Pulmonary Arterial Hypertension (PAH)

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure ≥ 25 mmHg at rest measured during right heart catheterization1. Pulmonary Arterial Hypertension (PAH) is the first one of five categories of PH1, which is hemodynamically characterized by pre-capillary pulmonary hypertension (pre-capillary PH). It is defined by pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) >3 Wood units, resulting from causes other than other diseases (including chronic respiratory diseases, chronic thromboembolic diseases and other rare diseases) that may result in pre-capillary PH2.
PAH is a group of diseases with similar clinical characteristics resulting from multiple underlying causes. Most of these causes are unknown. PAH is most likely to result from various damaging stimulations to the pulmonary blood vessels susceptible to damage (i.e., hereditary susceptibility or other risk factors). These stimulations cause vascular damage, endothelial dysfunction, and imbalance of many physiological processes including vasodilation, blood coagulation and cell growth3, leading to pulmonary vascular changes. These changes result in elevated pulmonary vascular resistance (PVR), which is the characteristic pathological change of PAH4. The progressive elevation in PVR is followed by elevated right ventricular (RV) afterload (resistance encountered after RV contraction), which impedes RV ejection and thereby causes a decrease in cardiac output (CO). The decrease in CO is followed by a reduced pulmonary blood flow, inevitably elevating RV stroke work to jump blood to the lungs and thereby causing hypertrophy and dilatation of RV. Consequently, systolic dysfunction occurred, finally causing failure or death of RV5,6.
The elevated PVR and mPAP resulting from pulmonary vascular lesions can be compensated initially by increased RV stroke work, so in the early stage of PAH, symptoms are usually present during or after exercise. In this stage, PAH has no specific clinical manifestation. Common symptoms, such as exertional dyspnea, dizziness and fatigue, are usually mild, which are also common in other diseases. These patients are often asymptomatic at rest2,1,4. Plus no obvious signs in the early stage, patients with early-stage PAH may not be diagnosed and treated in a timely manner. Even if they visit a hospital, the physician may also treat these symptoms as ones caused by stress or anxiety or even as general physical discomforts. The interval between the manifestations and the confirmed diagnosis is more than 2 years in at least 1/5 patients1.
Another common symptom of PAH is chest pain, which is caused by RV ischemia. Syncope, dizziness and palpitation are uncommon in PAH patients. With the progression of disease, patients with advanced PAH may develop hemoptysis, peripheral edema, hoarseness, and dyspnea at rest2,1,4.
It is recommended in both Chinese and foreign guidelines that PAH patients should receive general therapies (such as contraception, rehabilitation & exercise training, elective surgery, infection prevention, psychological support, and cautious travels) followed by supportive therapies (such as oral anticoagulants, diuretics, oxygen therapy, digoxin and other cardiovascular drugs, and iron)2,1. These measures are only used to alleviate symptoms instead of eliminating causes of PAH.
On this basis, PAH patients should receive vasodilation therapies, including the therapy with a high dose of calcium channel blockers and the targeted drug therapy for pathology of PAH. Only PAH patients who are tested positive during the acute pulmonary vasodilator testing (AVT) can be treated with a high dose of calcium channel blockers alone, and the AVT-negative PAH patients should be treated with targeted drugs2,1. The general PAH-targeted drugs include three major categories targeting the three major signaling pathways of pathogenesis of PAH (the endothelin (ET) pathway, the nitric oxide-cyclic guanosine monophosphate pathway (NO-cGMP) and the prostacyclin (PGI2) pathway).
It is recommended in the 2015 ESC/ERS Guidelines that the objective of PAH treatment is to allow patients to reach and maintain a low risk status that is associated with better exercise capability, quality of life, right ventricular function, and low risk of death2. A similar recommendation is also given in the Chinese Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (2018): It is recommended to carry out a multi-parameter comprehensive risk assessment every 3-6 months and to give adequate treatment with targeted drugs so as to allow patients to reach and maintain a low risk status1. In the latest Chinese and foreign guidelines, it is clearly recommended therapies should be developed and adjusted according to the patient's risk status. An intensive therapy will be required if patients who have already received a targeted therapy still stay in an intermediate- and high-risk status during follow-up2,7.

1. Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016;37:67–119.
2. 中華醫學會心血管病學分會肺血管病學組, 中華心血管病雜志編輯委員會. 中國肺高血壓診斷和治療指南 2018. 中華心血管病雜志 2018;46:933–964.
3. McLaughlin V V., Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol 2009;53:1573–1619.
4. 荊志成. 2010年中國肺高血壓診治指南. 中國醫學前沿雜志(電子版) 2011;3:62–81.
5. Domenighetti G. Prognosis, screening, early detection and differentiation of arterial pulmonary hypertension. Swiss Med Wkly 2007;137:331–6.
6. Handoko ML, De Man FS, Allaart CP, et al. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: Lessons from the left heart. Eur Respir Rev 2010;19:72–82.
7. Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019;53:1801889.