Biomarker Profiles in Heart Failure Patients With Preserved and Reduced Ejection Fraction

Abstract

Background: Biomarkers may help us to unravel differences in the underlying pathophysiology between heart failure (HF) patients with a reduced ejection fraction (HFrEF) and a preserved ejection fraction (HFpEF). Therefore, we compared biomarker profiles to characterize pathophysiological differences between patients with HFrEF and HFpEF.

Methods and results: We retrospectively analyzed 33 biomarkers from different pathophysiological domains (inflammation, oxidative stress, remodeling, cardiac stretch, angiogenesis, arteriosclerosis, and renal function) in 460 HF patients (21% HFpEF, left ventricular ejection fraction ≥45%) measured at discharge after hospitalization for acute HF. The association between these markers and the occurrence of all-cause mortality and/or HF-related rehospitalizations at 18 months was compared between patients with HFrEF and HFpEF. Patients were 70.6±11.4 years old and 37.4% were female. Patients with HFpEF were older, more often female, and had a higher systolic blood pressure. Levels of high-sensitive C-reactive protein were significantly higher in HFpEF, while levels of pro-atrial-type natriuretic peptide and N-terminal pro-brain natriuretic peptide were higher in HFrEF. Linear regression followed by network analyses revealed prominent inflammation and angiogenesis-associated interactions in HFpEF and mainly cardiac stretch-associated interactions in HFrEF. The angiogenesis-specific marker, neuropilin and the remodeling-specific marker, osteopontin were predictive for all-cause mortality and/or HF-related rehospitalizations at 18 months in HFpEF, but not in HFrEF (P for interaction <0.05).

Conclusions: In HFpEF, inflammation and angiogenesis-mediated interactions are predominantly observed, while stretch-mediated interactions are found in HFrEF. The remodeling marker osteopontin and the angiogenesis marker neuropilin predicted outcome in HFpEF, but not in HFrEF.

Keywords: biomarker; heart failure; multimarker; pathophysiology.

Figure 1

Heatmaps depicting correlation between biomarkers in HFrEF (A) and HFpEF (B). Biomarker correlations that did not pass the corrected P‐value (0.05/21) are black. Red entails a negative correlation, green entails a positive correlation. BUN indicates blood urea nitrogen; CRP, C‐reactive protein; EPO, erythropoietin; ESAM, endothelial cell‐selective adhesion molecule; GDF‐15, growth differentiation factor 15; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IL‐6, interleukin 6; MPO, myeloperoxidase; NGAL, neutrophil gelatinase‐associated lipocalin; NT‐proBNP, N‐terminal pro‐brain‐type natriuretic peptide; NT‐proCNP, amino terminal pro‐C‐type natriuretic peptide; PIGR, polymeric immunoglobulin receptor; proANP, pro‐atrial‐type natriuretic peptide; PSAP, prostate‐specific acid phosphatase; RAGE, receptor of advanced glycation end‐products; ST‐2, suppression of tumorigenicity 2; TGF‐β, transforming growth factor β; TNF‐α, tumor necrosis factor α; TNF‐α‐R1a, tumor necrosis factor α receptor 1a; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WAP4C, WAP 4 disulfide core domain protein.

Figure 2

Network analysis depicting associations between biomarkers in HFrEF (A) and HFpEF (B). Associations shown are those that passed the P‐value cutoff (0.05/21). Node size and color are based on the clustering coefficient. The edge betweenness was used as a criterion for the edges. BUN indicates blood urea nitrogen; CRP, C‐reactive protein; EPO, erythropoietin; ESAM, endothelial cell‐selective adhesion molecule; GDF‐15, growth differentiation factor 15; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IL‐6, interleukin 6; MPO, myeloperoxidase; NGAL, neutrophil gelatinase‐associated lipocalin; NT‐proBNP, N‐terminal pro‐brain‐type natriuretic peptide; NT‐proCNP, amino terminal pro‐C‐type natriuretic peptide; PIGR, polymeric immunoglobulin receptor; proANP, pro‐atrial‐type natriuretic peptide; PSAP, prostate‐specific acid phosphatase; RAGE, receptor of advanced glycation end‐products; ST‐2, suppression of tumorigenicity 2; TGF‐β, transforming growth factor β; TNF‐α, tumor necrosis factor α; TNF‐α‐R1a, tumor necrosis factor α receptor 1a; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WAP4C, WAP 4 disulfide core domain protein.

Figure 3

Kaplan–Meier curves depicting the relationship with outcome of osteopontin in tertiles, stratified to HFrEF and HFpEF. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Figure 4

Kaplan–Meier curves depicting the relationship with outcome of neuropilin in tertiles, stratified to HFrEF and HFpEF. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.