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ORIGINAL ARTICLE
Elevated plasma YKL-40 as a prognostic indicator in patients with idiopathic pulmonary arterial hypertension GUO CHEN,* TAO YANG,* QING GU, XIN-HAI NI, ZHI-HUI ZHAO, JUE YE, XIAN-MIN MENG, ZHI-HONG LIU, JIAN-GUO HE AND CHANG-MING XIONG State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
ABSTRACT Background and objective: Pulmonary vascular remodelling and inflammation have been implicated in pulmonary arterial hypertension (PAH). YKL-40, a marker of tissue remodelling and inflammation, has recently been recognized as a risk predictor of cardiovascular and inflammatory diseases. The study aimed to investigate a potential role of YKL-40 in predicting prognosis in idiopathic PAH (IPAH). Methods: Plasma YKL-40 levels were measured in 82 IPAH patients without current or previous PAHspecific treatment during right heart catheterization and in 54 healthy volunteers. Concurrent data included clinical, haemodynamic and biochemical variables. Results: Plasma YKL-40 levels were increased in IPAH patients compared with control subjects (median, interquartile range: IPAH: 24.90, 17.68–39.78 ng/mL; controls: 16.58, 14.20–19.64 ng/mL; P < 0.001). YKL-40 levels correlated with cardiac index (r = −0.244, P = 0.027) and N-terminal pro-brain natriuretic peptide (NT-proBNP, r = 0.263, P = 0.017). After a median follow-up of 578 days, YKL-40 outperformed NT-proBNP, uric acid, and 6-min walk distance in receiver operating characteristic (ROC) analyses in predicting both clinical worsening (area under the curve (AUC) 0.681) and death (AUC 0.717). Compared with patients with YKL-40 below the ROC-derived cutoff point (24.5 ng/mL), the high YKL-40 group showed higher pulmonary vascular resistance and serum uric acid levels, and showed more clinical worsening events and deaths in Kaplan–Meier analyses. Plasma YKL-40 was independently associated with clinical worsening in univariate and multivariate Cox analyses (all P < 0.05). Conclusions: Plasma YKL-40 might serve as a promising indicator of disease severity and prognosis in patients with IPAH.
Correspondence: Chang-Ming Xiong, No. 167, Beilishi Road, Xicheng District, Beijing, 100037, China. Email: xiongcm2000 @163.com *Guo Chen and Tao Yang contributed equally to this manuscript. Received 31 October 2013; invited to revise 5 December 2013; revised 27 January 2014; accepted 4 February 2014 (Associate Editor: O Jung Kwon). © 2014 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE The ability of YKL-40, an inflammation and remodelling marker, to predict prognosis of IPAH was explored. Plasma YKL-40 was significantly elevated in IPAH patients compared with healthy controls. Patients with higher YKL-40 had increased hemodynamic severity and right heart dysfunction. After follow-up, YKL-40 independently predicted clinical worsening in IPAH. Key words: chitinase-like protein, pulmonary hypertension, survival, YKL-40. Abbreviations: 6MWD, 6-min walking distance; AUC, area under the curve; BMI, body mass index; CRP, C-reactive protein; CV, coefficient of variation; IL, interleukin; IPAH, idiopathic pulmonary arterial hypertension; IQR, interquartile range; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; REVEAL, the Registry to Evaluate Early and Long-Term PAH Disease Management; RHC, right-sided heart catheterization; ROC, receiver operating characteristic curve; VSMC, vascular smooth muscle cell; WHO-FC, World Health Organization Functional Class.
INTRODUCTION Pulmonary arterial hypertension (PAH) is a rare disease characterized by progressive pulmonary vascular remodelling that leads to increased pulmonary vascular resistance (PVR) and subsequently right heart failure.1 Despite recent advances in PAHspecific therapies, prognosis of PAH remains poor, with a 5-year survival of 61.1% in a recent cohort of idiopathic, heritable and anorexigen-associated PAH.2 Evaluating prognosis is important because it influences the treatment strategy for PAH patients. However, prognosis assessment in PAH is difficult and is mostly based on invasive haemodynamics and subjective parameters like functional class.3 Thus, noninvasive biomarkers that can provide additional prognostic information are highly desirable.4 Respirology (2014) 19, 608–615 doi: 10.1111/resp.12283
YKL-40 predicts outcomes in PAH
YKL-40 (also referred as human cartilage glycoprotein 39 and chitinase 3-like 1) is a member of mammalian chitinase-like proteins broadly expressed by various cell types.5,6 As a marker of inflammation and tissue remodelling, elevated YKL-40 has been recently found in association with disease severity and mortality in many cardiovascular diseases.7–11 Circulating YKL-40 correlates with the degree of endothelial injury and vascular remodelling in diabetic nephropathy and atherosclerosis.9,12 Elevated YKL-40 predicts poor prognosis in chronic inflammatory conditions such as systemic sclerosis,13 stable coronary heart disease11 and heart failure.8 The underlying mechanisms may include the promotion of endothelial injury and angiogenesis, stimulation of vascular smooth muscle cells (VSMC) migration and proliferation, protection from apoptosis, enhancement of remodelling, and pro-inflammatory properties.14–18 Many inflammatory cytokines, like interleukin (IL) 1β, induce the expression of YKL-40.18,19 Interestingly, all of these mechanisms have been implicated in PAH. Until now, the role of YKL-40 in PAH has not been reported. Thus, the aim of the present study was to investigate a potential role of YKL-40 as a predictor of clinical outcomes in idiopathic PAH (IPAH).
METHODS Study population Subjects were enrolled at the Pulmonary Vascular Disease Center of Fuwai Hospital, Beijing, China, from October 2010 to December 2012. To maximize homogeneity of data, only patients from Chinese Han ethnicity who were diagnosed as IPAH for the first time without current or previous PAH-specific therapy were included. Exclusion criteria included the following: left ventricular ejection fraction less than 50%; pulmonary capillary wedge pressure (PCWP) greater than 15 mm Hg; history of pulmonary embolism; valvular or congenital heart diseases. Moreover, conditions known to influence YKL-40 levels were excluded, including chronic obstructive pulmonary disease, connective tissue disease, coronary heart diseases, systemic hypertension, hyperlipidaemia, chronic renal failure, diabetes mellitus, liver diseases, active infection and asthma. The criteria of diagnosis and recruitment are given in details in Supporting Information Appendix S1 in the online supporting information. The control group consisted of age- and sex-matched healthy volunteers without medical conditions and medications. All subjects gave written informed consent, and the study protocol was approved by the Institutional Review Board of Fuwai hospital (project approval number: 216). Clinical assessment Right-sided heart catheterization (RHC) was performed in all patients. Baseline mean pulmonary artery pressure, mean right atrial pressure (RAP), PVR, cardiac output, cardiac index and PCWP were measured. Other data collected included demo© 2014 Asian Pacific Society of Respirology
609 graphic information, body mass index (BMI), echocardiographic variables, treatment regimens, and biochemical markers including N-terminal pro-brain natriuretic peptide (NT-proBNP), big endothelin-1, high-sensitive C-reactive protein (CRP), serum uric acid, creatinine, total bilirubin, lipid profiles. Six-minute walking distance (6MWD) and World Health Organization Functional Class (WHO-FC) were assessed within 3 days of RHC. Simplified risk score derived from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL score) in each patient was calculated as described previously.20 The follow-up period was from the date of blood sampling to death or 21 October 2013 by hospital visit or telephone interview. Four clinical worsening events were prospectively assessed, including death due to any cause, lung transplantation, hospitalization for right heart failure, and the addition of another PAH-specific therapy or a switch from oral PAH-specific therapy to inhaled or intravenous prostanoids for clinical worsening. The cause of death was verified by medical records and death certificates.
YKL-40 measurement Before initiating medication, peripheral venous blood samples were collected during RHC in all patients. Samples were kept on ice and immediately (within 30 min) centrifuged at 2500 g for 15 min at 4°C and then stored at −80°C until analysis. Plasma YKL-40 levels were measured using a commercial two-site sandwich type enzyme-linked immunosorbent assay method (R&D Systems, Minneapolis, MN, USA), and samples were diluted by 50-fold according to manufacturer’s instructions. Measuring range was 0–4000 pg/mL, with intra-assay coefficient of variation (CV) less than 5% and interassay CV less than 7%. The minimum detectable dose of YKL-40 was 1.25–8.15 pg/mL. All measurements were performed by investigators blinded to subject characteristics and outcomes. Statistical analysis Data were summarized as mean ± standard deviation, number (%) and median (interquartile range (IQR)). For comparison of clinical data between two groups, unpaired t or Mann–Whitney tests were used for continuous data, and Pearson chi-square or Fisher’s exact tests were used for categorical data as appropriate. Correlations between YKL-40 and clinical variables were tested with Spearman’s methods. Receiver operating characteristic curves (ROC) assessing outcomes (clinical worsening and mortality) were used to determine cut-off values for YKL-40, and the area under the curve (AUC) was used to compare the prognostic values of different markers. Kaplan–Meier plots with log-rank tests illustrated outcomes during follow-up of patients grouped by YKL-40 levels. YKL-40 and some biomarkers were not normally distributed as shown by Kolmogorov–Smirnov tests and were natural logarithmic (Log) transformed Respirology (2014) 19, 608–615
610
G Chen et al.
before Cox analyses. Univariate Cox regression analyses were used to explore the prognostic value of each variable for clinical worsening, and variables with a P < 0.05 were further assessed in a forward stepwise multivariate Cox regression model. A value of P < 0.05 was considered statistically significant in all tests. Data were analysed with the SPSS V. 19.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS Baseline characteristics and YKL-40 levels A total of 82 IPAH patients and 54 control subjects were enrolled, and their characteristics are shown in Table 1. At the time of blood sampling, no patients had received PAH-specific therapy, digoxin, diuretics, anticoagulants, statins or angiotensin-converting enzyme inhibitors. Plasma YKL-40 (median (IQR)) was significantly higher in IPAH patients (24.90 (17.68–39.78) ng/mL) compared with healthy controls with similar age, gender and BMI (16.58 (14.20– 19.64) ng/mL, P < 0.001) (Fig. 1). YKL-40 levels correlated positively with age (r = 0.354, P = 0.001) and NT-proBNP (r = 0.263, P = 0.017), and negatively with cardiac index
Figure 1 Plasma YKL-40 levels in idiopathic pulmonary arterial hypertension (IPAH) patients and control subjects. Graph showing the distribution and medians of plasma YKL-40 levels in IPAH patients and control subjects. Statistical significance was determined with the Mann–Whitney test. **P < 0.001.
(r = −0.244, P = 0.027). No significant correlation was found between YKL-40 with other clinical variables.
YKL-40 and prognosis in IPAH The median duration of follow-up was 578 (range from 27 to 1268) days. Six patients died from right heart failure, and one died of sudden death. The cause of death of three patients could not be identified. One patient received lung transplantation. Another 12 patients experienced rehospitalization or escalation of therapies. From ROC analyses, the same cut-off value of 24.5 ng/mL for YKL-40 was derived for both clinical worsening (sensitivity, 82.6%; specificity, 61%; P = 0.011; Fig. 2a) and mortality (sensitivity, 90.0%; specificity, 54.2%; P = 0.027; Fig. 2b). In these analyses, YKL-40 outperformed other well-proven prognostic markers, including 6MWD, NT-proBNP and uric acid, albeit less powerful than the REVEAL score (Supporting Information Fig. S1). IPAH patients were divided into two groups by this cut-off value, and their clinical variables and treatment regimens are compared in Table 2. No significant differences were found between the two groups for echocardiographic variables, serum bilirubin and creatinine, while patients with higher YKL-40 were older. In terms of PAH severity, patients with high YKL-40 had lower cardiac index, higher PVR, higher NT-proBNP and uric acid levels. More patients in the high YKL-40 group received digoxin than in the low YKL-40 group (85.7% vs 65.0%), while other drug use were similar in both groups during follow-up. Kaplan–Meier analyses showed that the high YKL-40 group had more clinical worsening events and a higher mortality than the low YKL-40 group (Fig. 3).
Identification of the independence of YKL-40 in IPAH In Univariate Cox analyses, WHO-FC, PVR, RAP, uric acid, Log (NT-proBNP) and YKL-40 significantly predicted clinical worsening in IPAH. In multivariate Cox analysis, only RAP and plasma YKL-40 remained independent predictors for clinical worsening in IPAH (Table 3). Because YKL-40 levels correlated with
Table 1 Baseline characteristics of IPAH patients and control subjects Characteristics Age (years) Female (n, %) BMI (kg/m2) LogYKL-40 (ng/mL)
IPAH patients (n = 82)
Control subjects (n = 54)
P-value
31.7 ± 9.1 64 (78.0%) 22.23 ± 3.16 3.30 ± 0.54
29.8 ± 7.0 36 (66.7%) 21.68 ± 2.49 2.80 ± 0.29
0.182 0.141 0.285
ORIGINAL ARTICLE
Elevated plasma YKL-40 as a prognostic indicator in patients with idiopathic pulmonary arterial hypertension GUO CHEN,* TAO YANG,* QING GU, XIN-HAI NI, ZHI-HUI ZHAO, JUE YE, XIAN-MIN MENG, ZHI-HONG LIU, JIAN-GUO HE AND CHANG-MING XIONG State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
ABSTRACT Background and objective: Pulmonary vascular remodelling and inflammation have been implicated in pulmonary arterial hypertension (PAH). YKL-40, a marker of tissue remodelling and inflammation, has recently been recognized as a risk predictor of cardiovascular and inflammatory diseases. The study aimed to investigate a potential role of YKL-40 in predicting prognosis in idiopathic PAH (IPAH). Methods: Plasma YKL-40 levels were measured in 82 IPAH patients without current or previous PAHspecific treatment during right heart catheterization and in 54 healthy volunteers. Concurrent data included clinical, haemodynamic and biochemical variables. Results: Plasma YKL-40 levels were increased in IPAH patients compared with control subjects (median, interquartile range: IPAH: 24.90, 17.68–39.78 ng/mL; controls: 16.58, 14.20–19.64 ng/mL; P < 0.001). YKL-40 levels correlated with cardiac index (r = −0.244, P = 0.027) and N-terminal pro-brain natriuretic peptide (NT-proBNP, r = 0.263, P = 0.017). After a median follow-up of 578 days, YKL-40 outperformed NT-proBNP, uric acid, and 6-min walk distance in receiver operating characteristic (ROC) analyses in predicting both clinical worsening (area under the curve (AUC) 0.681) and death (AUC 0.717). Compared with patients with YKL-40 below the ROC-derived cutoff point (24.5 ng/mL), the high YKL-40 group showed higher pulmonary vascular resistance and serum uric acid levels, and showed more clinical worsening events and deaths in Kaplan–Meier analyses. Plasma YKL-40 was independently associated with clinical worsening in univariate and multivariate Cox analyses (all P < 0.05). Conclusions: Plasma YKL-40 might serve as a promising indicator of disease severity and prognosis in patients with IPAH.
Correspondence: Chang-Ming Xiong, No. 167, Beilishi Road, Xicheng District, Beijing, 100037, China. Email: xiongcm2000 @163.com *Guo Chen and Tao Yang contributed equally to this manuscript. Received 31 October 2013; invited to revise 5 December 2013; revised 27 January 2014; accepted 4 February 2014 (Associate Editor: O Jung Kwon). © 2014 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE The ability of YKL-40, an inflammation and remodelling marker, to predict prognosis of IPAH was explored. Plasma YKL-40 was significantly elevated in IPAH patients compared with healthy controls. Patients with higher YKL-40 had increased hemodynamic severity and right heart dysfunction. After follow-up, YKL-40 independently predicted clinical worsening in IPAH. Key words: chitinase-like protein, pulmonary hypertension, survival, YKL-40. Abbreviations: 6MWD, 6-min walking distance; AUC, area under the curve; BMI, body mass index; CRP, C-reactive protein; CV, coefficient of variation; IL, interleukin; IPAH, idiopathic pulmonary arterial hypertension; IQR, interquartile range; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; REVEAL, the Registry to Evaluate Early and Long-Term PAH Disease Management; RHC, right-sided heart catheterization; ROC, receiver operating characteristic curve; VSMC, vascular smooth muscle cell; WHO-FC, World Health Organization Functional Class.
INTRODUCTION Pulmonary arterial hypertension (PAH) is a rare disease characterized by progressive pulmonary vascular remodelling that leads to increased pulmonary vascular resistance (PVR) and subsequently right heart failure.1 Despite recent advances in PAHspecific therapies, prognosis of PAH remains poor, with a 5-year survival of 61.1% in a recent cohort of idiopathic, heritable and anorexigen-associated PAH.2 Evaluating prognosis is important because it influences the treatment strategy for PAH patients. However, prognosis assessment in PAH is difficult and is mostly based on invasive haemodynamics and subjective parameters like functional class.3 Thus, noninvasive biomarkers that can provide additional prognostic information are highly desirable.4 Respirology (2014) 19, 608–615 doi: 10.1111/resp.12283
YKL-40 predicts outcomes in PAH
YKL-40 (also referred as human cartilage glycoprotein 39 and chitinase 3-like 1) is a member of mammalian chitinase-like proteins broadly expressed by various cell types.5,6 As a marker of inflammation and tissue remodelling, elevated YKL-40 has been recently found in association with disease severity and mortality in many cardiovascular diseases.7–11 Circulating YKL-40 correlates with the degree of endothelial injury and vascular remodelling in diabetic nephropathy and atherosclerosis.9,12 Elevated YKL-40 predicts poor prognosis in chronic inflammatory conditions such as systemic sclerosis,13 stable coronary heart disease11 and heart failure.8 The underlying mechanisms may include the promotion of endothelial injury and angiogenesis, stimulation of vascular smooth muscle cells (VSMC) migration and proliferation, protection from apoptosis, enhancement of remodelling, and pro-inflammatory properties.14–18 Many inflammatory cytokines, like interleukin (IL) 1β, induce the expression of YKL-40.18,19 Interestingly, all of these mechanisms have been implicated in PAH. Until now, the role of YKL-40 in PAH has not been reported. Thus, the aim of the present study was to investigate a potential role of YKL-40 as a predictor of clinical outcomes in idiopathic PAH (IPAH).
METHODS Study population Subjects were enrolled at the Pulmonary Vascular Disease Center of Fuwai Hospital, Beijing, China, from October 2010 to December 2012. To maximize homogeneity of data, only patients from Chinese Han ethnicity who were diagnosed as IPAH for the first time without current or previous PAH-specific therapy were included. Exclusion criteria included the following: left ventricular ejection fraction less than 50%; pulmonary capillary wedge pressure (PCWP) greater than 15 mm Hg; history of pulmonary embolism; valvular or congenital heart diseases. Moreover, conditions known to influence YKL-40 levels were excluded, including chronic obstructive pulmonary disease, connective tissue disease, coronary heart diseases, systemic hypertension, hyperlipidaemia, chronic renal failure, diabetes mellitus, liver diseases, active infection and asthma. The criteria of diagnosis and recruitment are given in details in Supporting Information Appendix S1 in the online supporting information. The control group consisted of age- and sex-matched healthy volunteers without medical conditions and medications. All subjects gave written informed consent, and the study protocol was approved by the Institutional Review Board of Fuwai hospital (project approval number: 216). Clinical assessment Right-sided heart catheterization (RHC) was performed in all patients. Baseline mean pulmonary artery pressure, mean right atrial pressure (RAP), PVR, cardiac output, cardiac index and PCWP were measured. Other data collected included demo© 2014 Asian Pacific Society of Respirology
609 graphic information, body mass index (BMI), echocardiographic variables, treatment regimens, and biochemical markers including N-terminal pro-brain natriuretic peptide (NT-proBNP), big endothelin-1, high-sensitive C-reactive protein (CRP), serum uric acid, creatinine, total bilirubin, lipid profiles. Six-minute walking distance (6MWD) and World Health Organization Functional Class (WHO-FC) were assessed within 3 days of RHC. Simplified risk score derived from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL score) in each patient was calculated as described previously.20 The follow-up period was from the date of blood sampling to death or 21 October 2013 by hospital visit or telephone interview. Four clinical worsening events were prospectively assessed, including death due to any cause, lung transplantation, hospitalization for right heart failure, and the addition of another PAH-specific therapy or a switch from oral PAH-specific therapy to inhaled or intravenous prostanoids for clinical worsening. The cause of death was verified by medical records and death certificates.
YKL-40 measurement Before initiating medication, peripheral venous blood samples were collected during RHC in all patients. Samples were kept on ice and immediately (within 30 min) centrifuged at 2500 g for 15 min at 4°C and then stored at −80°C until analysis. Plasma YKL-40 levels were measured using a commercial two-site sandwich type enzyme-linked immunosorbent assay method (R&D Systems, Minneapolis, MN, USA), and samples were diluted by 50-fold according to manufacturer’s instructions. Measuring range was 0–4000 pg/mL, with intra-assay coefficient of variation (CV) less than 5% and interassay CV less than 7%. The minimum detectable dose of YKL-40 was 1.25–8.15 pg/mL. All measurements were performed by investigators blinded to subject characteristics and outcomes. Statistical analysis Data were summarized as mean ± standard deviation, number (%) and median (interquartile range (IQR)). For comparison of clinical data between two groups, unpaired t or Mann–Whitney tests were used for continuous data, and Pearson chi-square or Fisher’s exact tests were used for categorical data as appropriate. Correlations between YKL-40 and clinical variables were tested with Spearman’s methods. Receiver operating characteristic curves (ROC) assessing outcomes (clinical worsening and mortality) were used to determine cut-off values for YKL-40, and the area under the curve (AUC) was used to compare the prognostic values of different markers. Kaplan–Meier plots with log-rank tests illustrated outcomes during follow-up of patients grouped by YKL-40 levels. YKL-40 and some biomarkers were not normally distributed as shown by Kolmogorov–Smirnov tests and were natural logarithmic (Log) transformed Respirology (2014) 19, 608–615
610
G Chen et al.
before Cox analyses. Univariate Cox regression analyses were used to explore the prognostic value of each variable for clinical worsening, and variables with a P < 0.05 were further assessed in a forward stepwise multivariate Cox regression model. A value of P < 0.05 was considered statistically significant in all tests. Data were analysed with the SPSS V. 19.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS Baseline characteristics and YKL-40 levels A total of 82 IPAH patients and 54 control subjects were enrolled, and their characteristics are shown in Table 1. At the time of blood sampling, no patients had received PAH-specific therapy, digoxin, diuretics, anticoagulants, statins or angiotensin-converting enzyme inhibitors. Plasma YKL-40 (median (IQR)) was significantly higher in IPAH patients (24.90 (17.68–39.78) ng/mL) compared with healthy controls with similar age, gender and BMI (16.58 (14.20– 19.64) ng/mL, P < 0.001) (Fig. 1). YKL-40 levels correlated positively with age (r = 0.354, P = 0.001) and NT-proBNP (r = 0.263, P = 0.017), and negatively with cardiac index
Figure 1 Plasma YKL-40 levels in idiopathic pulmonary arterial hypertension (IPAH) patients and control subjects. Graph showing the distribution and medians of plasma YKL-40 levels in IPAH patients and control subjects. Statistical significance was determined with the Mann–Whitney test. **P < 0.001.
(r = −0.244, P = 0.027). No significant correlation was found between YKL-40 with other clinical variables.
YKL-40 and prognosis in IPAH The median duration of follow-up was 578 (range from 27 to 1268) days. Six patients died from right heart failure, and one died of sudden death. The cause of death of three patients could not be identified. One patient received lung transplantation. Another 12 patients experienced rehospitalization or escalation of therapies. From ROC analyses, the same cut-off value of 24.5 ng/mL for YKL-40 was derived for both clinical worsening (sensitivity, 82.6%; specificity, 61%; P = 0.011; Fig. 2a) and mortality (sensitivity, 90.0%; specificity, 54.2%; P = 0.027; Fig. 2b). In these analyses, YKL-40 outperformed other well-proven prognostic markers, including 6MWD, NT-proBNP and uric acid, albeit less powerful than the REVEAL score (Supporting Information Fig. S1). IPAH patients were divided into two groups by this cut-off value, and their clinical variables and treatment regimens are compared in Table 2. No significant differences were found between the two groups for echocardiographic variables, serum bilirubin and creatinine, while patients with higher YKL-40 were older. In terms of PAH severity, patients with high YKL-40 had lower cardiac index, higher PVR, higher NT-proBNP and uric acid levels. More patients in the high YKL-40 group received digoxin than in the low YKL-40 group (85.7% vs 65.0%), while other drug use were similar in both groups during follow-up. Kaplan–Meier analyses showed that the high YKL-40 group had more clinical worsening events and a higher mortality than the low YKL-40 group (Fig. 3).
Identification of the independence of YKL-40 in IPAH In Univariate Cox analyses, WHO-FC, PVR, RAP, uric acid, Log (NT-proBNP) and YKL-40 significantly predicted clinical worsening in IPAH. In multivariate Cox analysis, only RAP and plasma YKL-40 remained independent predictors for clinical worsening in IPAH (Table 3). Because YKL-40 levels correlated with
Table 1 Baseline characteristics of IPAH patients and control subjects Characteristics Age (years) Female (n, %) BMI (kg/m2) LogYKL-40 (ng/mL)
IPAH patients (n = 82)
Control subjects (n = 54)
P-value
31.7 ± 9.1 64 (78.0%) 22.23 ± 3.16 3.30 ± 0.54
29.8 ± 7.0 36 (66.7%) 21.68 ± 2.49 2.80 ± 0.29
0.182 0.141 0.285
