Diagnosis and Treatment of Pulmonary Hypertension

Pulmonary hypertension (PH) is a hemodynamic and clinical state defined as an increase in mean pulmonary arterial pressure ≥25mmHg at rest. Five groups of patients have been defined: group 1 as pulmonary arterial hypertension (PAH), group 2 as PH due to left heart disease, group 3 as PH due to lung diseases, group 4 as chronic thromboembolic PH, and group 5 as PH of other causes. PAH is a rapidly progressive and fatal disease with an incidence of 3 cases per million whereas incidence of PH due to left ventricular dysfunction is as high as 60-70% of all cases. Pulmonary capillary wedge pressure, invasively measured at rest, has been used to distinguish between pre(≤15mmHg ) and post-capillary (>15mmHg) PH. The early clinical symptoms and signs are subtle and non-specific, such as exertional dyspnea, fatigue, pre-syncope and progressive limitation of exercise capacity so the vast majority of patients have an advanced disease with World Health Organization functional class of III or IV at first presentation. The diagnostic approach in PH has the goal to evaluate the two main anatomic components: pulmonary vasculature and right ventricle in order to establish the diagnosis and identify the group of PH. The therapy for PAH patients includes three main components: general measures and supportive therapy; initial therapy with calcium channel blockers in vasoreactive or specific drugs approved for PAH in non-vasoreactive patients either single or in combination, and lung transplantation. All patients with PAH should be referred to PH expert centers for comprehensive diagnostic and therapeutic assessment.


Definition
Pulmonary hypertension (PH) is an increase of the mean pressure in the pulmonary artery (mPAP) and its value ranges from 25mmHg upwards.Depending on the hemodynamics, it is crucial to differentiate between "precapillary" and "post-capillary" PH.
Pre-capillary PH implies mPAP ≥25mmHg and pulmonary capillary pressure (PCWP) ≤15mmHg, which is why this type of hypertension is referred to as pulmonary arterial hypertension (PAH).On the other hand, post-capillary PH is defined as an increase of mPAP ≥25mmHg, whereas PCWP >15mmHg and it is commonly the PH resulting from the left heart weakness. 1e increase of pulmonary vascular resistance (PVR) is the basis of vascular pathophysiology in PH and it results in the escalation of pressure in pulmonary artery, which further causes pressure-load in the right ventricle (RV).Compensatory mechanisms induce the right ventricular dilatation so the basic determinants of symptomatology and patient prognosis are actually the pulmonary arterial pressure values and RV function.

Classification of pulmonary hypertension
Over the last decade, there have been a few changes in PH classification, especially when it comes to specific groups of patients.The most recent classification was adopted at the 2013 World Symposium on Pulmonary Hypertension held in Nice, according to which PH is divided into five groups with clearly defined sub-categories (Table 1). 1 Table 1.Clinical classification of pulmonary hypertension.At the moment of PAH diagnosis, more than 90% patients have already experienced changes in heart and lung X-rays although these changes are of poor sensitivity. 3,4Typical changes are as follows: "lifting" of heart top due to right ventricular hypertrophy, right ventricular enlargement, the expansion of the main branch of pulmonary artery and/or right interlobar artery, and significant reduction of peripheral pulmonary vascular network.High-Resolution Computed Tomography (CT) provides us with pertinent information on potential changes in pulmonary parenchyma and enables us to eliminate emphysema, bronchitis and interstitial lung disease diagnosis, infarction, and vascular and pericardial malformations.It may also be useful to diagnose pulmonary veno-occlusive disease with typical pulmonary abnormalities such as "milk glass image", interstitial edema and bilateral interlobular septal thickening. 7eaking of the acute pulmonary embolism diagnosis, the CT angiography has been a widely used method of choice and it has practically replaced the ventilationperfusion lung scan.[10] The criterion for diagnosing CTEPH on a V/Q scan is at least one massive defect after a minimum three-month effective anticoagulation therapy.The V/Q scan is 90-100% sensitive and 94-100% specific for diagnosing CTEPH.Possible errors for diagnosing CTEPH are caused by minor perfusion-like defects or nonsegmental perfusion abnormalities typical of otherwise caused PAH and pulmonary veno-occlusive disease. 11In addition, the classical segmental perfusion defects may disappear during the CTEPH terminal stage. 12Perfusion scintigraphy appears nonsegmented in cases of large central thrombotic masses in Eisenmenger syndrome or thrombus within aneurysm of pulmonary trunk or pulmonary artery branches in idiopathic PAH. 13 Laboratory tests of blood, and biochemical and immunological tests are an integral part of etiological treatment of patients suspected of PH and other organ failures.Other routine analyses are thyroid hormone values and transaminase values, particularly after introduction of endothelin receptor antagonist therapy (ERA).Serological tests are compulsory in order to diagnose potential connective tissue disease (CTD), hepatitis and human immunodeficiency virus (HIV) hidden behind PH.Up to 40% of patients suffering from idiopathic PAH have high antinuclear antibodies but in low titers (1:80). 14 most cases, TTE is an initial diagnostic method when there is a suspicion of PH, whereas right heart catheterization (RHC) is a necessary invasive diagnostic procedure for the definite diagnosis and evaluation of pulmonary vascular reactivity. 4The

Therapy
PAH therapy is a complex strategy which might be divided into three basic steps as follows: the initial approach and application of general measures, introduction of CCB therapy (only patients with positive vasoreactivity test) and/or specific PAH therapies, and finally, the third step which entails monitoring of the initial therapy response, introduction of combined PAH therapy, patient care during the terminal disease stage, and determining indications for lung transplantation.
General measures and supportive therapy.The recommendation is a regular physical activity which does not provoke symptoms and mandatory avoidance of severe physical exhaustion.6][17] patients are advised to have influenza and pneumococcal pneumonia vaccines as these cause 7% of total deaths with this group of patients. 14,15H supporting therapy entails the oral anticoagulant therapy, oxygen therapy, right heart insufficiency therapy, and correction of anemia syndrome.7][18] It is well-known that PAH patients also suffer from coagulation disorder and physiological fibrinolysis so it is crucial to take into account risks of venous thromboembolism (heart weakness and immobilization) and hemorrhage before the introduction of oral anticoagulant therapy.9][20] The oxygen therapy is indicated in all PAH patients with pO2 <60mmHg (8kPA) as hypoxia is one of major causes of vasoconstriction and this therapy decreases PVR.The usage of diuretics is indicated in all PAH patients with signs of right heart weakness or water retention.Digoxin improves stroke volume only in cases of acute aggravation in patients suffering from idiopathic PAH but its efficiency has not been proven for chronic usage. 21Digoxin is administered to PAH patients with acute aggravation primarily in order to slow down ventricular response in cases of atrial cardiac rhythm disturbance.The usage of ACE inhibitors, sartans, beta blockers and ivabradine is not recommended except in cases when these are an irreplaceable comorbidity therapy (eg.arterial hypertension, coronary heart disease).3][24] Eisenmenger patients are a particularly sensitive group because frequent and unfounded venipuncture cause these patients severe anemia syndrome, which further increases mortality rates. 25Therefore, prior to venipuncture, these patients should be examined by cardiologists specialized in PAH treatments. 26ecific therapy.The specific PAH patient therapy covers the following classes of medications: CCB, endothelin receptor antagonists (ERA), phosphodiesterase type 5 inhibitors (PDE-5i) and guanylate cyclase stimulators (sGC), prostacyclin analogues and prostacyclin receptor antagonists.It is well-known that only few patients suffering from idiopathic PAH have positive vasoreactivity test, which is the only indication for CCB therapy.The CCBs used in PAH therapy are nifedipine, diltiazem and amlodipine.In addition, their regular dosage is 120-240mg for nifedipine, 240-720mg for diltiazem and up to 20mg for amlodipine, depending on tolerance.4Endothelin receptor antagonists (ERA) are widely used in PH therapy due to the fact that these patients also suffer from activation in endothelial cells in both plasma and pulmonary tissue although it is still not quite clear if the increase of plasma endothelin-1 level causes PH or results from it. 27,28ERA medications used in current PH therapy for diagnostics and treatment of PAH are ambrisentan, bosentan and macitentan. 4e fact that pulmonary vascular network contains certain amounts of phosphodiesterase type 5 is the basis for the application of PDE-5i in PH therapy due to both consequential vasodilatation and antiproliferative effect.All three PDE-5 inhibitors approved for treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil) cause massive vasodilatation of pulmonary vascular network. 29,30Unlike PDE-5i, sGC (riociguat) increases cyclic guanosine monophosphate production (cGMP) and causes vasodilatation and antiproliferative effect. 31he efficiency of riociguat application in PH therapy has been proven positive when combined with ERA or prostanoid therapy in 2.5mg three times per day dosage in sense that it improves functional capacities of patients as well as hemodynamic parameters. 32Combination of riociguat and PDE-5i therapies is contraindicated due to strong hypotension.Balloon atrial septostomy (BAS) is a palliative method of PH treatment which results in the interatrial rightleft shunt targeting at the right heart decompression, improvement of left heart function, and enhancement of stroke volume.5][36] In addition, the treatment is optional for patients awaiting lung transplantation who show no significant clinical improvement after the maximum combined medicament therapy.
Ključne riječi: Plućna hipertenzija, desna komora, plućni kapilarni pritisak Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis 1**.Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 2.5 Congenital/acquired pulmonary veins stenosis 3. Pulmonary hypertension due to lung disease and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary disease with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude Picture 1 displays the usage of continuous-wave Doppler (CW) in order to show regurgitation of tricuspid (Picture 1, A) and pulmonary (Picture 1, B) valves in PAH patients.Systolic pressure in pulmonary artery (SPAP) equals the right ventricle systolic pressure (RVSP) and it is calculated on the basis of maximum speed of tricuspid regurgitation (TRPV) and estimated right ventricle pressure (RAP) in line with the following formula: RVSP = SPAP = 4xTRPV2 + RAP.The evaluation of the right atrial pressure (RAP) is performed on the basis of diameter of vena cava inferior (VCI) and respiratory variations of its diameter: with IVC >2.1 cm diameter and <50% diameter collapse with deep inspirium, the evaluated RAP is 15 mmHg (Picture 1, C).The diastolic pulmonary arterial pressure (DPAP) is calculated on the basis of the end-diastolic velocity of the pulmonary regurgitation (PRVED) in line with the following formula: DPAP = 4xPRVED2 + RAP (Picture 1, B).The mean pulmonary arterial pressure (MPAP) is calculated on the basis of systolic and diastolic pressures in line with the following formula: MPAP = 1/3 SPAP + 2/3 DPAP.[4][5][6]

Table 2 .
World Health Organization (WHO) functional class of patients with PAH.
Pulmonary function tests and analysis of arterial blood gas may identify the presence of respiratory diseases and pulmonary parenchyma illness.Patients suffering from PAH usually have mild to moderate lung volume reduction depending on the disease severity.The carbon monoxide diffusing capacity (DLCO) less than 45% is a bad prognosis sign and its differential diagnosis with PAH patients may indicate pulmonary veno-occlusive disease, PAH associated with scleroderma and parenchymal pulmonary disease.The chronic obstructive pulmonary disease which causes hypoxic PH is diagnosed on the basis of the irreversible airflow obstruction accompanied by an increase of residual volume, DLCO decrease, partial oxygen pressure (PaO 2 ), and increase of partial pressure of carbon dioxide (PaCO 2 ).
The transthoracic echocardiogram (TTE) is a widespread non-invasive cardiovascular diagnostic procedure pertinent for PAH patients as it helps set diagnosis and monitor the patients.TTE enables us to acquire a whole range of information as follows: evaluation of systolic, mean and diastolic pulmonary artery pressures, analysis of morphology and function of right ventricle and estimation of echocardiographic predictors of clinical outcomes in PAH patients.Graph 1. Algorithm for diagnosing pulmonary arterial hypertension (PAH).*p*adapted from: Galie N et al.Eur Heart J. 2016;37(1):67-119.(4)PH, pulmonary hypertension; RV, right ventricle; V/Q scan, a lung ventilation-perfusion scan; RHC, right heart catheterization; mPAP, Mean Pulmonary Arterial Pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; CTEPH, Chronic thromboembolic pulmonary hypertension , CT, a computed tomography Picture 1. Echocardiographic evaluation of pulmonary artery pressure.