Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a complex and multifactorial syndrome, partly unknown, characterized by a profound alteration of pulmonary vasculature and, consequentially, a rise in the pulmonary vascular load, leading to hypertrophy and remodeling of the right heart chambers. The World Health Organization assembles the several forms of PH into five clinical groups: group 1 includes pulmonary arterial hypertension, previously defined as idiopathic forms, group 2 is PH due to left-sided heart diseases, group 3 PH due to lung diseases, hypoxia, or both, group 4 due to pulmonary-artery obstruction, and group 5 PH, which includes forms with multifactorial or unclear mechanisms. In this chapter, we would like to delineate the clinical and hemodynamic definitions of PH and, for each group, we will describe the pathophysiological mechanisms, the diagnostic pathway, and the pharmacological approach and treatment. Finally, we would also like to focus on the latest trials and future therapeutic perspectives for this disease.

1. Introduction

Pulmonary hypertension (PH) is a complex and multifactorial syndrome, partly unknown, characterized by a profound alteration of pulmonary vasculature and, consequentially, a rise in the pulmonary vascular load, leading to hypertrophy and remodeling of the right heart chambers.

1.1 Basic principles of pulmonary circulation

Pulmonary circulation, includes a vast network of arteries, veins, and lymphatic vessels and is unique, both in function and volume: it is a low-pressure, low-resistance, highly distensible system, and it is capable of accommodating large increases in blood flow with none or minimal elevations of its pressure. During embryonic life, the pulmonary circulation is a low-flow and high-resistance circuit. After birth, once the baby takes his first breath, the high resistance in the lungs drops dramatically: from now on, blood can enter lungs for oxygenation. Oxygen relaxes the pulmonary vessels and causes closure of the fetal shunts: at this precise moment, the baby’s blood flow is identical to that of an adult [1]. Therefore, this vasculature dilates, in order to take in the entire cardiac output (CO), with high blood flow at low intravascular pulmonary arterial pressure (PAP). Anatomically, pulmonary arteries have thinner walls with less smooth muscle and lack of basal tone: this happens because of the elevated production of endogenous vasodilators and low production of vasoconstrictors from the endothelium of the pulmonary vessel walls. These mechanisms result in the maintenance of a normal pulmonary vascular resistance (PVR) [2]. Pulmonary circulation differs functionally from the systemic one because it carries mixed venous blood. Deoxygenated blood is channeled through the pulmonary artery directly in the alveolar/capillary units where gas exchange occurs and blood releases carbon dioxide and is replenished with oxygen. Then, oxygenated blood is carried back to the left atrium by the pulmonary veins, in order to be distributed to the systemic circulation.

1.2 Physiological bases of hemodynamic classification

In order to better understand the hemodynamic classification of PH, we should recall Poiseuille’s law, one of the most important laws of fluid dynamics (1):

$$\mathit{Q}=\left({\mathit{P}}_1-{\mathit{P}}_2\right)\mathit{\times }\pi {\mathit{r}}^4/8\mathit{\mu }\mathit{l}$$E1

Where Q is flow (l/min) and then Cardiac Output (CO), if we apply the equation to the pulmonary circulation; P₁ is mean pulmonary arterial pressure (mPAP), the pressure at the beginning of the pulmonary circulation, P₂ is the pulmonary artery wedge pressure (PAWP) equivalent to the left atrial pressure, the pressure at the end point of the pulmonary circulation, when measured at right heart catheterization in the absence of pulmonary vein stenosis. 8μl/πr⁴ is a measure of the pulmonary vasculature resistance (PVR).

According to Poiseuille’s law, pulmonary vasculature resistance (PVR) is inversely related to the fourth power of arterial radius: in this equation, l represents the length of the vessel, r its radius, and μ the viscosity of the fluid, in our case, blood. PVR is used to characterize PH because this parameter allows us to quantify abnormalities of the pulmonary vasculature, as it is mainly related to the anatomical geometry of small distal arterioles of the lung. PVR can also be expressed as (2):

$$\mathrm{PVR}=\left(\text{mPAP}–\text{PAWP}\right)/\mathrm{CO}$$E2

Therefore, PVR reflects the functional status of pulmonary vascular endothelium/smooth muscle cell coupled system, and it is also positively related to blood viscosity. Additionally, PVR may be influenced by changes in perivascular alveolar and pleural pressure. According to Poiseuille’s law mPAP depends on cardiac output, left atrial pressure, and PVR (3)

$$\text{mPAP}=\left(\mathrm{CO}\times \mathrm{PVR}\right)+\text{PAWP}$$E3

whereas pressure does not depend on the size of the body, and PAP from different patients can be evaluated without considerable differences in their body size [3, 4]. PAWP is an acceptable estimate of left atrial pressure (LAP) or left ventricular end-diastolic pressure (LVEDP) in the absence of mitral stenosis or pulmonary vein stenosis. Furthermore, PAWP and LVEDP are usually considered to be interchangeable, even if some pathological scenarios, such as atrial fibrillation, rheumatic disease, or large diameter of the left atrium are associated with a PAWP higher than LVEDP. PAWP and LVEDP measurements should be obtained at the end of the expiratory phase and the end of the diastolic phase, QRS gated [4].

2. Haemodynamic classification of PH

According to the European Society of Cardiology 2015 guidelines, PH is defined as an increase in mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest as assessed by right heart catheterization (RHC). Available data have shown that the normal mPAP at rest is 14 ± 3 mmHg with an upper limit of normal of approximately 20 mmHg [5]. This definition was updated at the sixth world symposium of PH, held in 2018 in Nice: the mPAP threshold was lowered from ≥25 to >20 mmHg [6]. Whatever the mPAP cut-off value considered for defining PH, it is important to emphasize that this value used in isolation cannot characterize a clinical condition and does not define the pathological process per se. According to Poiseuille’s law mPAP depends on cardiac output, left atrial pressure, and PVR (4).

$$\text{mPAP}=\left(\mathrm{CO}\times \mathrm{PVR}\right)+\text{PAWP}$$E4

Then, mPAP elevation may have several different causes with different prognoses and treatments, including high cardiac output syndromes (anemia, left−to−right shunts, AV fistula, and thyrotoxicosis.) or diseases characterized by high PWAP (left heart diseases) or high PVR because of pulmonary vascular disease [6]. Specifically, precapillary pulmonary hypertension due to pulmonary vascular disease is hemodynamically defined by a pulmonary artery wedge pressure (PAWP) ≤15 mmHg and an elevation in PVR of at least three wood units (WU).

Precapillary hypertension contrasts with postcapillary PH in which the PVR is less than 3 WU and the elevation in the mPAP is due to elevated filling pressures on the left side of the heart (PAWP > 15 mmHg) [7].

Postcapillary PH is further subclassified on the basis of the PVR, into isolated postcapillary PH (PAWP > 15 mm Hg and PVR < 3 WU) and combined pre- and post-capillary PH (PAWP > 15 mm Hg and PVR ≥ 3 WU). (See Table 1).

Definitions	Characteristics
Pre-capillary PH	mPAP > 20 mmHg
	PAWP ≤ 15 mmHg
	PVR ≥ 3 WU
Isolated post-capillary PH	mPAP > 20 mmHg
	PAWP > 15 mmHg
	PVR < 3 WU
Combined pre- and post-capillary PH	mPAP > 20 mmHg
	PAWP > 15 mmHg
	PVR ≥ 3 WU

Table 1.

Haemodynamic classification of PH.

3. Clinical classification of PH

Besides the haemodynamic classification, the clinical classification of PH is relevant and very helpful to choose the appropriate therapeutic pathway and, consequentially, estimate the prognosis of patients. Since the first world symposium of PH held in 1973, the clinical classification has been reviewed many times: in fact, due to the remarkable spread of PH in the last 40 years, new scientific pieces of evidence have been discovered, leading to a necessary update in the classification. The actual clinical classification was defined by the World Health Organization in 2018, during the Sixth World Symposium in Nice and it includes five major groups, classified according to similar clinical presentation, pathological findings, hemodynamic features, and treatment approaches (see Table 2).

1. Pulmonary arterial hypertension (PAH)	3. PH due to lung diseases and/or hypoxia
1.1 Idiopathic PAH	3.1 Obstructive lung disease
1.2 Heritable PAH	3.2 Restrictive lung disease
1.3 Drug- and Toxin-induced PAH	3.3 Other lung disease with mixed restrictive/obstructive pattern
1.4 PAH associated with	3.4 Hypoxia without lung disease
1.4.1 Connective Tissue Diseases	3.5 Developmental lung disorders
1.4.2 HIV infection
1.4.3 Portal Hypertension	4. PH due to pulmonary artery obstruction
1.4.4 Congenital Heart Disease	4.1 Chronic thromboembolic PH (CTEPH)
1.4.5 Schistosomiasis	4.2 Other pulmonary artery obstructions
1.5 PAH long-term responders to calcium channel blockers
1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement	5. PH with unclear and/ or multifactioral mechanisms
1.7 Persistent PH of the newborn syndrome	5.1 Hematological disorders
2. PH due to left heart diseases	5.2 Systemic and metabolic disorders
2.1 PH due to heart failure with reduced LVEF (HFrEF)	5.3 Others
2.2 PH due to heart failure with preserved LVEF (HFpEF)	5.4 Complex congenital heart diseases
2.3 Mitral and/or Aortic valve diseases
2.4 Congenital or acquired cardiovascular conditions leading to post-capillary PH

Table 2.

Updated clinical classification of pulmonary hypertension, according to the 6th PH world symposium of 2018, Nice, France.

Specifically, each group includes:

• Group 1: Pulmonary arterial hypertension (PAH)

• Group 2: PH due to left-sided heart disease

• Group 3: PH due to lung disease, hypoxia, or both

• Group 4: PH due to pulmonary artery obstruction

• Group 5: PH with multifactorial or unclear mechanisms

Making a correct diagnosis of PH is very complex, challenging, and time-demanding, and it can only be made in high expertise centers by a multidisciplinary team of cardiologists, pneumologists, radiologists, and rheumatologists. Diagnostic tools, include EKG, echocardiogram, blood tests analysis, pulmonary function test with diffusing lung capacity test for carbon monoxide, high-resolution CT scan, lung ventilation/perfusion scan, and right heart catheterization (RHC). RHC represents the gold standard for the final diagnosis: while performing it, the expert specialist should also complete the procedure, including a vasoreactivity test with short-acting selective vasodilators agents, in order to predict if patients will respond to treatment. At this point, after ruling out any other causes of increased mPAP, the diagnosis of PAH can be made, as it is a diagnosis of exclusion.

We will now analyze the various groups of PH based on their prevalence.

3.1 PH associated with left heart diseases (group 2)

3.1.1 Epidemiology

Due to the prevalence of left heart diseases in the general population, group 2 PH represents the most prevalent form of PH, responsible for 65% of PH cases [8]. Mostly, it is associated with heart failure (HF), but it can also be a complication in patients with left-side heart valvular and congenital diseases. The exact prevalence of PH is still not known because of variabilities in PH definitions with predominant echo-based literature data and referral bias. It has been estimated that about 60% of patients with heart failure with reduced ejection fraction (HFrEF) have pulmonary hypertension at presentation, while in patients with left ventricular diastolic dysfunction the prevalence of PH is 83% [8, 9].

3.1.2 Pathophysiology

The pathophysiology of this type of PH is multifactorial but mainly based on the effect of the hydrostatic pressure on the pulmonary vasculature, resulting in its change and remodeling. Both types of cardiac heart failure (preserved and reduced ejection fraction), other than valvular disease and congenital heart disease can lead to a passive increase of pressure in the left atrium (LA), and consequently, a decrease in its compliance. The LA has a key role in maintaining normal pulmonary pressure because it constitutes the connection between pulmonary circulation and systemic circulation, through the left ventricle [9]. Any increase in the LA pressure even mild perturbates the pulmonary hemodynamics. According to the Poiseuille’s law, the increase of pressure in the LA, the end point of the pulmonary circulation (P₂), will results in a proportional increase of the pressure at the beginning of the pulmonary circulation (P₁), to maintain the forward flow; therefore, the increase of LA pressure will result in a proportional and passive increase of the mPAP. In addition, the increased pressure transmitted back to the pulmonary vasculature promotes significant changes in the structural anatomy. The raised backward pressure causes lung capillary and small artery stress, as the barotrauma breaks the endothelial layer and promotes fluid and protein swelling in the interstitium. Therefore, the intimal layer undergoes fibrosis and the tunica media undergoes hypertrophy [10]. In this setting, the endothelium plays a central role in the local control of tone through the regulated release of nitric oxide (NO) and endothelin (ET): the dysregulation of pulmonary vascular tone involves alterations in these important counterbalancing systems, causing a decrease in the production of endogenous vasodilators NO and an increase in vasoconstrictors ET [10, 11].

The transition from alveolar-capillary stress failure to remodeling is clinically reflected by the rise of PVR in patients with long-standing post-capillary PH who develop combined pre- and post-capillary PH.

3.1.3 Impact on prognosis and clinical picture

PH due to left heart disease results in severe symptoms and worse exercise tolerance and exerts a negative impact on outcome with an evident poor prognosis. These patients are usually elderly, with a high prevalence of cardiovascular co-morbidities, such as obesity, hypertension, atrial fibrillation, diabetes, coronary artery disease, kidney disease, and metabolic syndrome [12]. The patient usually presents with symptoms related to left heart diseases, such as fatigue, exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema. The medical history can reveal a previous diagnosis of heart failure, systolic or diastolic, myocardial infarction, systemic arterial hypertension, or valvular disease (frequently mitral regurgitation). Findings of physical examination, include left-sided gallops, left-sided murmurs (particularly mitral), a displaced or sustained apical impulse, and pulmonary crackles in cases of pulmonary congestion. PH may be a cause of morbidity and mortality in patients with chronic heart failure; death and hospitalization for heart failure are greatly increased in patients with echocardiographic evidence of PH [13]. Apparently, PH has a major impact on right ventricle function, and this is a strong predictor of overall and event-free survival in chronic heart failure patients [14].

3.1.4 Therapy

After the diagnosis is made, the primary need is to start a therapy that has to focus on the global management and improvement of the underlying conditions, before treating the PH; lowering filling pressures in left-heart cavities is the goal of treatment in many forms of group 2 PH.

This can include percutaneous repair or surgery of the valvular heart disease and optimal pharmacological therapy for HF with reduced systolic function [15]. Other cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes, and obesity should be maintained under strict control. In the past years, many trials have been conducted in order to evaluate specific PAH therapies in treating group 2 PH patients: these studies were based on the idea that PH is due to a misbalance between the production of NO and ET. So, it has been supposed that ET receptor antagonists, prostanoids, and phosphodiesterase-5 inhibitors (PDE5-i) can play a role in slowing down the progression of the disease. Several trials were completed using prostanoids and ET receptor antagonists, but none of them have demonstrated the superiority of these treatments in terms of decrease in disease progression or increase in overall survival [16].

3.2 Pulmonary hypertension associated with lung diseases

PH associated with hypoxia and lung diseases is the second most common form of PH worldwide. It is associated with various lung diseases, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), obstructive sleep apnea (OSA), and, less frequently, cystic fibrosis [17] and high altitude exposure [18].

PH has a different prevalence in each of the cited lung diseases. Numerous studies in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV revealed that up to 90% of these patients have a mPAP >20 mm Hg [19]. The prevalence of PH in patients with ILD varies greatly according to the underlying disease and the severity of the disease: in idiopathic pulmonary fibrosis (IPF), mPAP values >20 mmHg was reported 8–15% of patients. Higher percentages, ranging from 30% to 50%, are found in advanced and end-stage (>60%) IPF cases [20].

3.2.1 Pathophysiology and differences of PH associated with COPD and ILD

The pathogenesis of the vascular remodeling correlated to COPD has not been fully clarified but appears to be caused by the mutual effects of hypoxia, pulmonary dysfunction with air trapping, and the toxic effects of smoking, leading to inflammation, endothelial dysfunction, and angiogenesis [21]. Hypoxia has both a direct and an indirect effect on pulmonary circulation remodeling: directly, it closes potassium channels of the smooth muscle cells, causing their contraction; indirectly, it acts on the genesis and the production of inducible transcription factors, such as hypoxia-inducible factor-1 (HIF-1), angiotensin II, and more growth factors that have a role in vasoconstriction, vascular remodeling, and neo-angiogenesis [22]. PH in ILD has a different pathogenesis: according to the latest scientific evidence, a recurring stress injury leads to impairment of epithelial cells and basement membranes, and this is consequently followed by exudation of fibrin and focal fibroblast activation and growth, resulting in fibrotic remodeling of lung parenchyma and pulmonary vessels. Specifically, all layers of the muscular pulmonary arteries show concentric and eccentric remodeling. Widespread hyperplasia is present in the intimal layer, media, and adventitia layers are thicker due to hypertrophy and/or hyperplasia of smooth muscle cells and fibroblasts, respectively [23]. Non-muscularized pulmonary arteries demonstrate neo-muscularization of the media and luminal narrowing. In response to these changes, capillary density increases in normal, non-fibrotic areas of the lungs, while in the fibrotic area of the lungs, there is vascular regression [24].

An interesting concept has been presented by Mura et al.: they were one of the first groups to compare gene expression with microarray in the lungs of patients with IPF. In this innovative study, the writers defined particular gene signatures that differentiate IPF patients with and without PH. The authors found that IPF patients without PH predominantly had a pro-inflammatory gene expression, while IPF patients with severe PH (mPAP > 40 mmHg) had a pro-proliferative gene signature expression. This study establishes a strong molecular difference between these two groups of patients, supporting the hypothesis of specific pathway activation during PH development in IPF patients [25]. Finally, with increasing evidence on certain molecular mechanisms driving PH development in IPF patients, the paradigm is slowly changing from a “passive state”, where PH development was only due to hypoxic vasoconstriction and loss of vascular bed density, to an “active process” where particular molecular and cellular pathways are involved [24].

PH can also be due to chronic up-regulation of hypoxic pulmonary vasoconstriction, caused by long-term exposure to high altitudes. This particular type of PH affects people residing at an altitude of 2500 meters or higher. The hypoxic stimulus leads to pulmonary vasoconstriction and, consequently, a rise in vascular resistance, in order to decrease perfusion of non-ventilated lung areas and increase blood flow to better-oxygenated areas. Scientific data suggests that genetics plays a role in PH predisposition, but the mechanisms are not clearly understood [18].

3.2.2 Impact on prognosis and clinical picture

PH is a poor prognostic indicator of chronic lung disease. Comparing the 5-year survival rate in patients with COPD, the survival is 36% in patients with PH, compared to the 62% in patients without PH [19]. Patients can present with a variety of symptoms, including shortness of breath, fatigue, cough, reduced exercise capacity, and syncope. Physical examination shows a louder second heart sound with a fixed or paradoxical splitting. Also, a systolic ejection murmur, increased by inspiration, may be heard over the left sternal border. Severe PH eventually leads to right ventricular failure with signs of systemic venous hypertension: this clinical condition was known as core pulmonale. The signs of right ventricular failure, include a high-pitched systolic murmur of tricuspid regurgitation, hepatomegaly, a pulsatile liver, ascites, and peripheral edema.

3.2.3 Therapy

Given the morbidity and mortality associated with PH in pulmonary diseases, there has been great interest in the treatment of these patients with pulmonary vasodilator therapy.

However, nowadays there are still no approved therapies for group 3 PH. In the last few years, many trials have been carried out, in order to examine and analyze if drugs approved for other forms of PH can play a role in the therapeutic pathway of these patients, with conflicting results. In addition to the lack of positive results in terms of prognosis, concerns have been raised about the potentially negative effect of pulmonary vasodilator therapy in worsening hypoxemia due to uncoupling of the ventilation/perfusion (V/Q) ratio in lung diseases. A few studies showed positive effects of pulmonary vasodilators, in the absence of worsening hypoxemia. For example, the SPHERIC-1 (Sildenafil and Pulmonary HypERtension In COPD), explored if Sildenafil can lower PVR and improve the quality of life of group 3 patients. After 16 weeks, the results were that sildenafil safely improved PVR, CO, and symptoms (evaluated with BODE score), in selected patients with COPD-associated severe PH [26]. In patients with ILD, several trials with pulmonary vasodilators have shown detrimental effects of these drugs in terms of symptoms and survival (i.e., Ambrisentan or Riociguat). Positive results have been shown in a randomized controlled trial involving 326 ILD-PH patients, randomized to inhaled treprostinil or placebo: in the inhaled treprostinil group, there was an improvement in exercise capacity, assessed with 6-min walking test [27]. However, more data from larger trials are needed to approve this therapy for COPD- or ILD- PH patients. Currently, therapy for group 3 PH is primarily directed at the treatment of the underlying disease, with general supportive therapy when right ventricular failure develops.

3.3 Pulmonary arterial hypertension

3.3.1 Epidemiology

Group 1 PH (or PAH) is a rare, highly complex, and progressive disorder that is incurable and ultimately can lead to premature death. PAH causes noteworthy physical, social, work, and emotional burdens among affected patients and their caregivers.

PAH affects from 15 to 50 people per million within the United States and Europe, and it usually affects women between 30 and 60 years of age [28]. However, it can occur in males and is often associated with worse clinical outcomes. The National Institutes of Health (NIH) was an important registry that collected PAH data between 1981 and 1985: it included 187 individuals, mostly Caucasian females, having idiopathic PAH. PAH-specific therapies were not available at that time, and registry participants had a median survival of 2.8 years (1 year, 68%; 3 years, 48%; and 5 years, 34%) [29]. Another milestone registry is the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), performed between 2006 and 2009 in the USA: results of this registry showed a 1-year survival rate of 91% among 2716 individuals who were enrolled. A supplementary analysis assessing long-term survival established survival rates of 85% at 3 years, 68% at 5 years, and 49% at 7 years from the time of diagnosis. The increases in survival rates were ascribed to several reasons, including availability of specific drugs, improved patient support, and hypothetically, a change in the PAH population cohort [30].

3.3.2 Pathophysiology

Group 1 PH includes many subgroups, such as idiopathic, heritable, drug, and toxin-induced, and PH associated with other diseases such as connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, and schistosomiasis. However, regardless of the primary conditions, patients show similar pathophysiological pathways, such as augmented pulmonary arterioles contractility, endothelial dysfunction, proliferation of smooth muscle cells, and the presence of in situ thrombi [31]. These lead to an increase in PVR, an increase in mPAP, and, consequently, a raise in right heart afterload. Although the right ventricle initially compensates for this augmented afterload through adaptive hypertrophy and remodeling, this process is not entirely benign and cannot be continued as overload is persistent over time; ultimately, the right ventricle dilates and fails. The ability of the right ventricle to adapt to this afterload is the key element in developing symptoms and determining survival, and eventually, it is the failure of the right ventricle that is the main cause of death in patients with PAH (Figure 1). Nowadays, three main pathways are recognized to underline these changes: nitric oxide (NO), endothelin-1 (ET1), and Prostacyclin (PGI₂). As previously explained, NO is a potent pulmonary vasodilator and it also inhibits platelet aggregation. It is produced by the NO synthetase enzyme, by converting L-arginine into L-citrulline. In PAH, there is a notable decrease in the production of NO and this causes vasoconstriction, proliferation of smooth muscle cells, inflammation, and finally thrombosis, due to the lack of platelets’ anti-aggregation properties. ET1 is a peptide produced by endothelial cells; it is a potent vasoconstrictor that stimulates smooth muscle cell division and proliferation. Its levels rise in the pulmonary and systemic circulation of PAH patients and its value negatively correlates with patients’ survival [32]. PGI₂ is a lipid mediator produced from arachidonic acid in the endothelium: its actions are similar to the NO ones, including reducing smooth muscle cell proliferation, promoting vasodilatation, and inhibiting platelets’ aggregation. PGI2 is antagonized by thromboxane A2 (TXA2), which counteracts its effects. In normal conditions, the quantities of these two peptides are in balance; instead, in PAH patients, there is an imbalance between the increased production of TXA2 and the lacking of PGI2. This causes platelet aggregation, proliferation of smooth muscle cells, vasoconstriction, and an increase in PVR. Moreover, patients with PAH have reduced production of prostacyclin as well as reduced expression of prostacyclin receptor and prostacyclin synthase [33].

Figure 1.

Pathophysiology of right ventricular failure in PAH. Pulmonary vascular remodeling, the hallmark of PAH, leads to increase RV afterload and RV wall tension. Initially, the right ventricle can cope with the increased RV afterload. Homeometric adaptation consists of adaptive hypertrophy and an increase in contractility of the RV as a response to the rise in RV afterload, with little or no dilatation, hence preserving cardiac output. However, in the long term, prolonged excessive afterload to the RV, maladaptive RV hypertrophy and ECM changes, inflammation and myocardial ischemia together lead to failure of the homeometric adaptation and consequently reduced RV contractility. This increases RV filling pressures and volume (heterometric adaptation) and an attempt to maintain stroke volume through the Starling principle. There is uncoupling of the RV from the pulmonary. RV dilatation and uncoupling, together with a significant negative interaction between the RV and LV, lead to a further increase in RV filling pressure and subsequent drop in cardiac output, precipitating a vicious cycle of events that lead to heart failure, hypotension, and shock. RV: Right ventricle and ECM: Extracellular matrix.

3.3.3 Clinical picture and prognostic factors of PAH

In the pre-symptomatic stage of PAH, increases in PVR and resting mPAP do not influence resting cardiac function, such as CO. By the time a patient presents with symptoms, even with “early” symptoms, (WHO functional class II) PVR is already significantly above normal, suggesting advanced pulmonary vascular remodeling. Many clinical symptoms or signs, such as peripheral edema and the onset of angina, can mark the moment in which the right ventricle function deteriorates. In particular, patients who begin to experience syncope or who experience an increase in the frequency of syncopal episodes have poor prognoses and require immediate attention: syncope has been proved to be an independent risk of poor survival [34]. Less common symptoms, include cough, hemoptysis, and hoarseness.

Patients must be assessed by:

• WHO functional class (FC) describes patients’ symptoms relating to their everyday activities and life. WHO-FC is a strong predictor of survival. Patients in WHO-FC I have no limitation of physical activity; WHO-FC II is characterized by minor limitation in physical activity; WHO-FC III is characterized by a manifest limitation of physical activity with no discomfort at rest; finally, WHO-FC IV is characterized by an inability to perform any physical activity, with evident signs of right ventricular failure.

• Exercise testing is measured with the 6-min walking test (6MWT) or with the cardiopulmonary exercise testing (CPET), a non-invasive method used to assess the performance of heart and lungs at rest and during exercise. CPET offers several benefits over 6MWT in assessing patients’ exercise capacity but requires specific technical equipment and must be performed by highly trained medical personnel.

• Biomarkers: the most used is brain natriuretic peptide (BNP). BNP precursor is secreted by heart cells and it is then splitted in the active BNP and a N-terminal fragment (NT-proBNP). Serum BNP/NT-proBNP levels have been exhibited to reflect right ventricular dysfunction severity in PAH, correlating with mPAP, PVR, and right ventricle mass, and inversely correlating with CO and ejection fraction [35].

• Echocardiography: many echocardiographic parameters can play a role in the assessment of PAH. One of the most important is pericardial effusion, due to decreased venous and lymphatic drainage from the myocardium [36]. Another relevant parameter is TAPSE, a measure of the right ventricular systolic function: a TAPSE<18 mm is associated with right ventricle systolic and diastolic dysfunction. Both of these factors have a great link with the prognosis of patients.

• Right heart catheterization (RHC), the gold standard method for diagnosing PAH: it should be performed at baseline and 3–4 months after the initiation of therapy, in order to understand if the patient is responding to treatment. Even if it is considered to be the gold standard, RHC has some disadvantages: it has to be performed in high expertise center and it is an invasive procedure.

Many scores can help predict survival and assess patient’s risk, such as the REVEAL 2.0 risk score, which takes into consideration 12 variables, such as demographic, comorbidities, NYHA class, vital signs, hospitalization, 6MWT, BNP, echocardiogram, RHC or the ESC/ESR score.

3.3.4 Treatment

PAH treatment is based on the severity of disease at diagnosis and on the evaluation of how the individual will respond to treatment, using a multiparametric risk stratification approach. Clinical, exercise, right ventricular function, and hemodynamic parameters are combined to outline a low-, intermediate- or high-risk status, according to the expected 1-year mortality. PAH remains a severe clinical condition, despite the availability over the past 15 years of multiple drugs interfering with the ET1, NO, and prostacyclin pathways (Figure 2). Therefore, the current progress observed in the medical therapy of PAH is not related to the detection of new pathways, but the development of new strategies of combination therapy and escalation of treatments based on clinical response.

Figure 2.

Biological pathways involved in the pathogenesis of PAH. Pre-pro-ET: Pre-pro-endothelin; pro-ET: Pro-endothelin; ET > −1: Endothelin-1ETA/ETB: ET receptor subtypes A and B; ERA: Endothelin receptor agonist; sGC: Soluble guanylate cyclase; sGCs: sGCs stimulator; PDE5: Phosphodiesterase type 5; PDE-5-i: PDE5 inhibitors; cGMP: Cyclic guanosine monophosphate (GMP); cAMP: Cyclic adenosine monophosphate; PGI2 analogues: Prostaglandin I2 analogues.

The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, or double or triple combination therapy. Additionally, treatment escalation is required in case low-risk status is not achieved in planned follow-up assessments. Usually, treatment starts with general supportive therapies: these measurements, include oxygen supplementation, supervised physical exercise, respiratory rehabilitation, diuretic therapy, and psychosocial support for the patient and his family [37]. Moreover, the fundamental milestone of the treatment is the specific therapy that address the three main specific pathways altered in PAH.

3.3.4.1 Drugs targeting the NO pathway

3.3.4.1.1 Sildenafil

It is a selective inhibitor of type 5 phosphodiesterase (5-PDEi), which specifically degrades cyclic guanosine monophosphate and its level is increased in pulmonary arteries. Normally, NO stimulates intracellular soluble guanylate cyclase resulting in increased levels of cGMP, which then acts to mediate smooth muscle relaxation; in PAH, there is a decrease in NO production from the endothelium. Therefore, sildenafil inhibits 5-PDEi, preventing degradation of cGMP and prolonging its effects. The SUPER-1 trial, a double-blind, and placebo-controlled trial demonstrated a significant increase in the walked distance of the 6MWT, in the WHO functional class and the hemodynamic parameters in the sildenafil group [38]. Thence, the SUPER-2 trial assessed long-term safety and tolerability of sildenafil treatment: it proved that the drug is generally well tolerated, and, after 3 years, the majority of patients (60%) who entered the SUPER-1 trial improved or maintained their functional status, and 46% maintained or improved 6MWT [39]. Common adverse effects of this therapy are diarrhea, dyspepsia, and flushing.

3.3.4.1.2 Tadalafil

It is an alternative molecule and has a better pharmacokinetic profile than sildenafil. In the PHIRST-1 trial, tadalafil demonstrated a significant improvement in 6MWT and hemodynamic parameters, such as mPAP and PVR [40]. Common adverse effects of this therapy are myalgia, flushing, and headache.

3.3.4.1.3 Riociguat

It is a direct activator of guanylate-cyclase, which synthesizes NO. In the 12-week PATENT-1 study, Riociguat was well tolerated and improved several clinically relevant end-points in patients with PAH who had never received a treatment or had been pretreated with endothelin-receptor antagonists or prostanoids. The PATENT-2 trial assessed the long-term safety and efficacy of Riociguat, which resulted to be safe in the long-term treatment of these patients [41].

3.3.4.2 Drugs targeting the ET1 pathway: endothelin receptor antagonist (ERA)

3.3.4.2.1 Bosentan

It is a dual acting ERA, binding to both the ETA and ETB receptors. Two subtypes of ET1 receptor exist: endothelin receptor subtype A (ETA) is mainly found in smooth muscle and also on fibroblasts, while ET 1 receptor subtype B (ETB) is expressed on smooth muscle and endothelial cells. Endothelial ETB activation mediates clearance of ET1 and vasodilatation by NO and prostacyclin release. Bosentan has been studied in several clinical PAH trials, such as BREATHE-1, TRUST, and EARLY [42], with generally positive results. One of the main problems with Bosentan is hepatotoxicity, which initially presents as a raised levels of alanine aminotransferase and aspartate aminotransferase.

3.3.4.2.2 Ambrisentan

It is an ERA that only blocks receptor ETA. It has been shown to increase exercise capacity and hemodynamics with an acceptable side-effect profile. It has also proven to be safely used in combination with other PAH-specific medications, especially with 5-PDEi. In the recent randomized trial ambition, it was proven that upfront dual therapy of ambrisentan and tadalafil considerably decreases the risk of clinical failure compared with monotherapy [43].

3.3.4.2.3 Macitentan

It is a dual ERA developed by adjusting the basic structure of bosentan, in order to increase the efficacity and safety, and it is approved for the treatment of PAH.

In contrast with bosentan, macitentan also has a longer binding with the ET1 receptor and a better tissue penetration [44]. One of the most important trials on Macitentan was the SERAPHIN trial, a multicenter, double-blind, randomized, placebo-controlled, and event-driven phase 3 trial. This trial demonstrated a significant reduction in morbidity and mortality in patients with PAH [45]. Common adverse effect is anemia.

3.3.4.3 Drugs targeting the prostacyclin pathway: prostacyclin analogues and prostacyclin receptor agonist

3.3.4.3.1 Epoprostenol

It is a synthetic prostacyclin, approved by FDA in December 1995 for the treatment of PAH. The pharmacological effects of epoprostenol are due to pulmonary and systemic arterial vasodilation. The effects on platelet aggregation are directly opposite to TXA₂. Epoprostenol has been demonstrated to be one of the safest treatment protocols for PH. It is also one of the best treatments to reduce the mortality rate in patients with idiopathic PAH [46]. Due to its short half-life (3–5 min), epoprostenol must be administered intravenously via continuous infusion pomp and a permanent tunneled catheter and, in order to maintain its safety-efficacy profile dose-dependent adjustments are necessary. Major adverse events are headaches, nausea/vomiting, flushing, myalgias, jaw pain, diarrhea, and upper respiratory tract infections.

3.3.4.3.2 Treprostinil

Treprostinil is an analog of Epoprostenol and can be administered by subcutaneous injection, intravenous infusion, or inhalation.

The several methods of administration, an extended half-life, and its stability at room temperature give treprostinil a pro over Epoprostenol, Iloprost, and Selexipag, the three other FDA-approved drugs targeting the prostacyclin pathway. Moreover, in clinical trials, treprostinil enhanced exercise capacity measured with 6MWT, quality of life, WHO functional class, and the clinical status of patients [47].

Usual adverse effects are dizziness, nausea, pain in the jaw and extremities, diarrhea, flushing, and headache.

3.3.4.3.3 Iloprost

It is a stable prostacyclin analog, available as an inhalant and intravenous preparation for PAH. The principal limitation of this inhaled formulation is the need for daily recurring iloprost inhalations, ranging from 6 to 9, and this can decrease patients’ compliance with pharmacological treatment.

3.3.4.3.4 Selexipag

It is an oral, non-prostacyclin, and IP receptor agonist, approved by FDA in December 2015. Its molecule is very stable and has a long half-life: its effects are vasodilation of the pulmonary circulation, inhibition of platelet aggregation, and anti-inflammatory effects. In the GRIPHON study, a phase 3 multicenter, randomized, double-blind, and placebo-controlled trial. 1156 patients with PAH were randomly assigned to receive either placebo or Selexipag. It resulted that among patients with PAH, the risk of the primary composite end point of death or complication related to PAH was significantly lower with Selexipag than with placebo. Instead, there was no significant difference in mortality between the two study groups [48]. Therefore, selexipag is indicated for use in patients with World Health Organization functional class (FC) II or III diseases. Common adverse effects are headache, diarrhea, and nausea.

Treatment is started with an oral combination therapy of two different types of drugs; then, patients are evaluated after 3–6 months. If patients are at high risk, triple therapy can be considered, adding parenteral prostanoids.

3.4 Chronic thromboembolic pulmonary hypertension

Chronic thromboembolic PH (CTEPH) is a specific subtype of PH, included within Group 4. It is characterized by partial obstruction or total occlusion of subsegmental, segmental, or larger pulmonary arteries by post-embolic fibrotic material. CTEPH incidence is uncertain due to difficulties in diagnosing this disease and lack of specific symptoms: incidence is estimated to be 4 cases per million [49]. Incidence after acute pulmonary embolism is estimated to vary between 0.4% and 9.1% [50]. The pathophysiology is peculiar: CTEPH is the result of partial and incomplete resolution of embolic clots after acute pulmonary embolism, because of impaired fibrinolysis.

The residual intraluminal thrombi phenomena of inflammation, fibrosis, and organization lead to development of typical CTEPH lesions characterized by yellow clots highly adherent to the pulmonary vascular wall, containing collagen, elastin, and inflammatory cells (in contrast to fresh and red clots of acute pulmonary embolism, mainly consisting of erythrocytes and platelets in a fibrin mesh). In addition, vascular remodeling characterized by intimal fibrosis and fibromuscular proliferation, similar to idiopathic PAH, has been described in small vessels distal to unoccluded arteries. The pathogenesis of this micro vasculopathy is not clear: it has been proposed that pulmonary blood flow redistribution from occluded vessels to non-obstructed areas leads in the long term to local high-flow pressure and shear stress promoting endothelial dysfunction [51].

Vascular remodeling resulting from incomplete clot resolution and microvasculopathy leads to increased pulmonary vascular resistance and right ventricular failure. Patients affected by CTEPH can display many and non-specific symptoms, such as shortness of breath on exertion in the early stages and at rest in advanced stages, chest pain, and increased fatigue.

Early diagnosis remains a challenge and it affects prognosis and survival rate.

The gold standard for diagnosis is RHC, which displays mPAP >20 mmHg, but it has to be associated with ventilation/perfusion (V/Q) scintigraphy that shows at least one large perfusion defect in one segment or two subsegments. CT scan has also shown an excellent diagnostic efficacy, and it is usually included in the diagnostic pathway of CTEPH. A correct and early diagnosis is of fundamental importance, as CTEPH is the only PH subtype suitable for a surgical treatment and potentially curable.

Treatment of choice is pulmonary endarterectomy (PEA): within the use of circulatory arrest and hypothermia, it implicates the removal of organized tissue from pulmonary vessels. The milestone of the surgical treatment is to define the operability of patient: this is based on age, comorbidities (diabetes mellitus, lung diseases, hypertension, asthma, and coronary heart disease) and anatomical reasons (inaccessible or distal thrombi). Although, the progress in diagnostic pathways and the accumulation of surgical experience have contributed to the latest surgical development, redefining the distal limits of PEA. Therefore, in expert centers, surgery can be performed successfully in patients with thromboembolism of the distal vessels. Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment and has been included in the treatment algorithm of CTEPH: it is reserved for patients that cannot undergo surgical treatment with PEA due to distal thrombi or continuous symptoms after surgery. It involves the insertion of a balloon catheter into pulmonary vessels to dilate pulmonary stenosis in order to improve hemodynamics parameters, clinical symptoms, exercise capacity, and RH compliance, with a low rate of complications [52]. Complications can occur during the procedure (vascular injury, wire perforation, vascular dissection, balloon over dilatation, and others) or after the procedure, and include lung injury, contrast-induced kidney injury, and peripheral access site problems.

Likely between 20% and 40% of patients cannot undergo either of these treatments or show residual PH after interventional therapy and are amenable to medical therapy. This includes diuretics, oxygen therapy, and lifelong anticoagulation. Anticoagulation therapy can be done with either warfarin or direct oral anticoagulants: the choice is up to the doctor, who evaluates bleeding risk, renal impairment, and decides which therapy suits better for the patient.

Riociguat has been approved for the treatment of CTEPH, it determines vasodilatation and has anti-fibrotic, anti-proliferative, and anti-inflammatory activity.

Other specific drugs are currently tested with positive results in these patients, such as Macitentan and Treprostinil [53].

4. A look to the future

PH is a complex and multifactorial disease, triggered and sustained by many pathological alterations. The three main modified pathways in PAH (NO, ET1, and PGI2) have been uncovered and targeted with appropriate pharmacological therapy, leading to an improvement in symptoms, quality of life, and survival of these patients.

In the next few years, scientists will focus their attention on researching new molecular targets that can have a role in the pathogenesis of the disease. For example, there is a trial ongoing on Rho-associated protein kinase (ROCK), which is involved in many cellular functions, such as smooth muscle cell contraction, cell migration, and others. It also has been demonstrated to play a role in the pathogenesis of PH. So, scientists are developing ROCK’s inhibitors [54]. Another target is apelin, an endogenous vasodilator, which levels are decreased in PAH. Therefore, apelin infusion is being considered and trials are still ongoing [55].

Other drugs target inflammation and immunity: Ubenimex has been tested in a clinical trial but reported no improvement of symptoms and exercise capacity, tested with 6MWT [56].

Additionally, cytokines like IL-6 are overexpressed in PH, so drugs that function as inhibitors of this cytokine can play a role in future pharmacological treatment and are still going through appropriate development and testing [57].

Also, therapy targeting BMPR2 pathway has been considered: it has been shown that there is a decreased expression of this gene in heritable PAH and 20% of idiopathic PAH [58].

Moreover, there is evidence that PAH patients usually have low levels of iron. Actual guidelines suggest that iron supplementations should be considered. Kramer et al., assessed with a long-term study the use of ferric carboximaltose in PAH patients with iron deficiency: iron supplementation has demonstrated an improvement in clinical status, exercise capacity, and a decrease in hospitalization rate [59]. This resulted in an increase in 6MWT distance and a better WHO-FC and, consequently, a decreased risk calculated by ESC/ESR risk score.

Conflict of interest

The authors declare no conflict of interest.