Elevated N-terminal pro-brain natriuretic peptide is associated with mortality in tobacco smokers independent of airflow obstruction

Abstract

Background: Tobacco use is associated with an increased prevalence of cardiovascular disease. N-terminal pro-brain natiuretic peptide (NT-proBNP), a widely available biomarker that is associated with cardiovascular outcomes in other conditions, has not been investigated as a predictor of mortality in tobacco smokers. We hypothesized that NT-proBNP would be an independent prognostic marker in a cohort of well-characterized tobacco smokers without known cardiovascular disease.

Methods: Clinical data from 796 subjects enrolled in two prospective tobacco exposed cohorts was assessed to determine factors associated with elevated NT-proBNP and the relationship of these factors and NT-proBNP with mortality.

Results: Subjects were followed for a median of 562 (IQR 252-826) days. Characteristics associated with a NT-proBNP above the median (≥49 pg/mL) were increased age, female gender, and decreased body mass index. By time-to-event analysis, an NT-proBNP above the median (≥49 pg/mL) was a significant predictor of mortality (log rank p = 0.02). By proportional hazard analysis controlling for age, gender, cohort, and severity of airflow obstruction, an elevated NT-proBNP level (≥49 pg/mL) remained an independent predictor of mortality (HR = 2.19, 95% CI 1.07-4.46, p = 0.031).

Conclusions: Elevated NT-proBNP is an independent predictor of mortality in tobacco smokers without known cardiovascular disease, conferring a 2.2 fold increased risk of death. Future studies should assess the ability of this biomarker to guide further diagnostic testing and to direct specific cardiovascular risk reduction inventions that may positively impact quality of life and survival.

Figure 1. Univariate Survival Analysis.

Kaplan-Meier survival curve of those with High (≥49 pg/mL) (solid line) versus Low (<49 pg/mL) (dashed line) NT-proBNP levels. Log-rank test = 0.02. NT-proBNP = N-terminal pro-brain natriuretic peptide.

Figure 2. Multivariable Survival Analysis.

Forrest plot showing survival hazard ratios. All variables were analyzed independently in a proportional hazard model incorporating group (patient cohort), age, gender, and degree of airflow obstruction (FEV1 percent predicted). Shown are estimated hazard ratio (diamonds) and 95% confidence intervals (whiskers). Due to missing values, the number of individuals differs slightly in each model, as follows: NT-proBNP (n = 779), Low BMI (n = 664), DLCO percent predicted (n = 665), RV/TLC ratio percent predicted (n = 569), mMRC dyspnea score (n = 761). Definitions of abbreviations: BMI = body mass index; DLCO = diffusion capacity for carbon monoxide; mMRC = modified Medical Research Council; NT-proBNP = N-terminal pro brain natriuretic peptide; RV/TLC = residual volume divided by total lung capacity.