Diagnosis and management of pulmonary hypertension due to left heart disease or pulmonary disease

Summary

In patients with left heart disease or pulmonary disease, the occurrence of pulmonary hypertension is associated with worse outcomes. Therefore, an accurate and timely diagnosis and differentiation between underlying causes are important, as management strategies differ depending on the aetiology. A structured diagnostic approach, from clinical suspicion to non-invasive assessments, can improve clinical decision-making and management. Recognition of patients with diagnostic uncertainty or a significant precapillary component is important, as these individuals may benefit from referral to pulmonary hypertension expert centres for further evaluation and consideration of targeted therapies.

Keywords

Diagnosis, Group 2 pulmonary hypertension, Group 3 pulmonary hypertension, pulmonary hypertension, right heart catheterisation  

List of abbreviations

PAWP: pulmonary arterial wedge pressure
PH: pulmonary hypertension
PVR: pulmonary vascular resistance
RHC: right heart catheterisation

Take-home messages

1. Pulmonary hypertension (PH) due to left heart disease (Group 2 PH) and pulmonary disease (Group 3 PH) is common and prevalence increases with an ageing and comorbid population.
2. A structured diagnostic approach integrating clinical assessment and multimodal non-invasive assessments is required to determine the likelihood and cause of PH.
3. Differentiating between Group 2 PH and Group 3 PH is important but can be challenging in patients with overlapping cardiac and pulmonary disease.
4. Right heart catheterisation (RHC) should be reserved for patients in whom pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) is suspected, or when further haemodynamic characterisation is needed to guide clinical decision-making, including treatment strategies.
5. Patients with diagnostic uncertainty or a significant precapillary component (PVR >5 WU) should be referred to PH expert centres. 

 
Patient-oriented message

Pulmonary hypertension is common in relation to left heart disease and pulmonary disease. It may add to the total symptom burden and reflect progression of the underlying disease. Accordingly, treatment of the underlying left heart and/or pulmonary disease should be carefully optimised. 

In rare cases, pulmonary hypertension may be associated with very high pulmonary vascular resistance or other causes, including pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. To ensure correct diagnosis and treatment, a thorough clinical and non-invasive assessment is needed, and in a few selected cases, invasive assessment by right heart catheterisation is required. 
     

Introduction

Pulmonary hypertension (PH), especially PH due to left heart disease or pulmonary disease, is becoming more common as the mean age of the general population increases. The overall global prevalence of PH is about 1% but increases to about 10% in individuals older than 65 years in some estimations [1]. As in many other areas, this growing population of elderly and more comorbid patients also calls for a change in mindset in PH diagnosis and management.  

Left heart disease and pulmonary disease are by far the most common causes of PH [2]. A recently published meta-analysis, based on data from more than 50,000 patients with left heart disease, reports a risk of PH (peak tricuspid regurgitation [TR] velocity >2.8 m/s) in 62-80% and a prevalence of manifest PH (peak TR velocity >3.4 m/s in combination with a mean pulmonary arterial pressure (mPAP) >20 mmHg) in 20-54%. This corresponds to approximately 2.7% of the general population being at risk of PH associated with left heart disease and approximately 1% having manifest PH and left heart disease [3]. Reported estimates of the prevalence of PH due to pulmonary disease are 18-50% in chronic obstructive pulmonary disease and 29-77% in interstitial pulmonary disease cohorts [1]. 

Recognition of PH in these at-risk patient populations is important. Increased pulmonary pressure places strain on the right ventricle (RV). Initially, the RV compensates by adaptive mechanisms, including right ventricular hypertrophy and increased contractility. With time, however, these adaptations cannot keep up with the increasing pressures as the underlying disease progresses, and the RV dilates to maintain cardiac output, ultimately leading to decompensated RV failure [4]. RV dysfunction is associated with advanced disease stages and constitutes a poor prognostic marker across all causes of PH. In severe PH, decompensated RV failure is a major cause of death. 

Because left heart disease and pulmonary disease are very common causes of PH, distinguishing between PH due to these diseases and the rare patient with pulmonary arterial hypertension (PAH) may be challenging in clinical practice. Correct diagnosis and identification of the underlying cause are crucial for guiding therapeutic and invasive treatment strategies and optimising patient management.      

Pulmonary hypertension definition

PH is defined as mPAP >20 mmHg at rest, measured by right heart catheterisation (RHC) [5]. Furthermore, exercise PH is defined by a disproportionate increase in mPAP relative to cardiac output during exercise.   

Based on haemodynamic and pathophysiological characteristics, PH is classified into five main groups (Table 1). 

Table 1. Pulmonary hypertension classification (mPAP >20 mmHg at rest, measured by right heart catheterisation).  

mPAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; WU: wood units 

Haemodynamically, Group 2 PH is characterised by an increased pulmonary arterial wedge pressure (PAWP) >15 mmHg (isolated post-capillary if pulmonary vascular resistance [PVR] ≤2 wood units [WU] or combined pre- and post-capillary, if PVR >2 WU), whereas Group 3 PH is characterised by PAWP ≤15 mmHg and PVR >2 WU.

Diagnosis of pulmonary hypertension

Clinical suspicion

The most common clinical symptoms and signs suggestive of PH and RV failure include dyspnoea on exertion, fatigue, rapid exhaustion, and peripheral oedema, all of which may be present in patients with left heart or pulmonary disease solely due to these pre-existing disorders. PH should be expected when there is a mismatch between the severity of symptoms and the known extent of left heart or pulmonary disease.

Non-invasive assessment

Echocardiography is the primary non-invasive test for PH. A peak TR velocity of <2.8 m/s is associated with a low probability of PH, and a peak TR velocity of >3.4 m/s indicates a high probability. 

In addition to echocardiography, clinical assessment should include the evaluation of risk factors for left heart disease, pulmonary disease, PAH and chronic thromboembolic pulmonary hypertension (CTEPH), as well as supplementary testing such as electrocardiography (ECG), biomarkers, pulmonary function test, and further imaging (Figure 1). 

Figure 1. Diagnostic algorithm for pulmonary hypertension.

Clinical suspicion of PH is followed by a multimodal non-invasive assessment to determine the most likely cause. Patients with mild PH and clear left heart or pulmonary disease should be managed by optimisation of the underlying condition. Right heart catheterisation is reserved for selected patients in whom haemodynamic assessment will influence management, particularly in cases of severe or disproportionate PH or diagnostic uncertainty. 

CTEPH: chronic thromboembolic pulmonary hypertension; ECG: electrocardiography; PAH: pulmonary arterial hypertenson; PFT: pulmonary function test; PH: pulmonary hypertension

Right heart catheterisation

Right heart catheterisation should be performed following a strictly standardised protocol to minimise errors and enhance diagnostic accuracy. Particular attention should be paid to correct zeroing and the appropriate timing of pressure measurements (end-respiratory) [5]. Additionally, atrial fibrillation introduces beat-to-beat variation, necessitating averaging over many heart cycles. Obesity and pulmonary disease may increase fluctuations in intra-abdominal and intrathoracic pressures, thereby influencing the measured pressures. 
Data suggest that PAWP >13 mmHg may indicate significant left heart disease, especially if the patient uses diuretics [6], and in patients with a PAWP of 12-18 mmHg, the final diagnosis of pre-capillary versus post-capillary PH should not rely solely on PAWP but rather on the complete presentation of the patient, including risk factors (obesity, atrial fibrillation, hypertension), echocardiographic findings, previous episodes with pulmonary oedema, et cetera [7].
 
Provocative testing with exercise RHC or fluid challenge during RHC may further aid in arriving at the correct diagnosis. Stress echocardiography may also be considered; however, invasive haemodynamic assessment during exercise remains the gold standard. 

Patients with even a mild degree of PH without obvious signs of left heart or pulmonary disease should be referred to PH centres for further diagnostic work-up following assessment of potential ventilation-perfusion mismatches indicative of CTEPH by a lung scintigraphy.

Differentiation between Groups 1, 2, and 3 PH

Distinguishing between PH due to left heart disease (Group 2 PH) and PH due to pulmonary disease (Group 3 PH) can be challenging, as these patients often share common risk factors and often coexist, particularly in elderly and comorbid patients. In addition, PAH (Group 1 PH), although very rare, must be considered as it requires specific treatment.

Patients with Group 2 PH often have a history of heart failure, atrial fibrillation, obesity, or systemic hypertension, as well as echocardiographic signs of left atrial enlargement, valvular heart disease, and left ventricular diastolic dysfunction. In contrast, features indicating Group 3 PH include significant impairment in pulmonary function, such as profoundly reduced diffusion capacity, hypoxaemia, and imaging findings consistent with parenchymal pulmonary disease.

Accurate differentiation between the different groups of PH is important, as it directly influences the clinical management of these patients. In patients with overlapping features, a comprehensive assessment that includes clinical history, findings, echocardiography, pulmonary function testing, imaging, and haemodynamics is necessary. In such cases, RHC – possibly with provocative testing – may be required to determine the predominant mechanism and to guide treatment. 

Pulmonary hypertension due to left heart disease (Group 2 PH)

The most common causes of PH due to left heart disease are heart failure with reduced or preserved ejection fraction and valvular disease, including mitral regurgitation and aortic stenosis. The development of PH is a serious complication in left heart disease conditions, often reflecting severe cardiac dysfunction. In heart failure with preserved ejection fraction (HFpEF), the development of PH is strongly associated with increased mortality [8]. Significant left ventricular (LV) systolic dysfunction and valvular heart disease are usually easy to detect by echocardiography, whereas discriminating between PAH and HFpEF is more challenging. Validated scoring systems such as H₂FPEF, HFA-PEFF and HFpEF-ABA scores can be used to support the HFpEF diagnosis and assess whether HFpEF is a more or less likely explanation of the symptoms observed (Table 2) [9-11]. These scores differ in complexity and required variables, with H₂FPEF and HFA-PEFF relying on echocardiographic and biomarker data, whereas the HFpEF-ABA score is a simplified tool that does not require echocardiography and may be used for initial risk stratification in a non-specialist setting. 

Table 2. HFpEF diagnostic scores.

BMI: body mass index; HFpEF: heart failure with preserved ejection fraction; PASP: pulmonary artery systolic pressure

Initially, PH in left heart disease is characterised by an isolated elevation of post-capillary pressure, reflecting elevated LV and left atrial filling pressures. Over time, the sustained retrograde transmission of elevated filling pressures through the pulmonary vascular system may lead to pulmonary vascular changes, including vasoconstriction, decreased nitric oxide (NO) availability, inflammation, and proliferation and hypertrophy of the arteriolar endothelium and media. This remodelling leads to the narrowing of the pulmonary arterioles and increased PVR, thus adding a precapillary component to the elevated pulmonary pressures. Combined pre- and postcapillary PH is associated with a noticeably worse outcome compared with isolated postcapillary PH [12]. 

Special considerations in the diagnosis and management of Group 2 PH

A high peak TR velocity in a patient with known left heart disease raises suspicion of PH. In cases of mild PH and clear evidence of left heart disease in the form of heart failure with reduced ejection fraction or significant valvular disease, further diagnostic work-up, including RHC, is usually not indicated, and efforts should be made to optimise management and treatment of the underlying left heart disorder. 

To avoid misclassifications, RHC should be performed only after optimisation of the underlying left heart condition, including volume status, and when the patient is stable. Additionally, echocardiographic score systems to help discriminate between isolated postcapillary and combined pre- and postcapillary PH in heart failure have also been suggested, but have not been validated in larger populations [13].

Even in the catheterisation laboratory, distinguishing between Group 2 PH and PAH can be challenging. In such cases, provocative manoeuvres such as invasive haemodynamic exercise testing or passive fluid loading may be used to differentiate between them. Discrimination and correct diagnosis are, however, important as PAH patients need targeted medical treatments with PAH-specific drugs, which might be harmful in Group 2 PH [14].  

Invasive assessment should be reserved for patients in whom further haemodynamic characterisation is expected to influence diagnosis, management, or referral for further evaluation. Thus, indications for RHC in left heart disease are:

1. Correct classification of PH in Group 2, excluding Group 1 PH (PAH) and Group 4 PH (CTEPH)    
2. Assessment of haemodynamic status to guide optimal heart failure therapy, particularly when combined pre- and postcapillary PH with a severe precapillary component is suspected, and further data may aid phenotyping and treatment decisions
3. Advanced heart failure and evaluation for heart transplantation

Therapeutic management of PH due to left heart disease

Management of PH due to left heart disease is primarily directed at optimisation of the underlying LV disorder, including correction of fluid overload, which is very important in the management of these patients. 

PAH-specific therapies have shown no clinical benefit in patients with Group 2 PH and may even be associated with harm [14, 15].

Pulmonary hypertension due to pulmonary disease (Group 3 PH)

Pulmonary hypertension due to pulmonary alveolar or parenchymal disease is the second most common cause of PH. Common underlying conditions include chronic obstructive pulmonary disease (COPD)/emphysema, interstitial pulmonary disease, combined pulmonary fibrosis and emphysema, and hypoventilation syndromes. 

PH secondary to pulmonary disease is precapillary and can be classified as non-severe (PVR <5 WU) or severe (PVR >5 WU), with severe PH linked to higher mortality compared with non-severe PH. However, patients with non-severe PH still face more severe symptoms, increased hospitalisation, and poorer outcomes in comparison with those with pulmonary disease without PH. 

Special considerations in the diagnosis and management of Group 3 PH

PH symptoms, most often dyspnoea, are also typical for the underlying pulmonary disorder, which makes the diagnosis of PH more difficult. PH should be considered when dyspnoea seems disproportionate to the degree of impairment in pulmonary function or if signs of RV failure – usually peripheral oedema – develop. In this situation, further evaluation may be considered.   

Echocardiography is a first-line test, but it is often more challenging in patients with pulmonary disease due to reduced acoustic windows. In practice, peak TR velocity measured by echocardiography is often inaccurate in advanced pulmonary disease, necessitating a broader panel of non-invasive tests to assess the likelihood of PH. In addition to echocardiography, these tests include ECG, biomarkers, assessment of risk factors for PAH/CTEPH/left heart disease, pulmonary function tests including diffusing capacity of the lungs for carbon monoxide (DLCO) and supplementary imaging with contrast-enhanced and/or high-resolution computed tomography (CT). On ECG, findings reflecting RV hypertrophy and RV strain, including right axis deviation, right bundle branch block, and ST depression and inverted T-waves in V1-V3, may indicate PH [16]. RV failure due to PH may also cause NT-proBNP elevation. CT findings such as pulmonary artery enlargement, RV outflow tract hypertrophy, larger septal angle, and lower LV area predict PH [17].  

Indications for RHC in pulmonary disease are:

1. Signs of severe PH or RV failure and need of invasive haemodynamics to aid phenotyping and treatment decisions.
2. Selected patients considered for pulmonary transplantation or surgical pulmonary volume reduction.  

Therapeutic management of PH due to pulmonary disease

As in Group 2 PH, management of Group 3 PH is primarily directed at optimisation of the underlying pulmonary condition, including oxygen therapy and non-invasive ventilation when indicated. In patients with COPD and severe PH, treatment with phosphodiesterase type 5 (PDE5) inhibitors have been shown to reduce PVR and improve quality of life, although no larger randomised controlled trial has been conducted [18]. 

Riociguat (a stimulator of soluble guanylyl cyclase) and endothelin receptor antagonists have been associated with clinical worsening in patients with interstitial lung disease with PH, and are not recommended [19, 20]. A study with inhaled treprostinil in COPD was stopped early because of signs of an increased risk of serious adverse events and risk of mortality [21].
 
In contrast, inhaled treprostinil has been shown to improve the 6-minute walk distance in patients with interstitial lung disease and PH [22]. Based on these findings, inhaled treprostinil has been approved in the US and Japan for the treatment of PH associated with interstitial lung disease, though the drug has not been approved for this indication in Europe. 

Impact on clinical practice

PH due to left heart disease (Group 2) and lung disease (Group 3) represent the most common forms of PH and are frequently encountered in an ageing population with a substantial comorbidity burden. Accurate distinction between these groups and PAH/CTEPH (Group 1/4 PH) is essential, as it directly influences management decisions. Accordingly, a structured diagnostic approach integrating clinical assessment with non-invasive investigations is recommended. RHC should be reserved for patients in whom haemodynamic assessment will influence diagnosis, management, or referral, particularly in cases of diagnostic uncertainty or suspected precapillary disease. 

Patients with Group 2 and Group 3 PH with a significant precapillary component (PVR >5 WU) or an unclear underlying mechanism may be referred to PH expert centres for further evaluation. In selected cases, targeted therapies may be considered on an individual basis, although robust evidence from randomised trials is currently lacking. Optimisation of the underlying left heart or pulmonary disease remains the cornerstone of treatment, while PAH-specific therapies should be avoided in Group 2 PH and in most Group 3 PH patients.