Idiopathic pulmonary arterial hypertension (IPAH) is a type of pulmonary arterial hypertension pathologically characterized by plexogenic pulmonary arteriopathy, consisting of medial hypertrophy of arteries, concentric or eccentric intimal hyperplasia, plexiform lesions, and necrotizing arteritis.
Etiology and pathogenesis
The etiology of idiopathic pulmonary arterial hypertension remains unknown to date. Currently, it is believed that its onset is related to genetic factors, autoimmunity, and dysfunction of pulmonary vascular endothelium and smooth muscle.
Genetic factors
11% - 40% of sporadic IPAH cases have variations in the bone morphogenetic protein receptor 2 (BMPR2) gene. Some cases have variations in the activin receptor-like kinase 1 (ALK1/ACVRL1) gene, endoglin, and SMAD9.
Immune and inflammatory responses
The immunoregulatory effect may be involved in the pathological process of IPAH. The anti-nuclear antibody level is significantly elevated in 29% of IPAH patients, but there is a lack of specific antibodies for connective tissue diseases. Infiltration of macrophages, T lymphocytes, and B lymphocytes can be seen in the plexiform lesions of IPAH patients, suggesting that inflammatory cells are involved in the occurrence and development of IPAH.
Dysfunction of pulmonary vascular endothelium
The contraction and relaxation of pulmonary blood vessels are jointly regulated by the contraction and relaxation factors secreted by the pulmonary vascular endothelium. The former mainly includes thromboxane A2 (TXA2) and endothelin-1 (ET-1), and the latter mainly includes prostacyclin and nitric oxide (NO). Due to the imbalance in the expression of the above factors, pulmonary vascular smooth muscle contracts, thereby causing pulmonary arterial hypertension.
Defects in potassium channels of vascular smooth muscle cells
Proliferation and hypertrophy of vascular smooth muscle can be seen. Functional defects in voltage-dependent potassium (K+) channels (Kv), reduced K+ efflux, and the cell membrane in a depolarized state allow Ca2+ to enter the cells, thereby causing vascular contraction.
Clinical manifestations
The symptoms of IPAH are non-specific. In the early stage, there are usually no symptoms, and discomfort is only felt during vigorous activities. As the pulmonary artery pressure increases, systemic symptoms can gradually appear.
Dyspnea is the most common symptom and is often the initial symptom, mainly manifested by dyspnea after activities, progressively exacerbated, and even present at rest. It is related to factors such as reduced cardiac output and imbalance of pulmonary ventilation and blood flow ratio.
Thoracodynia is caused by myocardial ischemia due to increased afterload of the right heart, increased oxygen consumption, and reduced coronary artery blood supply, and often occurs during activities or when hyperexcited.
Dizziness or syncope is caused by a sudden reduction in blood supply to the brain tissue due to reduced cardiac output, often occurs during activities, and sometimes can also occur during rest.
Usually little hemoptysis and sometimes massive hemoptysis can occur, leading to death.
Other symptoms include fatigue and asthenia, which are often easily neglected. 10% of patients have Raynaud phenomenon, and the thickened pulmonary artery compressing the recurrent laryngeal nerve can cause hoarseness (Ortner syndrome).
The signs of IPAH are all related to pulmonary hypertension and increased load on the right ventricle.
Auxiliary examination
Blood tests
Hemoglobin can increase, and is related to long-term hypoxia compensation. Brain natriuretic peptide can increase and has a certain correlation with the severity of the disease and the prognosis.
Electrocardiogram
The electrocardiogram cannot directly reflect the increase in pulmonary artery pressure, but it can suggest right heart enlargement or hypertrophy.
Chest x-ray examination
Chest x-ray signs suggesting pulmonary hypertension include:
- Expansion of the right lower pulmonary artery trunk, with transverse diameter ≥ 15mm or the ratio of the transverse diameter of the right lower pulmonary artery to the transverse diameter of the trachea ≥ 1.07, or a dynamic observation of a broadening of the right lower pulmonary artery trunk > 2mm
- Significant protrusion of the pulmonary artery segment or its height ≥ 3mm
- Dilated central pulmonary artery and thinned peripheral branches forming knuckle sign
- Significantly convex conus portion (45° in the right anterior oblique position) or its height ≥ 7mm
- Enlargement of the right ventricle
Figure 1 Frontal chest x-ray in pulmonary arterial hypertension
Echocardiography and Doppler ultrasound examination
Echocardiography and Doppler ultrasound examination are the most important non-invasive examination method for screening pulmonary hypertension. If the peak velocity of the tricuspid valve estimated by Doppler echocardiography is > 3.4m/s or the pulmonary artery systolic pressure is > 50 mmHg, pulmonary hypertension can be diagnosed.
Pulmonary function test
There can be mild to moderate restrictive ventilation disorders and diffusion dysfunction.
Blood gas analysis
Most patients have mild to moderate hypoxemia, which is caused by imbalance of ventilation and blood flow. Alveolar hyperventilation leads to a decrease in carbon dioxide partial pressure. Severe hypoxemia may be related to decreased cardiac output, concurrent pulmonary artery thrombosis, or patent foramen ovale.
Radionuclide lung ventilation/perfusion imaging
In patients with IPAH, the imaging can be diffuse sparse or basically normal, and is also an important means to exclude chronic embolic pulmonary hypertension.
Right heart catheterization and acute vasoreactivity test
Right heart catheterization is the gold standard for determining pulmonary hypertension. It can directly measure pulmonary artery pressure, measure cardiac output, calculate pulmonary vascular resistance, and determine whether there is left-to-right shunt, which is helpful for formulating treatment strategies.
Acute vasoreactivity test is to evaluate the reactivity of pulmonary blood vessels to short-acting vasodilators. Its purpose is to screen patients who may respond to oral calcium channel blockers. Drugs used in this test include inhaled iloprost, intravenous adenosine, and inhaled NO. The positive criterion for the acute vascular response test is a decrease in mPAP ≥ 10 mmHg and mPAP ≤ 40 mmHg, while cardiac output increases or remains unchanged. Generally, only 10% - 15% of IPAH patients can meet this criterion.
Diagnosis and differential diagnosis
If the pulmonary artery systolic pressure estimated by Doppler echocardiography is > 50 mmHg, and there are clinical manifestations, pulmonary arterial hypertension can be diagnosed. Definite diagnosis of pulmonary arterial hypertension requires the mean pulmonary artery pressure measured by right heart catheterization ≥ 25 mmHg. A diagnosis can only be established after various diseases that cause pulmonary hypertension are excluded.
Treatment
The treatment strategies include initial treatment and supportive treatment. Patients with a positive acute vascular response test are treated with high-dose calcium channel blockers, and those with a negative acute vascular response test are treated with targeted drugs. In patients with a poor treatment response, combination treatment and lung transplantation can be considered.
Initial treatment
It is recommended that females of childbearing age should use contraception. Vaccinations against influenza and Streptococcus pneumoniae should be given. Psychosocial support for patients should be provided. Patients with decreased physical strength should undergo necessary rehabilitation training on the basis of drug treatment. If surgery is required, epidural anesthesia is preferred rather than general anesthesia.
Supportive treatment
Autopsy of IPAH patients shows a high prevalence of in situ thrombosis in blood vessels. Abnormalities in the coagulation and fibrinolysis pathways have also been reported. Nonspecific high-risk factors for venous thromboembolism include heart failure and immobilization. All the above are the theoretical basis for the use of oral anticoagulants.
When decompensated right heart failure leads to fluid retention, increased central venous pressure, liver congestion, ascites, and peripheral edema, diuretics can be used to improve symptoms.
Hypoxia stimulation can cause pulmonary vascular constriction, increased blood viscosity due to polycythemia, and remodeling of pulmonary arterioles, accelerating the progression of IPAH. Patients with arterial oxygen partial pressure persistently lower than 8 kPa (60 mmHg) are recommended for oxygen therapy to maintain their arterial oxygen saturation continuously greater than 90%.
Digoxin can rapidly improve the cardiac output of IPAH and can be used to reduce the ventricular rate of atrial tachyarrhythmias in PAH patients.
Iron deficiency is associated with decreased exercise capacity and may also be associated with high mortality. Regular monitoring of iron status should be performed in patients. If there is iron deficiency, the etiology should be continuously sought, and iron preparations should be supplemented.
Vasodilators
A positive result in acute vasoreactivity test is an indication for calcium channel blockers (CCB). CCB are only effective in 10% - 15% of IPAH patients. CCB mainly include nifedipine, diltiazem, and amlodipine. Nifedipine is preferred for patients with bradycardia, and diltiazem is preferred for those with tachycardia. The indication needs to be reevaluated after 3 - 4 months of treatment.
Prostacyclin can not only dilate blood vessels and reduce pulmonary artery pressure, but also reverse pulmonary vascular remodeling with long-term administration. Common prostacyclin analogues include epoprostenol, iloprost, and beraprost. There are also prostacyclin receptor agonists, such as selexipag.
Inhaled nitric oxide (NO) is a treatment that selectively dilates the pulmonary artery without acting on the systemic circulation. However, due to the short duration of NO action and the inconvenient preparation of inhaled NO, its clinical application is not yet widespread.
Common endothelin receptor antagonists include bosentan, ambrisentan, and macitentan.
Phosphodiesterase (PDE)-5 inhibitors include sildenafil, tadalafil, and vardenafil.
Soluble guanylate cyclase (sGC) agonists are mainly riociguat. The combination of riociguat and PDE-5 inhibitors is not recommended.
Lung or cardiopulmonary transplantation
Patients with poor clinical outcomes after active medical treatment can undergo lung transplantation. Patients with pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) have a poor prognosis and lack effective medical treatment; once diagnosed with the above two diseases, lung transplantation should be considered. If there is irreversible damage to the cardiac structure or function, cardiopulmonary transplantation can be considered.
Health guidance
Life guidance to IPAH patients should be provided, publicity and education of relevant health knowledge should be strengthened, and pulmonary infections should be prevented.