This analysis is a large retrospective case-controlled study to examine the role of NT-proBNP in AECOPD-PH. Our findings suggest that NT-proBNP has a diagnostic efficacy to predict morbidity in patients with AECOPD-PH and 175.14 pg/mL is a predictive NT-proBNP threshold. And NT-proBNP has a weak correlation with severity of PH with AECOPD.
COPD is a common chronic disease, and its incidence has gradually increased recently (11). PH is a common complication of COPD, which seriously affects the prognosis and quality of life of patients (12). AECOPD-PH can cause death in severe cases (13). The prevalence of PH in AECOPD depends on the severity of the disease and the definition of PH.
In our research, we conducted a preliminary statistical analysis of demographic data and some biomarkers, and found that age, gender, complications, smoking and other indicators were statistically significant, in order to eliminate the influence of these confounding factors, PSM (caliper value = 0.05, 1:1 matched) was used to analyze data, NT-proBNP, TBIL and RDW were significantly different in the three groups (P<0.05), and these models did indicate that the results were stable and reliable. Then NT-proBNP, TBIL and RDW were performed by multivariate logistic regression analysis to test the predicting AECOPD-PH relevance, NT-proBNP and TBIL had statistical significance (P<0.05). Then ROC curve was used to examined the diagnostic efficacy of NT-proBNP and TBIL, and found that NT-proBNP was the most suitable biomarker for diagnosing AECOPD-PH (AUC = 0.651). Finally, NT-proBNP had a weak correlation with severity of AECOPD-PH.
PH increases natriuretic peptide secretion in the right-sided heart chambers. Gene expression of NT-proBNP is up-regulated in the right atria with increased pressures, disruption of the natriuretic peptide receptor NPR-A worsens hypoxia-induced PH (14). NT-proBNP is typically influenced by age, gender, and obesity in addition to renal function (15), in our research, first, we excluded the patients with renal insufficiency, then data analysis indicated age and gender indeed had a significant difference between COPD group and AECOD-PH group, however, BMI had no significant difference (P>0.05), it might be associated with low distribution of obesity in China. We and other studies revealed low NT-proBNP levels in stable COPD patients (16).
In the absence of a significant left heart disease, NT-proBNP serves as a biomarker of an increased workload of the right heart originating from pulmonary arterial hypertension (17, 18). We did not have the opportunity to assess the NT-proBNP levels during periods of stable COPD, since data have shown these values to be significantly lower than during AECOPD group or AECOPD-PH group. The results showed that elevated NT-proBNP levels predicted morbidity rather than severity of AECOPD-PH. First, we excluded chronic cardiac insufficiency in all enroll patients, NT-proBNP elevation was a result of AECOPD-PH, different statistical models were performed to draw a reliable and stable conclusion of the demographic data and different biomarkers in AECOPD and AECOPD-PH groups, we supported that NT-proBNP could predict the morbidity of AECOPD-PH, accordingly, in our study, elevated NT-proBNP levels (≥ 175.14 pg/mL) had a more significant predictive value than TBIL (AUC = 0.651 VS AUC = 0.590), which was diagnosed with sensitivity (61.7%) and specificity (63.8%). Based on the PASP values of echocardiography (it allows an estimation of the pulmonary artery pressure and gives an overall impression of the right and left heart deformities and function), the AECOPD-PH group was further divided into several subgroups (mild, moderate and severe). However, elevated NT-proBNP had a weak correlation with severity of AECOPD-PH (r = 0.299, P = 0.001). Macchia et al. supported that the assessment of NT-proBNP was useful for the detection of ventricular dysfunction in patients with COPD. A cut-off value of 160 pg/mL increased>10-fold the probability of finding ventricular dysfunction with echocardiography, it is basically consistent with our ROC results. For AECOPD patients, NT-proBNP measurement may help identify patients with PH. In multiple studies, NT-proBNP did not correlate with typical parameters used to evaluate severity of exacerbation such as hypoxia, hypercapnia type of exacerbation, or forced expiratory volume in the first second of expiration, our study also agreed with it. A few studies have demonstrated elevated BNP correlating with increasing mortality, either in hospital or long-term (19). This association has not been replicated in other studies with larger COPD populations, making the prior observation a potential consequence of a smaller sample size (20, 21). We were unable to assess the association of NT-proBNP independently in a multivariate analysis due to the low in-hospital mortality rate in our population.
For many years, RDW was almost exclusively used for the differential diagnosis of anemia. Recently it was increasingly investigated as a negative prognostic factor in variety of acute and chronic medical conditions, such as cardiovascular disease, community-acquired pneumonia (22). Several studies showed that increased RDW is associated with disease severity and long-term mortality in COPD patients (23–25). Ozgul et al. showed increased RDW values in COPD patients compared to controls as well as in smokers compared to nonsmokers (24, 26). In our study, unadjusted data and PSM models (calipers value = 0.05) all showed RDW indeed had a significant difference in AECOPD-PH group(P<0.05). However, in logistic regression analysis, elevated RDW had no statistic difference compared with low/moderately elevated RDW value (P>0.05). The results supported elevated RDW might not be associated with AECOPD-PH.
Total bilirubin (TBIL) has been considered as a powerful endogenous antioxidant in recent years. Liu et al. supported a different conclusion that the association between TBIL and diabetic retinopathy risk was not a simple linear association but a U-shaped curve (27), a cohort study based on 7685 middle-aged British men firstly revealed that there was a U-shaped relationship between TBIL and risk of ischemic heart disease (28). Our data analysis was similar to it, compared with TBIL < 13.8µmol/L, TBIL13.8-16.5µmol/L had a lower protective trend than TBIL > 16.5µmol/L (OR = 0.485, 95%CI: 0.280–0.841 and OR = 0.598, 95%CI: 0.413–0.864, respectively). And the actual U-shaped association might be the combination of antioxidation and liver toxicity effects (27). In our study, TBIL had a lower predictive value than NT-proBNP, and it had no significant difference in correlation with AECOPD-PH severity (P>0.05).
In conclusion, we suggest that NT-proBNP has strongly diagnostic efficacy to predict morbidity in patients with AECOPD-PH and 175.14 pg/ mL is a predictive NT-proBNP threshold. And NT-proBNP has a weak correlation with severity of PH with COPD. COPD complied with PH was not a common disease; we have tried our best to collect as much sample size as possible.
Our study also has several limitations, such as a retrospective, single‑center design and the lack of a healthy control group. In our population and the mixture of patients with chronic COPD may also have biased this observation (29). Most regretfully, since this is a large retrospective case-controlled study, too few patients were eventually included in the log-rank, and we cannot make statistics on the prognosis of NT-proBNP in predicting AECOPD-PH.