Classification and Clinical Features of Pulmonary Hypertension in Adults

Abstract

This chapter explores the clinical manifestations and initial diagnostic findings associated with pulmonary hypertension (PHTN) at different stages. The definition of PHTN, as proposed in the 6th World Symposium, considers a mean pulmonary arterial pressure at rest (mPAP) of greater than 20 mmHg (previously 25 mmHg) and a pulmonary vascular resistance equal to or exceeding 3 WU. PHTN is clinically classified into five groups: Group 1 includes idiopathic, hereditary, and other forms; Group 2 comprises PHTN due to left heart disease; Group 3 consists of PHTN associated with pulmonary diseases or hypoxia; Group 4 pertains to PHTN caused by pulmonary artery obstruction; and Group 5 encompasses cases with unclear or multifactorial etiologies. The classification of PHTN into these groups holds significant clinical value as it contributes to determining survival rates and treatment responses. The chapter elaborates on the clinical features observed throughout various stages of PHTN and highlights the abnormalities detected during initial diagnostic assessments. The in-depth details will also be outlined in subsequent chapters of the book.

1. Introduction

“Pulmonary hypertension” (PH) is characterized by increased mean pulmonary artery pressure (mPAP) of more than 20 mmHg at rest, calculated by the right-sided cardiac catheterization (RHC) [1]. PH refers to a diverse range of conditions marked by an increase in pulmonary vascular resistance that eventually results in right ventricular failure and early death [2]. Given the high burden of the disease, especially in the older population aged 65 years and above [3], the effectiveness of PH treatment is early diagnosis. However, early-stage PH is frequently disregarded because the presenting symptoms are either non-specific or manifest later in the course [2].

This chapter describes in detail the clinical characteristics seen at various phases of pulmonary hypertension, the newly accepted criteria, and the classifications of treatment groups. It further highlights the abnormalities appreciated during the first diagnostic evaluations and the appropriate treatment measures.

2. The newly proposed pulmonary hypertension criteria

The suggestion to reevaluate the hemodynamic definition of PH has been one of the most important recommendations at The Sixth World Symposium on Pulmonary Hypertension (WSPH) in 2018 [4]. In the sixth WSPH, the diagnostic criterion for mean pulmonary artery pressure (mPAP) was decreased from 25 mmHg or above to greater than 20 mmHg, measured via the right-sided cardiac catheterization in the supine position. The previous definition of pulmonary hypertension was a conclusion of an expert consensus by the World Health Organization based on clinical trials. However, over time, the accumulating data made the thresholds unreliable. Given the ethical concerns of an invasive procedure without an underlying pathology, it was impossible to measure the normative values of mPAP via RHC in individuals. One of the most important factors that led to a change in the criteria was a meta-analysis led by Kovacs et al. [5]. This study of 1187 participants from 13 countries concluded that the supine mPAP at rest was 14.0 ± 3.3 mmHg in healthy individuals, and it was unaffected by sex and ethnicity. The upper normal limit of mPAP was 20.6 mmHg in the supine position. Therefore, the mPAP value >20 mmHg was pathological after considering a 2 standard deviation increase to the mean value.

The reliability of the new criteria was under question, as it risked overdiagnosis of patients. Additionally, it raised questions regarding treatment pathways for individuals with previously defined “borderline mPAP values” between 20 and 24 mmHg [6]. In an extensive review of the available literature, a meta-analysis of 16, 482 patients concluded that patients with mild pulmonary hypertension with mPAP 19–24 mmHg had an increase in the risk of all-cause mortality (RR 1.52; 95% CI, 1.32–1.74; P < 0.001; I² = 47%) [7]. A retrospective analysis of 547 patients supported a similar conclusion. In such patients, an elevated mPAP between 21 and 24 mmHg was an independent predictor of poor survival probability [8].

Regardless of the statistical evidence to support a revised mPAP threshold, experts agree that a simple increase in mPAP alone is not sufficient or reliable to [6] derive a diagnosis of pulmonary hypertension. The physiological basis of this is the probability that it might also be due to a rise in cardiac output (CO) and pulmonary artery wedge pressure (PAWP). In order to hemodynamically characterize PH, as shown in Table 1, the sixth WSPH introduced pulmonary vascular resistance (PVR) as well as PAWP [9]. According to the 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension, this introduction allows pre-capillary pulmonary hypertension to be differentiated from elevated PAP. This is because it is important to differentiate pulmonary vascular disease (PVD) from left heart disease (LHD), elevated pulmonary blood flow, and increased intrathoracic pressure [10].

Definitions	mPAP	PAWP	PVR
Pre-capillary PH	>20 mmHg	≤15 mmHg	≥3 WU
Isolated post-capillary PH (IpcPH)	>20 mmHg	>15 mmHg	<3 WU
Combined pre- and post-capillary PH (CpcPH)	>20 mmHg	>15 mmHg	PVR ≥ 3 WU
Exercise PH	mPAP/CO slope between rest and exercise; >3 mmHg/L/min

Table 1.

Hemodynamic definitions of pulmonary hypertension.

A retrospective analysis aimed to define the relationship between PVR and survival in patients with mPAP > 20 mmHg. The study established that in patients with an mPAP threshold of greater than 20 mmHg, a linear relation between PVR and mortality for values < 6 WU was appreciated [11].

Inconsistencies were also noted in the PVR cut-off threshold, which was set at 3 WU in the sixth WSPH. Consequently, a recent study evaluated that PVR values ≥3 WU prevented an early Pulmonary arterial hypertension (PAH) diagnosis as a cut-off value ≥2 WU was already associated with pulmonary vascular disease [12]. The complete criterion for diagnosing pulmonary hypertension is mPAP greater than 20 mmHg, PAWP of 15 mmHg or less, and PVR greater than or equal to 3 WU [10]. Patients with pulmonary hypertension are categorized into three major groups: pre-capillary, post-capillary, and combined pre- and post-capillary PH. The pre-capillary PH is a primary elevation in the pulmonary arterial system. For example, conditions belonging to Groups 1, 3, 4, and 5, such as PAH, can lead to a mPAP >20 mmHg and PVR ≥2 WU. On the contrary, Groups 2 and 5 can result in either isolated post-capillary PH or combined pre- and post-capillary PH [13].

By revising the definition, a sizable subgroup of patients who were previously thought to be normal are now classified under PH. This revision emphasizes the importance of early diagnosis in the PH criteria [14]. Where there was skepticism around the increased number of patients from the revised criteria, it also hints at a possibility of a patient population being protected by being in the buffer zone two standard deviations above the normal. The REVEAL registry highlighted that a 2-year delay in the PH diagnosis and symptom onset had increased the burden of diseases [15]. This is compelling clinical justification to accept the newly defined pulmonary hypertension criterion for treatment and diagnosis.

3. Classification of pulmonary hypertension

Multiple clinical diseases are divided into groups by the WHO classification (Table 2) based on shared characteristics in the clinical presentation, pathological findings, hemodynamic characteristics, and therapeutic strategy [9, 10]. Therefore, the underlying causes of abnormal mPAP, PVR, and PCWP are divided into five main categories:

1. Pulmonary arterial hypertension (PAH).	Idiopathic. Hereditary. Drug and toxin-induced. pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis-like features in PAH. Persistent pulmonary hypertension of a newborn. Associated with the following diseases: Connective tissue disease. Portal hypertension. Congenital heart disease. Schistosomiasis. HIV infection.
2. Pulmonary hypertension due to left heart disease.	PH due to heart failure with preserved ejection fraction. PH due to heart failure with reduced ejection fraction. Valvular heart disease. Postcapillary PH due to Congenital/acquired cardiovascular conditions.
3. Pulmonary hypertension due to lung disease and/or hypoxia.	Obstructive lung diseases. Restrictive lung diseases. Pulmonary diseases with mixed restrictive/obstructive patterns. Hypoxia without lung disease. Developmental lung disorders. Alveolar hypoventilation syndrome.
4. Pulmonary hypertension due to pulmonary artery obstruction.	Chronic thromboembolic PH. Other pulmonary artery obstructions. Sarcomas. Other malignant tumors (renal, uterine, germ cell tumor of the testis, other tumors). Non-malignant tumors (uterine leiomyoma). Arteritis without connective tissue disease. Congenital pulmonary artery stenosis. Hydatidosis.
5. Pulmonary hypertension with unclear and/or multifactorial mechanisms.	Hematological disorders: chronic hemolytic anemia. myeloproliferative disorders. Systemic disorders like neurofibromatosis and sarcoidosis. Metabolic disorders like Gaucher disease, glycogen storage disease, Fibrosing mediastinitis, Chronic renal failure (with/without dialysis), Pulmonary tumorous thrombotic microangiopathy and HIV.

Table 2.

Clinical classification of pulmonary hypertension [10].

3.1 Group 1: pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is largely idiopathic, hereditary with a BMPR2 mutation carrier [16], or drug/toxin-induced, affecting females and the younger population. Besides these, some of the less common causes of PAH include veno-occlusive diseases, persistent pH of newborns, or underlying conditions such as connective tissue disorders, HIV, and portal hypertension. The algorithm to diagnose PAH is the absence of any alternative PH pathology and threshold values of mPAP >20, PWAP ≤ 15 mmHg, or PVR ≥ 3 WU, fulfilling the criteria for pre-capillary PH [17]. Group 1 is divided into two broad categories based on treatment and prognosis. The first subgroup includes patients with positive vasoreactivity testing. These are patients with a decrease of more than 10 mmHg but less than 40 mmHg in the Mpap [18]. This group of individuals has a better treatment response to calcium channel blockers and, thus, a good prognosis [19]. The second subgroup includes patients with pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease (PVOD). Treatment of this subgroup risks the development of pulmonary edema and, therefore, poor survival chances [20]. The 2022 ESC/ERS guidelines for diagnosing and treating pulmonary hypertension have established an updated list of drugs and toxins that possibly establish or aggravate the underlying PAH (Table 3) [10].

Definitive associations	Possible associations
Aminorex; Fenfluramine; Dexfenfluramine; Benfluorex; Mitomycin C (PVOD); Toxic rapeseed oil	Cocaine; Phenylpropanolamine; l-Tryptophan; St. John’s wort; Amphetamines; IFN-α and -β; Alkylating agents; Bosutinib; Direct-acting antiviral agents against; hepatitis C virus; Leflunomide

Table 3.

Drugs and toxins resulting in potential pulmonary hypertension [21].

3.2 Group 2: pulmonary hypertension due to left-sided heart disease (LHD) (PH-LHD)

As elaborated in Table 2, Group 2 includes a patient population with PH caused by a left-sided heart pathology. These can be due to heart failure with reduced or preserved LVEF, valvular heart diseases, or any pathology that results in post-capillary PH [20].

3.3 Group 3: pulmonary hypertension caused by chronic lung disease (CLD) (PH-CLD) and/or hypoxia

In this group of patients with PH due to lung diseases, chronic obstructive pulmonary diseases (COPD) are the most important cause [22]. Pulmonary hypertension results from a complex nature of decreased functional status and worsening hypoxemia [23]. Studies have identified that in individuals suffering from severe emphysema, the mPAP has an inverse relation with arterial PO2 and a direct association with PCWP. Consequently, there is a close relationship between mPAP, PVR, and the degree of alveolar hypoxia [24, 25]. Therefore, this category falls under the pre-capillary hemodynamic threshold ranges by the new definition.

3.4 Group 4: pH caused by pulmonary artery obstruction

In this subset of patients with PH, pathology arises from obstructed pulmonary arteries such as chronic thromboembolic PH (CTEPH), tumors, and pulmonary artery stenosis. CTEPH potentially results from chronic obstruction with thrombi and as a small vessel disease [25].

3.5 Group 5: miscellaneous mechanisms

Patients with a multifactorial pathophysiological response were often diagnosed with hematologic or systemic disorders, such as sickle cell anemia, sarcoidosis, glycogen storage disease, and Gaucher’s [21]. Therefore, it would be likely to find pre- and post-capillary PH mechanisms. The classification groups of PH are originally the same as proposed in the sixth WSPH and the 2015 ESC/ERS Guidelines for diagnosing and treating pulmonary hypertension [26]. Exceptions include updated recommendations that reposition vasoreactive patients with idiopathic pulmonary arterial hypertension (IPAH) [10].

4. Clinical characteristics

4.1 History and physical examination

Pulmonary hypertension (PH) comprises a heterogeneous group of disorders that result from various pathophysiological mechanisms but are all characterized by an elevated mean pulmonary arterial pressure (mPAP) of ≥20 mmHg at rest [9]. The early clinical symptoms of PH are typically nonspecific or easily attributable to comorbid conditions, including congestive heart failure, coronary artery disease, pulmonary embolism, and chronic obstructive pulmonary disease. Hence, diagnosis can be challenging and requires a stepwise evaluation [27]. A detailed history, physical examination, and a high suspicion index are essential to diagnosing PH [28]. The suspicion index should be particularly high in patients presenting with conditions associated with PH, including sickle cell anemia, systemic sclerosis, and HIV. There is a well-documented lag between symptom onset and clinical diagnosis, as evidenced in a study by Humbart et al., who reported that there is an average delay of 27 months from symptom onset to final diagnosis [29]. This delay may be attributed to a lack of screening guidelines for PH in asymptomatic individuals, including in high-risk groups, which contributes to a significant delay in diagnosis [18]. The hallmark initial manifestation of PH includes dyspnea on exertion, while multiple nonspecific symptoms may also be present. Dyspnea could be accompanied by exhaustion, chest tightness, or presyncope initially while exercising and then later at rest [26]. Clinical manifestations in accordance with the progression of PH have been given in Table 4. These include fatigue, generalized weakness, early exhaustion, tachycardia, hemoptysis, and syncope/presyncope or light-headedness [26]. Patients may also present with signs of advanced PH leading to right ventricular failure and systemic volume overload state such as weight gain, peripheral edema (e.g., ankle edema), ascites, and abdominal, jugular venous distention, hepatomegaly, hepatojugular reflex, and low-volume arterial pulses [26]. Pulmonary artery (PA) enlargement due to progressive PH may lead to physical manifestations comprising angina, i.e., chest pain on exertion, hoarseness of voice, cough, wheezing, lower respiratory tract infections, and atelectasis [30]. These symptoms manifest due to the compression of various anatomical structures by the enlarged PA, including the left main coronary artery (LMCA), left recurrent laryngeal nerve leading to Ortner Syndrome, and bronchi [13, 30]. Patients may also present with clinical signs owning to underlying comorbidities such as arthralgias, skin rash, cough, history of thrombosis, and daytime sleepiness [13]. Hence, not only a physical examination but also a patient’s family, sexual, and travel histories are equally essential when evaluating them for suspected PH. Multiple findings may be present on physical exam in patients with associated chronic lung diseases, including telangiectasias, Raynaud’s phenomenon, digital clubbing, ulceration, symptoms associated with gastroesophageal reflux, crackles/wheezing on lung auscultation, joint edema as well as erythema [13].

WHO functional class	Clinical characteristics
Class I	No symptoms; Can perform ordinary physical activity.
Class II	Comfortable at rest; Routine activities cause symptoms of dyspnea, fatigue, angina, or pre-syncopal features.
Class III	Comfortable at rest; Less than ordinary activity causes symptoms.
Class IV	Cannot perform any activity without symptoms. Dyspnea and/or fatigue at rest.

Table 4.

Clinical presentation of pulmonary hypertension.

4.2 Clinical findings on auscultation

Auscultatory examination suggestive of PH includes accentuated P2, i.e., second heart sound associated with the pulmonic component due to loud closure of the pulmonic valve at the base of the heart as the initial physical finding [31, 32]. As the disease progresses, right ventricular dysfunction occurs. This results in jugular venous distention due to elevated jugular venous pressure, which is seen with a prominent “a” wave with an eventual prominent “v” wave, suggesting tricuspid regurgitation [31]. Tricuspid (pan systolic murmur along the left sternal border that increases in intensity upon inspiration) and pulmonary regurgitation (diastolic murmur also known as the Graham Steell murmur along the left sternal border indicating pulmonary valve insufficiency), right-sided S3 and S4 gallop may be heard, while right parasternal heave may also be present on palpation [33]. Increased PA pressures and eventual RV heart failure may cause these. These may be associated with ascites, abdominal distention, hepatosplenomegaly, and dependent peripheral edema. As right heart failure progresses, pallor, delayed capillary refill, peripheral cyanoses, and dizziness may be evident, indicating decreased cardiac output [13].

4.3 Clinical findings on electrocardiogram

Electrocardiography (EKG) is one of the initial tests obtained from patients to confirm the presence of PH and identify the underlying etiology. The cardiac rhythm in patients with PH is usually sinus. However, electrical abnormalities exist due to RV and RA enlargement. Although a normal EKG report does not exclude the diagnosis of PH, an abnormal finding points toward severe disease, particularly QRS and QTc prolongation [34, 35, 36, 37, 38]. Other EKG changes are nonspecific and comprise signs of right-sided cardiac strain and chamber enlargement, including P-pulmonale, right ventricular strain, right-axis deviation, right bundle branch block (RBBB), right ventricular (RV) hypertrophy, and QTc prolongation. As the disease progresses, supraventricular tachycardia, including atrial fibrillation and atrial flutter, may manifest, while ventricular arrhythmia is rare [36]. The EKG findings suggestive of poor prognosis include the increased amplitude of P wave in lead II, P ≥ .25 mV in lead II, qR in V1, and the presence of World Health Organization (WHO) criteria for RV hypertrophy [35, 37]. This criterion includes a small S wave in lead V1 (R > 7 mm, S < 2 mm, and R/S ratio > 1), a tall R wave, a tall S wave with a small R wave in lead V₅ or V₆ (R/S ratio < 1), and right axis deviation (QRS axis > 90°) [33]. Electric abnormalities suggestive of right-sided cardiac strain comprise ST-segment depressions and T-wave inversions in the anterior leads, i.e., V1 through V4. Electrocardiographic features indicative of RA enlargement include a P-wave greater than 2.5 mm in leads II, III, and aVF [33].

4.4 Clinical findings on chest radiography

Pulmonary hypertension (PH) is frequently associated with bilateral enlargement of hilar structures representing the central, right, and left main PA. Chest radiography is abnormal in 90% of the patients with PH at the time of diagnosis [39], and clinical features usually show right-ventricular enlargement, a prominent central PA (PA enlargement), peripheral hypervascularity, water-shaped cardiac silhouette, and pruning of peripheral vessels [40, 41, 42]. In severe cases of PH, cardiac silhouette on chest radiograph indicates an enlarged RV causing cardiomegaly on the posteroanterior view and increased retrosternal filling on the lateral view [43]. In addition, clinical signs of left-sided heart disease are appreciated. These include pleural effusions, enlargement of the left heart, Kerley B lines, and signs of pulmonary diseases, such as flattened diaphragm (COPD), hyperlucency (COPD), volume loss, and reticular opacifications (fibrotic lung disease) may also be present [40, 41, 42].

4.5 Clinical findings on pulmonary function testing and arterial blood gas analysis

Patients with PAH demonstrate reduced diffusion lung capacity for carbon monoxide (DLCO), and low DLCO of <45% is associated with poor prognosis [44, 45]. Patients also present with slightly low partial pressure of oxygen (PaO2), which results in alveolar hyperventilation. This leads to low-to-low normal partial pressure of carbon dioxide (PaCO2) [46].

4.6 Clinical findings on chest computed tomography and abdominal ultrasound

A chest CT helps to identify additional information, which raises suspicion for PH. These clinical features include enlarged diameter of PA, ascending aorta/main PA diameter ratio of >0.9, and enlargement of right heart chambers (RA or RV). The PA diameter of ≥30 mm, with a right ventricular outflow tract thickness of ≥6 mm, and > 140 degrees of septal deviation or right ventricle/left ventricle ratio ≥ 1, is suggestive of PH [47]. Abdominal ultrasound may detect secondary liver and kidney damage as PH progresses, leading to liver abnormalities and/or portal hypertension [48].

4.7 Clinical findings on echocardiography

A transthoracic echocardiogram is considered to be the most important non-invasive diagnostic procedure to estimate the probability of PH, while right heart catheterization (RHC) is required for the confirmation of diagnosis as well as to guide therapy [26, 49, 50, 51]. The echocardiogram aids in grading the probability of PH into three categories, namely low, intermediate, and high probabilities, as laid down by the European Society of Cardiology guidelines shown in Table 5. The echocardiographic signs indicative of PH is given in Table 6.

Peak tricuspid regurgitant velocity (m/s)	Presence of other PH signs on echocardiography	Echocardiographic probability of PH
< 2.8 or not measurable	No	Low
<2.8 or not measurable	Yes	Intermediate
2.9–3.4	No	Intermediate
2.9–3.4	Yes	High
>3.4	Not required	High

Table 5.

Echocardiographic probability of PH [13].

Ventricles	RV/LV basal diameter/area ratio > 1.0	Flattening of the interventricular septum (left ventricular eccentric index > 1.1 in systole and/or diastole)	Tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio < 0.55 mm/mmHg
Pulmonary artery	Right ventricular outflow tract acceleration time < 105 ms and/or mid-systolic notching	Early diastolic pulmonary regurgitation velocity > 2.2 m/s	PA > Aortic root diameter; PA diameter > 25 mm
Inferior vena cava and right atrium	Inferior vena cava diameter > 21 mm with decreased inspiratory collapse (<50% with a sniff or < 20% with quiet respiration)	RA area (end-systole) > 18 cm^2

Table 6.

Echocardiographic signs suggestive of PH [13].

4.8 Clinical findings on cardiopulmonary exercise testing (CPET)

Clinical findings on cardiopulmonary exercise testing (CPET) is an important tool to identify the underlying cause of PH when clinical symptoms are induced by exercise. Pulmonary arterial hypertension (PAH) results in low oxygen pulse (VO2/HR), low peak oxygen uptake (VO2), elevated ventilatory equivalent for carbon dioxide (VE/VECO2), and a reduced end-tidal partial pressure of carbon dioxide (PETCO2) [52, 53].

5. Diagnostic evaluation

Despite advanced technological developments to evaluate PH, a considerable delay has been reported between symptom onset and clinical diagnosis. In accordance with the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL registry), 21% of the patients experienced a 2-year delay in receiving the final diagnosis of PH [54]. This persistent time lag in reaching final diagnosis across the past decades led to the 6th World Symposium of Pulmonary Hypertension (WSPH) task force to update the recommended diagnostic algorithm with the aim of facilitating a more efficient evaluative process [32]. For instance, patients who present with multiple confounding medical comorbidities are complex and challenging to treat, hence prompting the recommendation that they should be referred early to specialized PH centers known as Pulmonary Hypertension Care Centers accredited by the Pulmonary Hypertension Association to guide their long-term management [22, 54, 55, 56, 57]. Patients presenting with dyspnea in the absence of signs of specific heart or lung disease or those who present with clinical signs/symptoms indicative of PH should be carefully evaluated with a detailed medical and family history, thorough physical examination, monitoring of body vitals including blood pressure, pulse rate, oxygen saturation, and serum tests comprising brain natriuretic peptide (BNP)/N-terminal pro-BNP (NT-proBNP) with a resting electrocardiogram. This first stage points toward a potential cardiopulmonary cause. The second stage includes a detailed cardiac assessment using echocardiography and the lungs (if the medical history is indicative) using pulmonary function tests, chest imaging modalities comprising X-ray and computed tomography, as well as cardiopulmonary exercise testing in certain cases.

6. Conclusion

Pulmonary hypertension is a multifactorial disease-carrying a high risk of morbidity and mortality. It requires a specialized PH expert center to carry out consistent, detailed evaluation and management. The disease involves progressive loss and obstruction of the pulmonary vasculature, resulting in elevated mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), which can eventually lead to RV dysfunction and right ventricular heart failure. Careful assessment of medical history, physical examination, echocardiograms, and hemodynamic parameters are essential to identify and classify the different forms of PH.