Crosstalk between the heart and peripheral organs in heart failure

Abstract

Mediators from peripheral tissues can influence the development and progression of heart failure (HF). For example, in obesity, an altered profile of adipokines secreted from adipose tissue increases the incidence of myocardial infarction (MI). Less appreciated is that heart remodeling releases cardiokines, which can strongly impact various peripheral tissues. Inflammation, and, in particular, activation of the nucleotide-binding oligomerization domain-like receptors with pyrin domain (NLRP3) inflammasome are likely to have a central role in cardiac remodeling and mediating crosstalk with other organs. Activation of the NLRP3 inflammasome in response to cardiac injury induces the production and secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18. In addition to having local effects in the myocardium, these pro-inflammatory cytokines are released into circulation and cause remodeling in the spleen, kidney, skeletal muscle and adipose tissue. The collective effects of various cardiokines on peripheral organs depend on the degree and duration of myocardial injury, with systematic inflammation and peripheral tissue damage observed as HF progresses. In this article, we review mechanisms regulating myocardial inflammation in HF and the role of factors secreted by the heart in communication with peripheral tissues.

Experimental & Molecular Medicine (2016) 48, e217; doi:http://dx.doi.org/10.1038/emm.2016.20

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REVIEW

Crosstalk between the heart and peripheral organs in heart failure

James Won Suk Jahng, Erfei Song and Gary Sweeney

Mediators from peripheral tissues can inuence the development and progression of heart failure (HF). For example, in obesity, an altered prole of adipokines secreted from adipose tissue increases the incidence of myocardial infarction (MI). Less appreciated is that heart remodeling releases cardiokines, which can strongly impact various peripheral tissues. Inammation, and, in particular, activation of the nucleotide-binding oligomerization domain-like receptors with pyrin domain (NLRP3) inammasome are likely to have a central role in cardiac remodeling and mediating crosstalk with other organs. Activation of the NLRP3 inammasome in response to cardiac injury induces the production and secretion of the inammatory cytokines interleukin (IL)-1 and IL-18. In addition to having local effects in the myocardium, these pro-inammatory cytokines are released into circulation and cause remodeling in the spleen, kidney, skeletal muscle and adipose tissue. The collective effects of various cardiokines on peripheral organs depend on the degree and duration of myocardial injury, with systematic inammation and peripheral tissue damage observed as HF progresses. In this article, we review mechanisms regulating myocardial inammation in HF and the role of factors secreted by the heart in communication with peripheral tissues. Experimental & Molecular Medicine (2016) 48, e217; doi:http://dx.doi.org/10.1038/emm.2016.20

Web End =10.1038/emm.2016.20; published online 11 March 2016

INTRODUCTIONHeart failure and the role of inammationCardiovascular diseases are the leading cause of death worldwide, and heart failure (HF) is an important contributor to this statistic.1 When the heart is under stress or injured, it undergoes structural and functional changes termed cardiac remodeling.2 These include cardiac hypertrophy, brosis, apoptosis and altered metabolism.3 When an individual suffers from myocardial ischemia, it is intuitively important to re-perfuse the damaged area and re-establish the supply of blood to the damaged area. However, it has also been realized that some cellular events which occur during reperfusion may lead to worse outcomes, a phenomenon termed myocardial ischemia/reperfusion (I/R) injury.4

The various mechanisms underlying the detrimental effects of ischemia and subsequent reperfusion are complex and are not fully understood. Nevertheless, a number of clinical and animal studies suggest that inammation is a key contributor to adverse myocardial remodeling.4 Broadly speaking, inammation is a wound-healing process mediated by innate immune cells that recognize microbial and non-microbial sources of danger/stress. Inammation triggered in the absence of infection is termed sterile inammation. Multiple studies have highlighted the importance of targeting sterile

inammation in HF.57 Sterile inammation involves the secretion of inammatory cytokines and recruitment of innate immune cells, such as neutrophils and monocytes/ macrophages. However, prolonged exposure to inammatory cytokines will exacerbate adverse remodeling and enhance myocardial damage.8 Importantly, in addition to local adverse effects on cardiac remodeling, ischemia- or I/R-induced inammation in the heart releases pro-inammatory cytokines, such as interleukin (IL)-1 and IL-18, into circulation.

These, and other so-called cardiokines, can have signicant endocrine effects on other tissues, leading to damage in multiple peripheral organs.9 For example, prolonged exposure to IL-1 and IL-18 can lead to caspase-1-dependent cell death via pyroptosis.10,11 Thus, crosstalk from the heart to other tissues can elicit multi-organ damage as a consequence of ischemia-induced inammation.9 This review highlights the current knowledge of inammasome activation in the heart and its consequences on other organs.

Mechanisms regulating cardiac inammation in HF, focus on the NLRP3 inammasomeThe nucleotide-binding oligomerization domain-like receptors with pyrin domain (NLRP3) inammasome is a cytoplasmic protein complex composed of NLRP, apoptosis-associated

Department of Biology, York University, Toronto, ON, Canada

Correspondence: Dr G Sweeney, Department of Biology, York University, Toronto, ON, Canada M3J 1P3.

E-mail: mailto:[email protected]

Web End [email protected]

Received 20 November 2015; revised 10 December 2015; accepted 11 December 2015

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speck-like protein containing CARD (ASC), a caspase recruitment domain and pro-caspase-1.12,13 NLRP is composed

of C-terminal leucine-rich repeats, a central nucleotide domain (NACHT) and N-terminal effector pyrin domain. Upon recognizing patterns, either from a pathogenic source (pathogen-associated molecular patterns) or from a non-pathogenic source (danger/damage-associated molecular patterns, DAMPs), NLRP will recruit ASC, which, in turn, recruits pro-caspase 1, which will then get activated.14

Inammasomes are classied based on NLRPs, which recognize or sense different stimuli.15 The NLRP3

inammasome is the most widely studied to date due to its ability to recognize various cellular stressors and its strong relationship with diseases such as HF.16 The key consequence of inammasome activation is maturation of pro-inammatory cytokines, in particular IL-1 and IL-18. The generation of active forms of IL-1 and IL-18 is regulated at two steps: expression of pro-IL-1 and pro-IL-18 is mediated by nuclear factor kappa-light chain enhancer of activated B cells (NF-B), and processing to the mature form of IL-1 and IL-18 is mediated by active caspase-1 in the inammasome.14

Multiple DAMPs have been found to activate NLRP3 inammasomes, including monosodium urate, calcium phosphate crystals, cholesterol crystals, amyloid , hyaluronan, islet amyloid polypeptide, asbestos and silica.14 However, in

HF, we suggest that mitochondria have a critical role in initiating inammasome activation.17,18 In HF-associated

inammasome activation, the three main triggers are adenosine triphosphate (ATP), mitochondrial DNA (mtDNA), and reactive oxygen species (ROS) (see Figure 1). When cells undergo death they release ATP. Multiple studies have suggested that ATP directly activates the NLRP3 inammasome.19,20 High extracellular ATP levels activate P2X7 purinergic receptors to cause potassium efux. Low intracellular levels of potassium promote the assembly of

NLRP3 and ASC. In addition, it has been suggested that low intracellular potassium will also promote pannexin-1 membrane pore formation, further easing the access of inammasome activating agents.21 mtDNA has been established as a DAMP when liberated into the extracellular space.22,23 It was shown24 that the translocation of mtDNA to

the cytosol was associated with subsequent inammasome activation. A DNAse treatment reduced secretion of IL-1 in macrophages. It has also been reported25 that mitochondrial dysfunction and oxidized mtDNA directly activate the NLRP3 inammasome. Macrophages lacking mtDNA or treated with the oxidized nucleoside 8-OH-dG to confer competitive inhibition had severely attenuated IL-1

secretion. Mitochondrial marker and NLRP3 inammasome colocalization and a signicant activation of NLRP3

Figure 1 Mechanisms of NLRP3 inammasome activation in heart failure. Myocardial infarction (MI), ischemia or ischemia/reperfusion (I/R) injury induces cardiomyocytes to release ROS, ATP and mtDNA. ROS mediates autocrine and paracrine activation and nuclear translocation of NF-B, which regulates the transcription of pro-IL-1 and pro-IL-18. mtDNA directly primes NLRP3 and ATP via binding to P2X7 receptors and leads to potassium efux, a trigger for the assembly of NLRP3 inammasome. These collective effects result in activation of the NLRP3 inammasome-associated caspase-1, which processes pro-IL-1 and pro-IL-18 into mature IL-1 and IL-18 and can exacerbate local inammation. It can also be released into circulation to mediate endocrine effects. ATP, adenosine triphosphate;

IL, interleukin; mtDNA, mitochondrial DNA; NF-B, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NLR family, pyrin domain containing 3; ROS, reactive oxygen species; K+, potassium.

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inammasome upon mitochondrial membrane disruption have been shown.26 It was reported27 that activation of the NLRP3 inammasome in macrophages occurred due to an ATP-mediated ROS-dependent activation of phosphoinositide 3 kinase signaling. ROS stimulates the activation of NF-kB and increases the expression of pro-IL-1 and pro-IL-18.21

Mitochondrial regulation by autophagy in the heart Because all the mediators discussed above (ATP, mtDNA and ROS) may come from mitochondria, our hypothesis is that this organelle has a vital role in inammasome activation. Thus, mitochondrial integrity is a key limiting factor for NLRP3 inammasome activation. Furthermore, this may be especially relevant in the heart where cardiomyocytes have a higher mitochondrial content relative to other cell types. Overall, the heart is likely to be highly susceptible to mitochondria-derived DAMPs. Thus, effective regulation of damaged mitochondria is critical. Autophagy is a quality control system mediating degradation of protein aggregates and damaged organelles. Multiple studies have documented the importance of mitochondrial regulation by autophagy, specically referred to as mitophagy, in HF.28 Multiples studies have also now established a strong association between autophagy and inammasome activation. First, stimulating autophagy in macrophages using rapamycin can directly target precursors of IL-1 for degradation. Mice pretreated with rapamycin showed reduced circulating levels of IL-1 following a challenge with an inammatory stimulus.29 Using ATG16L1-decient cells, it was shown that autophagy was involved in endotoxin (lipopolysaccharide)-induced inammasome activation and increased IL-1 and IL-18 secretion.30 Another study31 reported that inammasomes can be directly sequestered into autophagosomes and destined for autophagic degradation. Nakahira et al.24 reported on the regulation of mtDNA-driven inammasome activation by autophagy. They deleted genes encoding key autophagy proteins LC3B and Beclin1, and found a signicant enhancement in caspase-1 activation and secretion of IL-1 and IL-18. Thus, defective autophagy-mediated quality control mechanisms resulted in enhanced inammasome activation via the accumulation of damaged mitochondria and reduced inammasome clearance in both in vitro and in vivo settings.

Distinct roles of cardiomyocytes, broblasts and immune cells in cardiac inammasome activationNumerous studies have now established a strong association between inammasome activation and adverse remodeling in HF. For example, both ASC-KO and caspase-1-KO mice exhibited a signicant reduction in infarct zone and brosis, as well as improved cardiac function after myocardial I/R injury.32 As highlighted in Figure 1, it has been proposed that activation of the inammasome occurs via cell-to-cell communication within heterogeneous cell populations of heart tissue, including cardiomyocytes, broblasts and innate immune cells.6,33 Kawaguchi et al.32 identied that both hematopoietic and non-hematopoietic cells are responsible

for secreting IL-1 after myocardial I/R injury, because only chimeric mice with ASC-KO bone marrow on an ASC-KO background showed reduction in infarct zone. They followed up with in vitro experiments in which hypoxia/reoxygenation stimulated inammasome activation in cardiac broblasts, but not in cardiomyocytes. This notion was supported by studies in adult cardiomyocytes in which NLRP3 inammasome activation was inhibited using either siRNA or pharmacological inhibitors. This resulted in fewer cell deaths but not IL-1

secretion.34 Upon permanent myocardial ischemia in both murine and rat models, myocardial broblasts were shown to be the primary source of IL-1 secretion in response to ATP released from damaged neighboring cells.35 Further work36 has also supported the notion of non-immune cell-mediated IL-1

and IL-18 secretion. This work concluded that mitochondrial ROS from cardiomyocytes acts as a trigger to prime the NLRP3 inammasome. Taken together, the data suggest that cardiomyocytes, cardiac broblasts and inltrating immune cells contribute via different roles toward inammation and cardiac remodeling in myocardial infarction (MI) (Figure 1).

CROSSTALK BETWEEN THE HEART AND ADIPOSE TISSUEAlterations in adipokine proles inuence the development of HFThere is a well-documented association between obesity and HF.2 Adipose tissue is clearly an important contributor to inammation in HF. Multiple studies have established both pro- and anti-inammatory effects of adipokines.37,38 In

obesity, adipose tissue undergoes changes induced by metabolic stress. It releases more pro-inammatory cytokines, including IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and less of the anti-inammatory cytokines, including IL-10 and adiponectin.3941 Visceral fat is the most important depot, which responds to metabolic stress in this way. There is a well-established positive correlation between visceral fat levels and HF.42 However, it is interesting to note that epicardial and pericardial fat depots exhibit a similar phenotype to visceral fat and have been strongly correlated with the progression of adverse cardiac remodeling.43 McKenney et al.44 observed increased epicardial adipose tissue after MIs, which correlated with a reduced adiponectin level after MI. In their study they compared pigs with or without adipectomy subjected to MI. They observed that the progression of adverse remodeling after the MI was attenuated, and the infarct zone size was diminished in adipectomized animals. This correlates with a previous observation in which a pig with myocardial I/R injury developed improved cardiac function, reduced infarct size and less tumor necrosis factor alpha (TNF) production with a greater production of IL-10 after intracoronary administration of adiponectin.45 In summary, whereas it is generally accepted that in obesity, the prole of adipokines from various fat depots mediates detrimental effects on the myocardium, the obesity paradox suggests that these adipokines can confer benecial effects during post-MI stages of remodeling.2

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Extensive epidemiological and clinical data suggest that type 2 diabetes increases the risk for HF independently of other risk factors, such as hypertension.46,47 One potential mechanism is that type 2 diabetes, often associated with obesity, leads to myocardial lipotoxicity that contributes to cell death, and thus, to cardiac dysfunction. Diabetic cardiomyopathy is also characterized by interstitial and perivascular brosis. A signicant increase in collagen deposition was found around intramural vessels and between myobers in heart biopsies in patients with diabetes.4850 Given that brosis is one consequence of inammation, IL-1 and other inammatory markers, such as brosis, signal the onset and progression of

HF in this way.5154

Cardiokine and endocrine effects on peripheral tissues in HF In recent years, there has been an increased realization of endocrine effects mediated by factors produced and secreted by the heart.55 Collectively, these are referred to as cardiokines. Ischemic stress results in a substantial change in the prole of cardiokines secreted from the myocardium.9,55 In particular,

upon activation of the inammasome and inltration of splenocytes in the infarct zone, the heart will release more pro-inammatory cytokines.9 Cardiac broblasts have been proposed as the principal source of inammatory signals in pathological conditions, although cardiomyocytes also contribute to the pro-inammatory environment in the myocardium by producing different cytokines and chemokines.56,57 Injured cardiac cells release damage-associated molecular pattern molecules, such as high-mobility group box 1, DNA fragments, heat-shock proteins and matricellular proteins, which instruct surrounding healthy cardiomyocytes to produce inammatory mediators. These mediators, mainly IL-1, IL-18, IL-6, MCP-1 and TNF, in turn activate versatile signaling networks within surviving cardiomyocytes and trigger leukocyte activation and recruitment.

Evidence for myocardial production of TNF has been controversial.58,59 However, it is now clear that TNF can be produced by isolated cardiomyocytes under certain conditions, such as treatment with lipopolysaccharide.6063 Similarly, increased expression of TNF in cardiac myocytes and broblasts isolated from failing hearts suggests that if exposed to pathophysiological stimuli, the heart has the capacity to produce TNF.64,65 IL-6 can be produced in most cells in the heart, including cardiomyocytes66,67 and broblasts.68,69

A lipopolysaccharide treatment or hypoxia-reoxygenation stimulated the production of IL-1 in isolated cardiac broblasts, while isolated cardiomyocytes did not respond to either treatment.32 A co-culture of cardiomyocytes with broblasts induced by an angiotensin-II treatment secreted much greater levels of IL-6 and TNF than cultures of broblasts alone, indicating that a paracrine action has a vital role in the production of pro-inammatory cytokines.70

Another good example of a cardiokine is atrial natriuretic peptide (ANP), which is produced mainly in the myocardium. Its expression is enhanced during myocardial stretching.71 ANP

has a benecial role in cardiac remodeling by acting in an autocrine or paracrine manner. For example, treatment with cultured cardiac myocytes with an antagonist of ANP receptor HS-142-1 increased expression of contractile protein genes, such as skeletal-actin and beta-myosin heavy chain, as well as the size of cardiomyocytes.72 ANP also contributes to oxytocin-induced protection in myocardial ischemiareperfusion injury by reducing lipid peroxidation in a nitric oxide-dependent mechanism.73

ANP receptors are found in adipose tissue and mediate effects, including enhanced lipolysis and energy expenditure, as well as altering adipokine production and release.7476 Thus,

natriuretic peptides can denitely inuence peripheral metabolism by acting on adipose tissue. Therapeutically targeting ANP action may confer metabolic and cardiovascular benets in the future.74

CROSSTALK BETWEEN THE HEART AND SPLEEN: THE CARDIO-SPLENIC AXISNeutrophil activation and leukocyte inltration in the heart are prominent features of MIs that exacerbate inammatory cytokine release and tissue damage.77 Indeed, the mononuclear phagocyte network undergoes extensive remodeling after MI. There are different subpopulations of monocytes residing in mice. These are converted from one to another upon inammatory responses after an MI. Monocytes are generally classied into two categories: migratory monocytes with inammatory characteristics, which express high levels of Ly6C and CC chemokine receptor CCR2 and low levels of fractalkine receptor CX3CR1 (Ly-6Chi,CCR2hiCX3CR1low), and reparative monocytes with anti-inammatory proles (Ly-6Clow,CCR2lowCX3CR1high).78 The exact mechanism of how each phenotype of monocytes regulates the inammatory response during an MI is complicated and is not resolved.79

However, under acute MI conditions, monocyte recruitment to the heart is very dynamic and largely dependent on the spleen. The spleen is one of most important lymphoid tissues. It has a role in ltering blood and regulating immune responses to circulating agents.80 The spleen contains large pools of undifferentiated monocyte reservoirs80,81 that

can undergo splenic hematopoiesis, increasing motility and pro-inammatory characteristics (Ly-6Chi).81 Recruitment of reparative monocytes (Ly-6low) ultimately helps resolve inammation and promote tissue healing.81,82

Dendritic cells (DCs), specialized for presenting antigens to T cells, also have an important role in the immune response to an MI.83 In an acute MI, both DCs and monocytes/ macrophages have been shown to positively contribute to tissue healing. Upon an initial cardiac inammatory response, DCs inltrate the infarcted area to confer a protective role. This is demonstrated with DC-ablated mice exhibiting greater adverse cardiac remodeling after an MI.84 In these mice, there was sustained expression of pro-inammatory cytokines, IL-1,

IL-18 and TNF, yet reduced IL-10 expression.84

Interestingly, under chronic MI conditions, the protective roles of splenocytes become detrimental. Mice with a long-term

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MI (8 weeks) showed profound splenic remodeling with a prolonged existence of pro-inammatory monocytes (Ly-6Chi)

and increased expression of alarmins.85 A splenectomy was performed to investigate the role of splenocytes (splenic monocytes/macrophages and DCs) in the progression of HF-associated inammation and post-MI remodeling. Intriguingly, mice without spleens showed less cardiac dysfunction. This was associated with attenuated monocytes/ DC inltration in the heart.85 When splenocytes from the mice with an MI were injected into normal mice, the recipient mice developed left ventricule (LV) dilation, cardiac hypertrophy, systolic dysfunction, myocardial apoptosis and brosis.85 How

ever, the recipient mice did not reveal changes in pro-inammatory cytokines in circulation, indicating that the adverse cardiac remodeling in chronic MI model was specically due to splenocytes. Therefore, there is a clear sequential activation of inammatory responses depending on the duration of MI via splenocyte-mediated crosstalk to the heart (Figure 2).

CROSSTALK BETWEEN THE HEART AND KIDNEY: CARDIO-RENAL AXISMultiple clinical studies have suggested that patients with chronic kidney disease experience extremely high mortality rates following acute MI.8689 This suggests that there is a strong crosstalk between the kidneys and heart. The association between end-stage renal disease and cardiovascular disease is often termed cardio-renal syndrome.90 The renin-angiotensin system (RAS), a signaling cascade responsible for regulating blood pressure, has a well-established critical role in cardio-renal syndrome.91 Ogawa et al.92 reported that nephrectomy in mice with an MI inuenced cardiac remodeling after the MI. The combination of nephrectomy and MI resulted in deteriorated left ventricular remodeling and RAS activation, oxidative stress and MCP-1. This observation was similar to transgenic mice overexpressing renin and angiotensinogen after a coronary artery ligation (CAL) surgery.92 This correlates with previous ndings that cardiomyocytes increase the expression of TNF and IL-1 family through activation of NF-kB and activator protein 1 transcription factor in response to angiotensin II.9395

Other than RAS, a new biomarker has been identied that strongly correlated with cardio-renal syndrome. HF patients with declined renal function exhibit elevated levels of neutrophil gelatinase-associated lipocalin (also known as lipocalin-2)96. Neutrophil gelatinase-associated lipocalin levels are strongly correlated with inammation and cardiac remodeling in HF patients with renal dysfunction.96

Pro-inammatory effects of lipocalin-2 are also known to induce endothelial dysfunction97,98 and promote apoptosis in

cardiomyocytes.99,100

In addition, cardiokines, such as ANP, can mediate endocrine effects on the kidney.101 They have effects on electrolyte balance and water excretion in the kidney by increasing glomerular permeability and ltration rate. ANP also antagonizes the deleterious effects of the reninangiotensin-aldosterone system activation.101103 Furthermore,

crosstalk between the heart and kidney are evident from the observation that worsening renal function manifests only in end-stage HF and is strongly related to mortality.104 Although cardio-renal interactions in HF are well established, many questions, especially mechanistic, remain unanswered.

CROSSTALK BETWEEN THE HEART AND SKELETAL MUSCLEWe now appreciate that HF is strongly associated with skeletal muscle wasting, which is typically not associated with general weight loss.105,106 Skeletal muscle in congestive HF patients

shows increased fatigability as well as decreased endurance and exercise capacity.105,106 Changes evident in muscle include

metabolic imbalance, increased degradation of myobrils and myocyte apoptosis. The signals mediating crosstalk from the heart need to be comprehensively identied.107,108 One

possibility is that generation of TNF from the failing heart has a detrimental effect on several processes in skeletal muscle.

NF-B is rapidly activated by TNF in differentiated skeletal

Figure 2 Crosstalk mechanisms in the cardio-splenic axis in heart failure, and their functional consequences on peripheral tissues. In acute myocardial infarction (MI), splenocytes (splenic monocytes/ macrophages and dendritic cells) migrate to the heart and mediate protective effects during the inammatory response. In chronic MI, cardiokines induce dramatic changes in the spleen, such that splenocytes develop inammatory proles. This exacerbates existing inammation in the heart and promotes adverse cardiac remodeling leading to cardiac dysfunction. Inammatory splenocytes also lead to peripheral organ damage. For example, kidney inammation results in enhanced activation of the renin-angiotensin system (RAS) and release of lipocalin-2. In vasculature, inammation results in adverse alterations in vascular tone and vascular cell proliferation. Skeletal muscle is also strongly affected by heart failure, at least in part via inammation resulting in cellular changes, such as sphingosine accumulation and muscle wasting. In adipose tissue, inammation results in reduced adiponectin levels and further increased levels of pro-inammatory adipokines (IL-6, MCP-1, IL-10). IL, interleukin; MCP-1, monocyte chemotactic protein 1.

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muscle cells, which directly induces skeletal muscle protein loss.109 Another proposed mechanism is that TNF induces sphingosine production, which then leads to induction of apoptosis in these cells.110 In addition, exercise attenuates the local expression of TNF, IL-1 and inducible Nitric Oxide

Synthase (iNOS) in skeletal muscle and decreases the catabolic wasting process in HF patients.34,111,112 Angiotensin-II is also produced by the heart under conditions of stress and contributes to cardiac hypertrophy and brosis.113 Studies have shown that there is a catabolic effect of angiotensin-II on skeletal muscle, suggesting its role in muscle wasting in HF.114,115

THERAPEUTIC APPROACHES TARGETING INFLAMMATION IN HFAs outlined above, myocardial inammation in HF is often detrimental to peripheral tissues. There have been several studies addressing consequences of manipulating HF-associated inammation.116 Targeting TNF has been extensively studied in numerous clinical trials. Patients who already have severe inammatory conditions, such as rheumatoid arthritis (RA), were treated with TNF inhibitors (etanercept, iniximab and adalimumab), which effectively reduced the inammatory activity and reduced the prevalence of HF complications.117

The data from two-large-scale trials with more than 2000 HF patients showed that etanercept treatment reduced the risk of mortality or morbidity in HF.64 Indeed, the US Food and Drug Administration has issued a directive concerning the use of etanercept in the population with HF.118 However, targeting TNF using a neutralizing antibody (iniximab) showed no improvement and perhaps even worsened the clinical condition of patients with chronic HF.119 Other studies indicated that patients treated with high-dose iniximab continued to show a worse outcome compared with other groups.57,120 Several other

agents have also been suggested to have potential as therapeutic tools for chronic HF because of their inhibitory effect on TNF, including the glutamic acid derivative thalidomide.121

Thalidomide prevents the accumulation of TNF by inducing the degradation of TNF messenger ribonucleic acid transcripts, and thus, protein production.121 The xanthine

derivative pentoxifylline has also been reported to have a role in therapeutic TNF modulation. Reduced TNF in the serum of patients treated with pentoxifylline was observed. This correlated with improved peripheral vasodilation and blood hemodynamics.122 Other studies demonstrated a signicant improvement in NYHA functional class in patients treated with pentoxifylline.123,124 However, the results were not reproduced

by another group,125 suggesting that the signicance of

Table 1 Cytokines/chemokines involved in crosstalk between the heart and peripheral organs

Cytokines/Chemokines Effect Reference IL-1, IL-189,3235 Neutrophil activation and leukocyte inltration 77

[@Spleen] increasing mobility and inammatory characteristics

of monocytes, and inltration of DCs to heart

78,8082

[@Heart] autocrine production of IL-6, TNF 71

Prolonged exposure led to pyroptosis 148,149

IL-6, IL-8, MCP-160,6769 Pro-inammatory cytokines 60,6769

DAMPs, HMGB1, DNA fragments, heat

shock proteins,

matricellular protein9,5557

56,57

[@Heart] autocrine effects to produce

pro-inammatory cytokines; IL-1, IL-18, IL-6, MCP-1, TNF

TNF58,59 Prolonged exposure led to pyroptosis 64,65

[@Skeletal Muscle] muscle wasting, sphingosine production, induction of apoptosis 109,110

ANP71 Paracrine effect: oxytocin production, reducing lipid peroxidation

with NO-dependent mechanism

73

72

[@Heart] autocrine effect on heart by increasing expression of contractile protein, actin and

myosin, and induce hypertrophy

75,76,150

[@Adipose Tissue] enhancing lipolysis and increasing energy

expenditure, adipokines production

[@Kidney] increasing glomerular permeability and ltration rate, antagonizing RAS activation 101103

IL-6, IL-8, MCP-137,38 Pro-inammatory cytokines 3941

IL-1037,38 Anti-inammatory cytokines 3941

Adiponectin37,38 [@Heart] reducing TNF production, increasing IL-10 production, reducing infarct size 45,55

Alarmins85 [@Heart] worsening cardiac dysfunction, inducing myocardial apoptosis, brosis 85

Angiotensin-II91 [@Heart] inducing cardiac hypertrophy/brosis, increasing expression of

TNF, IL-1 family cytokines

70,93,94,113

[@Skeletal Muscle] muscle wasting 114,115

Lipocalin-296 endothelial dysfunction, cardiomyocyte apoptosis 97100 Abbreviations: ANP, atrial natriuretic peptide; DAMPs, danger/damage-associated molecular patterns; DCs, dendritic cells; HMGB1, high-mobility group box 1;

IL, interleukin; MCP-1, monocytes chemoattractant protein-1; NO, nitric oxide; TNF, tumor necrosis factor alpha.

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targeting TNF is controversial and requires further exploration.126 This may be because pleiotropic TNF effects may be involved in many benecial physiologic, as well as pathologic, processes. For example, TNF provides endogenous cyto-protective signals that prevent cardiomyocyte apoptosis following ischemic injury.127 Additionally, TNF type 1 receptor deciency was associated with accelerated myocardial death.128 Overall, the cardiomodulatory effects of TNF and other cytokines likely depend on factors such as cell type and timing and extent of inhibition.

We propose that IL-1 is a major mediator between HF and peripheral tissues. In fact, multiple studies have targeted IL-1.

Canakinumab, a neutralizing antibody against IL-1, and anakinra, a recombinant IL-1 receptor antagonist, were shown to exert benecial effects on acute MI in animal models.129,130

Several clinical trials identied therapeutic benets by blocking IL-1.131,132 Anakinra successfully reduced adverse remodeling in patients with an MI and reduced the level of C-reactive protein, a common biomarker used to determine the severity of inammation.133,134 Patients diagnosed with HF were

treated with Anakinra and subjected to exercise performance testing. Two weeks of the Anakinra treatment signicantly increased oxygen consumption, decreased carbon dioxide retention and exercise performance with signicant reduction in IL-1, C-reactive protein and IL-6 serum proles.135 These correlated with a previous study in which patients with RA treated with Anakinra had improved cardiac function. A single injection of Anakinra resulted in increased blood ow in 3 h.136

The commercial usage of Anakinra was approved by Food and Drug Administration in 2001. However, it was for treating patients with RA not chronic HF, although multiple studies demonstrated cardiac benets of Anakinra in treating RA.137139

There also have been therapeutic efforts to target IL-18 and inammasome activation. A recombinant human IL-18 binding protein and neutralizing antibody for IL-18 have been developed, and initial clinical trials to treat patients with RAs are ongoing.140,141 In subjects with moderate to severe RA,

IL-18 binding protein shows a favorable safety prole and is well tolerated in healthy volunteers. Because IL-18 binding protein stays in circulation much longer than any other inhibitors previously described, it has attracted a lot of attention.141,142 Antagonists targeting P2X7 receptors have also been tested to potentially block inammasome activation.

Many successful cases have been shown; they limit neuronal damage and lung, liver and kidney injury in several animal models.143146 Currently, the safety and efcacy of P2X7 receptor antagonists are being investigated and have progressed to phase 2 clinical trials. However, their main use is to target inammatory bowel disease, RA and chronic obstructive airway disease.147

CONCLUDING REMARKSMyocardial ischemia- and I/R-induced inammation involve NLRP3 inammasome activation. One principal trigger for inammasome activation is the recognition of mitochondrial

DAMPs. This results in the production and secretion of pro-inammatory cytokines, including IL-1 and IL-18 (Table 1). These and other factors produced by the heart during inammation can have local effects. They can also crosstalk with other peripheral tissues via endocrine effects. For example, HF is associated with dramatic changes in the spleen, skeletal muscle wasting, alterations in adipose metabolism and kidney function. The extent and signicance of bidirectional crosstalk between the heart and other organs may have been underappreciated, but is now becoming more established and may represent a logical focus of therapeutic interventions in the future.

CONFLICT OF INTERESTThe authors declare no conict of interest.

ACKNOWLEDGEMENTSRelated research in the authors laboratory is funded by the Canadian Diabetes Association, the Heart & Stroke Foundation of Canada and the Canadian Institutes of Health Research. We thank Lesia Szyca for the excellent graphic illustration of Figures 1 and 2.

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