Pro-Inflammatory Biomarkers in Stable Versus Acutely Decompensated Heart Failure With Preserved Ejection Fraction

Abstract

Background: Underlying inflammation has been increasingly recognized in heart failure with a preserved ejection fraction (HFpEF). In this study we tested the hypothesis that pro-inflammatory biomarkers are elevated in patients with acutely decompensated HFpEF (AD-HFpEF) compared with patients with stable HFpEF (S-HFpEF).

Methods and results: Using a post hoc analysis the serum biomarkers tumor necrosis factor-alpha, high-sensitivity C-reactive protein interleukin 6 and pentraxin 3 (PTX3) and clinical, demographic, echocardiographic-Doppler and clinical outcomes data were analyzed in HFpEF patients enrolled in NHLBI Heart Failure Research Network clinical trials which enrolled patients with either AD-HFpEF or S-HFpEF. Compared to S-HFpEF, AD-HFpEF patients had higher levels of PTX3 (3.08 ng/mL versus 1.27 ng/mL, P<0.0001), interleukin-6 (4.14 pg/mL versus 1.71 pg/mL, P<0.0001), tumor necrosis factor-alpha (11.54 pg/mL versus 8.62 pg/mL, P=0.0015), and high-sensitivity C-reactive protein (11.90 mg/dL versus 3.42 mg/dL, P<0.0001). Moreover, high-sensitivity C-reactive protein, interleukin-6 and PTX3 levels were significantly higher in AD-HFpEF compared with S-HFpEF patients admitted for decompensated HF within the previous year. PTX3 was positively correlated with left atrial volume index (r=0.41, P=0.0017) and left ventricular mass (r=0.26, P=0.0415), while tumor necrosis factor-alpha was inversely correlated with E/A ratio (r=-0.31, P=0.0395).

Conclusions: Levels of pro-inflammatory biomarkers are strikingly higher in AD-HFpEF compared with S-HFpEF patients. PTX3 and tumor necrosis factor-alpha are correlated with echocardiographic-Doppler evidence of diastolic dysfunction. Taken together these data support the concept that a heightened pro-inflammatory state has a pathophysiologic role in the development of AD-HFpEF.

Keywords: biomarker; decompensated heart failure; diastolic dysfunction; diastolic heart failure; ejection fraction; heart failure; pro‐inflammatory biomarkers.

Figure 1

A, Box and whisker plots of median (solid lines within boxes) and interquartile ranges for pro‐inflammatory biomarkers in S‐HFpEF (RELAX) versus AD‐HFpEF (DOSE and ROSE) patients. Whiskers=ranges from bottom to top 25% of data values, excluding outliers. The latter are shown individually above the whiskers. Small circles and+signs within boxes=mean values. B, Box and whisker plots of pro‐inflammatory biomarkers for S‐HFpEF patients with a HF admission in the prior year versus other S‐HFpEF patients. C, Box and whisker plots of pro‐inflammatory biomarkers for all AD‐HFpEF patients versus S‐HFpEF patients with a HF admission during the prior year. AD‐HFpEF indicates acutely decompensated heart failure with a preserved ejection fraction; DOSE, Diuretic Strategies in Patients With Acute Decompensated Heart Failure; HFpEF, heart failure with a preserved ejection fraction; hs‐CRP indicates high‐sensitivity C‐reactive protein; IL‐6, interleukin 6; PTX3, pentraxin 3; RELAX, Effect of Phosphodiesterase‐5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction; ROSE, Renal Optimization Strategies Evaluation; TNF‐A, tumor necrosis factor‐α (see text).