The crosstalk between immune activation and metabolism in heart failure. A scientific statement of the Heart Failure Association of the ESC

Abstract

A better understanding of additional mechanisms of heart failure (HF) progression may allow a different and more complete phenotyping of the disease and identification of novel therapeutic targets. Persistent latent myocardial inflammation/immune activation in HF may represent an attempt to restore tissue homeostasis in the failing heart, where cardiomyocytes and immune cells undergo metabolic reprogramming, which allows them to deal with decreased availability of nutrients and oxygen. This status can trigger a metabolic crosstalk between immune cells and cardiomyocytes which, depending on the outcome, can either perpetuate the maladaptive remodelling of the heart, or determine an adaptive response. Therefore, the interplay between immune activation and metabolism is gaining recognition as a potential therapeutic framework. On these premises, future studies addressing novel HF treatments should attempt to evaluate the potential therapeutic role of direct metabolic and immunological crosstalk modulation. The aim of the present scientific statement from the Heart Failure Association of the ESC is to summarize the current evidence for the connection between inflammatory and immune activation and metabolic adaptation in the onset and progression of HF, in order to promote future strategies for the development of targeted-disease preventive and therapeutic measures.

Keywords: Aging; Heart failure; Immunometabolism; Inflammation; Maladaptive; Myocardial Metabolism; Therapy.

Figure 1

Cardiac energy metabolism in heart failure with reduced ejection fraction (HFrEF). Mitochondrial fatty acid oxidation, glucose oxidation, ketone oxidation, lactate oxidation and amino acid oxidation are the main sources of adenosine triphosphate (ATP) production in the heart. Cytoplasmic glycolysis is also a source of ATP production. In HFrEF, overall mitochondrial oxidative metabolism and ATP production is decreased, with glucose oxidation being markedly impaired. Fatty acid oxidation can also decrease as the severity of heart failure increases, or increase in settings such as obesity. In contrast, both glycolysis and ketone oxidation increase in HFrEF. Red arrows indicate direction of change in HFrEF. Blue text indicates the relative contribution of the various metabolic pathways to ATP production. ADP, adenosine diphosphate; NADH, nicotinamide adenine dinucleotide; TCA, tricarboxylic acid.

Figure 2

Immunological changes in heart failure. Myocardial injury can trigger the pathological process leading to heart failure involving multiple mechanisms. Indeed, the classical neurohormonal activation mediated by the circulatory and mechanical stress is paired with immunometabolic changes which flow in a state of persistent inflammation. The process is mediated by the activation of both adaptive and innate immunity and their interaction. The maladaptive remodelling of the heart resulting from the negative effects of each of the involved mechanisms is characterized by several alterations in cellular functions and a pro‐fibrotic state. ECM, extracellular matrix; NOD, nucleotide‐binding oligomerization domain‐like; TLR, Toll‐like receptor.

Figure 3

Adaptive role of immunity and interplay between metabolism and inflammation in heart failure. Inflammation plays a significant role in the pathophysiology of heart failure, acting both as a potentially adaptive response (blue lines) and as a contributor to disease progression (violet lines). Heart failure is both driven by and exacerbates a state of chronic inflammation, characterized by elevated levels of inflammatory cytokines, which are involved in recruiting immune cells to sites of injury, helping the removal of dead cells and promoting tissue repair and remodelling. Inflammatory signals can also stimulate angiogenesis. Additionally, inflammation contributes to the structural and functional remodelling of the heart in response to injury or stress by promoting adaptive cardiac hypertrophy. Finally, inflammatory cytokines are involved in remodelling the extracellular matrix of the heart by regulation of matrix metalloproteinases. Activated immune cells, such as macrophages and T cells, shift their metabolism towards glycolysis. This metabolic shift supports rapid proliferation and function of immune cells, promoting their activation and prolonging the adaptive inflammatory response. Inflammatory signals can also contribute to energy metabolism modification in cardiac cells to meet the increased energy demands during stress. This includes a shift from fatty acid oxidation to glucose utilization, which is a more efficient metabolic pathway, especially under ischaemic conditions. Inflammatory cytokines can activate the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS) which help to maintain blood pressure and perfusion of vital organs. Brown lines represent functions with conflicting or unclear evidence. While inflammation serves adaptive purposes, chronic and excessive inflammation can become maladaptive, contributing to the progression of heart failure. Persistent inflammation can lead to continuous cardiac remodelling, myocyte apoptosis and drive systemic effects contributing to cachexia and worsening overall health.

Figure 4

Cardiac ageing. The principal characteristic of cardiac ageing is a decreased tissue capacity for recovery and regeneration, and development of cardiac fibrosis and heart failure. A possible sequence of events could be initiated by a decline in mitochondrial function and accumulation of dysfunctional mitochondria producing and accumulating reactive oxygen species (ROS) that, in turn, could give rise to accumulation of damaged DNA as well as mitochondrial DNA damage and release. Additionally, mitochondrial dysfunction contributes to telomere shortening. The immune system is highly sensitive to shortening of telomeres as its competence depends on cell renewal and clonal expansion of T‐ and B‐cell populations. These effects drive immunosenescence and consequent inflammasome activation. In fact, the vicious circle between mitochondrial dysfunction and DNA damage can lead to a state of chronic low‐grade inflammation. Additionally, ROS could increase the release of mitochondrial DNA from the cellular cytosol, becoming a driver of inflammatory responses. In this context, preservation of mitochondrial morphology, dynamics, and function might be a main therapeutic approach to prevent cardiac ageing.

Figure 5

Targeting other sources of inflammation. Statins exert several beneficial pleiotropic effects in the vasculature and cardiac tissue. Obese visceral adipose tissue and epicardial adipose tissue promote pro‐inflammatory and lipid‐associated pathological effects as well as pro‐fibrotic actions, negatively impacting on cardiomyocyte function and survival as well as on cardiac fibrosis. Statins and several other established (in part non‐cardiac) and experimental pharmacological treatments inhibit these negative effects, positively influencing immunometabolism of the heart. ATGL, adipose triglyceride lipase; GLP1‐RA, glucagon‐like peptide‐1 receptor agonist; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor.