Crosstalk between the heart and peripheral organs in heart failure

Abstract

Mediators from peripheral tissues can influence the development and progression of heart failure (HF). For example, in obesity, an altered profile of adipokines secreted from adipose tissue increases the incidence of myocardial infarction (MI). Less appreciated is that heart remodeling releases cardiokines, which can strongly impact various peripheral tissues. Inflammation, and, in particular, activation of the nucleotide-binding oligomerization domain-like receptors with pyrin domain (NLRP3) inflammasome are likely to have a central role in cardiac remodeling and mediating crosstalk with other organs. Activation of the NLRP3 inflammasome in response to cardiac injury induces the production and secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18. In addition to having local effects in the myocardium, these pro-inflammatory cytokines are released into circulation and cause remodeling in the spleen, kidney, skeletal muscle and adipose tissue. The collective effects of various cardiokines on peripheral organs depend on the degree and duration of myocardial injury, with systematic inflammation and peripheral tissue damage observed as HF progresses. In this article, we review mechanisms regulating myocardial inflammation in HF and the role of factors secreted by the heart in communication with peripheral tissues.

Figure 1

Mechanisms of NLRP3 inflammasome activation in heart failure. Myocardial infarction (MI), ischemia or ischemia/reperfusion (I/R) injury induces cardiomyocytes to release ROS, ATP and mtDNA. ROS mediates autocrine and paracrine activation and nuclear translocation of NF-κB, which regulates the transcription of pro-IL-1β and pro-IL-18. mtDNA directly primes NLRP3 and ATP via binding to P2X₇ receptors and leads to potassium efflux, a trigger for the assembly of NLRP3 inflammasome. These collective effects result in activation of the NLRP3 inflammasome-associated caspase-1, which processes pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18 and can exacerbate local inflammation. It can also be released into circulation to mediate endocrine effects. ATP, adenosine triphosphate; IL, interleukin; mtDNA, mitochondrial DNA; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NLR family, pyrin domain containing 3; ROS, reactive oxygen species; K⁺, potassium.

Figure 2

Crosstalk mechanisms in the cardio-splenic axis in heart failure, and their functional consequences on peripheral tissues. In acute myocardial infarction (MI), splenocytes (splenic monocytes/macrophages and dendritic cells) migrate to the heart and mediate protective effects during the inflammatory response. In chronic MI, cardiokines induce dramatic changes in the spleen, such that splenocytes develop inflammatory profiles. This exacerbates existing inflammation in the heart and promotes adverse cardiac remodeling leading to cardiac dysfunction. Inflammatory splenocytes also lead to peripheral organ damage. For example, kidney inflammation results in enhanced activation of the renin-angiotensin system (RAS) and release of lipocalin-2. In vasculature, inflammation results in adverse alterations in vascular tone and vascular cell proliferation. Skeletal muscle is also strongly affected by heart failure, at least in part via inflammation resulting in cellular changes, such as sphingosine accumulation and muscle wasting. In adipose tissue, inflammation results in reduced adiponectin levels and further increased levels of pro-inflammatory adipokines (IL-6, MCP-1, IL-10). IL, interleukin; MCP-1, monocyte chemotactic protein 1.