Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets

Abstract

Inflammation has been recognized as a major pathophysiological contributor to the entire spectrum of human heart failure (HF), including HF with reduced ejection fraction, HF with preserved ejection fraction, acute HF and cardiogenic shock. Nevertheless, the results of several trials attempting anti-inflammatory strategies in HF patients have not been consistent or motivating and the clinical implementation of anti-inflammatory treatments for HF still requires larger and longer trials, as well as novel and/or more specific drugs. The present work reviews the different inflammatory mechanisms contributing to each type of HF, the major inflammatory mediators involved, namely tumor necrosis factor alpha, the interleukins 1, 6, 8, 10, 18, and 33, C-reactive protein and the enzymes myeloperoxidase and inducible nitric oxide synthase, and their effects on heart function. Furthermore, several trials targeting these mediators or involving other anti-inflammatory treatments in human HF are also described and analyzed. Future therapeutic advances will likely involve tailored anti-inflammatory treatments according to the patient's inflammatory profile, as well as the development of resolution pharmacology aimed at stimulating resolution of inflammation pathways in HF.

Keywords: acute heart failure (AHF); anti-inflammatory strategies; cardiogenic shock (CS); chronic heart failure (CHF); clinical trials; inflammation; inflammatory mediators.

FIGURE 1

Effects of major cytokines contributing to heart failure pathophysiology. DNA, deoxyribonucleic acid; ENaC, epithelial sodium channel; ET-1, endothelin-1; ICAM-1, intercellular adhesion molecule 1; IFN-γ, interferon gamma; IL-1, interleukin 1; IL-1β, interleukin 1 beta; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; IL-18, interleukin 18; IL-33, interleukin 33; NO, nitric oxide; NOS, nitric oxide synthase; iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; SERCA2, sarcoplasmic/endoplasmic reticulum calcium ATPase 2; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1; VSMCs, vascular smooth muscle cells.

FIGURE 2

Effects of other important inflammatory mediators contributing to heart failure pathophysiology. CRP, C-reactive protein; CS, cardiogenic shock; ET-1, endothelin-1; iNOS, inducible nitric oxide synthase; LDL, low density lipoprotein; MCP-1, monocyte chemoattractant protein-1; MPO, myeloperoxidase; NO, nitric oxide; NOS, nitric oxide synthase; PAI-1, plasminogen activator inhibitor 1; VSMCs, vascular smooth muscle cells.