Innate immunity and the failing heart: the cytokine hypothesis revisited

Abstract

Elevated levels of inflammatory mediators have been identified in patients with heart failure, including heart failure with reduced and preserved ejection fraction, as well as acute decompensated heart failure. Moreover, experimental studies have shown repeatedly that activation of inflammation in the heart provokes left ventricular remodeling and left ventricular dysfunction. Nonetheless, phase III clinical trials that have attempted to antagonize inflammatory mediators have been negative with respect to the primary end points of the trials, and in some patients, resulted in worsening heart failure or death. The following review will discuss how recent developments in the field of innate immunity have advanced our understanding of the role of inflammation in the pathogenesis of heart failure and will discuss the negative outcomes of the existing clinical trials in light of this new information.

Keywords: clinical trials; heart failure; inflammation; innate immunity.

Figure 1

Damage associated molecular patterns (DAMPs) are derived from dying cells that release their cytosolic content following myocardial injury, from degradation of the extracellular matrix, as well as by immune cells that become activated following tissue injury. (Key: ATP = adenosine triphosphate, HSP = heat shock protein; HMGB1 = high mobility box group 1 protein, IL-1α - interleukin-1α; IL-1R – interleukin receptor NALP = NACHT, LRR and PYD domains-containing protein 3 (cryopyrin); RAGE = receptor for advanced glycation end products, TLR = Toll-like receptor) (Reproduced with permission from Mann DL, The role of innate immunity in heart failure, in Heart Failure: A Companion to Braunwald’s Heart Disease, edited by Mann DL and Felker GM, 2015, pp 109-126. Elsevier/Saunders, Philadelphia, Pennsylvania).

Figure 2

Para-inflammation. The primary purpose of the inflammatory response in the heart is to resolve tissue injury, thereby allowing the heart to adapt to the abnormal conditions in the short-term, and ultimately to restore homeostasis and cardiovascular function in the long-term. If the abnormal condition is sustained, then a chronic inflammatory state persists in a tissue, which is referred to as para-inflammation. Para-inflammation is a graded response that can restore tissue homeostasis, or if sustained can contribute to further disease progression, by virtue of the deleterious effects of sustained inflammation on cardiac myocytes and the extracellular matrix.

Figure 3

Results of the RENAISSANCE, RECOVER AND RENEWAL trials. (A) Analysis of the “clinical status” composite score for the RECOVER and RENAISSANCE trials in the placebo and etanercept groups. (B) Kaplan-Meier analysis of the time to death or heart failure hospitalizations in the placebo and etanercept group (biw and tiw) in the RENEWAL analysis. (Reproduced with permission Mann DL. Activation of inflammatory mediators in heart failure. In: Mann DL, ed. Heart failure: A companion to Braunwald’s heart disease. 2nd ed. Philadelphia: Elsevier/Saunders; 2011. p. 163-84)

Figure 4

Results of the ATTACH trial. A, Kaplan-Meier rates of death and hospitalization for heart failure. B, Kaplan-Meier rates of hospitalization for any reason. (Key: PBO = placebo; HR = hazard ratio). (Reproduced with permission Mann DL. Activation of inflammatory mediators in heart failure. In: Mann DL, ed. Heart failure: A companion to Braunwald’s heart disease. 2nd ed. Philadelphia: Elsevier/Saunders; 2011. p. 163-84)

Figure 5

Biological properties of infliximab. (A) Infliximab (cA2 G1) is cytotoxic for cells that express TNF on their cell membranes (TNF +), whereas it is not cytotoxic for cells that do not express TNF on their membranes (SP2/O). The mechanism for the cytotoxic effects of infliximab was demonstrated using F(ab)2 fragments of infliximab, which lack the Fc domain and therefore cannot fix complement. As shown the F(ab)2 fragment of infliximab was not cytotoxic for TNF + cells. (B) Levels of immunoreactive TNF in patients who received placebo and infliximab (10 mg/kg) are displayed in relation to the circulating levels of infliximab (data are redrawn from figures 2 and 4). The dotted horizontal lines depict the upper and lower limits of the therapeutic window for infliximab. (Reproduced with permission Mann DL. Activation of inflammatory mediators in heart failure. In: Mann DL, ed. Heart failure: A companion to Braunwald’s heart disease. 2nd ed. Philadelphia: Elsevier/Saunders; 2011. p. 163-84)

Figure 6

Potential reasons for neutral/negative results targeting inflammation in heart failure. (A) Inflammation is not in the causal pathway of heart failure; (B) Of several causal pathways of heart failure, anti-inflammatory therapy targets a pathway that contributes to the syndrome of heart failure, but is not directly related to clinical outcomes (i.e., is a disease modifier) ; (C) Of several causal pathways of heart failure, anti-inflammatory therapy targets a pathway that contributes to the clinical outcomes, but has direct side effects that lead to worsening heart failure. (dotted lines = off-target mechanism(s) of action that might exist) (Adapted and modified from Fleming TR, DeMets DL: Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996;125:605-613).