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MarkkuPentikäinen

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 left ventricular heart failure, valvular defects and lung diseases causing hypoxaemia (such as chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis). Treatment of such patients consists of treating their underlying diseases; in most cases, they will not benefit from specific medication for PH.
  • Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare diseases with poor prognosis if untreated.
  • Symptoms caused by PAH (dyspnoea, fatigue, chest pain, fainting) may also occur with more common diseases. Therefore, the time from symptom onset to diagnosis is often long.
  • If PAH is suspected, echocardiography is the most important screening tool.
  • The diagnosis is confirmed by right heart catheterization. The diagnostic criteria include mean pulmonary artery pressure > 20 mmHg, left ventricular filling pressure (wedge pressure) HASH(0x2ed24a0) 15 mmHg and pulmonary vascular resistance > 2 Wood units.
  • Diagnostic investigations and choice of lines of treatment are concentrated at specialized centres (e.g. in university hospitals).

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
1.4.3 Portal hypertension
1.4.4 Congenital heart defect
1.4.5 Schistosomiasis
1.5 Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
1.6 Persistent PH of the newborn
2. Pulmonary hypertension (PH) due to left heart disease
2.1 Left-sided heart failure
2.1.1 Heart failure with preserved left ventricular systolic function (HFpEF, heart failure with preserved ejection fraction)
2.1.2 Heart failure with impaired left ventricular systolic function (heart failure with mid-range ejection fraction, i.e. HFmrEF and heart failure with reduced ejection fraction, i.e. HFrEF)
2.2 Valvular disease
2.3 Congenital or acquired heart disease leading to increased pulmonary venous pressure
3. PH due to lung disease or hypoxaemia
3.1 Chronic obstructive pulmonary disease/emphysema
3.2 Interstitial lung disease
3.3 Other lung disease associated with both restrictive and obstructive hypoventilation
3.4 Hypoventilation
3.5 Hypoxia in the absence of lung disease (such as extended stay in high altitudes)
3.6 Developmental disorder
4. PH associated with pulmonary arterial stenosis
4.1 Chronic thromboembolic PH (CTEPH)
4.2 Other obstruction of pulmonary arteries (e.g. tumours, arteritis, congenital stenosis, hydatidosis)
5. Increased pulmonary blood pressure developing by undefined or multiple mechanisms
5.1 Haematological disease: chronic haemolytic anaemia, myeloproliferative disorders
5.2 Systemic disease: sarcoidosis, pulmonary pulmonary histiocytosis, neurofibromatosis
5.3 Metabolic disorder, such as glycogen storage disease, Gaucher's disease
5.4 Chronic renal failure
5.5 Thrombotic microangiopathy
5.6 Fibrosing mediastinitis

Pulmonary arterial hypertension (PAH)

General remarks

  • In PAH, circulation in small pulmonary vessels is disturbed, leading to increased pulmonary blood pressure and finally to right heart failure.
  • There is an imbalance between the effects of mediators constricting (endothelin) and dilating (nitrous oxide, prostaglandins) blood vessels. Specific medication for PAH is targeted at such mediators.
  • Pathogenetically, small pulmonary arteries contract, the cells in the vascular walls proliferate, the walls are remodelled, and local blood clots form.
  • According to various studies, the prevalence of PAH is about 50/million inhabitants and incidence about 6/million inhabitants per 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 (limited scleroderma being the most common), and one in four have an underlying congenital heart defect. Even if a congenital heart defect (such as atrial or ventricular septal defect) is treated surgically, pulmonary hypertension may develop several years after the intervention..
  • The prognosis of PAH is poor. The annual mortality of patients with severe symptoms exceeds 20%, but in patients reacting well to treatment it is < 5%.

Symptoms and findings

  • The most common symptoms are dyspnoea on exertion and impaired exercise tolerance.
  • Other symptoms include general fatigue, chest pain, palpitations, cough and hoarseness.
  • In advanced disease, the patient will develop clinical signs of heart failure, i.e., oedema in the lower limbs and accumulation of fluid in the abdominal cavity (ascites). In severe disease, there may be episodes of unconsciousness in association with exertion.
  • 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, in particular, diagnosis is often delayed.
  • Auscultation of the heart: the most common abnormality is an accentuated second heart sound; a systolic 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, pitting oedema in the limbs, hepatomegaly, ascites, cyanosis.
  • In addition, the patient may exhibit signs of the underlying disease (e.g. Raynaud's phenomenon, sclerodactyly, telangiectasia, butterfly rash).
  • 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 right bundle branch block RBBB.
  • Of blood levels, plasma atriopeptin (proBNP and BNP) reflects the severity and the prognosis of the disease. Laboratory tests are used at the time of diagnosis to investigate the presence of any 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, echocardiography should be performed first.
    • Echocardiography provides an estimate of the level of pulmonary blood pressure and of whether PH is due to a disease affecting pulmonary circulation or the left heart (such as left ventricular failure or valvular disease).
    • If the findings are suggestive of a disease affecting pulmonary circulation, the patient should be referred to a specialized centre for diagnostic investigations (Table T1), i.e., isotope study of pulmonary ventilation and perfusion or CT angiography of pulmonary arteries, lung function tests, high resolution computed tomography of the lungs, as necessary, extensive blood tests, upper abdominal ultrasonography and sleep polygraphy, as necessary, often repeat echocardiography.
  • The diagnosis is confirmed by invasive right heart catheterization. The diagnostic criteria include elevated mean pulmonary artery pressure (> 20 mmHg), normal or low left ventricular filling pressure (wedge pressure HASH(0x2ed24a0) 15 mmHg) and increased pulmonary vascular resistance (> 2 Wood units). The subtype of the disease is defined when making the diagnosis (Table T1).
  • The treatment approach and prognosis depend on the severity of the disease. The level of symptoms (WHO/NYHA class, clinical heart failure, collapses), performance (6-minute walking test or spiroergometry), atriopeptin levels, right heart function on imaging, and findings on catheterization reflect the severity of the disease.

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 confirming the diagnosis by catheterization - not based on echocardiography alone.
  • -Available groups of drugs
  • 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 two drugs in tablet form (endothelin receptor antagonist and phosphodiesterase-5 inhibitor), but for high-risk patients (NYHA IV) a parenteral prostacyclin is also added to the regimen.
    • Treatment of elderly patients with several comorbidities is started more cautiously with only one drug in tablet form.
  • Diuretics are indicated in patients with right heart failure and fluid retention.
  • Long-term oxygen therapy is indicated in patients with partial pressure of oxygen in arterial blood permanently below 8 kPa or oxygen saturation < 92%. Some patients only need supplemental oxygen for physical activity.
  • Anaemia in patients with PAH requires investigation, and any iron deficiency should be corrected by tablets or by iron infusion.
  • Patients should receive influenza, COVID and pneumococcal vaccination to prevent severe infections.
  • Pregnancy and childbirth involve major risks. PH may be aggravated during pregnancy, and it is associated with foetal and maternal mortality. Endothelin receptor antagonists are teratogenic and cannot be used during pregnancy. For these reasons, pregnancy is not recommended, and female patients of fertile age should be offered contraceptive counselling.
  • Surgical operations and anaesthesia involve a significant risk of right heart failure and even death. Any invasive procedure in a patient with PH must be carefully considered and performed at a centre with experience of the treatment of patients with PH.
  • Physical activity improves the patients' performance and quality of life. As soon as the disease has been stabilized by medication, physical activity should be recommended as far as the symptoms allow.
  • Patients should be monitored regularly in specialized care.
  • 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 2% of patients with pulmonary embolism (PE). Age at the time of diagnosis is 64 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. The disease is found either in aetiological investigations of PH or based on sustained symptoms after 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 with certainty. A pulmonary ventilation/perfusion scan (isotope study) is essential for the diagnosis; a normal result excludes the possibility of CTEPH.
  • The diagnosis of CTEPH can be made if after 3 months of adequate anticoagulant therapy the right heart catheterization shows a mean pulmonary artery pressure of HASH(0x2ed2410) 20 mmHg, the pulmonary capillary wedge pressure is HASH(0x2ed24a0) 15 mmHg, the pulmonary vascular resistance is > 2 Wood units and the lung perfusion scan shows perfusion defects consistent with CTEPH. Some patients have normal haemodynamics at rest but significantly raised pulmonary blood pressure on exertion. This type of disease is called (pulmonary) chronic thromboembolic disease (CTED).
  • Treatment
    • Indefinite anticoagulant therapy is indicated for all patients. Diuretics and oxygen therapy are used as in PAH.
    • Surgical management (pulmonary endarterectomy) is the primary choice. It 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 concentrated at specialist centres, where patients should be referred for consideration of surgical treatment.
    • Nowadays balloon dilatation of pulmonary arteries can be used for patients for whom surgical treatment is not suitable or as complementary treatment after surgery.
    • Riociguat (soluble guanylate cyclase stimulator) is the first drug officially indicated for the treatment of CTEPH. When considered appropriate, also other specific PH medication can be used for the treatment of CTEPH, also in combination, as necessary.
  • Screening: Routine echocardiography is not recommended for all patients who have had a pulmonary embolism (PE). Echocardiography should, however, be carried out in patients who still have dyspnoea 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. After successful pulmonary endarterectomy, prognosis is good and the patient may be asymptomatic or have only few symptoms. Lung transplantation may be considered in patients with severe symptoms if they are otherwise eligible for organ transplantation.

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 referred to specialized care for further investigations.
  • If the basic investigations in specialized 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 (e.g. in university hospitals).

    References

    • Humbert M, Kovacs G, Hoeper MM ym. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; Aug 26 [PubMed]