PH is defined as an increase in mean pulmonary arterial pressure (mean PAP) to at least 25 mmHg at rest as assessed by right heart catheterisation. PH is categorised according to measurements of pulmonary capillary wedge pressure (PCWP) as pre-capillary (PCWP at or below 15 mmHg) or post-capillary (PCWP more than 15 mmHg). It is classified into five groups according to pathological, pathophysiological and therapeutic characteristics (table 2). The underlying mechanisms, diagnostic approaches, and prognostic and therapeutic implications are completely different in the different clinical groups.
|1.2.2 ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia)|
|1.3||Drug- and toxin-induced|
|1.4||Associated with (APAH)|
|1.4.1 Connective tissue diseases|
|1.4.2 HIV infection|
|1.4.3 Portal hypertension|
|1.4.4 Congenital heart disease|
|1.4.6 Chronic haemolytic anaemia|
|1.5||Persistent pulmonary hypertension of the newborn|
|1’||Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis|
|2||PH due to left heart diseases|
|3||PH due to lung diseases and/or hypoxia|
|3.1||Chronic obstructive pulmonary disease|
|3.2 I||nterstitial lung disease|
|3.3||Other pulmonary diseases with mixed restrictive and obstructive pattern|
|3.5||Alveolar hypoventilation disorders|
|3.6||Chronic exposure to high altitude|
|4||Chronic thromboembolic pulmonary hypertension|
|5||PH with unclear and/or multifactorial mechanisms|
|5.1||Haematological disorders: myeloproliferative disorders, splenectomy|
|5.2||Systemic disorders, sarcoidosis, pulmonary Langerhans’ cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis|
|5.3||Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders|
|5.4||Others: tumoral bstruction, fibrosing mediastinitis, chronic renal failure on dialysis|
Table 2 – Clinical classification of pulmonary hypertension. PAH: pulmonary arterial hypertension; BMPR2: bone morphogenetic protein receptor, type II; ALK1: activin receptor-like kinase 1 gene; APAH: associated pulmonary arterial hypertension. Reproduced and modified from Simonneau et al., 2009, with permission from the publisher.
It is still widely believed that PH is a rare condition; this is true for pulmonary arterial hypertension (PAH) (group 1) but the global burden of PH as a whole is currently unknown. Worldwide, its two most common causes are PH complicating the course of left heart disease (group 2) and PH complicating the course of chronic respiratory disease and/or hypoxia (group 3). CTEPH (group 4) complicates the course of 0.1–4% of patients with acute PE. Better awareness of this complication may result in an increase in detected cases. The burden of PH is certainly underestimated, both in developing and developed countries, and further well-designed studies are essential if we are to better understand and manage the disease in populations exposed to various risk factors.
Approximately half of patients with group 1 PH (PAH) have an associated disease (connective tissue diseases such as systemic sclerosis, congenital heart disease, portal hypertension and HIV infection), while the other half include idiopathic, heritable and appetite suppressant drug- (anorexigen-) induced PAH. The prevalence of PAH in Europe ranges between 1.5–5.2 cases per 100 000 people, with a predominance in women (female:male ratio 2:1). PAH can develop at any age (the mean age at diagnosis is 50 years). In some developing countries such as Brazil, prevalent diseases like schistosomiasis are associated with a high risk of PAH.
PAH results from chronic remodelling of the small pulmonary arteries leading to progressive vascular obstruction. CTEPH results from obstruction of the pulmonary vascular bed by nonresolving thromboemboli. PH due to heart disease is a consequence of chronically elevated post-capillary pressure. PH due to chronic lung diseases and/or hypoxaemia is due to persistent hypoxic pulmonary vasoconstriction and remodelling as well as loss of lung vessels due to underlying pulmonary emphysema or fibrosis.
Clinical manifestations and consequences
PH causes breathlessness, fatigue, reduced exercise capacity, chest pain, haemoptysis and hoarseness (left recurrent laryngeal nerve palsy). In the modern management era, PH is still a progressive and fatal disease, which often presents with signs of right heart failure, such as lower limb oedema, ascites, hypotension, presyncope and syncope.
PAH is notoriously difficult to recognise clinically. In the early stages of disease, patients are generally asymptomatic or mildly symptomatic. Indeed, initial symptoms are often rather unspectacular, and may lead patients, relatives and physicians to assume that they are simply unfit. Later, the symptoms are often attributed to a more common cardiorespiratory disease. As a result, there is commonly a substantial delay of 2 or more years before diagnosis and initiation of PAH treatment.
Clinical signs, symptoms and routine tests, such as electrocardiogram, arterial blood gases, chest radiography and pulmonary function, do not allow the physician to exclude or confirm PH. Doppler echocardiography is used to evaluate the right heart chambers and to estimate PAP. When PH is suspected, invasive right heart catheterisation is mandatory to confirm PH, define whether it is pre- or post-capillary and evaluate its severity.
Because of the progressive and nonspecific nature of PH symptoms, early PH detection is still a challenge. The implementation of screening programmes targeting high-risk patient groups should help to identify patients earlier. Recent screening programmes (based on Doppler echocardiography followed by right heart catheterisation if PH is suspected) have demonstrated that early diagnosis of PH is possible in patients with predisposing conditions, such as HIV infection, systemic sclerosis and sickle cell disease. Such screening programmes allow diagnosis of patients with markedly lower PAP, compared with those diagnosed in routine clinical practice. Similarly, after an acute episode of PE, persistent symptoms, as well as perfusion scan defects or elevation of PAP, may enable early detection of CTEPH.
There is no known method of preventing PAH; however, in patients at risk, early diagnosis allows earlier treatment. Appropriate treatment of chronic heart disease may prevent the development of post-capillary PH. Chronic respiratory disease and hypoxaemia should be treated with long-term oxygen therapy or assisted ventilation in order to prevent PH. Treatment and follow-up of acute PE is recommended to limit the risk of CTEPH.
Basic therapies include oral anticoagulation, diuretics and oxygen, if needed. PAH can be treated with drugs such as prostacyclin derivatives, endothelin receptor antagonists and type 5 phosphodiesterase inhibitors. Severe PAH is a well- recognised indication for lung transplantation. CTEPH can be cured with surgical pulmonary endarterectomy in eligible patients. PH due to chronic left heart disease and PH due to chronic lung disease and/or hypoxia should not be treated with PAH drugs. Treatment of the underlying heart or lung condition is recommended to prevent or treat PH complicating left heart or respiratory disease.
The natural history of PAH was described in the USA in the 1980s, when a cohort of patients with idiopathic/familial PAH were described and followed for up to 5 years. The study confirmed that PAH had a dismal prognosis, with a median survival of 2.8 years. Recent years have witnessed the approval of three classes of drugs for PAH and survival analyses have been performed in US and European registries. In a mixed cohort of incident and prevalent French PAH patients, 1-, 2-, and 3-year survival rates were 87%, 76%, and 67%, respectively. Better survival was observed in congenital heart disease when compared to idiopathic, familial and anorexigen- associated PAH or connective tissue diseases. In patients with idiopathic, familial and anorexigen-induced PAH, mortality is most closely associated with male sex, right ventricular haemodynamic function and exercise limitation. Thus, PAH remains a progressive, fatal disease even in the modern era of management. CTEPH can sometimes be cured by surgical pulmonary endarterectomy; however, in inoperable patients or if significant PH persists after surgery, the prognosis remains poor. PH due to chronic heart or lung disease usually reflects the severity of the underlying cardiopulmonary condition and this impacts adversely on the patient’s prognosis.
There is no cure for PAH and novel therapies are required. Prevention measures or early intervention in patients at risk of PH are needed.
A simple noninvasive PH diagnostic method is eagerly required. Better awareness of PH is essential for earlier diagnosis and management. The exact pathogenesis of PAH and CTEPH need further study in order for new preventative and/or curative tools to be developed for these severe conditions.