A3.3. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table A3.4. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitative interventions)

Table A3.5. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitative interventions)

Appendix A3. Reference Materials

Table A3.1. Starting and maximum doses of PAH-specific drugs

Note: *Dose delivered through the inhaler mouthpiece

Table A3.2. Distribution of drugs and toxins according to the risk level of pulmonary arterial hypertension development [6, 11]

Table A3.3. Main formulas for calculating hemodynamic parameters

Table A3.4. Probability of PH associated with left heart disease

Table A3.5. Follow-up monitoring of PAH patients

Notes: Follow-up intervals should be adjusted based on the clinical situation, PAH etiology, risk category, and comorbidities.

2

Basic laboratory tests include a complete blood count (CBC) with differential, INR (in patients receiving vitamin K antagonists), general clinical blood chemistry, and brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) assay

3

Additional laboratory tests (blood thyroid-stimulating hormone (TSH) level, blood troponin I and T levels, blood troponin T level, uric acid level, serum iron level, serum ferritin level, transferrin saturation) are performed depending on the patient's clinical features.

4

Assessment of acid-base balance and blood gases should be performed during the initial evaluation, while pulse oximetry may be used as a substitute during follow-up in stable patients.

Table A3.6. Diagnostic findings in patients with various forms of PH

Notes: HFpEF — heart failure with preserved ejection fraction; HFrEF — heart failure with reduced ejection fraction; sPAP — systolic pulmonary arterial pressure; VTE — venous thromboembolism; CTEPH — chronic thromboembolic pulmonary hypertension; DLCO — diffusing capacity of the lungs for carbon monoxide; RA — right atrium; RV — right ventricle; PA — pulmonary artery; PH — pulmonary hypertension; PaO₂ — partial pressure of oxygen; PaCO2 — partial pressure of carbon dioxide; PETCO2 — end-tidal partial pressure of carbon dioxide; EOV — oscillatory exercise ventilation phenomenon; VE/VCO2 — ventilatory equivalent for carbon dioxide; IPAH — idiopathic pulmonary arterial hypertension; LHD — left heart disease signs; PVOD — pulmonary veno-occlusive disease; V/Q SPECT — ventilation-perfusion single-photon emission computed tomography

Table A3.7. Recommendations on the efficacy of PAH-specific monotherapy (PAH Group I)

* With a positive vasoreactivity test in patients with IPAH/HPAH, PAH-l/t — dihydropyridine derivatives or diltiazem in maximally tolerated doses

Table A3.8. Recommendations on the efficacy of sequential combination PAH-specific therapy (PAH Group I) *

Table A3.9. Recommendations on the efficacy of initial combination PAH-specific therapy (PAH Group I) *

Table A3.10. Implementation of the diagnostic standard according to the level of the medical institution

Appendix B. Physician Action Algorithms

Figure 1. Diagnostic algorithm for pulmonary hypertension

Figure 2. Treatment algorithm for PAH (IPAH, HPAH, drug-/toxin-induced PAH, residual PAH after correction of simple systemic-pulmonary shunts,

CTD-PAH

Notes: 1. Oral PAH-specific therapy (ERA, PDE5i, riociguat, selexipag)

2. Decision on therapy escalation in 3–4 months to evaluate treatment outcomes

3. Presence of three or more risk factors for left heart disease

(arterial hypertension, type 2 diabetes mellitus, coronary artery disease, obesity, atrial fibrillation) or presence of lung disease combined with DLCO <45%

4. In case of severe adverse events, iloprost can be switched to selexipag**

Figure 3. Diagnostic algorithm for chronic thromboembolic pulmonary hypertension and chronic thromboembolic pulmonary disease

Notes: *using lung perfusion scintigraphy or lung perfusion scintigraphy combined with chest CT or selective pulmonary angiography (angiopulmonography); ** Signs of CTEPH/CTEPD on cardiopulmonary exercise testing: exercise capacity limitation and impaired pulmonary perfusion (decreased PETCO₂, increased P(a-ET)CO₂, EQ O₂, EQ CO₂, VE/VCO₂ slope or P(A-a)O₂); *** Coronary angiography if indicated.

Figure 4. Treatment algorithm for chronic thromboembolic pulmonary hypertension [12]

Appendix C. Patient Information

Pulmonary hypertension is a condition characterized by elevated pressure in the pulmonary vasculature resulting from various causes and diseases. Most frequently, pulmonary hypertension (PH) develops secondary to pre-existing heart, lung, or thrombotic conditions, and systemic connective tissue diseases. Less common causes of PH include chronic liver diseases and HIV infection. However, situations arise where the cause of PH cannot be identified; such cases are termed idiopathic pulmonary arterial hypertension (IPAH).

Symptoms of PH are non-specific and typically characterized by exertional dyspnea that progresses over time, generalized fatigue, and palpitations. Chest pain, dizziness, and exertional syncope are extremely unfavorable symptoms. Furthermore, the appearance of lower extremity edema, abdominal distention, and jugular venous distention and pulsation indicate severe right heart failure and signify an advanced stage of the disease.

PAH affects individuals of all ages and races, both men and women. Physicians of various specialties may diagnose and manage PH. The scope of diagnostic tests for PH is quite extensive and primarily includes echocardiography, pulmonary function testing, contrast-enhanced chest computed tomography, comprehensive abdominal ultrasound, and various blood tests. Identifying the etiology of PH may require consultations with a pulmonologist, rheumatologist, or infectious disease specialist. However, cardiologists possess the most extensive experience in managing PH patients, particularly those working in specialized centers equipped to perform cardiac catheterization—an essential procedure required to confirm the final diagnosis and determine patient management strategy.

Fundamentally, three hemodynamic variants of PH are distinguished, differing in pressure levels within the heart chambers and pulmonary artery: precapillary (arterial), postcapillary (venous), and mixed (arterial + venous) pulmonary hypertension. Determining the hemodynamic variant is only possible via invasive testing—cardiac catheterization. This procedure is crucial for verifying the diagnosis of pulmonary hypertension, establishing its type, and determining the feasibility of prescribing calcium channel blockers or PAH-specific medications (see List of Abbreviations). The presence of venous (postcapillary) pulmonary hypertension is a contraindication for PAH-specific therapy, as it is associated with increased hospitalizations for worsening heart failure and higher mortality.

Depending on its etiology, PAH can manifest at various ages and progress at different rates: either gradually, against the background of a pre-existing disease (congenital heart disease, scleroderma, pulmonary pathology, etc.), or quite rapidly in a patient without apparent causes, as seen in idiopathic PAH.

Given that exertional dyspnea is a primary symptom of pulmonary hypertension, patients with PH need to adjust their daily physical activity. Most patients living with pulmonary hypertension find that the active lifestyle they are accustomed to becomes beyond their capabilities. Priorities should be set between urgent matters and tasks that can wait, helping to focus on essential goals. Objectives must be realistic, with adequate time allocated for their completion. Advance travel planning and allowing ample time prevent rushing and exacerbating PH symptoms. Eventually, most patients have to leave their previous employment and seek less demanding work.

It is currently not established how physical exercise affects the prognosis of pulmonary hypertension. There are no specific physical therapy programs designed specifically for patients with pulmonary arterial hypertension. The scope of permissible safe physical activity is determined after a comprehensive evaluation at an expert PAH center by a cardiologist specializing in PAH. Competitive sports and heavy weightlifting are discouraged for patients with PAH. In most cases, the level of permitted physical activity is determined by the symptoms of the disease. Furthermore, discussing physical activity is only appropriate for patients who are on optimal PAH-specific therapy and free from symptoms such as dizziness/syncope, arrhythmias, hemoptysis, and lower extremity edema.

You should follow these rules to avoid harm: physical exercise must be stopped if signs such as general weakness, fatigue, a feeling of chest tightness, rapid heartbeat, dizziness, or excessive shortness of breath occur. Allow sufficient recovery time between exercises. Avoid outdoor physical activity during low or high temperatures or high humidity.

Patients with pulmonary arterial hypertension should avoid saunas and other forms of hydrotherapy, as well as massage and physiotherapeutic procedures.

Patients with pulmonary arterial hypertension are advised against staying at high altitudes (above 2,000 meters above sea level) or engaging in scuba diving.

It is recommended that you inform your family members and close friends about your diagnosis. Support from loved ones, both practically and emotionally, can significantly ease the daily burden and emotional strain. Consulting a medical psychologist and actively participating in patient support groups can positively influence your acceptance of the disease, adaptation to the uncertainty associated with a serious, chronic, life-threatening condition, and constructive collaboration with your attending physician.

Pregnancy is contraindicated for female patients with pulmonary arterial hypertension due to the high risk of maternal mortality both during pregnancy and in the postpartum period. Even in the event of a successful delivery, the course of pulmonary arterial hypertension significantly worsens postpartum. A pregnant patient with pulmonary arterial hypertension should be consulted by a PAH specialist cardiologist at an expert perinatal center as early as possible after pregnancy is detected to determine management tactics. It should be borne in mind that most PAH-specific medications can cause malformations and developmental anomalies in the fetus. Nevertheless, the extent of PAH-specific therapy during pregnancy is determined by the severity of the disease and the risk of mortality. Since breastfeeding places a heavy burden on the body, suppression of lactation is recommended for patients with pulmonary arterial hypertension.

If surgery is planned, a consultation with a PAH specialist cardiologist at an expert center is necessary. It is important to understand that the decision regarding the feasibility, timing, and methods of anesthesia must be made by a multidisciplinary team including a cardiologist, an anesthesiologist-intensivist, and the operating surgeon. Regional anesthesia is preferred over general anesthesia. Whenever possible, patients with PAH should be referred to major PH expert centers for elective surgical procedures.

Patients with PAH are susceptible to developing pneumonia, which can be fatal. Vaccination against influenza, pneumococcus, and SARS-CoV-2 is recommended. Exceptions may include patients with systemic connective tissue diseases and HIV infection, for whom vaccination decisions must be made taking into account the activity of the underlying pathology by rheumatologists and infectious disease specialists.

There are no specific diets or foods that can worsen the disease in pulmonary hypertension.

If edema develops in patients with PAH, dietary salt and fluid intake should be restricted. Table salt contains sodium, which regulates fluid balance in the body. When tissue fluid increases, blood volume also increases, which is accompanied by an increased workload on the heart. The permissible volume of fluid intake is determined individually by the attending physician, but most.of the time should not exceed 2 liters per day.

The following tips can help normalize fluid balance:

You should measure your fluid intake throughout the day, at least for the first few weeks. Two liters of fluid equals approximately 8 cups. Soups, ice cream, and gelatin must also be counted as fluids. Weight gain is one of the first signs of fluid retention. You must weigh yourself daily in the morning on an empty stomach and record your weight. If you gain 2 kg or more in a week while maintaining the same diet, you must notify your physician.

If dizziness or syncope occurs or recurs during physical exertion, or if you experience hemoptysis or palpitations, you should immediately inform your attending physician.

A pulmonary hypertension specialist can answer all questions related to the diagnosis of "pulmonary hypertension," lifestyle, and treatment in detail.

There is currently no cure for PH. However, there are targeted medications designed specifically for patients with pulmonary arterial hypertension. Regular intake of these drugs leads to a decrease in pulmonary vascular resistance and improved blood filling of the left chambers of the heart, which is accompanied by a reduction in shortness of breath and an increase in exercise tolerance. A PH specialist selects treatment appropriate to the patient's condition. All PH patients are different, so therapy is selected individually.

A patient with an established diagnosis of PH requires careful outpatient follow-up. The frequency of visits depends on the patient's baseline condition and can range from 1 month from the start of PAH-specific therapy (see List of Abbreviations) to 3–6 months. Regular medication intake strictly according to the treatment regimen is required. If diuretics are prescribed, daily monitoring of weight and diuresis is necessary; for warfarin**, monthly INR monitoring; when prescribing endothelin receptor antagonists (ATX antiplatelet agents except heparin) (bosentan**, ambrisentan**), monthly liver function tests (general clinical blood biochemistry) and hemoglobin level control 3 months after the start of therapy.

Pulmonary arterial hypertension is not a contraindication for air travel. However, patients with low resting oxygen saturation (<92% by pulse oximetry) should inform the airline of their potential need for oxygen support during the flight.

It is important for all patients traveling by air to other countries to carry medical documents regarding their diagnosis, the location of the nearest local PH center, and contact information for it.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Risk assessment* in patients with pulmonary arterial hypertension

Original title (if applicable): Comprehensive risk assessment in pulmonary arterial hypertension (three-strata model)

Source (official developer website, validation publication):

ESC/ERS Scientific Document Group, Humbert M. et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the 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 the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG) //European heart journal. – 2022. – Т. 43. – №. 38. – С. 3618-3731.

Type (underline): rating scale

Purpose: comprehensive risk assessment in patients with pulmonary arterial hypertension

Content (template):

Notes: In the cardiac MRI protocol, the following parameters indicate low, intermediate, and high risk of mortality — RV ejection fraction >54%; 37–54%; <37%, respectively; stroke index >40 mL/m²; 26–40 mL/m²; <26 mL/m²; RV end-systolic volume index <42 mL/m²; 42–54 mL/m²; >54 mL/m2, respectively [12].

Key (interpretation): in the table itself

Appendix G2. Borg Dyspnea Scale

Russian title: Subjective rating scale for perceived exertion (Borg scale) (Borg scale)

Original title: Borg rating of perceived exertion scale (RPE scale)

Source (official developer website, validation publication): https://www.brianmac.co.uk/borgscale.htm Borg GA (1982). "Psychophysical bases of perceived exertion". Med Sci Sports Exerc. 14 (5): 377–81. doi:10.1249/00005768-198205000-00012

Type (underline): rating scale

Purpose: Subjective assessment of exercise tolerance

Content: The patient receives instructions on how to rate dyspnea during exertion: from 0 points — calm breathing, no sensation of shortness of breath, up to 10 points — maximal dyspnea.

Key (Interpretation): compared with the results of a previous test (before therapy, during therapy, etc.)