**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**).

Specifically, each group includes:


Making a correct diagnosis of PH is very complex, challenging, and timedemanding, 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


#### **Table 2.**

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

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 hypoxiainducible 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

#### **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.*

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].

#### *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,

#### *Pulmonary Hypertension DOI: http://dx.doi.org/10.5772/intechopen.107281*

WHO-FC IV is characterized by an inability to perform any physical activity, with evident signs of right ventricular failure.


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.
