Positioning of inflammatory biomarkers in the heart failure landscape

Abstract

The clinical syndrome of heart failure is characterized by a systemic inflammatory response that contributes to end organ damage in the heart and circulation and can thus lead to worsening heart failure. The ensemble of inflammatory mediators that have been detected in heart failure patients include pro-inflammatory cytokines and their cognate receptors, as well as molecules secreted/released by macrophages (galectin-3 and pentraxin-3). Inflammatory biomarkers correlate with disease severity and prognosis across the broad spectrum of heart failure syndromes. Given the proliferation of new biomarkers that predict disease severity and prognosis in heart failure, it is reasonable to ask whether there is a current role for measuring inflammatory mediators in heart failure. This review will attempt to address this question, as well as review several novel approaches that have utilized inflammatory biomarkers to enhance risk stratification and prognosis in heart failure patients.

Fig. 1

The biology of cytokines and cytokine receptors. Pro-inflammatory cytokines are released by nucleated cell types residing in the heart, including cardiac myocytes. Cytokines exert their biological effects by binding to cognate cytokine receptors on cell membranes (left side of the diagram). Cytokine receptors can be proteolytically cleaved or “shed” from cell membranes, which releases the soluble extracellular ectodomain of the cytokine receptor into the extracellular space and/or circulation (middle of the diagram). Cytokine receptors retain their ability to bind cytokine and to inhibit the biological activities of cytokines by preventing cytokines from binding to cognate receptors on target cells (right side of the diagram)

Fig. 2

Kaplan–Meier survival analysis. The circulating levels of TNF (a), IL-6 (b), sTNFR1 (c), and sTNFR2 (d) were examined in relation to patient survival during follow-up (mean duration, 55 weeks; maximum duration, 78 weeks). For this analysis, the circulating levels of cytokines and cytokine receptors were arbitrarily divided into quartiles. Reproduced with permission from Deswal et al. [4]

Fig. 3

Serial measurements of pro-inflammatory cytokines and pro-inflammatory cytokine receptors in the VEST trial. Receiver operating curves are for three logistic regression models for 1 year mortality in the VEST trial. The three models use standard clinical variables only (no cytokines, C statistic of 0.73), standard variables and baseline cytokines only (C statistic of 0.74), and standard variables and serial cytokine measurements at baseline and 8, 16, and 24 weeks (C statistic of 0.81). Reproduced with permission from Subramanian et al. [33]