Chronic low-grade inflammation in heart failure with preserved ejection fraction

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently the predominant form of HF with a dramatic increase in risk with age. Low-grade inflammation, as occurs with aging (termed "inflammaging"), is a common feature of HFpEF pathology. Suppression of proinflammatory pathways has been associated with attenuated HFpEF disease severity and better outcomes. From this perspective, inflammasome signaling plays a central role in mediating chronic inflammation and cardiovascular disease progression. However, the causal link between the inflammasome-immune signaling axis on the age-dependent progression of HFpEF remains conjectural. In this review, we summarize the current understanding of the role of inflammatory pathways in age-dependent cardiac function decline. We will also evaluate recent advances and evidence regarding the inflammatory pathway in the pathophysiology of HFpEF, with special attention to inflammasome signaling.

Keywords: aging; arrhythmias; diastolic dysfunction; fibrosis; heart failure with preserved ejection fraction; inflammasome; inflammation.

FIGURE 1

Epidemiological prevalence of HFpEF and HFrEF by age and sex. Increasing prevalence of heart failure with preserved ejection fraction (HFpEF, a) and reduced ejection fraction (HFrEF, b) with age in both sexes. Reproduced with permission from (Ceia et al., 2002). Copyright © 1999–2021, John Wiley & Sons

FIGURE 2

NLRP3 inflammasome priming and activation. The priming signaling occurs by the activation of cytokines, damage‐associated molecular patterns (DAMPs), or pathogen‐associated molecular patterns (PAMPs), leading to the transcriptional activity of nuclear factor (NF)‐κB and upregulation of inflammasome components and cytokines (IL‐1β and IL‐18). Priming signals activate a complex cascade of events including potassium (K⁺) efflux, endoplasmic reticulum, and mitochondrial stress (Activation signaling). Activation of the NLRP3 inflammasome complex involves NLRP3 oligomerization, ASC polymerization, and recruitment of pro‐caspase‐1. Active NLRP3 inflammasome complex and pro‐caspase‐1 cleave pro‐IL‐1β and pro‐IL‐18 into the active forms, IL‐1β and pro‐IL‐18. Gasdermin D (GSDMD) is also cleaved (GSDMD^Nterm) forming pores and inducing pyroptosis. Cleavage of GSDMD also occurs via the non‐canonical pyroptosis pathway upon activation of caspases‐4/‐5/‐11 by cytosolic lipopolysaccharide (LPS). ASC, apoptosis‐associated speck‐like protein containing a CARD; GSDMD^Nterm, GSDMD amino‐terminal cell death domain; IFN, interferon; IFNR, interferon α/β receptor; IL‐1R1, interleukin‐1 receptor type 1; IL‐1β, interleukin 1β; NLRP3, NACHT, LRR, and PYD domains‐containing protein 3; ROS, reactive oxygen species; TLR, Toll‐like receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor. This figure was created in part with modified Servier Medical Art templates

FIGURE 3

Influential chronic low‐grade inflammasome in the development of HFpEF comorbidities. The collective impact of systemic inflammation caused by multiorgan dysfunction plays an influential role in HFpEF pathogenesis, which is associated with myocardial stiffness, concentric remodeling, cell death, and arrhythmias. This figure was created in part with modified Servier Medical Art templates

FIGURE 4

Impact of systemic and local inflammation on the pathogenesis of HFpEF. Multiple comorbidities induce a systemic inflammatory state leading to increased circulating levels of proinflammatory factors including interleukins‐6 and ‐1β (IL‐6 and IL‐1β), tumor necrosis factor (TNFα), soluble ST2 (sST2), and pentraxin 3 and upregulation of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and e‐selectin, which promote endothelial dysfunction. Subsequently, neutrophils and monocytes arrive and degranulate to amplify inflammation and oxidative stress. Macrophages arrive later and aid in clearing dead cell debris. As antigen‐presenting cells, they interface with helper T cells which, in the context of HFpEF polarize to TH1 and TH17 proinflammatory phenotypes. These helper T‐cell subsets orchestrate and perpetuate the inflammatory and fibrotic cycle. These events further amplify the dysfunction of endothelial and smooth muscle cells (EC and SMC, respectively), leading to increased production of reactive oxygen species (ROS) and decreased bioavailability of nitric oxide (NO), and consequently, hypertension. Systemic and coronary microvascular inflammation plays a decisive role in cardiac inflammation. A vicious inflammatory cycle is systemically and locally perpetuated to maintain high blood pressure and cardiac dysfunction. This figure was created in part with modified Servier Medical Art templates