Chronic obstructive pulmonary disease (COPD) is a common clinical disease with a high incidence and mortality rate, and is expected to be the 3rd leading cause of death worldwide by 2020, as well as the 5th leading economic burden of disease in the world. In a recent report, a survey of 20,245 adults in 7 regions of China showed that the prevalence of COPD accounted for 8.2% of people over 40 years of age. Pulmonary hypertension (PH) is an important comorbidity of COPD, and the mean pulmonary artery pressure (mPAP) is closely related to the severity of COPD and is an important factor in predicting patient prognosis. Compared with patients without PH, COPD patients with mPAP >25 mm Hg (1 mm Hg=0.133 kPa) have a significantly lower 5-year survival rate. In patients with moderate and severe airflow limitation, the risk of acute exacerbation was significantly increased if their mPAP was >18 mm Hg. In patients with severe airflow limitation requiring long-term oxygen therapy, the 5-year survival rate decreased from 62.2% to 36.3% if mPAP was >25 mm Hg.
I. Definition and classification of COPD-associated PH
The 2008 Dana Point Conference established the diagnostic criteria for pulmonary hypertension as: mPAP ≥ 25 mm Hg measured by right heart catheterization at rest at sea level or mPAP ≥ 30 mm Hg during exercise. it is generally accepted that COPD-related PH is defined as mPAP > 20 mm Hg; combined severe PH is defined as mPAP > 35 mm Hg, and patients with respiratory disease and/or hypoxemia. Pulmonary cardiopathy is defined as right ventricular hypertrophy and/or dilation secondary to PH due to respiratory disease.
Most COPD patients with clinically concurrent PH have mild to moderate elevation of PH. In some patients, however, PH is severely elevated without significant airflow limitation, a condition known as “disproportionate” PH. COPD-associated PH can be clinically manifested as either overt or covert hypertension. Overt PH refers to mPAP>20 mmHg at rest; recessive PH refers to mPAP in the normal range at rest, but increases significantly after exercise, with mPAP≥30 mmHg.
II. Epidemiology of COPD-associated PH
The epidemiology of COPD-associated PH lacks data from a sufficient sample because right heart catheterization is not possible on a large scale. Early studies concluded that about 6% of COPD patients can develop pulmonary heart disease each year, and autopsy data also confirmed the presence of right ventricular hypertrophy in about 40% of COPD patients, presumably with a significant incidence of COPD-associated PH. Weitzenblum et al. had reported the incidence of PH in 175 COPD patients (FEV1/VC of 40% and PaO2 of 63 mm Hg) to be 35%. Thabut et al. studied 215 patients with advanced COPD proposed for lung decompression or lung transplantation and showed that the incidence of PH was 36.7%, 9.8%, and 3.7% for mild (mPAP of 26-35 mm Hg), moderate (mPAP of 36-45 mm Hg), and severe (mPAP >45 mm Hg), respectively. In a large-scale study, about 50% of 998 COPD patients (FEV1/VC ≤ 60%) had mPAP > 20 mm Hg, and 5.8% of them had mPAP > 35 mm Hg.
III. Pathogenesis of COPD-related PH
Most scholars at home and abroad used to think that PH occurred in COPD patients because of hypoxemia. In recent years, it has been found that smoking rather than hypoxia is the most direct pathogenic factor, and endothelial dysfunction and endothelial smooth muscle proliferation eventually lead to pulmonary vascular remodeling are its pathological features [5]. Therefore, the exact pathogenesis of COPD combined with PH is unclear and may be the result of a combination of factors, including the following.
1. hypoxic pulmonary vasoconstriction (HPV).
hypoxia can act directly on pulmonary artery cell membrane ion channels to directly cause pulmonary vasoconstriction, in addition, hypoxia can indirectly cause pulmonary vasoconstriction by inducing the production of many endogenous constricting mediators
2. Abnormal vascular endothelial function.
It was found that abnormalities in pulmonary vascular endothelial function, including reduced eNOS expression and increased endothelin expression and activity, exist in both patients with mild or severe COPD and in the smoking population with normal lung function.
3. inflammatory mechanisms.
Inflammation may be the cause of structural and functional changes in the pulmonary circulation in early COPD, which may cause abnormalities in vascular endothelial function, and inflammatory cells may also produce a variety of cytokines and growth factors that act on vascular endothelial cells, smooth muscle cells and outer membranes, causing structural and functional changes in blood vessels.
4. Pulmonary vascular remodeling.
Under the interaction of long-term hypoxia, chronic inflammation, and various vasoactive substances and growth factors, pulmonary vascular outcomes can be altered, causing vascular remodeling. Studies suggest that smoking may not depend on changes in lung function and cause pulmonary vascular remodeling either directly or through inflammatory mechanisms.
5, Genetic factors.
eNOS, ACEI and other gene polymorphisms are related to COPD-associated PH.
6, Other.
Such as platelet dysfunction, pulmonary artery thrombosis, etc.
Four, the diagnosis of COPD-associated PH
1.Clinical manifestations
In addition to the symptoms of COPD, the symptoms related to PH are mostly non-specific, including dyspnea, mostly exertional, palpitations, shortness of breath, weakness, reduced labor endurance, and even telangiectatic breathing with slight activity. A small number of patients may present with chest pain, and hemoptysis is less common. When right heart failure occurs, there may be loss of appetite, nausea, abdominal distention and other signs of digestive stasis. In addition to the signs of COPD, cyanosis, increased heart rate, P2 hyperactivity, systolic murmur in the tricuspid region, and third and fourth heart sounds can be heard; if jugular venous filling, liver bruising and enlargement, and lower limb edema are present, they usually indicate right heart insufficiency.
2.Auxiliary examination
(1) Pulmonary function: Pulmonary function measurement can indicate the type and degree of respiratory dysfunction and is of great value in the diagnosis of underlying lung disease. Severe pulmonary function abnormalities mostly exist in PH, and pulmonary function measurements can also estimate the pulmonary circulation hemodynamics of COPD patients. It is generally accepted that pulmonary vascular resistance can be increased in COPD patients with FEV1 < 70% of the expected value.
(2) Electrocardiogram: The electrocardiogram changes are mainly related to the increased right ventricular load caused by PH and myocardial cell damage caused by hypoxia. They are characterized by right-sided electrical axis, right ventricular hypertrophy, and cis-clockwise transposition.
(3) Chest X-ray: In addition to the underlying lung disease, signs of PH and right heart enlargement can often be found. chest X-ray of patients with PH can show: dilated right inferior pulmonary artery with a transverse diameter ≥ 15 mm and its transverse diameter to tracheal transverse diameter ratio ≥ 1.07; dilated central pulmonary artery with slender peripheral vessels; protruding pulmonary artery segment ≥ 3 mm and protruding right anterior oblique pulmonary artery cone ≥ 7 mm.
(4) Echocardiography: Echocardiography can show the structure of each chamber of the heart, the movement of each valve and the changes of blood flow spectrum in large vessels more clearly, and can estimate the pulmonary artery pressure. The systolic pulmonary artery pressure measured by detecting the maximum tricuspid regurgitation velocity correlates significantly with the information obtained from right heart catheterization. tricuspid regurgitation is detected in 90-100% of patients with manifestations of right heart failure, with a reduced success rate in the absence of manifestations of right heart failure. the detection rate of high-quality tricuspid regurgitation signals is low in patients with COPD (24%-77%). Studies have shown that the difference between the pulmonary artery systolic pressure measured by echocardiography and the value measured by right heart catheter is 2.8 mm Hg. Considering that most COPD patients have mild to moderate elevated PH (mPAP < 35 mm Hg), a deviation of 2.8 mm Hg is high.
(5) Cardiopulmonary exercise test: Cardiopulmonary exercise test can evaluate the cardiopulmonary function of patients. Severe PH, especially “disproportionate” PH, often presents as a typical “heart failure” type. PH may be a rare cause of reduced exercise capacity in COPD patients, especially “disproportionate” PH. “The 6-minute walk test is easy to perform and reproducible. mPAP >35 mm Hg is significantly reduced in COPD patients compared to those with lower mPAP.
(6) Right heart catheterization (RHC): RHC is the gold standard for diagnosing PH, evaluating right heart function and measuring pulmonary artery pressure. rHC can directly measure right atrial, right ventricular, pulmonary artery and pulmonary artery embedding pressure to assess left heart filling pressure. rHC is an invasive test and requires related equipment, which is clinically dangerous and therefore cannot be used as a routine test for COPD patients.
V. Treatment of COPD-related PH
(1) Oxygen therapy: Long-term oxygen therapy and improved ventilation are the most effective treatments, which can improve the 6-minute walking distance of patients in the near future and improve the survival of patients in the long term. Ashutosh et al. divided COPD-associated PH patients into two groups according to their responsiveness to acute oxygen therapy, with those who had a decrease in mPAP of more than 5 mmHg after 24 hours of continuous inhalation of 28% oxygen being referred to as the “oxygen therapy responsive group” and the opposite group as the “oxygen therapy unresponsive group”. “The oxygen therapy non-responsive group. Long-term oxygen therapy was found to prolong the survival rate of the “oxygen therapy-responsive group” at 3 years of follow-up [6]. In conclusion, long-term oxygenation is recommended for cases of chronic hypoxemia coexisting with COPD-associated PH, which can delay the natural course of PH. Long-term oxygen therapy is recommended for the “oxygen therapy response group” subgroup of patients with COPD-associated PH, as it can prolong survival. The longer the duration of oxygenation, the better the effect, and it is recommended that the duration of oxygenation should be more than 15 hours per day.
(2) Non-specific vasodilator drugs: At present, the non-specific vasodilator drugs used in the treatment of COPD-related PH at home and abroad include calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), nitrates and α-receptor antagonists. Most studies have shown that short-term application of these drugs in patients with acute exacerbations of COPD and pulmonary heart disease results in lower pulmonary artery pressure and increased cardiac output. However, studies have also found that the application of these drugs can result in a decrease in partial pressure of oxygen, which is related to the inhibition of hypoxic pulmonary vasoconstriction and aggravation of the imbalance of pulmonary ventilation and blood flow ratio.
(3) Nitric oxide (NO): NO has the effect of selective pulmonary vasodilation. In patients with COPD-associated PH, NO inhalation therapy can improve hemodynamic parameters, but it affects oxygenation because it inhibits hypoxic pulmonary vasoconstriction response and aggravates ventilation/blood flow ratio dysregulation. The best oxygenation effect can be achieved with a small dose of NO (5 ppm) inhalation therapy, but the improvement of hemodynamic parameters is positively correlated with the dose, while high dose inhalation (40 ppm) therapy affects oxygenation to varying degrees. long-term NO inhalation therapy is not very feasible, and its effect on COPD-associated PH is unknown.
(4) New pulmonary vasodilators (targeted drugs): These drugs include prostacyclin and its analogs, endothelin receptor antagonists and phosphodiesterase 5 inhibitors. In addition to vasodilating, these drugs also have some antiproliferative effects and have encouraging effects on the treatment of arterial pulmonary hypertension such as IPAH. Archer et al. found that continuous intravenous application of epoprostenol in patients with COPD-associated PH resulted in a significant reduction in PVR at the beginning of the phase, but a rapid tolerance with a significant reduction in PaO2 after 24 hours. The study confirmed that the endothelin receptors were not effective in the treatment of COPD-associated PH. The study confirmed that the endothelin receptor antagonist bosentan did not exercise tolerance, pulmonary function, pulmonary artery pressure, or maximal oxygen uptake in patients with COPD-associated PH; instead, PaO2 decreased, alveolar-arterial partial pressure difference increased, and quality of life deteriorated. The effects of the phosphodiesterase 5 inhibitor sildenafil in COPD patients are poorly reported and conflicting. In patients with arterial pulmonary hypertension such as IPAH, bosentan works mainly by increasing cardiac output rather than reducing pulmonary artery pressure. In the presence of normal cardiac output (which is the case in the vast majority of COPD patients), pulmonary vasodilators such as bosentan or sildenafil do not work. Since COPD-associated PH is a complication of COPD, the key to treatment is to prevent the progression of COPD disease, and the new pulmonary vasodilators are of little value.
(5) Statins: Experimental animal studies have shown that simvastatin inhibits cigarette smoke-induced emphysema and pulmonary vascular remodeling and suppresses PH formation. Statins inhibit the synthesis of endothelin 1, reduce pulmonary artery systolic pressure and prolong exercise time. In addition, statins have antioxidant, anti-inflammatory and immunomodulatory effects, which can reduce the deterioration of COPD and delay the decline of lung function.
(6) Anticoagulation therapy: Patients with COPD-related PH are prone to pulmonary artery thrombosis in situ and aggravate PH due to abnormal vascular endothelial function, increased blood viscosity and reduced activity, and slow blood flow in the pulmonary circulation. Therefore, anticoagulation therapy should be given to inpatients and patients who are inactive for a long time, and low molecular weight heparin is often applied to prevent thrombosis.
(7) Pulmonary decompression and lung transplantation: pulmonary decompression may be beneficial for patients with COPD combined with significant emphysema. In general, COPD combined with severe PH (mPAP ≥ 35 mm Hg) is not a candidate for lung volume reduction. Instead, pulmonary decompression may have the adverse effect of causing shrinkage of the pulmonary vascular bed.PH may return to the normal range after lung transplantation in patients with COPD, and lung transplantation may be considered in all patients with severe PH who are younger than 65 years of age and have no comorbidities.