Eur Respir J 2010; 36: 819–825 DOI: / Elevated brain natriuretic peptide predicts mortality in interstitial lung disease R1 김 광 열

Introduction Across interstitial lung disease (ILD), survivalis universally poor when pulmonary hypertension (PH) is present. Elevated pulmonary vascular resistance measured by right heart catheter (RHC) strongly predicts rapid mortality across ILD patients --> but. Invasive and not always practicable. --> but. Invasive and not always practicable. The prognostic significance of brain natriuretic peptide (BNP) and echocardiographic parameters of right ventricular (RV) dysfunction in ILD patients, with reference to both overall and short-term mortality.

Introduction BNP(brain natriuretic peptide) - secreted in response to ventricular stretch by the cardiomyocytes - important marker of RV dysfunction - BNP concentrations correlate well with RHC parameters markers of RV dysfunction may be identifiable prior to development of overt PH. Furthermore, such markers may be useful in predicting survival. Thus, the goal of this study was to explore the prognostic value of vascular markers (including BNP and echocardiography) across ILD patients.

Methods Patient selection - all new ILD referrals and ILD patients being investigated for PH - Plasma BNP ->from 2005 to December 2007 (n=90) - follow up: lost(5), pul. Transplantation(2), die(28) Priori thresholds - BNP≥ 4 pmol·L -1 & BNP≥ 20pmol·L-1 ( - echocardiographic evidense of PH (Rt.ventricular systolic presure(RVSP)≥ 40mmHg) and moderate–severe PH (RVSP ≥50 mmHg or right heart dilatation)

MethodsInvestigations -brain natriuretic peptide(BNP): normal value < 4 pmol·L-1 -brain natriuretic peptide(BNP): normal value < 4 pmol·L-1 -> age- and sex-ajusted value is not available for this assay -> age- and sex-ajusted value is not available for this assay -> priori threshold: BNP>4 pmol·L-1, BNP > 20 pmol·L-1 -> priori threshold: BNP>4 pmol·L-1, BNP > 20 pmol·L-1 -Echocardiography -Echocardiography -> Rt. Atrial pressure(RAP): IVC size & movement on Respiration -> Rt. Atrial pressure(RAP): IVC size & movement on Respiration -> RVSP: sum of tricuspid peak gradient -> RVSP: sum of tricuspid peak gradient -> Pul. Acceleration Time(PAT): between onset and peak velocity -> Pul. Acceleration Time(PAT): between onset and peak velocity -> Rt. Aterial dilatation, RV dilatation, RV disfunction: present or -> Rt. Aterial dilatation, RV dilatation, RV disfunction: present or absent absent -> pul. HTN(PH): RVSP ≥ 40mmHg or Rt. Heart dilatation -> pul. HTN(PH): RVSP ≥ 40mmHg or Rt. Heart dilatation moderate-severe PH: RVSP ≥ 50 mmHg or Rt. Heart dilatation moderate-severe PH: RVSP ≥ 50 mmHg or Rt. Heart dilatation

MethodsInvestigation - pulmonary function test: performed all patients(predicted values were - pulmonary function test: performed all patients(predicted values were calculated according to the American Thoracic calculated according to the American Thoracic Society (ATS) and the European Respiratory Society (ATS) and the European Respiratory Society(ERS) guidelines) Society(ERS) guidelines) - Lung volumes (constant volume body plethysmograph), spirometric - Lung volumes (constant volume body plethysmograph), spirometric volumes and single-breath diffusion capacity of the lung for carbon volumes and single-breath diffusion capacity of the lung for carbon monoxide (DLCO) monoxide (DLCO) - Composite physiologic index(CPI) - Composite physiologic index(CPI) -> CPI = x(DLCO %) x(FVC %) x(FEV1 %) -> CPI = x(DLCO %) x(FVC %) x(FEV1 %) - 6-min walk test(6MWT): ATS/ERS guidelines, 55 patient, oxygen(n=10) - 6-min walk test(6MWT): ATS/ERS guidelines, 55 patient, oxygen(n=10)

Methods Statistical analysis - All analyses were performed using STATA statistical software (version - All analyses were performed using STATA statistical software (version 10.0; Stata Corp., College Station, TX, USA). 10.0; Stata Corp., College Station, TX, USA). - Group comparisons: unpaired t-test or Wilcoxon’s rank-sum test - Group comparisons: unpaired t-test or Wilcoxon’s rank-sum test - overall mortality: cox regression - overall mortality: cox regression - death within the first year: logistic regression - death within the first year: logistic regression - categorical variables: Kaplan- Meier curves - categorical variables: Kaplan- Meier curves - identifiy significant difference between categories: log-rank test - identifiy significant difference between categories: log-rank test - univariate relationship : Pearson’s or Spearman’s rank correlation test - univariate relationship : Pearson’s or Spearman’s rank correlation test - BNP thresholds: presence of PH and moderate-severe PH with Chi- - BNP thresholds: presence of PH and moderate-severe PH with Chi- squared test ( p-value <0.05, statistically significant) squared test ( p-value <0.05, statistically significant)

Results

Baseline characteristics

Correlation of BNP to parameter of pul. vascular impairment

Kaplan-Meier survival curve BNP < 20 pmol.L-1 BNP > 20 pmol.L-1 Without moderate-severe PH Moderate-severe PH

Overall vs 1yr survival

Baseline parameters characterised by BNP

Disscusion The prognostic value of BNP and echocardiography over the ILD population as a whole, independent of underlying disease severity. -> elevated BNP concentration and RVSP level-> increased motality -> elevated BNP concentration and RVSP level-> increased motality In advanced ILD there appears to be a final common pathway ->pulmonary vasculopathy has important prognostic implication across ->pulmonary vasculopathy has important prognostic implication across ILD, and may contribute to the final common pathway in ILD patient ILD, and may contribute to the final common pathway in ILD patient Raised BNP was associated with markers of Rt. Heart dysfunction -> elevated BNP may be a marker of early pulmonary vascular -> elevated BNP may be a marker of early pulmonary vascular impairment impairment

limitation Chose to study ILD in general, rather than an individual ILD subgroup Limited by its retrospective design and patient selection - wide range of disease severity - wide range of disease severity - focus: clinical suspicion of PH  BNP was performed routinely - focus: clinical suspicion of PH  BNP was performed routinely Construction of a staging system  low subgoup number

Conclusion Elevated BNP concentration and RVSP levels are linked to higher mortality across the ILD population, independent of the severity of the mortality across the ILD population, independent of the severity of the underlying lung fibrosis. underlying lung fibrosis. - BNP ≥ 20 pmol.L-1 & moderate-severe PH on echocardiogram - BNP ≥ 20 pmol.L-1 & moderate-severe PH on echocardiogram  increased mortality  increased mortality