The Early Detection of Pulmonary Hypertension

Background: Up to 1% of the world population and 10% of all persons over age 65 suffer from pulmonary hypertension (PH). The latency from the first symptom to the diagnosis is more than one year on average, and more than three years in 20% of patients. 40% seek help from more than four different physicians until their condition is finally diagnosed.

Methods: This review is based on publications retrieved by a selective literature search on pulmonary hypertension.

Results: The most common causes of pulmonary hypertension are left heart diseases and lung diseases. Its cardinal symptom is exertional dyspnea that worsens as the disease progresses. Additional symptoms of right heart failure are seen in advanced stages. Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, difficult to diagnose, and of particular clinical relevance because specific treatments are available. For this reason, strategies for the early detection of PAH and CTEPH have been developed. The clinical suspicion of PH arises in a patient who has nonspecific symptoms, electrocardiographic changes, and an abnormal (NT-pro-)BNP concentration. Once the suspicion of PH has been confirmed by echocardiography and, if necessary, differential-diagnostic evaluation with a cardiopulmonary stress test, and after the exclusion of a primary left heart disease or lung disease, the patient should be referred to a PH center for further diagnostic assessment, classification, and treatment.

Conclusion: If both the (NT-pro-)BNP and the ECG are normal, PH is unlikely. Knowledge of the characteristic clinical manifestations and test results of PH is needed so that patients can be properly selected for referral to specialists and experts in PH.

Pulmonary hypertension (PH) is a potentially life-threatening cardiopulmonary condition defined by a mean pulmonary artery pressure (mPAP) > 20 mm Hg, as measured with a right heart catheter. In PH, chronic vascular remodeling results in an increase in pulmonary vascular resistance (PVR) in the pulmonary circulation. Consecutive to this, pulmonary arterial pressure (PAP) and right heart afterload also increase, ultimately leading to right heart failure. PH is subdivided into five groups based on the underlying pathophysiology (Table 1) (1). In total, up to 1% of the world population and 10% of over 65-year-olds suffer from PH (2). The most common causes of PH include left heart diseases and lung diseases (2, 3). Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare and more difficult to diagnose. They are of particular importance since, unlike in the case of PH due to left heart disease or lung disease, specific treatment options are available. Due to nonspecific symptoms, the diagnosis of PAH and CTEPH is usually delayed (1). The latency in PAH and CTEPH from first symptom to diagnosis is more than 1 year on average (4, 5). However, in the United Kingdom for example, 20% of PH patients wait more than 3 years for a diagnosis, and 40% of patients seek help from more than four different physicians before their condition is diagnosed (4). In the USA, it can even take a median of over 2 years and require six different physicians to diagnose PAH (6). Delayed initiation of therapy is associated with increased right heart load, which is the determining factor in the prognosis of PH (7, 8). To ensure early diagnosis and prompt initiation of treatment, knowledge of typical symptoms and test results is essential in order to refer selected patients to specialists and experts (Table 2).

Table 1

Classification of pulmonary hypertension (modified from [1])

Table 2

Differential diagnostic criteria to distinguish between the PH subgroups (modified from [1, e15])

Methods

This review is based on publications retrieved by a selective literature search on the clinical picture of PH based on the current ESC/ERS guideline (1). The following search terms were used in a wide variety of combinations to select literature in Medline: “pulmonary hypertension,” “prevalence,” “incidence,” “symptoms,” “diagnosis,” “early detection,” “screening,” “electrocardiogram,” “bnp,” “nt-pro-bnp,” “echocardiography,” “chest x-ray,” “computed tomography,” “magnetic resonance imaging,” “pulmonary function test,” and “cardiopulmonary exercise test.” Only German- and English-language articles were taken into consideration.

Diagnostic algorithm

If PH is suspected on the basis of a combination of nonspecific symptoms, electrocardiographic changes, and measurement of (NT-pro-)BNP, echocardiography should be performed to confirm the suspicion of PH. In the case of uncertainty, suspicious patterns in cardiopulmonary exercise tests (CPET) can help in this process. Persistent suspicion of PH or suspected hemodynamically severe PH should prompt referral of patients to PH centers for diagnosis, classification, and treatment once group-2 or -3 PH has been excluded (Figure) (1, 13).

Figure

Diagnostic algorithm for the early detection of pulmonary hypertension (modified from [1, 13])

Patient history, symptoms, and signs

Symptoms of PH at disease onset are usually only observed during exercise, but later on even at rest (14). The cardinal symptom of PH is progressive exertional dyspnea (15). Other possible symptoms include reduced exercise capacity, chest discomfort, palpitations, edema, and syncope. More rarely, chest pain on exertion, hoarseness, cough, or hemoptysis occur. Right heart failure can cause distended and pulsatile jugular veins, hepatojugular reflux, hepatosplenomegaly and ascites, peripheral cyanosis, dizziness, pallor, cold extremities, and prolonged capillary refill time. Typical findings on auscultation include a loud second heart sound, the presence of a third and/or fourth heart sound, as well as a systolic murmur (tricuspid regurgitation) and/or a diastolic murmur (pulmonary regurgitation) (13, 14, 15, 16). Although the common symptoms of PH (eTable 1) are nonspecific, PAH or CTEPH should always be considered as a differential diagnosis, since there are specific treatments for these two entities.

eTable 1

Frequency of clinical symptoms and signs of pulmonary hypertension at the time of diagnosis (e14, e48, e49)

The patient history can prompt suspicion of the etiology possibly underlying PH (Table 2). Typical risk factors such as previous embolism/thrombosis (in particular, fulminant pulmonary embolism), thrombophilia (in particular, antiphospholipid syndrome and elevated factor VIII), certain comorbidities (malignancy, myeloproliferative disorders, chronic osteomyelitis, chronic inflammatory bowel disease, and treated hypothyroidism), previous splenectomy, presence of a ventriculoatrial shunt, and infections of chronic venous accesses or devices (for example, pacemakers) are suggestive of CTEPH (17, 18, 19). Risk factors for PAH include certain disorders (connective tissue diseases, especially systemic sclerosis; portal hypertension; HIV infection; certain heart defects; schistosomiasis), certain mutations (for example, BMPR2 mutations), or the abuse of certain drugs or toxins (for example, methamphetamines or appetite suppressants) (1).

Electrocardiogram

Typical electrocardiographic changes in PH (Figure 1, eTable 2) include:

• Right axis deviation or SI-QIII/SI-SII-SIII type
• Right ventricular hypertrophy
• Large R waves in V1 and V2 and deep S waves in V5 and V6
• Right bundle branch block
• qR pattern in V1 as well as ST depressions and T-wave inversions, particularly in leads V1–V3, II, III, and aVF (20, 21, 22, 23, 24, e62).

Figure 1

ECG signs of pulmonary hypertension Left: QRS axis > 120°, center: P pulmonale (0.4 mV in II), right: inverted T waves V1–V5

eTable 2

Frequency of electrocardiographic signs in pulmonary hypertension

Right axis deviation (QRS axis >90°), qR pattern in V1, and low S-wave amplitude in V1 (≤ 0.2 mV) have high positive predictive values (93%, 95%, and 100%, respectively) in adults with suspected PH (25, 26). However, a normal electrocardiogram does not reliably exclude PH, since it can be completely normal in mild PH (21, 27, 28). In autopsy studies, ECG parameters for right ventricular hypertrophy show high specificity (83–100%), but only low sensitivity (18–44%) (29, 30). In addition, the positive and negative predictive values (PPV, NPV) for ECG criteria of right ventricular hypertrophy (0–100%, 18–44%) are insufficient for reliable diagnosis/exclusion (26, 31). Having said that, if the ECG and (NT-pro-)BNP are normal, PH is unlikely (32, 33).

Laboratory diagnostics

(NT-pro-)BNP is a marker of a decompensated cardiovascular state and is released from the myocardium during pressure and/or volume stress (34, 35). It is often elevated in patients with PAH and CTEPH (36, 37, 38, 39). However, a high false positive rate should be expected in the case of additional left heart disease since it is by no means PH-specific (39). A meta-analysis showed that (NT-pro-)BNP values were able to detect PAH in patients with systemic sclerosis with a sensitivity and specificity of only 67% and 84%, respectively (40). However, if not only the (NT-pro-)BNP level but also the ECG is normal, PH is unlikely (32, 33).

Echocardiography

By considering the peak systolic velocity of tricuspid regurgitation (TRV) as the main parameter alongside other secondary echocardiographic findings (Figure, Figure 2, eTable 3), it is possible to estimate the echocardiographic probability of PH. Meta-analyses have shown that echocardiography is able to detect PH with a sensitivity of 83–87% and a specificity of 72–86% (e1, e2, e3). However, there is evidence that its sensitivity for the detection of PAH may be lower (71–76%), while comprehensive data on its quality in CTEPH are lacking (e1, e4). Furthermore, significant inaccuracies (± 10 mm Hg difference to invasive measurement) are observed in the estimation of systolic pulmonary artery pressure (sPAP) in 48% of patients (e5). Moreover, TRV cannot be determined in all patients, since only 90% of patients with PH exhibit tricuspid valve regurgitation (e6). In such cases, secondary echocardiographic findings are of great importance. Additional signs of left heart pathology (left heart enlargement, valvular disorders, reduced left ventricular ejection fraction) should prompt consideration of group-2 PH (e7, e8).

Figure 2

Echocardiographic signs of pulmonary hypertension Top: severe triscupid valve regurgitation in continuous-wave (CW) Doppler TRV > 3.4 m/s, bottom: paradoxical septal motion with ‘D’ sign in the parasternal short axis

eTable 3

Echocardiographic signs of pulmonary hypertension (1, e59, e60, e61)

Cardiopulmonary exercise tests

Particularly in patients without risk factors for PAH or CTEPH, CPET (for example, spiroergometry) can indicate a pulmonary vascular component to the underlying symptoms, even if echocardiography points to an intermediate probability, and can be helpful in establishing the diagnosis (Table 2) (1, 16). There is evidence that CPET is better able to detect PAH and CTEPH in early stages than is echocardiography (e4, e9, e10, e11, e12). Furthermore, in the case of exertional dyspnea of unclear etiology, it is possible to differentiate between PH and other heart and lung diseases and, in the presence of PH, between PAH and CTEPH (1, 16, e13). The assessment of a CPET requires specialized knowledge and should be performed by experienced personnel (e14). However, CPET are not able to reliably confirm PH (16).

Exclusion of group-2 or group-3 pulmonary hypertension

For patients with non-severe PH in groups 2, 3, or 5, there is no evidence that they benefit from PAH-specific medication. Thus, for these patients, the focus of treatment is on the underlying disease and a referral to a PH center does not appear necessary (1).

Pulmonary function tests and blood gas analysis

Typically, pathological pulmonary function patterns are found in PH due to lung diseases (obstructive/restrictive lung disorder, for example in COPD/interstitial lung disease). Pulmonary function tests may be completely normal in PAH or CTEPH (Table 2) (1).

Chest radiography

Imaging with chest X-ray shows signs such as enlargement of the right heart silhouette, dilatation of the pulmonary arteries, and pruning of peripheral pulmonary vessels, pointing to the presence of PH (14, 16, e16). However, normal findings do not rule out PH (1). Moreover, left heart disease or lung disease may be discovered as a possible cause of PH (Table 2) (14, e16).

Computed tomography of the chest

Chest computed tomography (CT) can yield important indications of PH: for example, an enlarged pulmonary artery diameter > 30 mm (sensitivity: 58–75%, specificity: 81–90%, positive predictive value [PPV]: 96–98%, negative predictive value [NPV]: 24–32%), a pulmonary-artery-to-aorta ratio > 0.9 (sensitivity: 65–86%, specificity: 55–89%), or right heart enlargement (e16, e17, e18, e19, e20, e21).

In addition, computed tomography pulmonary angiogram (CTPA) can reveal signs of CTEPH (e22, e23, e24). If CTEPH is clinically suspected and evaluated by experts—in contrast to cases where there is no clinical suspicion and sensitization for radiological signs of CTEPH is lacking—the diagnostic accuracy of CTPA is high (98% sensitivity, 99% specificity, PPV: 94%, NPV: 100% versus 28% sensitivity) (e25). Furthermore, computed tomography is able to yield indications of left heart disease and lung diseases (Table 2) (e16).

Cardiac magnetic resonance imaging

Although cardiac magnetic resonance imaging (MRI) is the gold standard for the determination of right ventricular volume and function, it plays a secondary role in the diagnosis of pulmonary hypertension since it is unable to reliably exclude this disorder (e15, e16, e26). However, if PH is present, one may notice a reduced right ventricular ejection fraction and hypertrophy or dilatation of the right heart (e15). MRI may also point to other chronic heart diseases (Table 2) (1).

Referral to a PH center

Persistent suspicion of PH or suspected hemodynamically severe PH should prompt referral of patients to PH centers for diagnosis, classification, and treatment once group-2 or -3 PH has been excluded, since these centers appear to be superior to other centers in terms of diagnosis and treatment (1, 13, e27, e28). If characteristic mismatches are found on ventilation-perfusion scintigraphy, CTEPH should be hemodynamically confirmed by means of right heart catheterization. By measuring and calculating mPAP, PVR, and pulmonary arterial wedge pressure (PAWP), it is possible to verify the diagnosis, classify PH (pre-/post-capillary), and determine hemodynamic severity. Finally, CTPA and digital subtraction angiography or pulmonary artery angiography are used to assess the operability of CTEPH. If CTEPH is ruled out based on the absence of mismatches on ventilation-perfusion scintigraphy (gold standard, sensitivity: 90–100%, specificity: 90–100%), one should consider PAH in the presence of risk factors. If right heart catheterization reveals PH, additional tests are able to diagnose the definitive cause of PAH or PH of multifactorial or unclear etiology (1, 14, 16, e29).

Screening and early detection

The diagnosis of PAH and CTEPH takes on average more than 1 year, and most patients present at advanced stages of disease. Retrospective investigations of the French PAH registry, the IntinérAIR-Sclérodermie program, and the European CTEPH registry suggest that early treatment of PAH and CTEPH could prolong survival (4, 5, e27, e30, e31, e32). Screening the general population is not recommended and would lead to an immense use of resources in the healthcare system as well as overdiagnosis due to unduly high rates of false-positive results, particularly for the rare subtypes of PAH and CTEPH (1).

Screening in PAH

Asymptomatic high-risk groups (systemic sclerosis [prevalence: 8–19%] [e4, e33]), BMPR2 mutations (penetrance: 14–42%, prevalence: 70%, annual incidence: 2.3% [e34, e35]), portal hypertension prior to liver transplantation (prevalence: 2–9% [e36, e37]) as well as first-degree relatives of patients with heritable PAH) should be screened (1, 13). For patients with systemic sclerosis, one of the established algorithms (DETECT, ASIG) should be used (e4, e38). Additional CPET may be judicious if the risk of PAH is low, in order to avoid unnecessary right heart catheterization (e9, e10). Annual echocardiographic screening can be recommended for patients with portal hypertension who are listed for liver transplantation, since mortality is higher in severe PH following liver transplantation (71% mortality in the first 36 months) (e26, e37, e39). In the case of hereditary components (heritable PAH and, in particular, BMPR2 mutations), first-degree relatives should be offered genetic counseling and, if they test positive for the genotype, screening with, for example, annual echocardiography (1, 13).

Furthermore, efforts should be made to ensure early detection of symptomatic patients in risk groups (portal hypertension [prevalence: 2–6 %] [13]), HIV infection (prevalence: 0.5% [e40]), other connective tissue diseases, and congenital heart defects (prevalence: 3–7% [e41, e42]) (1, e30). If portal hypertension is present but the patient is not being prepared for liver transplantation, echocardiographic screening is recommended (1, 13). In the case of HIV infection, screening for PAH should be performed if signs of the first symptoms are seen or in the presence of more than one risk factor. There are no clear recommendations on the extent of screening in HIV infection (13). For congenital heart defects, screening should be carried out 3–6 months after the defect has been corrected and then at further appropriate intervals, much like patients with persistent left-to-right shunt, by means of patient history, physical examination, ECG, and echocardiography(13).

Screening in CTEPH

Since the thrombi usually dissolve after pulmonary embolism (PE), general screening for CTEPH following PE is not currently recommended (e43, e44). However, given that this does not occur in all patients and CTEPH occurs in 3.2% of PE survivors, echocardiography and ventilation-perfusion scintigraphy should be performed to search for perfusion defects in the case of persistent or new-onset dyspnea following PE (e43, e45, e46). CPET may also be diagnostically helpful (e11, e12). The optimal time for the early detection of CTEPH is probably in the 3- to 6-month range following PE (e43, e46). One study was able to diagnose CTEPH at 4 months post PE using an algorithm comprising an assessment of CTEPH probability (risk factors and symptoms), ECG criteria, NT-pro-BNP values, and echocardiography, with a sensitivity and specificity of 85% and 100%, respectively (PPV: 100%, NPV: 100%) (e47).

Conclusion

Pulmonary hypertension is a common disease in old age. While rare, PAH and CTEPH are particularly important since specific treatment forms are available. The diagnosis of PH is challenging due to its nonspecific symptoms and is often delayed. Having said that, echocardiography is able to quickly and reliably assess the probability of PH. A complementary cardiopulmonary exercise test may be helpful in certain situations. Moreover, normal ECG and (NT-pro-)BNP findings largely rule out PH. The definitive diagnosis, classification, and treatment require hemodynamic confirmation by means of right heart catherization and are performed in PH centers once PH due to left heart disease or lung disease has been excluded. Certain risk groups benefit from screening for PAH or CTEPH. In the early detection of PH, particular importance is attached to primary medical care, since it is from here that selected patients should be referred to specialists and experts.

Conflict of interest statement
MR has received speaker’s fees from Janssen-Cilag, Bayer, OMT, and MSD. He received honoraria for the preparation of the manuscript from Janssen-Cilag. He is a member of the Advisory Board of Janssen-Cilag and Bayer.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 28 March 2023, revised version accepted on 26 September 2023.

Translated from the original German by Christine Rye.

Corresponding author
Dr. med. Dr. habil. Dirk Bandorski
Semmelweis Universität, Medizinische Fakultät
Lohmühlenstrasse 5, 20099 Hamburg, Germany

Cite this as
Ley L, Grimminger F, Richter M, Tello K, Ghofrani A, Bandorski D: The early detection of pulmonary hypertension. Dtsch Arztebl Int 2023; 120: 823–30. DOI: 10.3238/arztebl.m2023.0222

►Supplementary material

eReferences, eTables:
www.aerzteblatt-international.de/m2023.0222

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