Pulmonary Hypertension: Classification and Treatment Principles

Definition and Pathophysiology

Pulmonary hypertension (PH) is a heterogeneous pathophysiological disorder characterized primarily by elevation of pulmonary arterial pressure. It may arise from pulmonary vascular disease, left-sided cardiac disease, chronic lung disease or hypoxia, chronic thromboembolic obstruction, or a range of miscellaneous conditions. Because several mechanisms may coexist, diagnosis and classification must integrate haemodynamics with the patient’s clinical context and the results of all relevant investigations.

Haemodynamic definition

At rest, PH is defined invasively by a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg. The haemodynamic phenotype is then determined using pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR):

The source material also presents a CpcPH threshold of PVR ≥3 Wood units in an overlapping clinical classification table; the principal haemodynamic definition uses PVR >2 Wood units.

PVR is essential for identifying a precapillary pulmonary vascular component. PAWP is used to distinguish pulmonary venous hypertension caused by left heart disease from pulmonary vascular disease. Although a PAWP of 12 mmHg represents the upper limit of normal in some assessments, a threshold of ≤15 mmHg remains the recommended criterion for precapillary PH, partly because this value has been used in therapeutic studies of pulmonary arterial hypertension (PAH). The threshold is not absolute: patient phenotype, risk factors for heart failure with preserved ejection fraction, echocardiographic findings, and left atrial size must also be considered.

Patients with mPAP greater than 20 mmHg, PAWP ≤15 mmHg, and PVR ≤2 Wood units may have increased pulmonary blood flow rather than pulmonary vascular disease. This state is termed unclassified PH. Potential explanations include congenital heart disease, liver disease, airway or lung disease, and hyperthyroidism; follow-up and investigation of the cause of increased flow are appropriate.

Exercise PH is defined by an mPAP/cardiac output slope greater than 3 mmHg/L/min from rest to exercise. This response is age dependent and may rarely occur in healthy people older than 60 years. The abnormal slope does not itself distinguish precapillary from postcapillary disease. A PAWP/cardiac output slope greater than 2 mmHg/L/min may help identify a postcapillary mechanism.

Clinical classification

The clinical classification comprises five groups:

• Group 1: Pulmonary arterial hypertension

• Group 2: PH due to left heart disease

• Group 3: PH due to chronic lung disease, hypoxia, or sleep-disordered breathing

• Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic pulmonary disease

• Group 5: PH with unclear or multifactorial mechanisms

PAH is a distinct and uncommon form of precapillary PH. It is defined haemodynamically by precapillary PH in the absence of CTEPH, lung disease, or another explanatory cause. PAH reflects marked pulmonary arterial remodelling, with fibroproliferative, plexogenic, and sometimes thrombotic changes that may result in near-total obliteration of affected vessels. Genetic, molecular, and acquired factors may interact in its development.

PAH may be idiopathic, heritable, drug associated, or associated with conditions such as systemic sclerosis, HIV infection, cirrhosis, and sickle cell disease. The classification also recognizes vasoreactivity subgroups among patients with idiopathic PAH, including acute responders and non-responders.

Left heart disease is the most common risk factor for PH. It produces postcapillary PH through elevation of left atrial and pulmonary venous pressure. In some patients, chronic postcapillary pressure elevation is accompanied by pulmonary arterial remodelling, producing CpcPH.

Right ventricular pathophysiology

The clinical consequences of PH extend beyond the pulmonary circulation. Progressive pulmonary vasculopathy increases right ventricular (RV) afterload. Failure of the RV–pulmonary arterial unit to adapt may lead to RV–pulmonary arterial uncoupling and right-sided heart failure. RV dysfunction is a high-risk finding and is a major determinant of clinical deterioration.

Systemic consequences may include impaired renal function, skeletal muscle dysfunction, reduced physical fitness, and broader impairment of cardiovascular performance.

Clinical Presentation and Symptoms

Symptoms are usually nonspecific and are principally related to progressive RV dysfunction resulting from pulmonary vascular disease. Associated diseases and comorbidities may alter the clinical presentation.

The principal clinical problem is progressive limitation of cardiopulmonary function. Worsening World Health Organization functional class (WHO-FC) is an important marker of disease progression and should prompt investigation for the cause of deterioration.

Clinical presentation may be modified by the underlying PH group:

• PAH may occur without an identifiable secondary cause or in association with systemic sclerosis, HIV, cirrhosis, sickle cell disease, or drug exposure.

• Group 2 PH occurs in the context of left heart disease.

• Group 3 PH accompanies chronic lung disease, hypoxia, or sleep-disordered breathing.

• Group 4 disease is associated with chronic thromboembolic obstruction and may produce symptoms even when resting PH is absent, a situation encompassed by chronic thromboembolic pulmonary disease (CTEPD).

• Group 5 PH occurs in diseases with unclear or multifactorial mechanisms.

Evaluation and Physical Examination

Evaluation should be multidisciplinary and, where possible, coordinated through a specialist PH centre. The diagnostic process should not rely on a single measurement or test. Instead, haemodynamics, clinical phenotype, comorbidities, imaging, and cardiopulmonary testing should be interpreted together.

History

The medical history should seek evidence of:

• Left heart disease and risk factors for heart failure with preserved ejection fraction

• Chronic lung disease, hypoxia, or sleep-disordered breathing

• Previous venous thromboembolism or chronic thromboembolic disease

• Systemic sclerosis and other connective tissue disease

• HIV infection

• Cirrhosis or portal hypertension

• Sickle cell disease

• Congenital heart disease

• Exposure to drugs or toxins associated with PAH

• Family history suggesting heritable PAH

• Pregnancy or potential pregnancy in women with PAH

Clinical assessment should include disease severity, functional capacity, comorbidities, treatment access, economic considerations, and patient preferences.

Physical examination

The source material identifies physical examination as a component of clinical assessment but does not provide a complete catalogue of physical findings. Findings reflecting RV pressure or volume overload may include right-sided cardiac enlargement, systemic venous congestion, and manifestations of right-sided heart failure. Echocardiographic correlates include right atrial enlargement, inferior vena cava and hepatic vein dilation, and reduced respiratory variation of the inferior vena cava.

Diagnostics

Electrocardiography

The source material lists electrocardiographic abnormalities associated with PH but does not provide their specific findings. Detailed ECG interpretation is therefore not covered here.

Chest radiography and computed tomography

Radiographic signs of PH and associated abnormalities are recognized components of diagnostic evaluation, but the source material does not enumerate them. It does, however, emphasize that imaging should identify both pulmonary vascular disease and potential underlying conditions.

Echocardiography

Transthoracic echocardiography is central to the noninvasive assessment of suspected PH. It can estimate pulmonary pressure, assess RV structure and function, and identify potential causes such as left heart disease and congenital shunts.

Typical echocardiographic features include:

• RV dilation and hypertrophy

• Right atrial enlargement

• Flattening of the interventricular septum, usually during systole and sometimes also during diastole

• Dilation of the pulmonary artery

• Inferior vena cava and hepatic vein dilation

• Reduced inspiratory variation of the inferior vena cava

• Systolic notching of the pulmonary valve

• Tricuspid regurgitation with increased peak velocity

• Progressive RV systolic dysfunction

A tricuspid regurgitation velocity of at least 3.0 m/s is described as a typical Doppler finding. In the absence of RV outflow obstruction, RV systolic pressure approximates pulmonary artery systolic pressure.

The pulmonary artery systolic pressure may be estimated as:

PASP = 4 × (peak tricuspid regurgitation velocity)² + estimated right atrial pressure

Estimated right atrial pressure is derived from inferior vena cava size and inspiratory collapsibility. When both are normal, a value of 3 mmHg is used; if one is abnormal, 8 mmHg is used; and if both are abnormal, 15 mmHg is used.

Important limitations apply:

• An absent or off-axis tricuspid regurgitation jet may prevent measurement or underestimate pressure.

• Severe tricuspid regurgitation may lead to underestimation because right atrial pressure is markedly elevated.

• Pulmonary artery acceleration time is a potential Doppler marker but has limited reproducibility.

RV assessment should be systematic. Measures include:

• RV fractional area change

• Tricuspid annular plane systolic excursion (TAPSE)

• RV Tei index

• Tricuspid annular systolic velocity (S′)

• RV longitudinal and free-wall strain

• RV ejection fraction

• Three-dimensional RV volumes indexed to body size

These indices may provide prognostic information.

Echocardiography can also help identify alternative or associated causes, including left heart disease and congenital shunts such as ventricular septal defect, patent ductus arteriosus, and atrial septal defect.

Cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging is incorporated into contemporary risk assessment, particularly through prognostic RV and cardiac measurements. The source material does not specify the individual magnetic resonance parameters or thresholds.

Right heart catheterization

Right heart catheterization is the definitive method for establishing the haemodynamic diagnosis. It measures mPAP, PAWP, cardiac output, and PVR, allowing classification as precapillary, isolated postcapillary, combined pre- and postcapillary, or unclassified PH.

Interpretation requires attention to clinical context. For example, a patient with left heart disease may have a low PAWP after diuresis and appear to have precapillary PH despite an underlying postcapillary mechanism. Volume status and the timing of measurements therefore matter.

Cardiac catheterization may also be used for diagnostic manoeuvres, including exercise assessment and other provocative testing, although the source material does not detail all manoeuvres.

Vasoreactivity testing

Vasoreactivity testing is relevant to patients with presumed idiopathic, heritable, or drug-associated PAH. The source material identifies recommended test compounds and their dosing in a dedicated table but does not provide the individual compounds or doses in the supplied text.

Patients with a positive vasoreactivity test may be considered for calcium channel blocker therapy. Long-term continuation of high-dose calcium channel blockers is recommended in patients with idiopathic, heritable, or drug-associated PAH who are in WHO-FC I or II and show marked haemodynamic improvement, defined by mPAP less than 30 mmHg and PVR less than 4 Wood units. If the initial response is insufficient for long-term control and additional PAH therapy is required, continuation of calcium channel blocker therapy should be considered.

Diagnostic integration

The diagnostic algorithm should proceed from suspicion to detection and confirmation:

• Recognize unexplained dyspnoea or clinical features suggestive of PH.

• Perform noninvasive assessment, particularly echocardiography.

• Identify possible left heart, lung, thromboembolic, congenital, systemic, or drug-related causes.

• Confirm haemodynamics with right heart catheterization when indicated.

• Assign both the haemodynamic category and the clinical PH group.

• Refer high-risk, complex, or suspected PAH/CTEPH cases promptly to a PH centre.

Biomarkers and Laboratory Findings

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a component of contemporary risk assessment and follow-up in PAH. The updated follow-up model uses NT-proBNP alongside WHO functional class and 6-minute walking distance to assign patients to low, intermediate-low, intermediate-high, or high risk.

The source material does not provide specific NT-proBNP cut-offs, nor does it provide a complete laboratory profile for PH. It does identify chronic kidney disease as a systemic manifestation associated with PH and recognizes diseases such as HIV infection, cirrhosis, sickle cell disease, and connective tissue disease as clinically relevant associated conditions.

Treatment and Management

General principles

PAH is rare, life-threatening, and best managed at specialist PH centres in collaboration with local physicians. Management should be comprehensive and individualized. Before treatment decisions are made, patients and their families should receive timely information regarding anticipated benefits and risks, enabling shared decisions with the clinical team.

Initial therapy should be based on multiparameter risk assessment. Relevant considerations include:

• PH subtype

• Disease severity

• RV function and haemodynamics

• Cardiopulmonary comorbidities

• Access to therapies

• Economic factors

• Patient preference

Treatment strategies should distinguish patients with cardiopulmonary comorbidities from those without them.

Supportive and general measures

Comprehensive PAH care may include:

• Supplemental oxygen

• Diuretic therapy to optimize volume status

• Psychosocial support

• Standardized exercise training

These measures complement, rather than replace, disease-targeted therapy. Volume management is particularly relevant when RV dysfunction and systemic venous congestion are present.

PAH-targeted pharmacotherapy

The source material identifies the principal therapeutic classes used in PAH:

• Endothelin receptor antagonists

• Phosphodiesterase-5 inhibitors

• Soluble guanylate cyclase stimulators

• Prostacyclin analogues

• Activin-signalling inhibition with sotatercept

• Calcium channel blockers in selected vasoreactive patients

The dosing table for adult PAH medication is referenced, but the supplied material does not provide the individual drug names, doses, titration schedules, or administration details. Specific doses therefore cannot be stated from the available source.

Initial treatment should be selected according to risk. Combination therapy has increasing importance, and the revised algorithm emphasizes combination strategies rather than relying routinely on oral monotherapy. In patients presenting at intermediate risk but with severe haemodynamic impairment, initial triple therapy including an intravenous or subcutaneous prostacyclin analogue may be considered. Examples of severe haemodynamic impairment include:

• Right atrial pressure ≥20 mmHg

• Cardiac index <2.0 L/min/m2

• Stroke volume index <31 mL/m2

• PVR ≥12 Wood units

The decision must also account for comorbidities, treatment feasibility, and patient preference.

Calcium channel blockers

Calcium channel blockers are reserved for appropriately selected patients with idiopathic, heritable, or drug-associated PAH who demonstrate a positive acute vasoreactivity response. Continued high-dose therapy is recommended when the patient remains in WHO-FC I or II and achieves near-normal haemodynamics, including mPAP <30 mmHg and PVR <4 Wood units.

Patients with a positive vasoreactivity test but inadequate long-term response to calcium channel blockers require additional PAH therapy; continuation of calcium channel blocker treatment should be considered in that setting.

Sotatercept

Sotatercept is identified as an activin signal inhibitor and as a newly approved treatment for PAH. The source material does not provide dosing, administration, eligibility criteria, or detailed outcome data.

CTEPH and CTEPD

Group 4 disease includes CTEPH and CTEPD without resting PH. CTEPD recognizes patients who may have symptoms, perfusion defects, and organized fibrotic pulmonary arterial obstruction despite not meeting resting haemodynamic criteria for PH.

Management of CTEPH is multimodal. Therapeutic options include:

• Pulmonary endarterectomy

• Balloon pulmonary angioplasty

• Medical therapy

• Combined or sequential approaches according to anatomy, operability, haemodynamics, and centre expertise

Balloon pulmonary angioplasty has been upgraded within the therapeutic algorithm for patients with inoperable CTEPH, in combination with medical therapy. The source material also indicates that long-term anticoagulation is recommended when the risk of recurrent pulmonary embolism is intermediate or high, or when there is no history of venous thromboembolism; the specific anticoagulant and dose are not supplied.

PH due to left heart disease

Left heart disease is the most common cause of PH. Its management requires attention to the underlying cardiac disorder and to volume status. The source material notes that some postcapillary PH may respond to decongestion. It also highlights the difficulty of distinguishing a precapillary phenotype from a postcapillary mechanism after diuresis, because PAWP may fall into the apparently normal range.

The supplied material does not provide a complete treatment algorithm or drug recommendations for PH associated with left heart disease.

PH due to lung disease and hypoxia

Group 3 PH is associated with chronic lung disease, hypoxia, and sleep-disordered breathing. The source material notes that management recommendations have been updated and that PH-targeted drugs require specific consideration in this group. It does not provide the complete treatment regimen or drug doses.

Pregnancy

Pregnancy in PAH requires management by a dedicated Pregnancy Heart Team and a PH expert experienced in diagnosis, medical treatment, anticoagulation, and antepartum, peripartum, and postpartum care. Untreated idiopathic PAH is described as highly lethal, whereas PAH therapies are associated with longer median survival. The source material does not provide a pregnancy-specific medication schedule or delivery plan.

Guideline Recommendations

The principal recommendations conveyed in the source material are:

• Define resting PH invasively by mPAP >20 mmHg.

• Use PAWP and PVR to distinguish precapillary from postcapillary disease.

• Retain PAWP ≤15 mmHg as the practical threshold for precapillary PH while interpreting it with phenotype, risk factors, and echocardiographic findings.

• Classify patients both haemodynamically and clinically; the two classifications are complementary.

• Refer high-risk or complex patients promptly to specialist PH centres.

• Base initial PAH therapy on comprehensive multiparameter risk assessment.

• Incorporate cardiopulmonary comorbidities, access, economic considerations, and patient preference into initial treatment decisions.

• Emphasize combination therapy in the PAH treatment algorithm.

• Consider intravenous or subcutaneous prostacyclin-containing triple therapy in selected intermediate-risk patients with severe haemodynamic impairment.

• Continue high-dose calcium channel blockers only in appropriately selected vasoreactive patients with idiopathic, heritable, or drug-associated PAH who achieve marked clinical and haemodynamic improvement.

• Use a refined four-strata risk model at follow-up, incorporating WHO-FC, 6-minute walking distance, and NT-proBNP.

• Consider balloon pulmonary angioplasty, together with medical therapy, in inoperable CTEPH.

• Provide long-term anticoagulation in CTEPH when recurrent pulmonary embolism risk is intermediate or high, or when there is no previous venous thromboembolism history.

• Manage PAH during pregnancy through a specialized multidisciplinary team.

Prognosis and Follow-up

PH is associated with substantial morbidity, particularly when RV dysfunction develops. RV dysfunction is a high-risk feature that promotes right-sided heart failure. Prognosis is influenced by the degree of pulmonary vascular disease, RV adaptation, haemodynamics, comorbidities, and treatment response.

In PAH, worsening WHO functional class is one of the most concerning indicators of progression. Clinical deterioration should trigger reassessment to identify potentially reversible causes, treatment failure, worsening RV function, or progression of the underlying disease.

Risk assessment

The contemporary approach uses:

• A three-strata model for initial assessment, categorizing patients as low, intermediate, or high risk.

• A four-strata model during follow-up, dividing intermediate risk into intermediate-low and intermediate-high categories.

Follow-up variables include:

• WHO functional class

• 6-minute walking distance

• NT-proBNP

• Haemodynamic status

• RV function

• Echocardiographic findings

• Cardiac magnetic resonance prognostic indicators

The source material does not provide the exact four-strata cut-offs or a prescribed follow-up interval.

Long-term care

Long-term management should be coordinated between the PH centre and local physicians. Follow-up should reassess symptoms, functional class, exercise capacity, biomarkers, RV performance, haemodynamics when clinically indicated, treatment tolerance, and adherence. Patients with clinical worsening require expedited evaluation.

In patients with unclassified PH, clinical follow-up is generally recommended, with investigation directed toward increased pulmonary blood flow and its possible causes.

For CTEPH and CTEPD, follow-up should account for residual obstruction, pulmonary pressure, RV function, symptoms, anticoagulation, and suitability for multimodality intervention. The supplied material does not specify a standardized surveillance schedule.

Summary

PH is defined by an invasively measured mPAP greater than 20 mmHg and is classified using PAWP and PVR into precapillary, isolated postcapillary, combined pre- and postcapillary, or unclassified haemodynamic patterns. Clinical classification into five groups identifies the predominant underlying disease mechanism.

The central pathophysiological consequence is increased RV afterload, with progressive RV dysfunction and right-sided heart failure driving symptoms and prognosis. Echocardiography provides essential noninvasive assessment, but right heart catheterization is required for definitive haemodynamic characterization. PAH management should occur in specialist centres, use multiparameter risk assessment, and combine supportive care with appropriately selected targeted therapies. CTEPH requires consideration of pulmonary endarterectomy, balloon pulmonary angioplasty, medical therapy, and anticoagulation. Ongoing reassessment of functional status, exercise capacity, NT-proBNP, RV function, and haemodynamics is fundamental to long-term management.