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Increased Pulmonary Blood Pressure: Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

Essentials

  • The most common causes of increased pulmonary blood pressure (pulmonary hypertension, PH) are heart failure, valvular defects and lung diseases causing hypoxaemia (such as chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis).
  • Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), on the other hand, are rare diseases that it is important to differentiate from more common causes of PH. The prognoses of untreated PAH and CTEPH are quite poor but the treatment of these diseases has developed significantly during the 21st century.
  • Increased pulmonary blood pressure (pulmonary hypertension) denotes a state where the mean pulmonary artery pressure (measured invasively via right heart catheterization) is higher than 25 mmHg. If the systolic pulmonary artery pressure assessed by echocardiography exceeds 50 mmHg, the patient probably has increased pulmonary blood pressure.
  • Echocardiography is the most important screening tool for increased pulmonary blood pressure. If the patient is found to have a disease clearly explaining the increased pulmonary blood pressure (heart failure, lung disease), no further examinations are necessarily needed and treatment should consist of the best possible treatment of the underlying disease.
  • If PAH or CTEPH is suspected, an extensive diagnostic workup (incl. right heart catheterization) and expertise in many fields are always needed. Therefore, examination and treatment of these diseases are concentrated in specialist centres with expertise in these diseases.

Classification

  • See table T1.

Classification of increased pulmonary blood pressure

1.Pulmonary arterial hypertension (PAH)
1.1 Idiopathic (IPAH)
1.2 Heritable
1.3 Drug- or toxin-induced
1.4 Associated PAH (APAH) associated with:
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart defect
1.4.5 Schistosomiasis
1´. Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
1´´. Persistent PH of the newborn
2. Increased pulmonary blood pressure due to left heart disease
2.1 Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired obstruction of the cardiac left in-/outflow tract and congenital cardiomyopaties
2.5 Congenital/acquired stenosis of pulmonary veins
3. Increased pulmonary blood pressure due to lung disease and/or states causing hypoxaemia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other lung disease associated with both restrictive and obstructive hypoventilation
3.4 Sleep-disordered breathing
3.5 States causing alveolar hypoventilation
3.6 Extended stay in high altitudes
3.7 Developmental disorder
4. Chronic thromboembolic PH
4.1 CTEPH
4.2 Other conditions causing obstruction of pulmonary arteries (e.g. angiosarcoma, other intravascular tumours, arteritis)
5. Increased pulmonary blood pressure developing by undefined and/or multiple mechanisms
5.1 Haematological states: chronic haemolytic anaemia, myeloproliferative disorders, status post splenectomy
5.2 Systemic diseases: sarcoidosis, pulmonary, histiocytosis, lymphangioleiomyomatosis, neurofibromatosis
5.3 Metabolic disorders, e.g. Gaucher's disease, thyroid disorders
5.4 Other: e.g. mediastinal fibrosis, chronic renal failure

Pulmonary arterial hypertension (PAH)

General

  • The central mechanism in the pathogenesis of PAH is proliferation and remodelling of the walls of the small distal pulmonary blood vessels, and progressive obstruction of the pulmonary blood vessels leading to increased pulmonary vascular resistance and finally to right heart failure.
  • In PAH there is endothelial dysfunction in small pulmonary arteries leading to an imbalance between vasoactive mediators (e.g. prostacyclin, nitrous oxide and endothelin), which are responsible for the dilatation and constriction of the vessels as well as for enhancing or inhibiting vascular proliferation. Many pharmaceutical agents affecting these mechanisms have been introduced into clinical use in the 21st century, which has significantly influenced the treatment of the disease.
  • According to various studies, the prevalence of PAH is about 15-60/million and incidence about 5-10/million inhabitants/year. Currently, the average age at time of diagnosis is 50 to 65 years, and about two thirds of patients are female.
  • Of all patients with PAH (table T1) slightly less than half have idiopathic pulmonary arterial hypertension (IPAH) and about half have pulmonary arterial hypertension associated with other disease (APAH). Other groups of disease are rare.
  • About 50% of patients with APAH have some connective tissue disease (systemic sclerosis and systemic lupus erythematosus being the most common), and about 20 to 25% have an underlying congenital heart defect. Other causes of APAH, such as portal hypertension, are clearly rarer.
  • The prognosis of PAH is poor. Even with current treatment modalities, about 15% of patients die during the first year. The prognosis of PAH associated with a congenital heart defect is the best, and the prognoses of idiopathic PAH and PAH associated with systemic sclerosis or HIV infection are the worst.

Symptoms and findings

  • Symptoms usually develop gradually. As the basic investigations (auscultation of the lungs and heart, blood tests, ECG, chest x-ray, lung function tests) may remain normal at the initial stage, diagnosis is often delayed.
  • The most common symptoms are impaired exercise tolerance and dyspnoea on exertion.
  • Other symptoms include general fatigue, chest pain, palpitations, cough and hoarseness.
  • In advanced disease, the patient will develop oedema in the lower limbs, and the abdomen may be distended due to the accumulation of tissue fluid in the abdominal cavity. In severe disease, there may be episodes of unconsciousness.
  • Auscultation of the heart: the most common abnormality is an accentuated second heart sound; a tricuspid valve regurgitation murmur, a diastolic pulmonary valve regurgitation murmur and ventricular gallop may also be present.
  • Other clinical signs that may be present: right ventricular heave, jugular venous distension, oedema in the limbs, hepatomegaly, ascites, cyanosis.
  • In addition, the patient may exhibit signs of the underlying disease (e.g. Raynaud's phenomenon, butterfly rash, sclerodactyly, telangiectasia).
  • The chest x-ray usually remains totally normal during the early stages. As the disease progresses, dilatation of the pulmonary artery and its main branches, as well as diminished peripheral lung vascular markings , become evident. Dilatation of the right side of the heart can best be seen on a lateral projection.
  • The most common ECG findings consist of a ”P pulmonale”, T wave inversion in leads V1-V3, right axis deviation and RBBB.
  • There are no specific laboratory tests to measure increased pulmonary blood pressure, but plasma BNP, urate and TnI tests are used to monitor the progress of the disease. In specialized care, laboratory tests are used at the time of diagnosis to investigate the presence of underlying diseases contributing to PH (HIV antibodies, liver function tests, antinuclear antibodies, thyroid function tests, etc.).

Diagnosis of PAH

  • If the signs and symptoms are suggestive of increased pulmonary blood pressure, the patient should be referred to specialized care for further investigations. In such cases, echocardiography should be performed first. If significantly elevated pulmonary blood pressure is suspected, the most common causes of increased pulmonary blood pressure (table T1) should be excluded by appropriate examinations: extensive computerized tomography of the chest, lung function tests, sleep polygraphy, as necessary, coronary contrast study, isotope study of pulmonary ventilation and perfusion, often repeat echocardiography.
  • If, after these examinations, the diagnosis is still unclear or PAH (or CTEPH) is suspected, right heart catheterization is indicated. This should be performed at a centre with sufficient experience and expertise in the examination and treatment of patients with PH.
  • PAH is defined by values measured by right heart catheterization, i.e. mean pulmonary artery pressure > 25 mmHg and mean pulmonary capillary wedge pressure < 15 mmHg and the pulmonary vascular resistance > 3 WU (Wood Units). In addition, other causes, such as lung diseases, states causing hypoxaemia, and chronic thromboembolic pulmonary hypertension, should be excluded by appropriate examinations.
  • When making the diagnosis, an accurate diagnosis should be sought, the severity of the disease defined and an attempt made to assess the prognosis. These should be used to choose treatment and make a follow-up plan.

Treatment and monitoring of PAH Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension, Prostacyclin for Pulmonary Hypertension, Inhaled Iloprost for Pulmonary Hypertension, Subcutaneous Trepostinil for Pulmonary Hypertension, Phosphodiesterase 5 Inhibitors for Pulmonary Hypertension, Exercise-Based Rehabilitation for Pulmonary Hypertension, Riociguat for Pulmonary Hypertension

  • Specific medication should only be started after thorough investigations by doctors with expertise on the subject - not based on echocardiography alone.
  • Five groups of drugs are available:
  • Pharmacotherapy is chosen based on the severity of the disease, any coexisting medication and comorbidities. Nowadays it is recommended to start the treatment directly with a combination of at least two drugs in tablet form, but for patients with NYHA class IV symptoms, the primary treatment is parenteral prostacyclin. Monotherapy with only one drug in tablet form is started only for those with a very mild PAH.
  • Diuretics are indicated in patients with right heart failure and fluid retention.
  • Indefinite anticoagulant therapy should be considered for all patients with IPAH with no contraindications. In other patients with PAH, the benefits and risks of anticoagulant therapy should be considered on an individual basis. In PAH associated with portopulmonary hypertension or HIV infection, anticoagulant therapy is not recommended at all.
  • Digoxin can be considered for lowering the heart rate in patients with atrial tachyarrhythmia.
  • Non-pharmacological treatment
    • Long-term oxygen therapy is indicated in patients with partial pressure of oxygen in arterial blood permanently below 8 kPa.
    • The patient should stop smoking.
    • Physical exercise and weight management are very important.
    • Contraceptive precautions should be taken.
  • Patients should be monitored in specialized care every 3 to 4 months. The aim of the treatment is to improve performance and prognosis.
  • Lung transplantation is still an important option for patients with insufficient response to pharmacotherapy and otherwise eligible for organ transplantation.

Chronic thromboembolic pulmonary hypertension (CTEPH)Riociguat for Pulmonary Hypertension

  • Develops in about 0.5-2% of patients with pulmonary embolism (PE). Age at the time of diagnosis is 63 years on average. Men and women are evenly affected.
  • When CTEPH is diagnosed, about 50-75% of the patients are aware that they have a history of pulmonary embolism.
  • Signs, symptoms and diagnosis are the same as for PAH. It should be noted that a normal CT scan result does not exclude CTEPH. A pulmonary ventilation/perfusion scan (isotope study) is essential for the diagnosis; a normal result excludes the possibility of CTEPH. Pulmonary angiography is carried out if surgical management is an option.
  • The diagnosis of CTEPH can be set if after 3 months of adequate anticoagulant therapy the right heart catheterization shows a mean pulmonary artery pressure of HASH(0x2fcaf98) 25 mmHg, the pulmonary capillary wedge pressure is HASH(0x2fcb3a0) 15 mmHg, the pulmonary vascular resistance is > 3 WU and the perfusion scan shows significant perfusion defects. Additionally, there may be findings that support the diagnosis in CT, MRI or pulmonary artery angiography.
  • Treatment
    • Surgical management (pulmonary thromboendarterectomy) is the primary choice and can be used for patients with sufficiently proximal pulmonary arterial constriction and sufficiently good general health to make this a feasible option.
    • Surgical treatment is usually concentrated at specialist centres, where patients should be referred for consideration of surgical treatment.
    • Nowadays also balloon dilatation of pulmonary arteries can be used as complementary or, in some cases, even as primary treatment.
    • Riociguat (soluble guanylate cyclase stimulator) is the first drug officially indicated for the treatment of CTEPH. Nevertheless, surgical treatment is still the primary choice for CTEPH, and medication should not be started before the possibilities for surgical treatment have been appropriately investigated.
    • Indefinite anticoagulant therapy is indicated for all patients. Diuretics and oxygen therapy are used as in PAH.
    • Specific PAH pharmacotherapy has also been used to treat CTEPH if surgical treatment is contraindicated, but scientific evidence of its efficacy in the treatment of CTEPH remains inconclusive.
  • Screening: routine echocardiography is no longer recommended for all patients who have had a pulmonary embolism (PE). Echocardiography should, however, be carried out in patients whose functional capacity remains decreased 3 months after PE. If signs of elevated pulmonary pressure are detected, further investigations in a specialist centre (e.g. right heart catheterization) are indicated.
  • The prognosis of untreated CTEPH is poor. Lung transplantation may be considered if thromboendarterectomy is contraindicated.

Chain of treatment and criteria for referral

  • If increased pulmonary blood pressure is suspected and no obvious underlying disease can be identified or the causal relationship is not clear, the patient should be transferred to specialist medical care for further investigations.
  • If the basic investigations in specialist care do not reveal a condition that could induce increased pulmonary blood pressure, or if the clinical picture is suggestive of PAH or CTEPH, a referral to a specialist centre for more specific investigations and treatment is indicated.
  • The diagnostic workup of PAH and CTEPH, as well as the diagnosis, beginning of treatment and monitoring, at least during the initial stages, should be concentrated at specialized centres.

    References

    • Galiè N, Humbert M, Vachiery JL et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37(1):67-119. [PubMed]