Editor’s Choice- Activation of the innate immune system in the pathogenesis of acute heart failure

Acute heart failure syndromes account for more than 950,000 annual emergency department visits in the United States1 and represent a major healthcare burden in western societies.2,3 Virtually all patients with chronic heart failure will experience at some point an acute exacerbation that requires admission to the hospital.4 Despite therapeutic advances, acute heart failure remains a life-threatening condition with a mortality rate in most registries ranging from 4% to 7%. The rate of rehospitalisation is also very high; almost 30% of the patients are readmitted within 3 months following discharge.5 Our limited success in preventing recurrent hospitalisations in patients with heart failure reflects, at least in part, our superficial understanding of the pathophysiological basis for the acute exacerbations. Traditional clinical experience teaches that acute heart failure exacerbations may be triggered by a wide range of precipitating factors, both cardiovascular (such as ischaemia, arrhythmic events, hypertensive crises, etc.) and non-cardiovascular (including infections, anaemia, renal or pulmonary disease and non-compliance with medical treatment or dietary restrictions). Although this perspective remains extremely useful in managing patients with acute heart failure, there is a need to deepen our understanding of the underlying pathophysiological mechanisms, by identifying specific cellular events and molecular signals that may mediate the functional deterioration. Understanding of the mechanistic underpinnings of acute heart failure exacerbations is crucial in order to develop new therapeutic strategies. Prolonged, excessive or dysregulated activation of the immune system has been implicated in the pathogenesis and progression of chronic heart failure.6 The innate immune system has evolved to protect multicellular organisms from pathogens and to initiate a reparative response to ‘danger signals’ following tissue injury. Because the evolutionary pressures that led to the development of innate immune responses were related to protection from pathogenic organisms or traumatic injury, responses to sterile myocardial injury may be excessive for the delicate requirements of the myocardium.7 Thus, in the heart, immune responses triggered by injurious stimuli may perturb the relation between structure and function, leading to catastrophic consequences such as cardiomyocyte death, inflammation and fibrosis. Both experimental studies in animal models and clinical investigations have suggested an important role for innate immune pathways in chronic heart failure. Activation of Toll-like receptors, the central effectors of the innate immune response has been documented in injured and failing hearts and has been suggested to play an important role in cardiac remodelling.8 Another vital component of the innate immune response, the complement system, is composed of more than 30 proteins organised into proteolytic cascades, which are activated in response to the recognition of pathogen-associated molecular patterns, antigen–antibody complexes or danger signals released by injured cells.9 Activation of the complement cascade has been documented in patients with chronic heart failure10,11 and has been suggested to participate in disease progression. Although experimental evidence suggests that activation of inflammatory and immune responses may contribute to the pathogenesis of chronic heart failure, whether innate immunity mediates acute heart failure exacerbations remains unknown. In the current issue of the journal, Trendelenburg and co-workers12 examined the possible link between the activation of innate immunity and acute decompensated heart failure by measuring levels of complement activation products in the peripheral blood of patients admitted with an acute exacerbation of heart failure. The authors found that, when compared with healthy individuals, patients with acute heart failure exhibited increased plasma levels of the complement activation proteins C4d, C3a and sC5b-9. Complement protein levels were significantly higher in individuals with an infectious cause triggering the exacerbation, in comparison to individuals with other precipitating factors. Complement activation did not predict mortality within 2 years after the acute event. The study has several major limitations. First, the control group consisted of healthy individuals and was not adjusted for age or gender or the presence of comorbid conditions that could affect complement levels. Thus, the observed differences in complement activation between acute heart failure patients and control individuals may be due to the presence of comorbidities, or may simply reflect the presence of chronic heart failure. An adjusted control group of individuals with chronic heart failure is needed, in order to test whether acute exacerbations activate the complement cascade. Second, complement protein levels in the peripheral blood may not directly reflect myocardial localisation but may be due to activation of the cascade in other tissues. Third, the activation of innate immune signalling and downstream secretion of pro-inflammatory mediators was not systematically studied. Despite these limitations, the study supports a very attractive concept, suggesting that in some patients with heart failure, activation of innate immune pathways may accompany (and possibly even trigger) an acute exacerbation. Moreover, the findings raise several intriguing questions: Which cellular events are responsible for sudden activation of the innate immune system in patients with chronic heart failure? Does innate immune activation play a causative role, or does it simply represent an epiphenomenon reflecting the systemic consequences of decompensated acute heart failure? If causative links between innate immune activation and acute heart failure do exist, which specific immune-mediated events cause cardiac dysfunction? Does evidence of immune activation identify a subset of patients who may benefit from a brief course of targeted anti-inflammatory intervention? Elevated complement activation proteins in the blood of patients with an acute heart failure exacerbation may reflect myocardial production and activation of complement components in response to injury, or the release of complement proteins due to a systemic condition (such as infection, or systemic inflammatory disease) (Figure 1). Patients with infection as a precipitating factor exhibited the highest levels of complement activation proteins, supporting the potential role of innate immune signalling in this subpopulation. In the myocardium, a wide range of stimuli, including ischaemia and pressure overload may trigger the local synthesis of complement components by cardiomyocytes, vascular endothelial cells or macrophages. Local activation of the complement cascade and deposition of complement components has been documented in the experimental models of myocardial ischaemia.13 Activation of neurohumoral pathways in response to pressure overload may also activate the complement cascade. C5a levels were found to be increased in hypertensive individuals. Moreover, in a mouse model of angiotensin infusion complement activation mediated inflammatory activation.14 Thus, in patients with a hypertensive crisis, the stimulation of neurohumoral signalling may activate the complement cascade in the myocardium contributing to decompensation. Microvascular endothelial cells may be an important site of complement activation in the failing heart. Cytokine stimulation of endothelial cells induces complement activation that is not only bound to the cells, but is also deposited in the subendothelial extracellular matrix.15 The schematic illustration proposes a cell biological paradigm for the potential involvement of complement activation in acute heart failure. In patients with chronic heart failure precipitating factors such as infection, ischaemia or pressure overload may trigger activation of the complement cascade, contributing to functional decompensation. Activated complement components may stimulate a pro-inflammatory programme in cardiac microvascular endothelial cells (EC), thus promoting inflammatory monocyte (Mo) recruitment, may induce cytokine expression in macrophages (Ma), and may trigger degranulation and cytokine production in cardiac mast cells (MC). C5a stimulation of cardiomyocytes (CM) may suppress contractile function and stimulate the synthesis of pro-inflammatory cytokines. Activation of a pro-inflammatory environment in the myocardium may overwhelm the limited functional reserve of patients with chronic heart failure causing an acute exacerbation. Considering the pathophysiological heterogeneity of acute heart failure, elevated circulating complement activation proteins may identify a patient subpopulation with immune-mediated decompensation who may benefit from brief and targeted anti-inflammatory interventions (such as interleukin (IL)-1 blockade). TNF: tumour necrosis factor In host defence, complement actions are mediated through three broad effector limbs: (a) assembly of the membrane attack complex and subsequent lysis of the targeted pathogen; (b) opsonisation of the target, leading to phagocytosis by macrophages and neutrophils; and (c) activation of pro-inflammatory cascades. In patients with heart failure, complement activation may play an important role in triggering systolic dysfunction by stimulating the secretion of pro-inflammatory cytokines that suppress contractile function, such as tumour necrosis factor (TNF)-α and interleukin (IL)-1β. Complement may stimulate several myocardial cell types, including cardiomyocytes, microvascular endothelial cells, cardiac macrophages and mast cells (Figure 1).16 In macrophages, C5a is known to induce pro-inflammatory cytokine synthesis.17 In mast cells, C3a and C5a may trigger degranulation and promote the release of chemokines and TNF-α.18,19 Endothelial cells respond to C5a by increasing the expression of adhesion molecules, chemokines, cytokines and chemokine receptors;20 these effects may promote local inflammation. In cardiomyocytes, complement-mediated signalling may stimulate cytokine expression and cause contractile dysfunction.21 Due to their limited functional reserve, patients with chronic heart failure may be particularly susceptible to modest elevations in activated complement components and may respond with significant suppression of contractile function. In chronic heart failure, elevations in complement proteins identified a subpopulation with a higher incidence of adverse events.22 In the current study, complement proteins did not predict death within 2 years, failing to support a role for complement activation as a prognostic biomarker in patients with decompensated heart failure. However, assessment of complement activation may serve as a valuable tool for pathophysiological stratification of heart failure patients, by distinguishing acute episodes of inflammation-driven decompensation, or by identifying patient subpopulations susceptible to recurrent immune-mediated heart failure exacerbations. Such insights may have important therapeutic implications, identifying patients who may benefit from a brief course of targeted anti-inflammatory therapy. A recent study demonstrated that IL-1 blockade with anakinra reduced C-reactive protein levels in patients with acute decompensated heart failure,23 suggesting effective inhibition of inflammatory signalling. Whether brief inhibition of the innate immune response is beneficial in subsets of patients with acute heart failure has not been tested. Effective treatment of complex cardiovascular conditions, such as heart failure, is hampered by their pathophysiological heterogeneity.24 The expanding use of relevant biomarkers and sophisticated imaging strategies will allow us to stratify patients on the basis of underlying pathophysiological perturbations, providing the basis for mechanism-driven therapy. The author declares that there is no conflict of interest. The author’s laboratory is supported by grants from the National Institutes of Health (R01 HL76246 and R01 HL85440), and the US Department of Defense (PR151134 and PR151029).