It has been shown a positive effect by using endothelin receptor antagonists, phosphodiesterase 5-inhibitors and prostacyclin analogs to prevent vascular proliferation, remodeling and dilating pulmonary arteries in PAH patients. The use of the above medications is referred to PAH targeted therapy. Current guidelines clearly recommend that PAH-targeted drugs should not be used in patients with mild pulmonary hypertension related to chronic lung diseases[1].This is because some studies have reported that PAH-targeted drugs may worsen gas exchange in chronic lung disease due to the inhibition of hypoxic vasoconstriction, which cause pulmonary blood flow from more seriously to less seriously affected lung segments [21-24]. However, based on smaller case series, patients in severe PH-CLD might benefit form PAH-targeted therapy [10,15]. Guidelines has recommended that patients with severe PH-CLD should be included in prospective clinical trials to investigating the effects of PAH-targeted therapy [15]. Our study retrospectively analyzed the effects of PAH targeted drugs and survival in that subgroup patients to provided more effective information for guiding clinical practice. Our study shows that PAH-targeted therapy can improve the NT-proBNP, PaO2 and oxygenation index of patients in severe PH-CLD, but it cannot improve the prognosis of the patients; cardiac index and right cardiac index is an independent risk factor predicting the prognosis of patients. Pulmonary hypertension is a common complication of CLD, especially in patients with advanced lung disease, which can reach 50%. The occurrence of pulmonary hypertension is often related to the decline of the patient's motor function and the deterioration of hypoxemia, which affects the survival rate of patients [25-26]. On the basis of a similar degree of airflow limitation in patients with COPD, the 5-year survival rate of patients with mPAP>25mmHg decreased from 62.2% to 36.3% compared with those without elevated pulmonary artery pressure [27], in patients with bronchiectasis, combined The blood oxygen saturation of PH patients decreased by 4-8%, and the 5-year survival rate decreased by 33.2% [28]. Similarly, the risk of death in patients with IPF complicated by PH increased significantly. The results of the study showed that when sPAP ≤ 35 mmHg, 36-50 mmHg>50mmHg, the median survival time gradually decreased, respectively 4.8, 4.1 and 0.7 years [29].
Changes in lung parenchymal structure caused by lung diseases can reduce pulmonary capillary bed and increase the pulmonary vascular resistance. It has been confirmed that most patients have an mPAP between 20 and 30mmHg caused by chronic lung disease [30] and furthermore, the rate of PH progression in lung disease is normally slow. Weitzenblum et al. [31] conducted a 5-year study on COPD patients, which mainly using right heart catheters to monitor the progress of pulmonary artery pressure, they found that the average pulmonary artery pressure increased by about 0.5mmHg per year. However, a subset of patients develop severe PH that was defined as the mPAP was>35mmHg and present with severe hypoxemia, hypercapnia, and very low CO diffusing capacity (DLCO), which progressive gas exchange abnormalities are disproportionate to ventilatory impairment. Therefore, it gave rise to the idea with “out of proportion” PH. The NICE Guidelines have suggested categorizing the disease as severe PH-CLD which hemodynamic thresholds is mPAP greater than 35 mm Hg or mPAP greater than or equal to 25 mm Hg combined with a low cardiac index (<2.5 L/min/m2) [10].
Chaouat et al.[4] and Thabut et al. [5] summarized the clinical features of severe PH-CLD. All patients showed obvious exertional dyspnea, severe hypoxemia, hypocapnia and severely decreased DLCO. But patients in severe PH-CLD described by our study demonstrated grossly impaired DLCO, relatively mild airflow obstruction, hypoxemia and hypocapnia, despite similar haemodynamics. It may because the patients in our study are not limited to restrictive lung diseases, but also include COPD, bronchiectasis and other diseases that can cause pulmonary ventilation dysfunction, and most of the patients have received oxygen therapy which can improved hypoxemia. In addition, these are only 30.61% smokers in our study. Animal experiments show that smoking can enhance the expression of pulmonary artery vascular growth factor in rats and up-regulate its downstream tyrosine kinase receptors, both can cause inflammatory vascular remodeling [32]. Changes in the pulmonary vascular bed and vascular remodeling are the main factors causing hypoxia on the basis of the same degree of airway obstruction and decreased diffusion function. Therefore, the patients in our study may differ from previous studies due to the lack of vascular changes caused by smoking.
PAH targeted therapy can improve NT-proBNP in patients with severe PH-CLD, but it can’t improve NYHA function class and echocardiographic parameters. NT-proBNP is mainly secreted by the ventricles and is a powerful predictor of heart failure [33]. It is not only proved to be related to right ventricular function in patients with idiopathic pulmonary hypertension [34], but also an indicator of right heart dysfunction and can predict the survival in patients with severe PH-CLD [35]. There was no significant difference in age and renal function between the two groups in our study. NT-proBNP only reflects the patient's cardiac function status. Therefore, we hypothesized that PAH targeted therapy can improve the patient’s right heart function, but due to the short follow-up time, the cardiac structural indicators measured by echocardiography in the early follow-up period will not change significantly. Moreover, emphysema and lung lesions reduce the quality of ultrasound imaging, thereby reducing the sensitivity and specificity of echocardiography [36], and it is difficult to find early changes in the heart structure. Rechecking the right heart catheterization every 3-6 months to early assess the patient's efficacy is of guiding significance for timely adjustment and formulation of individualized treatment plans.
Our research shows that PAH-targeted drugs can improve PaO2 and oxygenation index in arterial blood gases in patients with severe PH-CLD. Different from previous reports that PAH-targeted drugs worsen their oxygenation or do not affect PaO2 [15,37] may therefore account for the degree of pulmonary vascular remodeling, types of PAH targeted drugs and approach of administration. One of the main driving forces behind the development of pulmonary hypertension in the context of underlying lung disease is pulmonary arterial vasoconstriction caused by hypoxia. Many studies have shown a close relationship between the degree of alveolar hypoxia and mPAP or pulmonary vascular resistance [5,6]. But several studies have found that reversing hypoxemia with oxygen therapy does not completely reverse pulmonary hypertension in COPD patients [38-39]. It is obvious that hypoxia may not be the only mechanism leads to the development of PH-CLD. Furthermore, pathologic studies in subjects with lung disease have identified remodeling of the pulmonary vessels and it will aggravated as the disease progresses [40-41]. Hypoxemia in these patients may be due to a significant decrease in circulatory reserve function rather than impaired respiratory function [42] so that PAH targeted therapy can improve patients' pulmonary vascular remodeling to improve hypoxemia. On the other hand, in our study, only 5-phosphodiesterase inhibitors and prostacyclin analogs were used in patients and both of them may selectively and preferentially expand the pulmonary blood vessels in the lighter lung area. It has been reported [43] that phosphodiesterase 5 inhibitor and inhaled iloprost, treprostinil, or nitric oxide in advanced lung disease may improve patients’ arterial oxygenation, DLCO, dyspnea and quality of life because of their mode of distribution. In contrast, other studies have found that endothelin receptor inhibitors can worsen the gas exchange process of patients with lung diseases by changing the sensitivity of the carotid body to hypoxia [44].
Very few controlled trials have evaluated the impact of targeted therapy on survival. Lange et al.[45] compared patients who received PAH therapy with a control cohort which received no PAH therapy and they found the survival was significantly better in patients who received PAH therapy, while we found PAH targeted therapy cannot improve the prognosis of patients with severe PH. This may be explained that their study included patients with mild-to-moderate PH in survival analysis and only severe PH patients in our study. Direct comparison with our cohort is therefore not possible. But undeniably, this difference may also be caused by the small sample size and short follow-up time of this study. Our study found although the patients who received PAH therapy have worse right heart function and oxygenation, and their condition is relatively more serious, the changes in NYHA functional class and their survival seem to be significantly better, which suggests that PAH-targeted drug therapy has a certain effect. However, we have not yet fully clarified the efficacy of PAH-targeted therapy in patients with severe PH-CLD, which may be reflected in the quality of life and symptoms. Further research is required to investigate the function of PAH-targeted drugs.
As in previous studies [35], right atrial pressure and cardiac index turned out to be predictors of survival and both of them were derived from right heart catheterisation. This reaffirms existing recommendations to obtain invasive haemodynamic measurements at the time of diagnosis. Moreover, cardiac index and right atrial pressure are indicators of right ventricular dysfunction. Right ventricular dysfunction is common in patients with lung disease, and it is more obvious with pulmonary hypertension [46]. In a cohort study of COPD patients, Freixa et al. [46] reported that about 30% of patients with echocardiographic enlargement of the right ventricle, and evidence of chronic cor pulmonale was found in more than 40% of COPD patients [47]. Right ventricular hypertrophy was observed in autopsy of 2/3 of patients with chronic bronchitis [48] and 1/3 of patients with emphysema [44]. When mPAP>25mmHg indicates that at least 50% of the pulmonary vascular bed has been damaged, which has a significant impact on right ventricular function [49]. Sato et al. [50] used cardiac magnetic resonance to assess the structure and function of the right heart in patients with pulmonary hypertension, and they found that the occurrence of PH would lead to right ventricular hypertrophy, a decrease in reserve function, and a decrease in right ventricular ejection fraction. Decreased right ventricular function leads to decreased CI and increased right atrial pressure. It is failure of the RV that leads to increased morbidity and mortality in PH. Our study demonstrates that right atrial pressure and CI predicts survival on multivariate analysis. This may reflect that improving patient RV function will become one of the targets of future treatment in severe PH-CLD.
Insufficient
Our research has several limitations. First, most of the patients are seriously ill and suffered from cardiac insufficiency and decreased exercise capacity, so that they can’t complete the 6-minute walking distance test, which results in the lack of this objective indicator for evaluating patients' activity endurance; Second, the number of cases is small, and no further subgroup analysis can be done to explore whether the effects of PAH targeted drugs on different lung diseases are consistent; Third, our study is a retrospective, single-center study, which may have caused selection bias. The specific role of PAH targeted therapy needs further study.