Targeting Mediators of Inflammation in Heart Failure: A Short Synthesis of Experimental and Clinical Results

Abstract

Inflammation has emerged as an important contributor to heart failure (HF) development and progression. Current research data highlight the diversity of immune cells, proteins, and signaling pathways involved in the pathogenesis and perpetuation of heart failure. Chronic inflammation is a major cardiovascular risk factor. Proinflammatory signaling molecules in HF initiate vicious cycles altering mitochondrial function and perturbing calcium homeostasis, therefore affecting myocardial contractility. Specific anti-inflammatory treatment represents a novel approach to prevent and slow HF progression. This review provides an update on the putative roles of inflammatory mediators involved in heart failure (tumor necrosis factor-alpha; interleukin 1, 6, 17, 18, 33) and currently available biological and non-biological therapy options targeting the aforementioned mediators and signaling pathways. We also highlight new treatment approaches based on the latest clinical and experimental research.

Keywords: heart failure; inflammation; interleukins; mitochondria; pro-inflammatory cytokines.

Figure 1

Inflammatory pathways trigger cardiomyocyte dysfunction in heart failure. Mitochondrial damage due to excessive mechanical and oxidative stress and decrease in mitochondrial quality control releases oxidized and hypomethylated mtDNA fragments and ATP, which along with other end-products, represent danger signals inside cardiomyocytes. These are perceived by three sensor systems: TLR9, the NLRP3 inflammasome, and the cGAS/STING complex. TLR9 triggers the IKK kinase that inactivates IκB, an inhibitory molecule on the Rel A/p50 complex of NF-κB; consecutively, this translocates to the nucleus. IL-6, TNF-α, and NLRP3 are among the primary target genes transcriptionally regulated by NF-κB. NLRP3 activates caspase-1, generating elevated levels of IL-1β and IL-18. TLR9 receives other activating signals from ligand-binding IL-1 and TNF RI complexes. The latter may also induce caspase-8 and caspase-3 through FADD, sensitizing the cell to apoptosis. IL-1β, IL-6, and TNF-α induce hypertrophy and suppress contractility, perturbing Ca²⁺ homeostasis and reducing myofilament Ca²⁺ sensitivity. When secreted in the extracellular space, they also recruit inflammatory cells together with peroxynitrite radicals generated by excessive activation of iNOS. Several other proinflammatory cytokines interact with critical steps of NF-κB activation, as IL-17 and IL-18 trigger IκB, IL-15 facilitates its nuclear translocation, whereas IL-33 upregulates gene transcription. For these reasons, IL-1β, IL-6, TNF-α, IL-17, IL-18, and IL-33 may all be putative therapeutic targets in heart failure.