1. Overview of the disease
Pulmonary arterial hypertension (PH) refers to a clinical and pathophysiological syndrome in which the structure or function of the pulmonary blood vessels is altered by a variety of heterologous diseases (etiologies) and different pathogenesis, resulting in increased pulmonary vascular resistance and pulmonary artery pressure, followed by right heart failure and even death.
2. Hemodynamic definition and clinical classification
1. Hemodynamic definition
- PH是指海平面、静息状态下，经右心导管检查（RHC）测定的肺动脉平均压（mPAP）≥25mmHg（1mmHg=0.133kPa）
- In normal adults, the mPAP at rest is (14.0±3.3) mmHg, and its upper limit does not exceed 20 mmHg
2. Clinical classification
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3. Epidemiology and pathogenesis
1. Epidemiology
(1) Arterial pulmonary hypertension: the incidence of PAH in adults is about 2.4/million person-years, and the prevalence is about 15/million, with congenital heart disease (CHD)-related PAH, hereditary PAH (HPAH), drug- and toxin-related PAH (DPAH) being common, and connective tissue disease (CTD) being the most common among the related factors PAH. CHD-PAH refers to the increase in pulmonary pressure caused by the body-lung shunt CHD, which is the most common cause of PAH in mainland China.
(2) Pulmonary hypertension caused by left heart disease: Left heart disease is the most common cause of PH, and the epidemiological data are still unclear, among which PH-HFpEF is 36~83% and PH-HFrEF is 40~75%.
(3) Pulmonary hypertension caused by lung disease and/or hypoxia: COPD is the most common cause, with a related prevalence of 20~91%, while the prevalence associated with pulmonary fibrosis combined with emphysema (CPFE) is higher.
(4) Pulmonary hypertension caused by chronic thromboembolic pulmonary hypertension and/or other pulmonary artery obstructive lesions: CTEPH is the most common, and the incidence varies greatly, and the mainland data show that the incidence of CTEPH after 2 years of PTE (acute pulmonary thromboembolism) is about 1.3%.
(5) PH in children: epidemiological data are mainly derived from Europe and the United States, with an annual incidence of 4~10/million and a prevalence of 24~40/million in Europe and an incidence of 5~8/million and a prevalence of 26~33/million in the United States.
2. Pathogenesis
The pathogenesis of PH is complex, which is the result of the joint action of multiple factors and links, including external factors (hypoxia, tobacco, dust, other physical and chemical biological factors, etc.), internal factors (genetics, development, structure, disease, etc.) and interaction factors (microecology, infection, immunity, drugs, etc.). A variety of vasoactive molecules, a variety of ion channels, and multiple signaling pathways are involved in the occurrence and development of PH diseases.
- The level of pulmonary artery pressure depends on the combined effect of pulmonary blood flow and pulmonary vascular resistance (PVR). PVR is mainly composed of pulmonary arterioles, pulmonary capillaries, and pulmonary venous resistance. PH can be triggered by any structural and functional abnormality that can lead to increased pulmonary blood flow and/or increased pulmonary vascular resistance.
- PH due to left heart disease is mainly due to abnormal increase in pulmonary artery pressure caused by left heart systolic and diastolic dysfunction and/or left heart valve disease, and its pathophysiological characteristics are increased left heart filling pressure, pulmonary venous return obstruction, and pulmonary venous pressure, resulting in secondary pulmonary artery pressure.
- PH due to lung disease and/or hypoxia is a type of PH due to long-term destruction of the lung parenchyma or interstitium, hypoxia, and secondary damage to the pulmonary vascular bed. The pathophysiological mechanism involves hypoxia-related pulmonary vasoconstriction/remodeling, vascular endothelial and smooth muscle dysfunction, inflammation, and hypercoagulability
- There are many pathogenic factors and complex pathogenesis of CTEPH, and some patients are a long-term complication of acute PTE. After acute PTE, the thrombus is incomplete and organizes, resulting in a persistent increase in PVR, causing pulmonary vascular remodeling, and eventually right heart failure.
4. Diagnosis of the disease
(1) Clinical manifestations
The clinical symptoms of PH lack specificity, mainly manifested as symptoms related to progressive right heart insufficiency, often induced after exertion, manifested as fatigue, dyspnea, chest tightness, chest pain and syncope, and some patients can also present with dry cough and exercise-induced nausea and vomiting. Patients with advanced disease may have symptomatic onset at rest. With the aggravation of right heart insufficiency, edema of the ankles, lower limbs, and even the abdomen and the whole body may occur. The underlying or concomitant conditions that cause PH also have corresponding clinical manifestations.
(2) Right heart catheterization and acute vascular reaction test
RHC is the standard method for diagnosing and evaluating PH, and hemodynamic data can be obtained through RHC, including right atrial pressure, right ventricular pressure (systolic, diastolic, and mean pressure), pulmonary artery pressure (systolic, diastolic, and mean pressure), pulmonary artery wedge pressure (PAWP), cardiac output, mixed venous oxygen saturation (SvO2), and PVR, which are helpful for determining the presence of intracardiac left-to-right shunts, evaluating response to pulmonary vasodilators, and formulating treatment strategies. The positive criteria for acute vascular reaction test are: the mPAP decreases by ≥ 10 mmHg after treatment, and the mPAP value decreases to ≤40 mmHg, and the cardiac output increases or does not change. Usually only 10% of patients with IPAH meet the criteria for positivity.
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(3) Diagnostic process
- Suspicious diagnosis (clinical and echocardiographic screening)
- Confirmed diagnosis (hemodynamic diagnosis)
- Seeking the cause (diagnosis of the cause)
- Functional assessment (severity assessment)
(4) Relevant recommendations
- Echocardiography is recommended as the non-invasive test of choice in patients with suspected PH (1C)
- 推荐V/Q显像用于原因不明的PH患者筛查CTEPH（1C）
- RHC is recommended as a confirmatory test for suspected PAH or CTEPH (1C)
- Genetic counseling is recommended for first-generation asymptomatic family members of patients with IPAH, HPAH, HHT, and known genetic mutations (2C)
- Evaluation of PH (e.g., echocardiography, cardiopulmonary exercise tests, etc.) is recommended for individuals with genetic mutations (2C)
5. Common pulmonary hypertension and its treatment
(1) General treatment
【Recommendations】
1. It is recommended that PAH patients undergo exercise rehabilitation training on the basis of medication under the guidance of a professional doctor (1A)
2. Contraception is recommended for women of childbearing age with PAH (1C)
3. When PAH patients undergo elective surgery, it is recommended to give preference to local anesthesia or epidural anesthesia, and try to avoid general anesthesia (2C)
4. Recommend that patients with PAH receive influenza virus or pneumonia vaccination to prevent infection (1C)
5. Recommend psychosocial support for patients with PAH (1C)
(2) Basic treatment
【Recommendations】
1. Individualized anticoagulation therapy is recommended for patients with IPAH, HPAH, and appetite suppressant-associated PAH (2C)
- Early autopsy of IPAH patients found thrombosis in more than half of patients, and anticoagulation was associated with improved prognosis. Since then, meta-analyses have shown that anticoagulation with warfarin can improve the prognosis of patients with IPAH; However, most of these studies were retrospective studies before the era of targeted therapy, and data from randomized controlled studies were lacking. Recent PAH registry studies and systematic retrospective analyses have shown that anticoagulation therapy has different effects, and anticoagulation therapy does not benefit patients with SSc-PAH and even increases the risk of death.
2. Diuretic therapy is recommended for patients with PAH with right heart insufficiency and fluid retention (1C)
- Diuretics can improve fluid retention, increased central venous pressure, hepatic stasis, and multiple serous effusions in patients with decompensated right heart failure, but there are no randomized controlled studies of diuretics. Commonly used diuretics include diuretics (furosemide, torsemide) and aldosterone receptor inhibitors (spironolactone). In recent years, the draining diuretic vasopressin V2 receptor antagonist (tolvaptan) has also been tried in such patients without reducing the effective circulating blood volume, but the exact efficacy and safety need to be confirmed by further clinical studies.
3. Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, β-blockers, nitrates or ivabradine are not recommended for patients with PAH (unless combined with left-sided heart disease, such as hypertension, coronary heart disease, etc.) (1C)
4. Iron metabolism testing (1C) is recommended for patients with PAH, and iron supplementation is recommended for patients with iron deficiency and PAH (intravenous iron supplementation is preferred) (2C)
- Studies have shown that patients with PAH, including IPAH, CHD-PAH, and CTD-PAH, often have iron deficiency, and iron deficiency is associated with PAH severity and prognosis. Intestinal iron absorption is reduced in patients with IPAH, and only 44% of patients with iron deficiency have a mildly elevated ferritin after 4 weeks of oral iron therapy
(3) Specific treatment
1. CCB drugs
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2.内皮素受体拮抗剂（endothelin receptor antagonist, ERA）
(1) Bosentan
(1) The first synthetic ERA drug is a dual antagonist of endothelin receptors A and B
(2) It can improve exercise tolerance, cardiac function grade, hemodynamic parameters and time to clinical deterioration in patients with IPAH, CTD-PAH, CHD-PAH, HIV-PAH
(3) Studies have shown that the 3-year survival rate of the bosentan treatment group is better than that of traditional treatment
(2) Anrisentan
(1) Ambrisentan is a highly selective endothelin A receptor antagonist, and studies have shown that two doses of 5mg and 10mg of ambrisentan can significantly improve the 6MWD of patients, showing a more obvious dose-response relationship.
(2) Sequential treatment with ambrisentan for 24 weeks in patients with PAH who did not respond well to PDE5 inhibitor therapy could significantly improve the exercise tolerance and hemodynamic parameters of patients.
(3) Compared with monotherapy, the initial combination of ambrisentan and tadalafil can significantly reduce the incidence of clinical deterioration events and improve exercise tolerance.
(3) Macitentan
(1) A new generation of dual ERA with better tissue penetration and receptor affinity.
(2) Marcitentan 10mg monotherapy or combination therapy can significantly reduce the risk of disease deterioration/death and mortality or hospitalization rate due to PAH, and improve patients' 6MWD, WHO functional class, quality of life, hemodynamic parameters and NT-proBNP.
3. PDE5 inhibitors
NO is an important vasodilator that achieves vasodilatory effects by maintaining intracellular cyclic guanosine monophosphate (cGMP) concentrations in vascular smooth muscle cells. Pulmonary vasculature contains a large amount of PDE5, which is a cGMP-degrading enzyme. PDE5 inhibitors can cause vasodilation by reducing the degradation of cGMP and increasing its concentration. In addition, PDE5 inhibitors also have antiproliferative effects.
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4.可溶性鸟苷酸环化酶（sGC）利奥西呱
- The novel sGC agonist has a unique mechanism of dual activation of sGC, and its effect does not depend on the level of NO in vivo, and can increase the level of cGMP in plasma alone or in combination with NO, causing vasodilation and anti-remodeling effects.
- It can significantly improve exercise tolerance, hemodynamics, and cardiac function classification in patients with PAH, reduce the level of NT-proBNP, and reduce the incidence of clinical deterioration events.
- Combined with sildenafil for PH, the incidence of hypotension is significantly increased, and there is no significant difference in hemodynamic parameters or exercise capacity, therefore, the combination of PDE5 inhibitors and riociguat is not recommended.
5. Prostacyclin analogues and prostacyclin receptor agonists
Prostacyclin is produced by vascular endothelial cells, has a potent vasodilatory effect, and is currently the strongest inhibitor of endogenous platelet aggregation. Studies have shown that the expression of prostacyclin synthase in the pulmonary arteries of patients with PAH is reduced, and the level of metabolism in the urine is reduced, and synthetic prostacyclin analogues can be used to treat PAH.
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【Recommendations】
1. For patients with IPAH, HPAH, and DPAH, if the acute vascular reaction test is positive, it is recommended to use tolerated high-dose CCBs (1C), and close follow-up is recommended, and the patient's functional status and hemodynamic indexes (1C) are evaluated for 3~6 months; Treatment with CCBs is not recommended if acute vascular reaction testing is not performed or negative (2C)
2. Targeted drug combination therapy is recommended for PAH in the early stage of the disease (low or intermediate risk) (1B)
3. Recommend targeted drug combination therapy for patients with high-risk PAH, and intravenous prostacyclin analogues (1A) should be included in the regimen
(4) Targeted drug combination therapy and drug-drug interactions
1. Targeted drug combination therapy
It is recommended to start combination therapy with PAH and achieve it as soon as possible. For treatment-naïve patients with PAH, if they are in a low- or intermediate-risk state, they should be started with targeted drug therapy with different pathways, and if they are in a high-risk state, they should be started with intravenous prostacyclin targeted drug therapy.
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2. Drug interactions
Bosentan is an inducer of the cytochrome P450 isoenzymes CYP2C9 and CYP3A4, and its concentration decreases when the drug metabolized by this isoenzyme is applied simultaneously with bosentan, and inhibition of these enzymes increases the plasma concentration of bosentan.
Sildenafil is metabolized by the cytochrome P450 isoenzymes CYP3A4 (primary pathway) and CYP2C9 (secondary pathway), and in the presence of CYP3A4 substrates, inhibitors, and CYP3A4 substrates combined with receptor blockers, sildenafil bioavailability and clearance decrease. To avoid systemic hypotension, caution is required when PAH-targeted therapy is combined with antihypertensive drugs, such as β-blockers and angiotensin-converting enzyme inhibitors.
来源:Dobutamine