Inflammatory pathways in heart failure with preserved left ventricular ejection fraction: implications for future interventions

Abstract

Many patients with symptoms and signs of heart failure have a left ventricular ejection fraction ≥50%, termed heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous syndrome mainly affecting older people who have many other cardiac and non-cardiac conditions that often cast doubt on the origin of symptoms, such as breathlessness, or signs, such as peripheral oedema, rendering them neither sensitive nor specific to the diagnosis of HFpEF. Currently, management of HFpEF is mainly directed at controlling symptoms and treating comorbid conditions such as hypertension, atrial fibrillation, anaemia, and coronary artery disease. HFpEF is also characterized by a persistent increase in inflammatory biomarkers. Inflammation may be a key driver of the development and progression of HFpEF and many of its associated comorbidities. Detailed characterization of specific inflammatory pathways may provide insights into the pathophysiology of HFpEF and guide its future management. There is growing interest in novel therapies specifically designed to target deregulated inflammation in many therapeutic areas, including cardiovascular disease. However, large-scale clinical trials investigating the effectiveness of anti-inflammatory treatments in HFpEF are still lacking. In this manuscript, we review the role of inflammation in HFpEF and the possible implications for future trials.

Keywords: Cardiovascular; Epidemiology; Global; Hypertension; International.

Graphical Abstract

The comorbidity-inflammation paradigm in heart failure with preserved ejection fraction (HFpEF). Unhealthy ageing and highly prevalent comorbidities induce a chronic, low-grade, systemic inflammatory state, which drives the progression from healthy myocardium towards HFpEF. CKD, chronic kidney disease; CMD, coronary microvascular dysfunction; COPD, chronic obstructive pulmonary disease; HFpEF, heart failure with preserved ejection fraction; IBD, inflammatory bowel disease; T2DM, Type 2 diabetes mellitus.

Figure 1

The inflammatory pathways. Chronic, low-grade systemic inflammation activates nucleotide oligomerization domain-like receptor family, pyrin domain-containing (NLRP3) inflammasome, leading to the cleavage and activation of pro-inflammatory cytokines. Inflammation also promotes endothelial dysfunction, atherosclerosis, and vascular injury. All these alterations may contribute to the development of heart failure with preserved ejection fraction (HFpEF). CMD, coronary microvascular dysfunction; eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule-1; IL-1β, interleukin-1β; IL-6, interleukin-6; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; TNF-a, tumour necrosis factor-a; VCAM, vascular cell adhesion molecule; VSMC, vascular smooth muscle cell.

Figure 2

Clinical trials targeting inflammatory pathways in patients with heart failure. Many different biochemical pathways are involved in inflammation-driven heart injury and can be targeted at different levels. Drugs are in bold, while clinical trials are in italics (trials that included patients with HFpEF are marked blue). ‘*’ denotes trials/studies that met their primary endpoint. BET, bromodomain and extra-terminal motif; CCL2, C–C chemokine ligand 2; CCR2, C–C chemokine receptor Type 2; cGMP, cyclic guanosine monophosphate; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate; HFpEF, heart failure with preserved ejection fraction; IL-1β-R, interleukin-1β receptor; MPO, myeloperoxidase; NLRP3, nucleotide oligomerization domain-like receptor family, pyrin domain-containing; NO, nitric oxide; PDE5, phosphodiesterase-5; sGC, soluble guanylate cyclase; TNFR, tumour necrosis factor receptor.