Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults

INTRODUCTION — Patients suspected of having pulmonary hypertension (PH) undergo extensive diagnostic testing. The purpose of diagnostic testing is to confirm that PH exists and identify the underlying cause so that appropriate treatment can be administered.

The clinical features, diagnostic evaluation, and diagnostic criteria for PH are reviewed here. Epidemiology, pathogenesis, treatment, and prognosis are discussed separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

ETIOLOGIES AND TERMINOLOGY — When evaluating patients with suspected PH, good working knowledge of the etiologies and classification is important. Patients with PH are classified into five groups based upon etiology and mechanism (table 1) [1]. Patients in group 1 are considered to have pulmonary arterial (PA) hypertension (PAH), which has several causes (eg, inheritable causes, drugs, connective tissue disease), whereas patients in group 2 (due to left-sided heart disease), group 3 (due to chronic lung disorders and hypoxemia), group 4 (due to PA obstructions), and group 5 (due to unidentified mechanisms) are considered to have PH. When all five groups are discussed collectively, the term PH is used.

PH can also be classified as pre- or postcapillary PH. Precapillary PH is due to a primary elevation of pressure in the PA system alone (eg, PAH), while postcapillary PH is due to elevations of pressure in the pulmonary venous and pulmonary capillary systems (pulmonary venous hypertension; eg, group 2). In practice, some patients have mixed pre- and postcapillary features (table 2).

CLINICAL MANIFESTATIONS — Symptoms and signs of PH are nonspecific [2]. Patients typically present with exertional dyspnea and fatigue that progresses over time until severe PH with overt right ventricular (RV) failure develops.

Patients with an underlying cause of PH may also have the signs and symptoms of the causative disorder (eg, connective tissue disease, heart failure, chronic lung disease [CLD]).

The diagnosis is often delayed because the presenting features of PH are frequently attributed incorrectly to age, deconditioning, or a coexisting or alternate medical condition. As a result, PH is often not suspected until symptoms become severe or serious. It has been estimated that more than 20 percent of patients have symptoms of PH for longer than two years before it is recognized [3]. This is particularly prevalent among patients younger than 36 years and in those with coexisting medical conditions.

Symptoms — Common symptoms include the following:

●Dyspnea and fatigue – The most common initial symptoms of PH are exertional dyspnea, lethargy, and fatigue and are due to an inadequate increase in cardiac output during exercise [4,5].

●Symptoms of RV failure – Symptoms of RV failure develop as PH progresses and include the following:

•Exertional chest pain – Exertional chest pain (ie, angina) is usually due to subendocardial hypoperfusion caused by increased RV wall stress and myocardial oxygen demand. However, it is occasionally caused by compression of the left main coronary artery by an enlarged pulmonary artery (PA), particularly in patients with a PA trunk at least 40 mm in diameter [6-8].

•Exertional syncope – Exertional syncope is an unusual symptom that is due to insufficient increase in cardiac output during activity or reflex bradycardia from mechanoreceptor activation in the RV.

•Weight gain from edema – Peripheral edema is due to RV failure, increased right-sided filling cardiac pressures, and extracellular volume expansion.

•Anorexia and/or abdominal pain and swelling – Anorexia and/or abdominal pain in the right upper quadrant is due to passive hepatic congestion. The patient may also complain of increase in abdominal girth from ascites.

Uncommon symptoms include cough, hemoptysis, and hoarseness. The hoarseness is caused by compression of the left recurrent laryngeal nerve by a dilated main PA (Ortner syndrome) resulting in unilateral vocal cord paralysis. Palpitations from arrhythmias (eg, atrial fibrillation or flutter) are a rare presenting feature of PH.

Examination — Patients with PH may develop the following physical signs:

●Initial findings – The initial physical finding of PH is usually increased intensity of the pulmonic component of the second heart sound, which may become palpable as PH progresses. The second heart sound is narrowly split or single (ie, normal) in patients with preserved RV function. (See "Auscultation of heart sounds" and "Auscultation of cardiac murmurs in adults" and "Examination of the precordial pulsation".)

●Signs of RV failure – As PH progresses the following signs of RV failure may be evident [9]:

•Jugular venous pressure (JVP) abnormalities – The JVP is typically elevated. Initially, a prominent "a" wave is seen, while a prominent "v" wave indicates significant tricuspid regurgitation and often severe RV failure. (See "Examination of the jugular venous pulse".)

•Right-sided auscultatory findings that are augmented with inspiration may be heard including:

-A right-sided third or fourth heart sound (ie, a gallop) in association with a left parasternal heave or a downward subxiphoid thrust.

-Wide splitting of the second heart sound.

-A holosystolic murmur of tricuspid regurgitation and, in more severe disease, a diastolic pulmonic regurgitation murmur.

•Hepatomegaly, a pulsatile or tender liver, peripheral edema, ascites, and pleural effusion (ie, signs of severe decompensated RV failure) [10]. Splenomegaly is rare but may be seen in PAH due to schistosomiasis or portopulmonary hypertension.

Imaging — While the chest radiograph may be normal in a few patients, it classically shows enlargement of the central pulmonary arteries with attenuation of the peripheral vessels, resulting in oligemic lung fields (figure 1). RV enlargement (diminished retrosternal space), right atrial dilatation (prominent right heart border), and pleural effusions may also be seen as PH progresses. Evidence of underlying CLD or heart failure may also be present.

Chest computed tomography (CT) may have findings similar to those seen on chest radiography (ie, signs of PH and/or underlying etiology) but are typically appreciated in greater detail on CT. The main PA/ascending aorta diameter ratio ≥1 is also suggestive of PH on CT [11]. Unless PH is due to venous thromboembolism, ventilation-perfusion (V/Q) imaging is usually normal or has reduced peripheral perfusion.

Among patients with inheritable pulmonary arterial hypertension, additional CT features have been described including neovascularity and perivascular halos [12].

Imaging can help narrow the differential among the causes of PH [13], which is discussed separately. (See 'Assess for chronic lung disease and hypoxia (group 3 PH)' below and 'Assess for pulmonary artery obstruction (group 4)' below.)

Electrocardiography — The electrocardiogram (ECG) may be normal in patients with PH who do not have RV strain. Signs of RV hypertrophy or strain include right-axis deviation, an R wave/S wave ratio greater than one in lead V1, incomplete or complete right bundle branch block, or increased P wave amplitude in lead II (P pulmonale) due to right atrial enlargement (figure 2 and figure 1). Most ECG signs are specific but not sensitive for the detection of RV disease. ECG changes do not correlate with disease severity or prognosis [14].

Laboratories — PH in itself is not associated with specific diagnostic laboratory abnormalities, although the brain natriuretic peptide (BNP) values may be elevated due to RV wall stretch. Elevated BNP, however, can also be found in left ventricular failure and in chronic renal insufficiency.

INITIAL DIFFERENTIAL DIAGNOSIS — Since PH presents initially as exertional dyspnea, the differential diagnosis is wide. In many cases, clinical history and examination; pulmonary function tests; chest imaging including chest radiography, chest CT, and ventilation-perfusion scanning; and echocardiography can together help distinguish the likely etiology of dyspnea and/or confirm the clinical suspicion for PH. For example, a young patient with a history of allergies who has intermittent dyspnea following allergy exposure and no other supportive findings of PH is unlikely to have PH, while an older adult with a known risk factor (eg, connective tissue disease) and supportive signs of PH is more likely to have PH. The evaluation and differential diagnosis of dyspnea are described separately. (See "Approach to the patient with dyspnea".)

In contrast, in patients who present with symptoms and signs of right ventricular failure (eg, peripheral edema, exertional chest pain, exertional syncope, and right upper quadrant pain), the differential diagnosis becomes considerably narrower:

●Left-sided heart failure – Left ventricular systolic and diastolic heart failure are well-known causes of peripheral edema, right upper quadrant pain due to hepatic congestion, and syncope due to arrhythmias or insufficient cardiac output. Exertional chest pain may also occur. Left-sided heart failure and PH can be distinguished via echocardiography and/or right and left heart catheterization (LHC). (See "Heart failure: Clinical manifestations and diagnosis in adults" and 'Sufficient left heart disease (group 2 PH)' below.)

●Coronary artery disease – Myocardial ischemia is the most common cause of exertional chest pain, and it can also cause ischemia-induced arrhythmias with exertional syncope. Coronary artery disease is identified by stress testing and/or LHC. (See "Stress testing for the diagnosis of obstructive coronary heart disease".)

●Liver disease – Acute and chronic liver diseases cause peripheral edema, and the former can also cause right upper quadrant pain. Liver disease can be detected by liver function testing and right upper quadrant ultrasound. Liver biopsy is the gold standard, but it is seldom necessary. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)

●Budd-Chiari syndrome – Budd-Chiari syndrome refers to thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. It causes peripheral edema due to venous outflow obstruction and right upper quadrant pain due to hepatic congestion. Budd-Chiari syndrome can be identified by Doppler ultrasonography, CT, magnetic resonance imaging (MRI), or venography. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis".)

INITIAL DIAGNOSTIC EVALUATION (NONINVASIVE TESTING) — Diagnostic testing is indicated whenever PH is suspected. The purpose of the diagnostic testing is to confirm that PH exists, determine its severity, and identify its cause (table 1).

Suspecting pulmonary hypertension — PH should be suspected in patients with progressive dyspnea or unexplained dyspnea, fatigue, or syncope (see 'Clinical manifestations' above). Most patients present as an outpatient with subacute or chronic symptoms, while others who are at known risk of PH come to the attention of a clinician due to screening evaluations (see 'Screening for pulmonary hypertension' below); a few patients present acutely as inpatients.

In all cases, a detailed history evaluating the nature of their dyspnea should be performed (see "Approach to the patient with dyspnea"). Patients should be questioned specifically about illicit drug use, ingestion of diet pills or toxins known to increase the risk of PH (eg, appetite suppressants, rapeseed oil, benfluorex, cocaine, some tyrosine kinase inhibitors), cigarette smoking, their occupation or hobbies, a family history of PH or early death, and a history of congenital heart disease. A history of symptoms consistent with or a known diagnosis of connective tissue diseases (CTDs), risks factors for human immunodeficiency virus (HIV) or liver disease, and a history of travel to regions endemic for schistosomiasis should also be sought. A detailed past medical history should be obtained to determine the presence or absence of chronic lung or heart disease, previous thromboembolism, sleep-disordered breathing, thyroid disorders, chronic renal failure, or metabolic disorders. The ECG should be examined closely for signs of right ventricular (RV) hypertrophy or strain and imaging reexamined for subtle signs of interstitial or chronic lung disease (CLD), developmental abnormalities, and PH.

Echocardiography — Once PH is suspected, the initial test of choice is transthoracic echocardiography (TTE), which then determines the sequence of subsequent testing. Importantly, patients with evidence of severe PH and/or patients with significant symptoms should be referred to a PH center for rapid evaluation. TTE evaluates the following:

●The probability of PH using the tricuspid regurgitant jet velocity (TRV). TRV can also be used to estimate the pulmonary artery (PA) systolic pressure (ePASP). (See 'Tricuspid regurgitant jet velocity' below.)

●The assessment of RV size, wall thickness, and function (image 1). (See 'Right ventricle overload and other signs of pulmonary hypertension' below.)

●The potential contribution of left-sided heart disease to PH (if PH is identified on TTE). (See 'Sufficient left heart disease (group 2 PH)' below.)

In general, experts use a combination of the TRV and ePASP together with echocardiographic findings suggestive of RV hypertrophy/strain when evaluating the probability of PH (figure 3 and table 3) [15]. PH is suggested echocardiographically when the TRV is ≥2.8 m.s^-1; the ePASP exceeds 35 mmHg in younger adults or 40 mmHg in older adults; and/or when RV size, wall thickness, and function are abnormal, understanding that PH may still be present even in the absence of these findings. Although estimation of the ePASP is practical and still used by many experts, ePASP may poorly correlate with values obtained by right heart catheterization (RHC) [16-18], which may, in part, be due to variability in the measurement of right atrial pressure (RAP), which is necessary for calculating ePASP (see "Echocardiographic assessment of the right heart", section on 'RA pressure'). Thus, we and others support guidelines issued by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) and endorsed by the 6^th World Symposium on Pulmonary Hypertension (WSPH) [1,19] that propose use of the peak TRV together with echocardiographic findings of PH rather than ePASP to report the echocardiographic probability of PH. Regardless of whether the TRV or ePASP is used, these values should always be interpreted together with clinical suspicion and signs of RV dysfunction to facilitate the decision about proceeding with additional testing for PH.

Tricuspid regurgitant jet velocity — Tricuspid regurgitation is commonly encountered in patients with PH (movie 1 and movie 2) [20]. The ePASP can be calculated with Doppler echocardiography using the formula: ePASP = (4 × [TRV]²) + RAP.

We prefer the newer guidelines issued by the ESC/ERS in 2015 [19], which are endorsed by the 2018 6^th WSPH [1]. The guidelines place greater emphasis on using the peak TRV rather than ePASP on echocardiography to report the echocardiographic probability of PH; these criteria are listed on the table (table 3).

What constitutes "other echocardiographic signs of PH" is defined below. (See 'Right ventricle overload and other signs of pulmonary hypertension' below.)

However, many experts still use older 2009 guidelines issued by the ESC/ERS and the International Society for Heart and Lung Transplantation that suggest the following [21]:

●PH is likely if the ePASP is >50 mmHg and the TRV is >3.4 m.s^-1

●PH is unlikely if the ePASP is ≤36 mmHg, the TRV is ≤2.8 m.s^-1, and there are no other suggestive findings of PH on TTE

●PH is possible if the ePASP is >36 mmHg and ≤50 mmHg and the TRV is >2.8 and ≤3.4, and there are findings suggestive of PH on TTE

Studies that compare ePASP with values obtained from RHC report poor correlation [16-18]. However, a major limitation of these studies is that testing is performed at different times (eg, days or weeks apart) and under different medical conditions (eg, awake versus sedated). Nonetheless, while echocardiography detects PH with greater accuracy than clinical history and examination, its greatest value is the assessment of RV anatomy and function as well as the detection of underlying left-sided heart disease [22,23]. In our practice, we consider echocardiography and invasive hemodynamic assessment (RHC and a left ventricular end-diastolic pressure) to be complementary studies in the assessment of patients with PH.

Detailed discussion of the measurement of PA and right-sided atrial and ventricular pressures by echocardiography is provided separately. (See "Echocardiographic assessment of the right heart", section on 'Hemodynamics'.)

Right ventricle overload and other signs of pulmonary hypertension — TTE signs of RV pressure overload include systolic flattening of the interventricular septum and hypertrophy of the RV free wall and trabeculae (image 2 and movie 3). As the RV fails, there is dilation and hypokinesis, flattening and reverse curvature of the interventricular septum (ie, bulging into the left ventricle), right atrial dilation, and tricuspid regurgitation (movie 4). Other findings associated with PH are pulmonic insufficiency and midsystolic closure of the pulmonic valve [24,25], resulting in midsystolic notching on the PA Doppler flow, reduced RV outflow Doppler acceleration time, enlarged PA diameter ≥25 mm, and enlarged inferior vena cava with decreased inspiratory collapse.

Some of these features have been incorporated into the 2015 guidelines issued by the ESC/ERS [19], which are endorsed by the 6^th WSPH [1]. These guidelines suggest that PH is supported when signs from at least two of the following categories are present (table 3):

●The ventricles – RV/left ventricle basal diameter ratio >1.0; flattening of the interventricular septum (ie, left ventricular eccentricity index >1.1 in systole and/or diastole).

●The PA – RV outflow Doppler acceleration time <105 ms and/or midsystolic notching; early diastolic pulmonary regurgitation velocity >2.2 m.s^-1; PA diameter ≥25 mm.

●The inferior vena cava and right atrium – Inferior vena cava diameter >21 mm with decreased inspiratory collapse (<50 percent with a deep inspiration or <20 percent with quiet inspiration); right atrial area (end-systole) >18 cm².

Further details regarding echocardiographic assessment of RV wall and function are provided separately. (See "Echocardiographic assessment of the right heart", section on 'Chamber size and wall thickness'.)

Low probability of pulmonary hypertension on echocardiography — When the echocardiogram does not suggest PH, clinicians need to be guided by clinical suspicion/judgment for PH, although no predictors or scores exist to categorize patients as low, moderate, or high suspicion for PH.

●For those in whom the suspicion is low, the diagnostic evaluation should be directed toward alternative diagnoses. In this population, RHC is rarely performed unless their symptoms are unexplained by alternate diagnoses. (See "Approach to the patient with dyspnea".)

●For those in whom the clinical suspicion for PH is intermediate or high, progressing with an evaluation for PH that may involve RHC is appropriate. There is significant variability in the approach. For example, RHC may not be necessary in those with obvious group 2 or 3 PH, while the threshold to perform RHC is lower if group 1 PA hypertension (PAH) is suspected. Some experts in this setting perform exercise testing with a cardiopulmonary exercise test (CPET) or with exercise echocardiography. The rationale for this approach is that mild or subtle PH or exercise-induced PH may be suggested, and therefore exercise testing may help identify a subset of patients that may warrant RHC [26,27]. However, exercise testing is subject to misinterpretation, the details of which are discussed below. (See 'Exercise-induced pulmonary hypertension' below and 'Assess for chronic lung disease and hypoxia (group 3 PH)' below.)

Intermediate or high probability of pulmonary hypertension on echocardiography (assess left heart) — When the probability of PH on echocardiography is intermediate or high, the underlying cause of PH needs to be assessed (table 1). Importantly, patients with evidence of severe PH and/or patients with significant symptoms should be referred to a PH center for rapid evaluation.

●Initial evaluation focuses on the identification of left heart disease (LHD) that is sufficient to explain PH (ie, group 2 PH; LHD-PH); several additional noninvasive tests targeted at the evaluation of LHD may be needed to support this assessment. When there is enough LHD to explain the degree of estimated PH, RHC is not needed unless another indication for RHC is present (eg, suspicion for precapillary disease or therapeutic indication). (See 'Sufficient left heart disease (group 2 PH)' below.)

●If there is no or insufficient LHD on echocardiography to explain PH, additional investigations targeted at other suspected etiologies are necessary (ie, group 1, 3, 4, and 5 PH). The sequence and extent of investigations vary among experts, the details of which are discussed below. (See 'Insufficient left heart disease' below.)

RHC is required in some but not all patients. Selecting patients for RHC is discussed below. (See 'Sufficient left heart disease (group 2 PH)' below and 'Insufficient left heart disease' below and 'Right heart catheterization' below.)

Once the diagnosis and the underlying cause is determined, further investigations may be necessary to confirm the suspected PH classification. (See 'Postdiagnostic testing and classification' below.)

Sufficient left heart disease (group 2 PH) — Echocardiography can evaluate left ventricular systolic and diastolic function, valve function, pericardial effusions, and intracardiac shunts (movie 5 and movie 6), all of which can cause or contribute to PH. When the echocardiogram is suggestive of PH, clinicians should determine whether there is enough LHD on the echocardiogram to explain the degree of estimated PH. Many patients in this category do not require further testing to confirm the diagnosis of LHD-PH (ie, group 2 PH). However, patients may need to undergo RHC for therapeutic indications. For example, RHC is indicated if patients are being considered for advanced heart therapies including heart transplantation or mechanical assist devices. RHC is also performed in those in whom coexistent precapillary PH (table 2) is suspected; in such cases, candidacy for left heart therapies as well as PH-specific therapy or candidacy for therapeutic trials may be determined by hemodynamic values obtained on RHC. Further discussion on indications for RHC in patients with LHD-PH is provided separately. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults" and 'Right heart catheterization' below.)

Assessing what constitutes LHD that is sufficient to explain PH is challenging. The presence of significant LHD may be obvious in patients who have left atrial (LA) dilation in conjunction with severe left ventricular systolic dysfunction or severe mitral or aortic valve disease. However, the presence of heart failure with preserved ejection fraction (HFpEF) may be subtle on echocardiography and consequently missed. Although poorly studied, most experts agree that the demonstration of a dilated LA is indicative of chronically elevated LA pressure, thereby supporting PH due to left-sided cardiac disease [22]. Nonetheless, if there is uncertainty regarding the contribution of LHD to PH, right and left heart catheterization is typically performed. (See "Echocardiographic evaluation of the atria and appendages" and "Echocardiographic evaluation of left ventricular diastolic function in adults" and "Echocardiographic evaluation of the aortic valve" and "Echocardiographic evaluation of the mitral valve".)

To address the challenges associated with LHD assessment, the 6^th WSPH has proposed an evaluation that relies on the integration of several lines of echocardiographic and nonechocardiographic evidence to determine whether there is sufficient LHD to explain PH, thereby facilitating the decision to proceed with invasive right (and left) heart catheterization [28].

●Low probability – Patients <60 years old; no obesity, hypertension, dyslipidemia, glucose intolerance, or diabetes; no previous cardiac intervention (coronary and valvular); no atrial fibrillation or structural LHD; and no signs of left heart abnormalities on ECG, echocardiography including assessment for diastolic function, cardiac MRI, or CPET. These patients have insufficient LHD to explain PH discovered on echocardiography and should be investigated as such. (See 'Insufficient left heart disease' below.)

●Intermediate probability – Patients 60 to 70 years old; one to two of the following: obesity, hypertension, dyslipidemia, glucose intolerance or diabetes; have no previous cardiac intervention, currently have paroxysmal atrial fibrillation; no structural LHD is present; have mild LVH on ECG; have no LA dilation with grade <2 diastolic dysfunction on echocardiography; have elevated V_E/VCO₂ slope on CPET. The impact of LHD in this group is uncertain, and as such, most patients in this category should have an RHC, particularly when other risk factors for PH are present (eg, systemic sclerosis [SSC], thromboembolic disease), RV abnormalities are present, or dyspnea is unexplained.

●High probability – Patients >70 years old; two of the following: obesity, hypertension, dyslipidemia, glucose intolerance, or diabetes; have previous cardiac intervention, currently have atrial fibrillation (paroxysmal or persistent), and structural LHD is present; have left bundle branch block or left ventricular hypertrophy (LVH) on ECG; LA dilation and tissue Doppler of elevated left heart filling pressure on echocardiography; and mildly elevated minute ventilation/carbon dioxide uptake (V_E/VCO₂) slope on CPET; and LA strain or LA/right atrial ratio >1 on cardiac MRI. These patients have sufficient disease to explain PH, and most do not need RHC for diagnostic purposes but may need RHC for other reasons (eg, evaluation for therapeutic evaluations). (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults" and 'Right heart catheterization' below.)

PH from HFpEF (diastolic dysfunction) is a growing group of patients who are being diagnosed with PH [29]. Patients with obesity can also develop an extreme form of diastolic dysfunction sometimes referred to as an "obesity-associated restrictive cardiomyopathy" [30,31]. It is characterized by fatty infiltration of cardiac myocytes, restrictive physiology, and marked elevation in left and right heart filling pressures. These patients can also progress to severe PH secondary to an occlusive vasculopathy of the small PAs and arterioles, similar to PAH [32]. Echocardiographic signs of HFpEF can confirm the diagnosis of HFpEF, but they are imperfect and subject to limitations (see "Echocardiographic evaluation of left ventricular diastolic function in adults", section on 'Diagnosis of diastolic dysfunction'). However, one group has described the value of a scoring assessment (0 to 9) that combines easily obtained clinical and echocardiographic variables to determine the probability of HFpEF (H₂FPEF) in euvolemic patients with dyspnea [33]: obesity (body mass index >30 kg/m²; 2 points), atrial fibrillation (3 points), age >60 years (1 point), treatment with ≥2 antihypertensives (1 point), echocardiographic E/é ratio >9 (1 point), and ePASP >35 mmHg (1 point). The scoring assessment and probability calculation was based on data from 414 patients, all of whom underwent RHC. Patients were considered to have HFpEF if they had an elevated mean pulmonary capillary wedge pressure at rest (≥15 mmHg) or with exercise (≥25 mmHg). The H₂FPEF score better discriminated those with dyspnea from HFpEF from euvolemic patients with dyspnea due to noncardiac causes (a score >7 is associated with a >95 percent chance of having HFpEF). This score could help clinicians more accurately identify those with HFpEF and those patients who may benefit from further evaluation for PH. The study has yet to be externally validated. Further details regarding the echocardiographic signs of HFpEF are described separately. (See "Echocardiographic evaluation of left ventricular diastolic function in adults".)

Insufficient left heart disease — Patients who have no LHD or LHD that appears insufficient to explain the degree of estimated PH should undergo additional diagnostic testing to look for a noncardiac etiology that may be the cause of or contribute to PH. (See 'Assess for chronic lung disease and hypoxia (group 3 PH)' below and 'Assess for pulmonary artery obstruction (group 4)' below and 'Assess for other etiologies (group 1 and 5)' below.)

Among noncardiac etiologies of PH, CLD and chronic thromboembolic disease are the most common causes, such that many experts investigate for these conditions first. However, the sequence and extent of testing varies considerably among experts.

For example, some experts prioritize testing according to the clinical suspicion for individual etiologies:

●Patients with risk factors or symptoms of CLD should, at minimum, undergo pulmonary function testing (PFT), including a diffusing capacity for carbon monoxide (DLCO), chest high-resolution CT (HRCT), and six-minute walk testing (6MWT). Further testing including overnight oximetry, testing for sleep-disordered breathing, and CPET may also be appropriate, if indicated. (See 'Assess for chronic lung disease and hypoxia (group 3 PH)' below.)

●Patients with a history or risk factors for venous thromboembolism should undergo ventilation-perfusion (V/Q) scanning, while patients with evidence of PA obstruction (eg, from tumors) may undergo detailed imaging, including pulmonary angiography or MRI. (See 'Assess for pulmonary artery obstruction (group 4)' below.)

In contrast, other experts prefer to obtain several tests at once, regardless of the clinical suspicion for select diseases, and include testing for conditions commonly associated with group 1 PAH, including autoimmune serologies, HIV serology, and liver function tests. Regardless of how testing proceeds, clinicians should understand that if a diagnosis of PH is eventually reached, additional tests may need to be done to accurately classify their PH and allocate an appropriate treatment strategy. (See 'Postdiagnostic testing and classification' below.)

Following testing, the decision to proceed with RHC needs to be made. In general, we suggest the following:

●If an alternate etiology is not readily identified, then patients should undergo RHC specifically to evaluate for idiopathic PAH (IPAH). (See 'Right heart catheterization' below.)

●If a potential cause is identified, RHC is not always necessary but may be indicated in select patients, the details of which are discussed below. (See 'Assess for chronic lung disease and hypoxia (group 3 PH)' below and 'Assess for pulmonary artery obstruction (group 4)' below and 'Assess for other etiologies (group 1 and 5)' below.)

Assess for chronic lung disease and hypoxia (group 3 PH) — Several tests are appropriate for evaluating the presence of PH due to CLD (CLD-PH) and hypoxia. The most common tests initially performed include chest HRCT, PFTs, and 6MWT. Notably, echocardiography may be less reliable in patients with severe emphysema.

Test results should be interpreted collectively. As an example, PH in the setting of hypoxemia, bullous emphysema, and severe obstruction is more consistent with CLD-PH, while a marked reduction in the DLCO (eg, <60 percent predicted) together with severe exertional hypoxemia and venous congestion on chest HRCT should prompt consideration of pulmonary veno-occlusive disease (PVOD). When pulmonary dysfunction is severe enough to explain the degree of PH on echocardiography (eg, severe pulmonary dysfunction and mild PH), RHC is not indicated. RHC is usually reserved for those in whom the severity of PH on echocardiography is not explained by the severity of their underlying CLD (eg, moderate to severe PH with mild or no lung disease) or for those in whom an alternate etiology is suspected or LHD is suspected. When there is uncertainty, RHC should be performed. Selecting patients with CLD for RHC is discussed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Patient selection for right heart catheterization'.)

Initial tests that are commonly obtained include:

●Chest HRCT – Clues as to a possible underlying cause of PH are apparent on the chest radiograph but are better appreciated on chest HRCT. In the majority of cases, chest HRCT serves to distinguish group 3 PH from group 1 PAH (table 1). For example, the findings of reticular or nodular opacities may suggest interstitial lung disease (ILD), hyperinflation and bullae may suggest obstructive lung disease, or developmental abnormalities (eg, sequestration) may be appreciated. In contrast, normal lung fields may suggest IPAH (ie, group 1 PAH).

Chest HRCT may show combined features of emphysema and ILD or, in patients with SSc, combined features of ILD and venous congestion from left heart failure may be appreciated; alternatively, lung fields may be normal in patients with SSc to suggest SSc-PAH. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Types of pulmonary involvement'.)

Clues to nonpulmonary etiologies may also be evident on chest HRCT. For example, patchy opacities, Kerley B lines, and lymphadenopathy may suggest pulmonary edema from left ventricular failure or PVOD, or a large central mass may be seen causing obstruction of the PA to suggest group 4 PH. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Computed tomography'.)

●PFTs – Full PFTs (spirometry, lung volumes, diffusing capacity) are obtained to rule out significant CLD or to identify and characterize underlying lung disease that may be contributing to PH.

In patients with PH, a low DLCO is the most common finding [34,35]. However, this is a nonspecific sign since many conditions can lower the DLCO, including emphysema, ILD, anemia, and cigarette smoking. However, severe reductions in DLCO <40 percent predicted or reductions considered to be out of proportion to the severity of underlying lung disease should prompt suspicion for CLD-PH. A severe reduction in the DLCO in the absence of lung disease on PFTs or chest CT should raise the suspicion for PAH, including that due to PVOD. In patients with SSc, a DLCO that is decreased disproportionately to the forced vital capacity (FVC; ie, FVC percent/DLCO percent >1.6) has also been described as a predictor for the development of SSc-PAH. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Abnormal pulmonary function (low diffusion)'.)

Minor de novo abnormalities on spirometry and lung volumes can occur in PH itself. However, abnormalities of greater severity are more likely to be due to underlying lung disease. It is usually severe ILD (with lung volumes below 70 percent of predicted) or obstructive lung disease (eg, forced expiratory volume in one second <60 percent predicted) that produces PH. Thus, in most circumstances, PH should not be attributed to lung disease if all components of the PFTs are only mildly abnormal.

Further information on PFTs is provided separately. (See "Overview of pulmonary function testing in adults".)

●Assessment of oxygenation – Since hypoxemia in the absence of lung disease can cause PH, several tests may be performed to evaluate for the presence of hypoxemia. These include resting oxygen saturation and exercise testing such as a 6MWT. (See "Overview of pulmonary function testing in adults", section on 'Submaximal exercise testing'.)

Overnight oximetry may also be helpful since desaturation during sleep is common in patients with PH [36] but is also common in patients with severe CLD and sleep apnea.

Other forms of testing are sometimes performed:

●CPET – The performance and interpretation of CPET should only occur in a facility with expertise in exercise physiology. CPET is useful in determining the nature of exercise limitation in patients with unexplained dyspnea and provides clues as to whether there are cardiac, pulmonary, or mixed limitations to dyspnea. Thus, it can prompt consideration of RHC. It is not specific for the diagnosis of PH but can help suggest the diagnosis. A lower peak oxygen uptake (VO₂), decreased cardiac reserve, and preserved ventilatory reserve may indicate PH. In contrast, decreased VO₂ in those with decreased ventilatory reserve may indicate dyspnea primarily due to lung disease, while a decreased cardiac reserve may suggest cardiac limitation. CPET is also useful for determining the severity of exercise limitation in those eventually diagnosed with PH. (See "Cardiopulmonary exercise testing in cardiovascular disease".)

●Assess for sleep-related breathing disorders (SRBDs) – Sleep testing may also be performed depending upon the clinical suspicion for SRBDs, including obstructive sleep apnea (OSA). Sleep testing may not be necessary if there is no clinical suspicion for an SRBD and a sufficient explanation for PH is found. However, an SRBD should be excluded if a diagnosis of IPAH is being entertained. (See 'Postdiagnostic testing and classification' below.)

Polysomnography is the gold standard diagnostic test for SRBDs. However, home testing may be the only option for initial sleep testing if third-party payers do not approve polysomnography or if uncomplicated moderate to severe OSA is suspected. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults" and "Home sleep apnea testing for obstructive sleep apnea in adults" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Selecting home or in-laboratory testing'.)

Assess for pulmonary artery obstruction (group 4) — The most common etiology in this group is chronic thromboembolic disease-related PH (CTEPH). Other obstructions to PA flow (small-medium-large arteries) including tumors, PA stenosis or arteritis (in the absence of CTD), and parasitic obstructions are rare (table 4).

The detection of CTEPH is an important step in the diagnostic evaluation of PH since CTEPH is potentially reversible with surgery. For most patients, V/Q scanning is the preferred imaging modality [13]. A normal V/Q scan accurately excludes chronic thromboembolic disease with a sensitivity of 96 to 97 percent and a specificity of 90 to 95 percent [37]. When the V/Q scan suggests that chronic thromboembolic disease exists (ie, mismatched defects in the large/central PAs), CT pulmonary angiography (CTPA) is often performed prior to obtaining contrast-enhanced pulmonary angiography; the latter is the gold standard and is necessary to confirm obstruction and to define the location and extent of disease if CTPA is not adequate (image 3). However, this evaluation is best done in a center with expertise in CTEPH. For this reason, most experts make a clinical diagnosis of CTEPH in patients with PH on echocardiography who have clear evidence of chronic thromboembolic disease on V/Q scan; diagnostic RHC is not necessary, and the patient is referred to a CTEPH center where extensive evaluation that includes RHC with pulmonary angiography can be performed. For patients in whom V/Q scanning cannot be performed, CTPA or magnetic resonance pulmonary angiography (MRPA) is acceptable. The diagnostic accuracy of V/Q scanning, CTPA, and MRPA in patients with suspected CTEPH is discussed separately. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

Similarly, V/Q scanning and CTPA are useful for identifying PH due to tumor obstructions or stenoses in large- and medium-size PAs. Small tumor emboli can obstruct multiple small PAs and arterioles and will not be evident on chest imaging. Further testing may be required depending upon the suspected reason for PA obstruction. Identifying the causes (eg, sarcoma or benign stenosis) is important since some are amenable to debulking or dilation, while others may be fatal. While not always indicated, in some cases, RHC may be useful.

Assess for other etiologies (group 1 and 5) — The absence of convincing LHD, CLD and/or hypoxia, or PA obstructions in patients with PH on echocardiography narrows the differential to several etiologies of PH including group 1 PAH (table 1) and several rare etiologies associated with group 5 PH (eg, hematologic disorders, metabolic disorders, sarcoidosis, chronic renal failure, complex congenital heart disease, segmental PH) (table 5). RHC is indicated in most cases, particularly those with suspected group 1 PAH. (See 'Group 1: Pulmonary arterial hypertension' below and 'Group 5: PH due to multifactorial mechanisms' below.)

Conditions that predispose to PH are typically already known, and it is rare for a new diagnosis to be discovered during the evaluation of PH. Laboratory findings may suggest the possibility of an underlying explanation for PH (eg, hemolytic anemia in patients with sickle cell disease; liver dysfunction in those with cirrhosis; or erythrocytosis, thrombocytosis, or leukocytosis in those with myeloproliferative disorder). Thyroid disorders are not uncommon in patients with group 1 PAH and may be associated with abrupt deterioration of PH. Patients with CTD-associated PAH may have an antibody profile consistent with the underlying CTD (eg, antinuclear antibody, rheumatoid factor, anticentromere, antitopoisomerase, anti-ribonucleic acid [RNA] polymerase III, anti-double-stranded deoxyribonucleic acid [DNA], anti-Ro, anti-La, and U1RNP antibodies), and patients with vasculitis may be positive for antineutrophil cytoplasmic antibody. Patients with CTEPH may have underlying coagulopathies including anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2-gylycoprotein antibodies. In the appropriate clinical setting, laboratory studies looking for evidence of schistosomiasis are appropriate (eg, stool and urine parasites). (See "Diagnosis of sickle cell disorders" and "Schistosomiasis: Diagnosis".)

Investigations for rare causes of PH should be performed when suspected (eg, Hughes-Stovin syndrome, Behçet syndrome, and sarcoidal angiitis).

Cardiopulmonary exercise testing, while helpful in delineating reasons for exercise intolerance, is generally nonspecific diagnostically but may be supportive of PH. Similarly, fluid challenge or passive leg raising to look for subclinical heart failure remain investigational [28,38].

RIGHT HEART CATHETERIZATION — Right heart catheterization (RHC) is generally performed with the goal of confirming the diagnosis of PH to support treatment decisions and assessing the contribution of left-sided heart disease (LHD). Less frequently, RHC is indicated in those with congenital heart disease to assess complex hemodynamics for the selection of appropriate PH therapy.

●Confirm PH – In select individuals, RHC is necessary to confirm the diagnosis of PH, while in others, a clinical diagnosis is acceptable. Clinical and hemodynamic definitions of PH are discussed below. (See 'Diagnosis' below.)

Examples of patients who need diagnostic RHC include:

•Patients with a low probability of PH on echocardiography who have a clinical suspicion discordant with that finding. (See 'Low probability of pulmonary hypertension on echocardiography' above.)

•Patients with a moderate to high probability of PH on echocardiography in whom there is uncertainty regarding the contribution of LHD to PH (eg, patients with severe PH who have mild LHD or in whom undetected diastolic dysfunction is suspected). (See 'Sufficient left heart disease (group 2 PH)' above and "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults", section on 'Right heart catheterization'.)

•Patients in whom the severity of the PH is not explained by the severity of the underlying lung disease (eg, severe PH with mild chronic lung disease). (See 'Assess for chronic lung disease and hypoxia (group 3 PH)' above and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Right heart catheterization is indicated'.)

•Patients in whom an etiology of PH remains undetermined after extensive noninvasive investigations (ie, suspected idiopathic pulmonary arterial [PA] hypertension [PAH]).

•Patients in whom a strong component of pulmonary vascular disease (ie, precapillary disease) is suspected.

•Patients in whom mixed etiologies are suspected (eg, group 2/3 PH, group 1/2).

•Selected patients with suspected group 5 PH.

Provocative testing during RHC with exercise or fluid challenge may be done in some cases when, for example, LHD-PH or exercise-induced PH is suspected. However, this type of RHC testing is only performed in a limited number of centers and can be subject to misinterpretation since they are difficult to perform, they are complicated by errors due to rapid respiratory cycles, and little consensus exists on the diagnostic criteria for exercise-induced PH.

●Contribution of LHD – RHC can distinguish PH due to LHD (ie, group 2 PH) from noncardiac-related PH. Making this distinction is important since unlike those with group 1 PAH, most patients with LHD-PH are not candidates for PH-specific therapy. Hemodynamically, pulmonary capillary wedge pressure (PCWP) ≥15 mmHg indicates elevated left atrial pressure from LHD that is not seen in other forms of PH. The elevated PCWP ≥15 mmHg should, ideally, be additionally confirmed by directly measuring the left ventricular end-diastolic pressure by left heart catheterization (LHC) [39]. In many cases, both RHC and LHC are performed in the same setting, while in other circumstances, they are performed separately. Other criteria required for the diagnosis of LHD-PH are discussed below. (See 'Group 2: PH due to left heart disease' below.)

●Assess congenital heart disease – The presence and/or severity of a congenital or acquired left-to-right shunt can be assessed using oximetry on RHC and provide additional information when noninvasive studies are not definitive. However, it is important to keep in mind that even a large atrial septal defect may have no significant left-to-right shunt in a patient with associated severe PAH since patients may have right-to-left shunt or bidirectional shunt and therefore the defect may not be detected readily by RHC oximetry either. (See "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'Cardiac catheterization'.)

●Baseline assessment of severity and vasoreactivity testing – RHC provides estimates of PA, right ventricle, and right atrial pressures that can be followed for patients who meet criteria for PH-specific therapy. While there are no hard cutoffs to define mild, moderate, or severe PH by RHC data, most experts consider a mean PA pressure ≥45 mmHg as severe PH. Vasoreactivity testing on RHC may also be necessary before therapy commences. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

DIAGNOSIS

Definitions — In many patients, the diagnosis of PH is made clinically using a constellation of clinical findings and noninvasive testing. For example, a clinical diagnosis is commonly made in patients with PH that is explained by significant left heart disease (LHD) or by chronic lung disease (CLD). In contrast, other patients require a hemodynamic diagnosis using right heart catheterization (RHC; eg, patients with suspected idiopathic pulmonary arterial [PA] hypertension [PAH]). Hemodynamically, a mean PA pressure (mPAP; supine and at rest) of >20 mmHg [40] is now considered diagnostic of PH based upon data measuring mPAP in healthy individuals, which confirmed that an mPAP of 8 to 20 mmHg at rest is normal [27]. While in the past, PH was hemodynamically defined by an mPAP of ≥25 mmHg [41], this cutoff was somewhat arbitrary and targeted at avoiding the overdetection of PH.

In addition, for patients with precapillary PH (ie, disease confined to the PA bed, such as patients with group 1 PAH (table 2)), the mPAP is no longer used in isolation to define PH, and an elevated pulmonary vascular resistance (PVR) of ≥2 Wood units is also included [42]. The cutoff for PVR of 2 Wood units can also be used to detect patients with other forms of PH who have a significant component of precapillary disease. For example, some patients with group 2 PH (ie, LHD-PH, also known as postcapillary PH or venous PH) have combined pre- and postcapillary PH. Similarly, patients in group 3 (PH due to CLD and/or hypoxia), patients in group 4 (eg, PH due to chronic thromboembolism [CTEPH]), and many patients in group 5 also have precapillary disease. The importance of an elevated PVR ≥2 Wood units is not just diagnostic for precapillary disease but also portends a poor prognosis and may have therapeutic implications for starting PH-specific medications or for surgery in those with CTEPH.

Normal hemodynamic values of recumbent adults are listed in the table (table 6).

Postdiagnostic testing and classification — PH is classified into five groups, based upon etiology and mechanism (table 1 and table 5 and table 4) [40]. PAH refers to group 1. PH refers to any of group 2 through 5 and is also used when referring to all five groups collectively. PH can also be classified as precapillary PH (ie, that involving the PA system) or postcapillary PH (ie, that confined to the pulmonary venous system) (table 2). Once PH is confirmed, a preliminary classification should be assigned. At this point, we recommend reviewing all available data and, if necessary, obtaining additional diagnostic testing to confirm the suspected classification. In the sections below, we discuss the diagnostic criteria necessary for each classification. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

Group 1: Pulmonary arterial hypertension — The diagnosis of PAH requires RHC to demonstrate an mPAP ≥20 mmHg at rest and a PVR ≥2 Wood units [18] (see 'Definitions' above). Several additional criteria to exclude the remaining categories of PH must also be met:

●Mean pulmonary capillary wedge pressure (PCWP) ≤15 mmHg (to exclude PH due to LHD [ie, group 2 PH]). (See 'Sufficient left heart disease (group 2 PH)' above.)

●CLDs and other causes of hypoxemia are mild or absent (to exclude PH owing to CLD or hypoxemia [ie, group 3 PH]). (See 'Assess for chronic lung disease and hypoxia (group 3 PH)' above.)

●Venous thromboembolic disease and PA obstructions are absent (to exclude group 4 PH). (See 'Assess for pulmonary artery obstruction (group 4)' above.)

●Certain miscellaneous disorders are absent, including systemic disorders (eg, sarcoidosis, chronic renal insufficiency), hematologic disorders (eg, myeloproliferative diseases and chronic hemolytic anemias), and metabolic disorders (eg, glycogen storage disease). The purpose is to exclude PH with unclear multifactorial mechanisms (group 5 PH). (See 'Assess for other etiologies (group 1 and 5)' above.)

In addition, clinicians should ensure that all of the etiologies associated with this class have been investigated. In general, most of the testing has already been performed during the initial workup, but additional studies should be obtained for diagnoses that may have been missed. This step is critical for those with suspected idiopathic PAH (IPAH). Below are all of the conditions associated with group 1 PAH that should be considered:

●Idiopathic and heritable PAH (1.1 and 1.2) – PAH due to an unknown mechanism (IPAH) and heritable genetic defects (heritable PAH [HPAH]) are clinically indistinguishable; while IPAH has no detectable cause, HPAH is associated with inheritable genetic defects, the details of which are discussed separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Idiopathic and heritable'.)

Genetic testing for inheritable diseases in patients with IPAH is somewhat controversial and practice varies widely. While some experts routinely test for common inheritable disorders associated with PAH, other experts only test those with a strong family history or when no family history is available (eg, adoption). Guidance from the International Consortium for Genetic Studies in PAH suggest genetic testing in patents with the following [43]:

•A family history of PAH

•IPAH

•Anorexigen-induced PAH

•Congenital heart disease PAH

What genetic studies to include is also unclear. The most common mutations occur in the gene encoding bone morphogenetic protein receptor 2 (BMPR2). Other mutations associated with PAH have been identified in genes encoding activin-like kinase type 1 receptor, 5-hydroxytryptamine (serotonin) transporter (5HTT), endoglin, mothers against decapentaplegic homolog 9 (SMAD9), caveolin 1 (CAV1), potassium channel subfamily K member 3 (KCNK3), and eukaryotic translation initiation factor 2-alpha kinase (EIF2AK4). Guidance from International Consortium for Genetic Studies in PAH suggest testing for BMP/transforming growth factor-beta family mutations, ATPase 13A3, KCNK3, EIF2AK4, and several others [43]. However, while many PH centers have the capability to test for BMPR2, testing for less common genetic mutations may require testing in specialty laboratories (ie, not commercially or widely available) and is therefore subject to variability. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Genetic mutations'.)

●Drugs and toxins (1.3) – Clinical history should identify drugs or toxins that are either definite or possible risk factors for the development of PAH. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Drugs and toxins'.)

●PAH associated with the following systemic disorders (1.4):

•Connective tissue diseases (CTDs) – Systemic sclerosis (also called scleroderma) and several other CTDs (eg, rheumatoid arthritis, systemic lupus erythematosus, Raynaud disease, mixed CTD) can be associated with PAH. Obtaining serology for antinuclear antibody, rheumatoid factor, anticentromere, antitopoisomerase, anti-RNA polymerase III, anti-double-stranded DNA, anti-Ro, anti-La, and U1RNP antibodies is appropriate. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening" and "Pulmonary manifestations of systemic lupus erythematosus in adults" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis".)

•HIV – PAH occurs in a small percentage of HIV-infected patients and the diagnosis is typically known during evaluation, but serology should be sent if not already known. (See "Pulmonary arterial hypertension associated with human immunodeficiency virus".)

•Portal hypertension – PAH associated with portal hypertension (most often due to chronic liver disease) is referred to as portopulmonary hypertension. The diagnosis of portal hypertension is typically known during the PH evaluation, but, if not already done, liver function tests should be obtained. (See "Portopulmonary hypertension".)

•Congenital heart disease – This class includes patients with PH due to left-to-right intracardiac or extracardiac shunts (atrial, ventricular, and great artery defects), including those who develop PAH following closure. Patients with PAH due to congenital inflow/outflow tract obstruction and congenital cardiomyopathies are not included in this group. Other forms of PAH due to congenital heart disease (eg, corrected transposition of the great arteries, and those with atrial redirection surgery) cannot be classified as PAH and are listed as part of group 5 PH, underscoring the need for assessment of patients with all forms of congenital heart disease and PAH/PH at a center with the expertise in PH. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis".)

•Schistosomiasis – PAH can develop in patients infected with schistosomiasis species, particularly those with hepatosplenic involvement. Stool and urine for parasites should be sent in appropriate patients as an initial testing. No further testing is typically required unless the suspicion for schistosomiasis is high. (See "Schistosomiasis: Diagnosis".)

●PAH with overt features of venous/capillary involvement (1.5) – Unlike PAH, which involves the small muscular pulmonary arterioles, pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis, which are now thought to be the same disease, is characterized by extensive diffuse occlusion of the pulmonary veins resulting in tortuous dilation of the pulmonary capillaries. Patients in this class are usually diagnosed clinically without performing a lung biopsy. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

●Persistent PH of the newborn (1.6) – Persistent PH of the newborn due to abnormal pulmonary vasculature development in term or late preterm infants is discussed separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Group 2: PH due to left heart disease — LHD-PH may be diagnosed clinically when there is sufficient LHD on echocardiography (with or without other confirmatory testing) to explain PH (see 'Sufficient left heart disease (group 2 PH)' above and 'Definitions' above). For patients in whom RHC is performed, an mPAP ≥20 mmHg, PCWP ≥15 mmHg, and a normal or reduced cardiac output is consistent with a hemodynamic diagnosis of LHD-PH. Important adjunct information is the presence of left atrial (LA) enlargement on an echocardiogram and a left heart catheterization (LHC) to confirm an elevated left ventricular end-diastolic pressure. All other causes of PH should also be reasonably ruled out.

Confirmation with LHC is often performed because the PCWP may be falsely elevated in up to 5 percent of patients [39]. This may be due to dilatation of the PAs and incomplete "wedging" of the balloon catheter [44].

Once LHD-PH is confirmed, patients should be allocated into one of the following categories: LHD-PH due to heart failure with preserved or reduced ejection fraction (group 2.1), heart failure with reduced ejection fraction (group 2.2), valvular heart disease, or congenital or acquired conditions leading to postcapillary PH (group 2.3; eg, restrictive cardiomyopathy, constrictive pericarditis, LA myxoma, congenital or acquired inflow/outflow tract obstruction, and congenital cardiomyopathies).

Importantly, patients with LHD-PH (ie, isolated postcapillary PH, also known as venous PH) need to be distinguished from those who have combined pre- and postcapillary PH (table 2), particularly for those in whom left heart interventions (eg, transplant, assist devices) are being considered. Patients in the combined group may be pathogenetically different from those with isolated postcapillary hypertension. PH-specific therapy has not proved beneficial in patients with LHD-PH whether they have isolated postcapillary PH or mixed pre- and postcapillary PH. Further, these drugs may prove harmful by inducing pulmonary edema. Consideration should be given to referring these patients to specialized PH centers.

Further details regarding PH in left heart failure are provided separately. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults".)

Group 3: PH due to chronic lung disease and/or hypoxemia — The diagnosis of PH due to CLD and/or hypoxemia is made by the demonstration of PH on RHC or echocardiogram and evidence of moderate to severe lung dysfunction and/or hypoxemia. Other classes of PH should also be reasonably ruled out, including PAH due to CTD, HIV, or liver disease; PH due to LHD; and PH due to PA obstructions (eg, thromboembolic disease). Patients are allocated into PH due to obstructive lung disease (group 3.1), restrictive lung disease (group 3.2), mixed obstructive and restrictive lung disease (group 3.3), PH associated with hypoventilation (group 3.4) hypoxia without lung disease (group 3.5), or PH due to developmental disorders (group 3.6). (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Diagnosis'.)

Group 4: PH due to pulmonary artery obstructions — Group 4 PH includes mostly patients with CTEPH (group 4.1) as well as PH due to PA obstructions (group 4.2; eg, benign or malignant tumors, arteritis in the absence of CTD, congenital PA stenosis, parasites).

Group 5: PH due to multifactorial mechanisms — Patients with PH who do not clearly fit into group 1 through 4 may fall into this group. They can be further classified into:

●5.1 – Hematologic disorders such as chronic hemolytic anemia (eg, sickle cell disease [SCD], beta thalassemia, or spherocytosis) and myeloproliferative disorders. (See "Pulmonary hypertension associated with sickle cell disease".)

●5.2 – Systemic or metabolic disorders including sarcoidosis, pulmonary Langerhans histiocytosis X, and neurofibromatosis.

●5.3 – Metabolic disorders including Gaucher disease, and glycogen storage disease.

●5.4 – Chronic renal failure and PH associated with hemodialysis. (See "Pulmonary hypertension in patients with end-stage kidney disease".)

●5.5 – Pulmonary tumor thrombotic microangiopathy. (See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management", section on 'Pulmonary hypertension'.)

●5.6 – Fibrosing mediastinitis.

PH is, in general, an uncommon manifestation of these disorders and when suspected, referral to a center with expertise is advisable. Among them, SCD is the best studied. The most frequent cause of PH in SCD is left-sided heart disease, but some patients also have disease that mimics group 1 PAH and group 4 PH, highlighting the multifactorial nature of PH in this group. (See "Pulmonary hypertension associated with sickle cell disease".)

PH can complicate chronic renal insufficiency with or without hemodialysis in the absence of fluid overload. (See "Pulmonary hypertension in patients with end-stage kidney disease", section on 'Initial diagnostic evaluation'.)

Lymphangioleiomyomatosis was originally classified as group 5 PH but has since been reclassified as group 3 PH.

A new disorder was added to group 5 PH, known as segmental PH. Segmental PH refers to the development of PH in segments of the lung rather than the entire lung. It can be encountered in patients with congenital heart disease (eg, anomalous PA) and has notable similarities to PAH [45].

Exercise-induced pulmonary hypertension — Patients with exercise-induced PH have normal resting pulmonary pressures but develop PH during exercise. However, the exact threshold that is diagnostic of exercise-induced PH is somewhat controversial. Combining mPAP >30 mmHg at maximal exercise with total PVR >3 mmHg/minute/L^-1 has been reported to have a diagnostic sensitivity and specificity of 0.93 and 1, respectively [46]. Another systematic review reported that the PA wedge pressure (PAWP) reaches 20 mmHg in adults >40 years old and suggested that a threshold of at least 25 mmHg was an appropriate cutoff for "normal" PAWP during exercise [47]; these results need to be validated further before they can be used for the diagnosis of exercise-induced PH. Standardization of exercise protocols to provoke exercise-induced PH remains problematic, and the overall natural history and significance of the condition are unclear.

SCREENING FOR PULMONARY HYPERTENSION — Select high-risk groups are evaluated for PH using echocardiography. Screening asymptomatic patients at risk of developing PH is discussed separately:

●Systemic sclerosis. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Screening'.)

●HIV. (See "Pulmonary arterial hypertension associated with human immunodeficiency virus", section on 'Suspecting PAH'.)

●Portopulmonary hypertension. (See "Portopulmonary hypertension", section on 'Early detection in chronic liver disease'.)

●Congenital heart disease. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'When to suspect PH-CHD'.)

●Heritable etiologies – The 6^th World Symposium on Pulmonary Hypertension suggests an evaluation for pulmonary arterial hypertension (PAH; eg, exercise testing, annual echocardiography) in patients who are asymptomatic carriers of genetic mutations known to cause PAH [1]. They also suggest echocardiography in those with hereditary hemorrhagic telangiectasia (HHT) and those who have a family history of HHT who are symptomatic, have heart failure, or have hepatic arteriovenous malformations. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

●Sickle cell disease. (See "Pulmonary hypertension associated with sickle cell disease", section on 'Screening and risk stratification'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pulmonary hypertension (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Patients with pulmonary hypertension (PH) initially present with exertional dyspnea and fatigue. As PH progresses, the signs and symptoms of right ventricular (RV) failure develop (eg, exertional chest pain or syncope, loud P2, elevated jugular venous pressure, right-sided murmurs, edema, right upper quadrant pain, ascites, and pleural effusion) (figure 1). The diagnosis is often delayed because the symptoms are frequently attributed incorrectly to age, deconditioning, or a coexisting or alternate medical condition. (See 'Clinical manifestations' above.)

●Differential diagnosis – The differential diagnosis of early PH is wide because there are many causes of exertional dyspnea. However, once PH progresses to RV hypertrophy and failure, the differential diagnosis narrows and includes left-sided heart failure, coronary artery disease, liver disease, and Budd-Chiari syndrome. (See 'Initial differential diagnosis' above.)

●Diagnostic evaluation – Once PH is suspected, the initial test of choice is transthoracic echocardiography (table 3), which then determines the sequence of subsequent testing. Importantly, patients with evidence of severe PH and/or patients with significant symptoms should be referred to a PH center for rapid evaluation. (See 'Initial diagnostic evaluation (noninvasive testing)' above.)

•Low suspicion for PH – When there is a low probability of PH on echocardiography and the clinical suspicion for PH is also low, evaluation should be directed toward alternative diagnoses. If the clinical suspicion for PH remains high despite the echocardiographic findings, the threshold for right heart catheterization (RHC) should be lower, especially when group 1 pulmonary arterial (PA) hypertension (PAH) is suspected. (See 'Low probability of pulmonary hypertension on echocardiography' above.)

•Intermediate or high suspicion for PH with significant left heart disease (LHD) on echocardiography – When there is an intermediate or high suspicion for PH and enough LHD on the echocardiogram to explain the degree of estimated PH, RHC is not typically required. Assessing what constitutes LHD that is sufficient to explain PH is challenging, and many experts use a combination of clinical and echocardiographic features (in particular, left atrial [LA] dilation) as well as other noninvasive tests to make this assessment. (See 'Sufficient left heart disease (group 2 PH)' above.)

•No or insufficient LHD on echocardiography – When there is no or insufficient LHD on echocardiography to explain PH, additional investigations targeted at other suspected etiologies are necessary (ie, group 1, 3, 4, and 5 PH). The sequence and extent of investigations vary among experts.

Common tests performed include pulmonary function testing, chest high-resolution CT, six-minute walk testing, ventilation-perfusion (V/Q) scanning, and laboratory tests (eg, autoimmune serologies, HIV serology, and liver and thyroid function tests). Depending upon clinical suspicion or test results, additional tests that may be appropriate include overnight oximetry, testing for sleep-disordered breathing, cardiopulmonary exercise testing, stool and urine parasite testing, and coagulation profile tests. (See 'Insufficient left heart disease' above.)

-Patients with significant lung dysfunction – For patients whose pulmonary dysfunction is severe enough to explain the degree of PH on echocardiography, RHC is not typically indicated. RHC is usually reserved for those in whom the severity of PH on echocardiography is not explained by the severity of their underlying chronic lung disease (CLD) or for those in whom an alternate or contributing etiology is suspected (eg, precapillary disease or LHD). (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Patient selection for right heart catheterization'.)

-Patients with suspected thromboembolic disease – For patients with PH on echocardiography who have clear evidence of chronic thromboembolic disease on V/Q scan (ie, chronic thromboembolic PH [CTEPH]), diagnostic RHC is not necessary, and the patient is referred to a CTEPH center where extensive evaluation that includes RHC with pulmonary angiography can be performed. For patients in whom PA obstruction is suspected, evaluation of the etiology is necessary (eg, further imaging), and while not always indicated, in some cases, RHC may be useful. (See 'Assess for pulmonary artery obstruction (group 4)' above and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Diagnostic evaluation'.)

-Others – For patients with PH on echocardiography who have insufficient LHD, CLD and/or hypoxia, or PA obstructions, RHC is typically performed, mostly to evaluate for PAH. (See 'Assess for other etiologies (group 1 and 5)' above.)

•When to perform RHC – RHC is generally performed with the goal of confirming the diagnosis of PH, assessing the contribution of LHD, and estimating the severity of PH. Less frequently, RHC is indicated in those with congenital heart disease to assess complex hemodynamics for the selection of appropriate PH therapy. (See 'Right heart catheterization' above.)

●Diagnosis – In many patients, the diagnosis of PH is made clinically using a constellation of clinical findings and noninvasive testing (eg, patients with mild PH that is explained by significant LHD or CLD). In contrast, other patients require a hemodynamic diagnosis using RHC (eg, patients with suspected idiopathic PAH). Hemodynamically, a mean PA pressure (mPAP; supine and at rest) >20 mmHg is considered diagnostic of PH. (See 'Diagnosis' above.)

●Classification – Clinical studies and additional information provided by RHC are necessary to then classify the patient into an appropriate PH category (groups 1 through 5) (table 1). (See 'Postdiagnostic testing and classification' above.)

•Group 1 – The diagnosis of PAH requires RHC that demonstrates mPAP >20 mmHg at rest, pulmonary vascular resistance ≥2 Wood units, and a mean pulmonary capillary wedge pressure (PCWP) <15 mmHg. In addition, all other causes of PH should be absent (or mild). Once PAH is diagnosed, additional testing to investigate all of the etiologies associated with PAH should be performed (eg, connective tissue disease screen, HIV serology, liver function tests, genetic testing). (See 'Group 1: Pulmonary arterial hypertension' above.)

•Group 2 – LHD-PH may be diagnosed clinically when there is sufficient LHD on echocardiography (with or without other confirmatory testing) to explain PH. Hemodynamically, an mPAP ≥20 mmHg, a PCWP ≥15 mmHg, and a normal or reduced cardiac output are consistent with LHD-PH. The presence of LA enlargement on echocardiography and an elevated left ventricular end-diastolic pressure on left heart catheterization are also useful confirmatory tests. All other causes of PH should also be reasonably ruled out. (See 'Group 2: PH due to left heart disease' above and "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults", section on 'Diagnosis and evaluation'.)

•Group 3 – The diagnosis of PH due to CLD and/or hypoxemia is made by the demonstration of PH on RHC or echocardiogram and evidence of moderate to severe lung dysfunction and/or hypoxemia in the absence of other classes of PH. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Diagnosis' and 'Group 3: PH due to chronic lung disease and/or hypoxemia' above.)

•Group 4 – Group 4 PH can be diagnosed by echocardiography or RHC and supported by pulmonary imaging demonstrating the presence of thromboembolic or other occlusion of the proximal or distal pulmonary vasculature in the absence of other causes of PH. (See 'Group 4: PH due to pulmonary artery obstructions' above and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Diagnosis'.)

•Group 5 – Patients with unclear etiologies or mechanism have group 5 PH. Most patients are diagnosed hemodynamically and have supportive testing for underlying disorders that fall in this category. (See 'Group 5: PH due to multifactorial mechanisms' above and "Pulmonary hypertension associated with sickle cell disease", section on 'Diagnosis' and "Pulmonary hypertension in patients with end-stage kidney disease".)