The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

Abstract

Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.

Keywords: Autoimmune cardiomyopathy; Diabetic cardiomyopathy; Genetic cardiomyopathy; Hypertensive cardiomyopathy; Immune system; Ischaemic cardiomyopathy; Macrophage; Peripartum cardiomyopathy; T-cell; Toxic cardiomyopathy; Viral cardiomyopathy.

Figure 1

Interaction between select neurohormonal systems and components of innate immunity. Casp‐1, caspase‐1; CLR, C‐type lectin receptor; DAMP, danger‐associated molecular pattern; ECM, extracellular matrix; HF, heart failure; HSP, heat‐shock protein; IL, interleukin; NLR, NOD‐like receptor; PAMP, pathogen‐associated molecular pattern; TLR, Toll‐like receptor; TNF, tumour necrosis factor.

Figure 2

Role of natriuretic peptides in the innate immune system, showing its anti‐inflammatory actions in neutrophils (A, yellow) and in macrophages (B, blue). (A) Recent data have suggested that the anti‐inflammatory effect of B‐type natriuretic peptide (BNP) is attenuated in acute heart failure patients. (B, left section) In ischaemia/reperfusion, post‐conditioning of BNP protects against myocardial injury. (B, middle section) The lipopolysaccharide (LPS)‐induced expression of tumour necrosis factor (TNF)‐α and inducible nitric oxide synthase (iNOS) is inhibited by atrial natriuretic peptide (ANP). (B, right section) C‐type natriuretic peptide receptors (NPR‐C) or clearance receptors are coupled to adenylyl cyclase inhibition through a subsequent decrease in intracellular levels of cyclic adenosine monophosphate (cAMP) and/or to phospholipase C (PLC) activation. Akt, protein kinase B; AP1, activator protein 1; ANP, atrial natriuretic peptide; ATP, adenosine triphosphate; CNP, C‐type natriuretic peptide; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; HF, heart failure; HMGB1, high mobility group box 1 protein; IL, interleukin; NF‐κB, nuclear factor kappa B; NO, nitric oxide; NPR‐A, atrial natriuretic peptide receptor; NPR‐B, B‐type natriuretic peptide receptor; O₂ ^‐, superoxide; PI3K, phosphoinositide 3‐kinase.

Figure 3

Immune activation in different heart failure aetiologies. (A) The impact of systemic inflammation on the progression of heart failure with preserved ejection fraction (HFpEF). (B) The immune mechanisms associated with myocardial infarction as an example of heart failure with reduced ejection fraction. NF‐κB, nuclear factor kappa B.

Figure 4

Immune mechanisms in different phases in ischaemic, toxic cardiomyopathy and viral myocarditis. DAMP, danger‐associated molecular pattern; DCM, dilated cardiomyopathy; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species; TLR, Toll‐like receptor; TNF, tumour necrosis factor.