C-Reactive Protein and N-Terminal Pro-brain Natriuretic Peptide Levels Correlate With Impaired Cardiorespiratory Fitness in Patients With Heart Failure Across a Wide Range of Ejection Fraction

Abstract

Background: Impaired cardiorespiratory fitness (CRF) is a hallmark of heart failure (HF). Serum levels of C-reactive protein (CRP), a systemic inflammatory marker, and of N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of myocardial strain, independently predict adverse outcomes in HF patients. Whether CRP and/or NT-proBNP also predict the degree of CRF impairment in HF patients across a wide range of ejection fraction is not yet established. Methods: Using retrospective analysis, 200 patients with symptomatic HF who completed one or more treadmill cardiopulmonary exercise tests (CPX) using a symptom-limited ramp protocol and had paired measurements of serum high-sensitivity CRP and NT-proBNP on the same day were evaluated. Univariate and multivariate correlations were evaluated with linear regression after logarithmic transformation of CRP (log₁₀) and NT-proBNP (log_N). Results: Mean age of patients was 57 ± 10 years and 55% were male. Median CRP levels were 3.7 [1.5-9.0] mg/L, and NT-proBNP levels were 377 [106-1,464] pg/ml, respectively. Mean peak oxygen consumption (peak VO₂) was 16 ± 4 mlO₂•kg^-1•min^-1. CRP levels significantly correlated with peakVO₂ in all patients (R = -0.350, p < 0.001) and also separately in the subgroup of patients with reduced left ventricular ejection fraction (LVEF) (HFrEF, N = 109) (R = -0.282, p < 0.001) and in those with preserved EF (HFpEF, N = 57) (R = -0.459, p < 0.001). NT-proBNP levels also significantly correlated with peak VO₂ in all patients (R = -0.330, p < 0.001) and separately in patients with HFrEF (R = -0.342, p < 0.001) and HFpEF (R = -0.275, p = 0.032). CRP and NT-proBNP did not correlate with each other (R = 0.05, p = 0.426), but independently predicted peak VO₂ (R = 0.421, p < 0.001 and p < 0.001, respectively). Conclusions: Biomarkers of inflammation and myocardial strain independently predict peak VO₂ in HF patients. Anti-inflammatory therapies and therapies alleviating myocardial strain may independently improve CRF in HF patients across a large spectrum of LVEF.

Keywords: biomarker; cardiopulmonary exercise testing; cardiorespiratory fitness; heart failure; myocardial strain; systemic inflammation.

Figure 1

Distribution of LVEF, CRP, and NT-proBNP levels in the population. Histogram showing the distribution of (A) LVEF, (B) CRP levels, and (C) NT-proBNP levels in the population. LVEF, Left Ventricular Ejection Fraction.

Figure 2

CRP as predictor of CRF in HFrEF and HFpEF. Correlations are shown in (A) between CRP and Peak VO₂ in patients with HFpEF (R = −0.459, P < 0.001) and with HFrEF (R = −0.282, P < 0.001) and in (B) between CRP and TET in patients with HFpEF (R = −0.345, P < 0.001) and with HFrEF (R = −0.336, P < 0.001). VO₂, Oxygen uptake; HFpEF, Heart Failure with preserved Ejection Fraction; HFrEF, Heart Failure with reduced Ejection Fraction; TET, Treadmill Exercise Time.

Figure 3

NT-proBNP as predictor of CRF in HFrEF and HFpEF. Correlations are shown in (A) between NT-proBNP and Peak VO₂ in patients with HFpEF (R = −0.275, P = 0.032) and with HFrEF (R = −0.354, P < 0.001) and in (B) between NT-proBNP and TET in patients with HFpEF (R = −0.459, P < 0.001) and with HFrEF (R = −0.437, P < 0.001). VO₂, oxygen uptake; HFpEF, Heart Failure with preserved Ejection Fraction; HFrEF, Heart Failure with reduced Ejection Fraction; TET, Treadmill Exercise Time.

Figure 4

Discriminative value of CRP and NT-proBNP for reduced CRF. ROC curves depicting the discriminative value of CRP in (A) and of NT-proBNP in (B) for reduced CRF defined as Peak VO₂ <10 mlO₂•kg⁻¹•min⁻¹(AUC = 0.660, P = 0.014 for CRP and AUC = 0.749, P < 0.001 for NT-proBNP). ROC curves depicting the discriminative value of CRP in (C) and NT-proBNP in (D) for reduced CRF defined as Peak VO₂ <14 mlO₂•kg⁻¹•min⁻¹ (AUC = 0.658, P < 0.001 for CRP and AUC = 0.608, P = 0.003 for NT-proBNP). ROC, Receiver operating characteristic; CRF, Cardiorespiratory Fitness; VO₂, oxygen uptake; AUC. Area Under the Curve.