TR

E N D S I N

C

A R D I O V A S C U L A R

M

E D I C I N E

26 (2016) 1–11

Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Vagus nerve modulation of inflammation: Cardiovascular implications Brian Olshansky, MDn Cardiac Electrophysiology, University of Iowa Hospitals, Iowa City, IA

abstra ct The vagus nerve modulates inflammatory responses in various organ systems. Emerging evidence indicates that the vagus can have profound and complex effects on cardiovascular function, remodeling, arrhythmias, and mortality by several mechanisms. In heart failure and during ischemia, an adverse inflammatory response can occur. The vagus nerve may modulate cardiovascular disease and outcomes by affecting inflammatory responses. Here, evidence for and components of the vagus inflammatory reflex are reviewed and evidence for and implications of effects of vagus activation on inflammation in the cardiovascular system are considered. & 2016 Elsevier Inc. All rights reserved.

Introduction The vagus nerve regulates sinus (i.e., heart) rate and AV nodal conduction. Traditionally, this is where the thinking ends when it comes to the vagus nerve and cardiovascular physiology. However, the vagus nerve modulates inflammatory responses in various organ systems and in animal models [1,2]. However, emerging evidence indicates that the vagus nerve can have profound and complex effects on cardiovascular function, remodeling, arrhythmias, and mortality by other mechanisms [3]. In heart failure and during ischemia, an adverse inflammatory response can occur. Thus, the vagus nerve may modulate cardiovascular disease and outcomes by affecting inflammatory responses [3–7]. Here, evidence for and components of the vagus inflammatory reflex are reviewed and evidence for and implications of effects of vagus activation on inflammation in the cardiovascular system are considered.

Organization of the parasympathetic nervous system Cardiovascular parasympathetic innervation occurs centrally via the right and left vagus nerves. Effects can be rapid and/or

phasic (e.g., respiratory variation) or prolonged and tonic (related to localized central processing or ganglionic gating) [8]. Selective neural and hormonal modulation occurs centrally, at local cardiac ganglia, and via intracellular signaling in specific target cardiac cells. The vagus nerve has afferent and efferent pathways. Afferent sensory baro/mechanoreceptors located in the heart and major blood vessels and chemoreceptors in the carotid bodies transmit signals centrally to the nucleus tractus solitarius, hypothalamus, and brainstem tegmental nuclei, providing feedback from the cardiovascular system to the central nervous system. Efferent preganglionic extensions at medial medullary sites (nucleus ambiguus, nucleus tractus solitarius, and dorsal motor nucleus) are modulated by “higher centers” in the forebrain (hypothalamus, amygdala, and insular cortex), constituting the central autonomic network. All activity extends peripherally through the vagus to post-ganglionic neurons, located in ganglia (cardiac fat pads), activated via nicotinic receptors, and then, post-synaptically, via muscarinic end-organ receptors. In the normal resting state, parasympathetic, not sympathetic, activity regulates the sinus node. Acute stress initiates the vagus withdrawal and sympathetic stimulation; longstanding physical activity enhances resting vagus activation and suppresses exercise-induced sympathetic tone. Vagus

The author has indicated that there are no conflicts of interest. n Corresponding author. Tel.: þ1 319 331 0342, þ1 319 356 2344 (office); fax: þ1 319 384 6247. E-mail addresses: [email protected], [email protected] (B. Olshansky). http://dx.doi.org/10.1016/j.tcm.2015.03.016 1050-1738/& 2016 Elsevier Inc. All rights reserved.

2

T

R E N D S I N

C

A R D I O V A S C U L A R

activation inhibits sympathetic activity pre-synaptically [9] and post-synaptically, thus nullifying sympathetic activation completely at rest. Abrupt vagus activation can inhibit sympathetic activation that may occur with exercise, blood loss, or hypotension due to a tachyarrhythmia. This is known as “accentuated antagonism.” Likewise, sympathetic activation can inhibit parasympathetic activation. The vagus nerve fibers co-exist. “A-” fibers are myelinated, the largest, and fastest conducting. Afferent fibers include slow-conducting unmyelinated C-fibers and small diameter A-delta fibers, whereas small, thin, non-myelinated postganglionic C-fibers and intermediate-diameter and intermediate-conducting pre-ganglionic myelinated B-fibers in efferent fascicles contribute to cardio-inhibition mediated at the level of the heart by muscarinic (M2) receptors. Efferent fascicles contain large myelinated A-β fibers belonging to the laryngeal bundle and cardio-inhibitory A-δ fibers that excite post-ganglionic neurons in cardiac fat pads (autonomic ganglia) via nicotinic receptors, affecting ganglionic transmission and ultimately parasympathetic activation via local neurons. Vagus efferent activation, tonic or phasic, depends on where fibers originate (nucleus ambiguus or dorsal motor nucleus) [10]. Nerves from these two nuclei differ in morphology, conduction velocity, firing, and effect on cardiac function [11,12]. Neurons from the nucleus ambiguus are thinly myelinated, have strong effects on heart rate, and are more phasic, whereas the neurons in the dorsal motor nucleus are non-myelinated and have a smaller effect on heart rate but greater effects on AV conduction and contractility. The effects from the dorsal motor nucleus are more tonic. Vagus innervates predominately the sinus and the AV nodes, but extensions are distributed throughout the heart in a non-uniform epicardial/endocardial and regional fashion and not directly parallel to sympathetic innervation. Postganglionic (efferent) parasympathetic cholinergic fibers affect cardiac tissue through cardiac muscarinic (M) receptors. M2 receptors predominate, although, M3 and M4 receptors have been identified in the heart with density varying by location, cell type, and disease. In heart failure, defective parasympathetic cardiac control exists and the influence of vagus diminishes even at rest [13–15]. This may actually occur before, or in connection with, elevation in sympathetic “tone” [16,17]. In heart failure, cardiac parasympathetic control is attenuated, ganglionic transmission and nicotinic receptor number is reduced, muscarinic receptor density can increase, and acetylcholinesterase activity can decrease [18]. M2 receptor density and sensitivity may change in part due to M2 receptor antibodies associated with remodeling in heart failure [19] (significance unknown [20,21]). In heart failure, parasympathetic withdrawal is associated with a shift from M2 to M3 and/or M4 receptors on cardiac structures [22] and pro-inflammatory cytokines [23].

ME

D I C I N E

26 (2016) 1–11

tumor necrosis factor (TNF-α), Il-6, IL-1β, IL-18, high mobility group box 1 (HMGB1) and other pro-inflammatory cytokines that influence the pathogenesis of sepsis, ulcerative colitis, rheumatoid arthritis, and inflammatory disorders. Chronic inflammation has been not only linked to insulin resistance, metabolic complications, obesity, and several noncardiovascular consequences but also linked to myocardial damage, heart failure progression, and cardiovascular death. TNF-α and HMGB1 released by activated immune or damaged tissue cells can cause organ damage and failure. During sepsis, HMGB1 promotes epithelial cell permeability, leading to multi-organ system failure, and can cause death. Release depends upon NLRP3 inflammasome activation that mediates pro-inflammatory cytokines IL-1β, IL-8, and capsace-1. Inflammasomes cause “pyroptosis,” a form of pro-inflammatory programmed cell death [24]. Components of innate immunity include T-helper (TH) cell lymphocytes subclassed as TH-1 secreting interferon-γ, IL-2, and TNF-β, and TH-2 secreting IL-4, IL-10, and IL-13 [25]. These cytokines, in concert with activated macrophages and natural killer cells, become major constituents of cellular immunity. IL-12, TNF-α, and other cytokines stimulate nitric oxide synthesis and other inflammatory mediators, driving a chronic, delayed-type, inflammatory response.

Cholinergic response to inflammation Work from the 1970s pointed to the importance of cholinergic stimulation on T-cell cytotoxicity. More recently, Borovikova et al. [26] described that acetylcholine or direct vagus nerve stimulation via a nicotinic pathway attenuates TNF-α, IL-1β, IL-6, and IL-18 release during endotoxemia in rats and prevents septic shock. Tracey delineated peripheral and central cholinergic anti-inflammatory pathways involving the α7 subunit of the nicotinic acetylcholine receptor (α7nAchR). This essential pathway regulates intracellular control of cytokine transcription and translation [27,28]. Inflammatory cells (T lymphocytes and B lymphocytes, monocytes, macrophages, and neutrophils) have α7nAchRs on their cell surfaces [29]. α7nAchR activation inhibits capase1, HMGB1, and pro-IL-1β release. NLRP3 inflammasomes are inhibited by the α7nAchR [30]. JAK–STAT (Janus kinase–signal transducer and activator of transcription) factors signaling anti-inflammatory pathways for various cytokines depend on JAK2 activation by α7nAchR and subsequent STAT3 activation by mechanisms within macrophages that inhibit pro-inflammatory nuclear factor, NF-κB p65 [31,32]. In an animal model of intestinal manipulation, vagus stimulation affects STAT3 in macrophages and decreases surgery-induced inflammation [31]. When STAT1 and STAT3 were inhibited in rat peritoneal macrophages exposed to lipopolysaccharides, HMGB1 mRNA levels decreased [33].

Local inflammatory responses The inflammatory reflex Pathogen- and danger-associated molecules recognized by toll-like receptors and nucleotide-binding oligomerization design domain-like receptors on immune cell surfaces release

Regulatory pathways of cytokine production have been elucidated [2,34], but cytokine production regulated by neural

T

R E N D S I N

C

A R D I O V A S C U L A R

pathways is termed as “the inflammatory reflex” [2,34,35], a bidirectional cholinergic (afferent and efferent) pathway that regulates visceral function, maintains homeostasis, and affects inflammation via tonic vagus activation (Fig. 1).

The afferent arm of the vagus inflammatory reflex Cytokines activate the vagus nerve fibers traveling centrally to the nucleus tractus solitarius in the medulla oblongata [35] from nodose and jugular ganglia. The fibers communicate between the brainstem, the hypothalamus (causing adrenocorticotropic hormone release), and the forebrain (integrating visceral sensory information and coordinating autonomic function and behavioral responses) to affect glucocorticoid release and inhibit pro-inflammatory cytokines [36] after ascending the vagus nerve sensory signals are processed and then activate, reflexively, efferent pathways [37]. IL-1β receptors, in concert with prostaglandin-dependent mechanisms, are part of a chemosensory afferent pathway that initiates “sickness behavior” (and eliminated by vagus transection in animal models). Lipopolysaccharides also activate toll-like Receptor 4 in the nodose ganglia, suggesting that inflammatory molecules also activate afferents above visceral nerve endings. Vagotomy fails to suppress high-dose, endotoxin-induced, IL-1β in the brain and increases blood corticosterone levels [38]. Vagus afferent pathways play a dominant role in peripheral inflammatory responses to lowlevel cytokines, whereas acute inflammatory responses may be due to humoral mechanisms.

The efferent arm of the vagus inflammatory reflex Vagus stimulation suppresses pro-inflammatory cytokines in animals with endotoxemia, and acetylcholine releases TNF-α, IL-1β, and IL-18 from lipopolysaccharide-stimulated macrophages [26]. In human macrophage cell cultures, acetylcholine inhibits TNF-α, IL-1β, IL-6, and IL-18 release in a dose-dependent manner when exposed to lipopolysaccharides. The inhibitory effect of acetylcholine on the lipopolysaccharide-induced TNF-α response is mediated primarily by α-bungarotoxinsensitive nicotinic receptors. Inhibition occurs through posttranscriptional suppression [26]. Efferent vagus nerve fibers release acetylcholine in the reticuloendothelial system, (spleen, liver, and gastrointestinal tract) [35]. The α7nAchR, important for anti-inflammatory signaling, exists on macrophages, monocytes, dendritic cells, T cells, and endothelial and non-neuronal cells. Acetylcholine/nicotine binding to α7nAchR on peripheral macrophages stimulates JAK and STAT anti-inflammatory pathways, inhibits NF-κB, and, by preventing cytokine synthesis and release, i.e., inhibits inflammation [32,35,39]. Macrophages bind αbungarotoxin and antagonists of α7nAchR, indicating that macrophages express subunits of α7nAchR. The essential role of the α7 subunit modulating cholinergic anti-inflammatory responses was defined in α7nAchR gene knockout mice [40]. In animals with intact vagus nerves, efferent vagus activation inhibits serum TNF-α during endotoxemia [26]. Serum TNF-α levels were higher, and hypotension was worsened

ME

D I C I N E

26 (2016) 1–11

3

with vagotomy [26], indicating that vagus activation has an anti-inflammatory response [26]. These, and other, data regarding the vagus anti-inflammatory reflex may or may not pertain to the heart and may or may not be beneficial. Tracey elucidated mechanisms by which vagus stimulation initiates and modulates such responses [1,2,28,35]. Cultured macrophages express nicotinic receptors composed of five α7 subunits. These subunits are required for acetylcholine inhibition of TNF-α release [28]. When exposed to lipopolysaccharides, α7 subunit-deficient mice expressed more inflammatory cytokines than wild-type mice. Vagus stimulation inhibits TNF-α synthesis in wild-type mice but not in α7deficient mice. Therefore, α7nAchR is essential to inhibit cytokine synthesis in the cholinergic anti-inflammatory pathway. The α7nAchR activation inhibits HMGB1 [41,42], a mediator of tissue injury and inflammation, released from human macrophages exposed to endotoxin. In experimental mouse model of sepsis, nicotine decreased HMGB1 levels subsequently reducing mortality in a dose-dependent manner [42], and suggesting that nicotinic agonists for the α7nAchR might be a therapeutic target to treat sepsis. Galantamine, a centrally acting acetylcholinesterase inhibitor, affects systemic and organ-specific TNF-α production during endotoxemia, supporting a central link in the inflammatory reflex. When given to α7nAchR-deficient mice, TNF-α was not suppressed, indicating the central vagus reflex requires peripheral α7nAchR activation as well [43]. The spleen is a main source of circulating TNF-α during systemic inflammation (Fig. 2). TNF-α levels are lowered similarly by the vagus nerve stimulation or by splenectomy [44], supporting the concept of a splenic vagus nerve inflammatory reflex. However, vagus innervation of the spleen is uncertain, and, while innervation has been suggested to disynaptic (such that preganglionic vagus neurons via an intermediate neuron affect post-ganglionic splenic sympathetic neurons) [45], Martelli et al. [46–48] have challenged the concept that innervation is cholinergic; rather it may be sympathetic. Martelli postulates that a subset of T (memory CD4þT) lymphocytes synthesizes acetylcholine instead affecting TNF-α withdrawal during endotoxemia. The issue can be addressed by defining the nerves as “adrenergic” or “cholinergic,” which offers an advantage of precision. The adrenergic splenic nerve is a motor nerve to the spleen, which controls the release of acetylcholine from specialized T cells. As defined by numerous laboratories, this is neither sympathetic nor parasympathetic. Rather, it is a discrete neural circuit that suppresses cytokine release in spleen under the control of the vagus nerve stimulation terminating on macrophages that express α7nAchR that inhibit TNF-α release and inflammasome activation. Ongoing investigation into the sensory components of this and other circuits is likely to advance knowledge of the neurophysiology and the neurotransmitters underlying multiple aspects of immunity, beyond controlling cytokines. To understand the potential reflex mechanism better, Rosas-Ballina et al. [49]studied xanomeline, a central-acting M1 receptor agonist developed for Alzheimer's disease and schizophrenia. Xanomeline significantly suppressed TNF-α, alleviated “sickness behavior,” and increased survival during

4

T

R E N D S I N

C

A R D I O V A S C U L A R

ME

D I C I N E

26 (2016) 1–11

Fig. 1 – Components of the purported inflammatory reflex are shown schematically. Inflammatory mediators are released by macrophages and other immune cells. Neuronal interconnections between the NTS, AP, DMN, NA, and higher forebrain regions (not shown) integrate afferent signaling and efferent vagus output that regulate immune activation and suppress proinflammatory cytokines. AChE, acetylcholinesterase; AP, area postrema; DMN, dorsal motor nucleus of the vagus nerve; LPS, lipopolysaccharide; mAChR, muscarinic acetylcholine receptor; NA, nucleus ambiguus; NLRs, nucleotide-binding oligomerization domain-like receptors; NTS, nucleus tractus solitarius; TLR4, toll-like receptor 4. (Adapted with permission from Pavlov and Tracey [38]). endotoxemia, suggesting that, with intact vagi, splenic nerve, signaling was possible through a central mechanism. In animals with intact vagi, efferent activation inhibits TNFα during endotoxemia [26] without augmenting corticosteroid

or IL-10 levels. Serum TNF-α levels were higher and hypotension was worsened with vagotomy [26], indicating that the vagus nerve activation is anti-inflammatory [26]. Also, resolution mediators of inflammation, netrin-1, and resolvin

T

R E N D S I N

C

A R D I O V A S C U L A R

ME

D I C I N E

26 (2016) 1–11

5

Fig. 2 – Efferent vagus nerve activity may affect activation of splenic T-cell-derived acetylcholine release and acetylcholine release from efferent vagus nerves in other organs. Inhibition of NF-κB nuclear translocation and activation of JAK2–STAT3mediated signaling cascade may affect cholinergic α7nAChR-mediated control of pro-inflammatory cytokines. ACh, acetylcholine; β2AR, β2 adrenergic receptor; JAK2, Janus kinase 2; α7nAChR, α7 nicotinic acetylcholine receptor; NA, noradrenaline; NF-κB, nuclear factor κB; STAT3, signal transducer and activator of transcription 3. (Adapted with permission from Pavlov and Tracey [38]). D1 [50] are impaired by vagotomy. These, and other, data may or may not pertain to the heart and may or may not be beneficial.

Mental stress and inflammation Stress can initiate a chronic damaging inflammatory response, affect the healing process, and lead to the “sickness syndrome.” Psychological stress can affect inflammatory cytokines TNF-α, IL-1β, and IL-1-6. Males had less (even reduced) cytokine production during mental stress, whereas women, particularly postmenopausal women, have increased levels [51]. Levels increase for men and women during recovery. Other data support the relationship between IL-6 and TNF-α levels after mental stress. Exercise and physical fitness were associated with smaller inflammatory cytokine

responses to acute mental stress likely due to parasympathetic activation [52]. An inverse relationship between fitness and IL-6 exists with a lower inflammatory cytokine response but less pronounced heart-rate variability reduction in physically fit people. Self-esteem and cardiovascular and inflammatory responses to acute stress may be related [53]. Greater selfesteem is associated with smaller TNF-α and IL-1Ra responses after acute stress. Lack of self-esteem may be responsible for chronic inflammatory conditions, even atherosclerosis. Further, physical activity may enhance parasympathetic tone and activate the cholinergic anti-inflammatory pathway to restrain chronic inflammation and chronic diseases, including cardiac disease [54]. While exercise may reduce oxidative stress and inflammation long term, it can increase both in the short term and have acute damaging effects. Even if an anti-inflammatory reflex is present with

6

T

R E N D S I N

C

A R D I O V A S C U L A R

the vagus nerve activation, it is not clear where and how this reflex occurs in cardiovascular conditions.

Anti-inflammatory benefits of vagus nerve stimulation in the heart Vagus nerve stimulation protects against ventricular fibrillation in an ischemic canine coronary artery occlusion model [55,56]. Similarly, in murine chronic heart failure and postmyocardial infarction models, vagus stimulation slows heart rate, improves hemodynamics, and reduces risk of death (86% vs. 50%, P ¼ 0.008) [57]. With myocardial ischemia and reperfusion, vagus nerve stimulation decreases infarct size and reduces macrophages in myocardium at risk independent of rate [58]. The nicotinic pathway appeared to be the explanation. The timing of vagus stimulation may be important for effects to be seen. In a swine model of left anterior descending coronary occlusion (ischemia) and reperfusion, vagus stimulation applied after coronary occlusion but not with reperfusion reduced ventricular fibrillation, infarct size, and IL-4 (but not TNF-α) and improved cardiac function [59]. Vagus stimulation preserves endothelial relaxation, decreases TNF-α and IL-1β, increases STAT3 phosphorylation, and inhibits NF-κB by M3 and α7nAchR pathways [60]. During ischemia and reperfusion, vagus stimulation prevents shock and markedly reduces TNF-α levels in serum, heart, and liver [61]. Vagus stimulation could be emulated by melanocortin peptide, adrenocorticotropin, and γ-2-melanocyte-stimulating hormone by central muscarinic pathways, suggesting the possibility of developing a drug therapy [56]. In rodents, larger infarct size is associated with elevated TNF-α and increased TNF receptor-1/TNF receptor-2 ratios. Vagus nerve stimulation ameliorates ischemia-induced cardiac dysfunction by inhibiting TNF-α-mediated signaling [62]. Vagus nerve stimulation (or acetylcholine) protects the mouse heart against acute ischemia injury by up-regulating beneficial TNF receptor-2 and down-regulating destructive TNF receptor-1 expression [63]. In swine, low-amplitude left vagus stimulation attenuates infarct size by 60/89% (continuous/intermittent stimulation), improves ventricular function, decreases ventricular fibrillation, and reduces cardiac mitochondrial reactive oxygen species depolarization and swelling during acute ischemia/ reperfusion injury by muscarinic receptor modulated of mitochondrial function [64]. In canines, low-level bilateral vagus tragus (auricular) stimulation improves left ventricular size, contractile and diastolic function, reduces collagen I, collagen III, TGF-β1, and MMP-9 expression in left ventricular tissue, and reduces high-sensitivity C-reactive protein and NT-pro-BNP [65]. Sinoaortic denervation in rats causes fibrosis and infiltration in the myocardium and blood vessels and reduces acetylcholine transporter and α7nAchR expression [66]. Angiogenesis after myocardial infarction is attenuated in α7nAchR knockout mice; in cultured cardiac microvascular endothelial cells of vascular endothelial growth factor, expression depends upon α7nAchR [67]. In heart failure, TNF-α, IL-1 β, IL-6, and IL-18 increase [6,23,68–70], but vagus stimulation reduces these markers to

ME

D I C I N E

26 (2016) 1–11

near normal. In canines [4], vagus nerve stimulation decreases C-reactive protein levels, markedly elevated four and eight weeks after chronic pacing, to near baseline and control levels. Low-level vagus stimulation normalizes C-reactive protein, IL-1-6, TNF-α, pro-ANP, and pro-BNP levels in a canine heart failure model and left ventricular function improves [71]. During chronic mitral regurgitation in dogs, vagus nerve stimulation results in higher cardiac output and forward stroke volume and reduces NT-pro-BNP and C-reactive protein levels, but left ventricular ejection fraction, end-diastolic dimension, and collagen volume fraction did not change [72].

Is cardiac inflammation modulated by the spleen? A critical question remains is cardiac inflammation modulated by the spleen? Ismahil et al. [73] have addressed this. In a mouse model of coronary ligation-induced heart failure, (vs. sham controls), pro-inflammatory macrophages were noted in the heart. Splenectomy reversed pathological cardiac remodeling and inflammation in heart failure animals. Further, splenocytes transferred from heart failure mice to normal recipients migrated to the heart and induced left ventricular dilatation, dysfunction, and fibrosis. Recipient mice also exhibited monocyte activation and splenic remodeling similar to heart failure mice. What remains to be understood is whether vagus activation has a direct cardiac or an indirect (via the spleen) anti-inflammatory effect.

Clinical data: Inflammation and the vagus Inflammation may be responsible for or contribute to heart failure progression [74–76]. Inflammatory mediators may be etiology dependent and disease specific [77]. Selected heart failure patients have increased levels of TNF-α, IL-1β, IL-6, IL-18 [78–82], soluble intercellular adhesion molecule [83], and other inflammatory markers [84]. Levels of these constituents are associated with heart failure progression and outcomes [78–81]. While cytokines may simply indicate presence of disease rather than cause, it is unlikely that they are innocent bystanders [85]. What remains uncertain is if cytokines or their reduction modulate outcomes and remodeling. For individuals with viral cardiomyopathy, an immune inflammatory response, rather than viral damage, may cause progressive cardiomyopathy and worsen outcomes [86,87]. Inflammatory pathways activated during cardiomyocyte hypertrophy are attenuated by peroxisome proliferatoractivated receptors PPARα and PPARδ [88]. Inflammatory cytokines may be deleterious as they can also affect sympathetic activation [89]. Obesity and diabetes have been associated with inflammatory responses that cause cardiac injury and ventricular dysfunction [90]. In ischemic disease, inflammatory mediators may be essential for infarct healing [91], but inflammation can persist beyond the healing process. While some inflammation mediators may be harmful, it also may be beneficial [92]. Elevated cytokine levels relate directly to deterioration of functional class and left ventricular ejection fraction [78,79].

T

R E N D S I N

C

A R D I O V A S C U L A R

Circulating inflammatory cytokines are independent predictors of mortality in patients with advanced heart failure [93]. Cytokines can influence myocardial contractility, induce hypertrophy, and promote apoptosis, contributing to ventricular dysfunction and remodeling [94]. A meta-analysis (9493 cases and 13,971 controls) evaluated the risk of idiopathic dilated cardiomyopathy based on TNF-α 238G/A and IL-6-572G/C gene polymorphisms in a Pakistani population. The 238G/A polymorphism was associated with cardiovascular disease in an Asian subgroup. IL-6-572G/C polymorphisms were associated with the variant GCþCC vs. the GG genotype [95]. In another meta-analysis, IL-6 gene (174G/C and 572G/C) polymorphisms were associated with the risk for coronary artery disease [96]. C-reactive protein levels have been associated with mortality in patients with idiopathic dilated cardiomyopathy. Of 84 consecutive cardiomyopathy patients, 23 developed cardiac events and 18 died of cardiac causes. High-sensitivity C-reactive protein 41 mg/L (P ¼ 0.008) was an independent predictor of cardiac events [97]. In a large patient cohort, coronary artery disease was associated with increased IL-6 values (odds ratio ¼ 2.14; 95% CI: 1.45–3.15) similar to that for C-reactive protein and similar to many other prospective studies [98]. C-reactive protein level predicted cardiac events in patients undergoing percutaneous coronary revascularization in a meta-analysis [99]. Evaluating 33 studies involving 34,367 patients with 4119 major adverse cardiac events, and, allcause death, myocardial infarction, coronary revascularization restenosis, there was a relationship between C-reactive protein levels despite heterogeneity across studies.

Immunomodulation and heart failure outcomes Traditional cardiovascular drugs have little influence on cytokines or the inflammatory reflex that may be present in heart failure. As studies suggest that regulation of inflammation may improve cardiac performance [6,100], immune modulatory therapy emerged as a possible new treatment for heart failure [6]. Cytokine-targeted therapy has been attempted to reduce the pro-inflammatory effects of TNF-α purported to cause worsening ventricular dysfunction. Two trials, the Randomized Etanercept North AmerIcan Strategy to Study AntagoNism of CytokinEs (RENAISSANCE) and the Research into Etanercept CytOkine antagonism in VEntriculaR dysfunction (RECOVER) trials, tested the TNF-α blocker etanercept [100]. Etanercept had no effect on clinical status, death, or a chronic heart failure hospitalization endpoint. The anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial tested infliximab [101]. These trials did not show a beneficial effect of reducing this inflammatory cytokines [102]. The reasons for these results remain uncertain [75]. A novel approach to immune modulation was tested in the Advanced Chronic heart failure Clinical Assessment of Immune Modulation therapy (ACCLAIM) study [103]. In this trial, device-based immunomodulation therapy was applied. Blood samples were exposed ex-vivo to controlled oxidative stress that led to apoptosis of leukocytes, resulting in reduction of inflammatory cytokine production and up-regulation

ME

D I C I N E

26 (2016) 1–11

7

of anti-inflammatory cytokines. In this double-blinded, placebo-controlled study, no significant benefit of therapy was seen. In two pre-specified subgroups including those with no history of previous myocardial infarction and those with NYHA functional class II heart failure (n ¼ 689) therapy was associated with a 26% (0.74; 95% CI: 0.57–0.95; P ¼ 0.02) and a 39% (0.61; 95% CI: 0.46–0.80; P ¼ 0.0003) reduction in the risk of primary endpoint events, respectively. The significance of these findings is unclear, as precise mechanisms of immune modulation are not completely understood. Other therapies have been tested including immunoglobulin or interferon treatment, immune-absorption, antioxidants therapies, and pentraxins [104]. It is possible that reduction of IL-1, IL-6, IL-18, macrophage inflammatory protein-1 α, monocyte chemo-attractant peptide (MCP)-1, and cardiotrophin-1 [78,79,81] may improve outcomes. Furthermore, targeting other inflammatory mediators, IL-6, or specific signaling pathways such as JAK–STAT, Shp2/Ras/ErK, or PI3K/Akt may provide beneficial effects.

Potential anti-inflammatory mechanisms of vagus nerve stimulation The relationship between cardiac vagus nerve activity and cytokine levels was tested in human subjects. The Coronary Artery Risk Development in young Adults (CARDIA) study was designed to understand contributors to changes in cardiovascular disease risk factors during transition from adolescence through young adulthood to middle age. In this study, RR interval variability, an index of cardiac vagus nerve modulation, and C-reactive protein and IL-6 levels were measured in 757 subjects. Univariate analysis revealed that all indices of RR interval variability were strongly and inversely related to IL-6 and C-reactive protein levels. In a multivariate model including gender, race, age, smoking, physical activity, systolic blood pressure, body mass index, and disease, there was a significant inverse relationship between heart rate variability and inflammatory markers. These findings are consistent with the hypothesis that efferent vagus activity is inversely associated with cytokine and inflammation in humans [105].

Clinical implications of cardiovascular disease and the inflammatory reflex The data, mostly from animal models, implicate that the vagus nerve is a modulator of the inflammatory reflex via a nicotinic receptor pathway. The vagus nerve may affect an inflammatory response in the heart. Local receptor activation may affect inflammation outside of the autonomic nervous system. The temporal relationship between inflammation and benefit or harm with regard to cardiovascular disease remains open to some question. The mechanism of benefit or harm has not been determined and both are potentially possible with regard to vagus nerve stimulation and cardiovascular disease. Any relationship that is seen may not be mechanistic and simply indicative of an association between inflammation and outcomes. Data from clinical trials to date

8

T

R E N D S I N

C

A R D I O V A S C U L A R

may have attempted to reduce the inflammatory markers when they themselves may not be the direct cause of the problem or mediator of progressive harm.

What have recent clinical heart failure trials shown? Data from the NECTAR trial [106] did not show benefit of vagus nerve stimulation regarding remodeling in NYHA Functional Class II/III heart failure patients with impaired ventricular function. Several issues are worth noting: (1) the “safety” endpoints appeared to be going in the direction of benefit with vagus nerve stimulation, although numbers were small. Mortality and heart failure hospitalizations were markedly reduced, although not necessarily statistically so in the vagus nerve stimulation group; (2) the enrolled patients did not have markers of inflammation present. The reason is not clear but those with long-standing fibrotic cardiomyopathic disease would not benefit from an anti-inflammatory approach. Those with a recent acute event for which there is a potential for remodeling, i.e., early after the development of cardiomyopathy or myocardial infarction, is where benefits would be more likely to be seen. Moving forward, proper selection of patients for clinical trials would need to consider the presence of inflammatory markers that are markedly elevated, as these patients are more likely to show remodeling and outcome endpoint. It may be time to consider an approach of multiple smaller clinical trials where iterative changes can be made to study design in an effort to optimize outcomes, before moving to large, decisive trial designs.

ME

D I C I N E

cardiomyopathy, stress and other conditions can affect pathophysiology and outcomes in heart disease. However, all cardiomyopathies are not necessarily associated with or affected by inflammation to the extent that an antiinflammatory approach will alter outcomes especially when a chronic fibrotic process has become manifest. Evidence from animal models indicates the possibility that vagus stimulation can affect inflammation and outcomes, including remodeling and survival. Similar data have not yet translated into the clinical realm, although there does appear to be a relationship between vagus nerve activation and inflammation in humans. While these data are quite inspiring, further clinical work needs to be performed to establish the potential value of vagus nerve activation, especially of the α7nAchR pathway in inflammatory cells to influence outcomes of those who have developing cardiovascular disease.

re fe r en ces

[1] [2] [3]

[4]

[5]

Further caveats [6]

Although a potent anti-inflammatory vagus reflex has been demonstrated, it is not clear if this reflex would influence the heart, cardiovascular physiology, and outcomes. Firstly, an inflammatory response would need to be a current problem and one that could be suppressed. Secondly, such suppression would need to be shown to be beneficial. Thirdly, the site of the inflammation would need to be affected by the vagus at that site; inflammation and innervation are local, not global. Fourthly, the site of the inflammation may be modulated by local receptors (perhaps even nicotinic) but by simulation outside of the autonomic nervous system. Finally, it is not clear that an inflammatory response in other organs that respond to vagal activation would necessarily be present in the heart or even be beneficial. There may be differential local effects that are good and bad and temporally dependent.

[7]

[8]

[9]

[10] [11]

[12]

Conclusion [13]

The vagus nerve has complex effects on the cardiovascular system. A vagus nerve anti-inflammatory reflex has been documented and involves several organ systems other than the heart. Animal data indicate the vagus nerve regulates an anti-inflammatory reflex in the heart. Cardiac inflammation present during myocardial ischemia, myocardial infarction,

26 (2016) 1–11

[14]

[15]

Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005;19:493–9. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289–96. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008;118:863–71. Zhang Y, Popovic ZB, Bibevski S, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail 2009;2:692–9. Jankowska EA, Ponikowski P, Piepoli MF, Banasiak W, Anker SD, Poole-Wilson PA. Autonomic imbalance and immune activation in chronic heart failure—pathophysiological links. Cardiovasc Res 2006;70:434–45. Aukrust P, Gullestad L, Ueland T, Damas JK, Yndestad A. Inflammatory and anti-inflammatory cytokines in chronic heart failure: potential therapeutic implications. Ann Med 2005;37:74–85. Gong KZ, Song G, Spiers JP, Kelso EJ, Zhang ZG. Activation of immune and inflammatory systems in chronic heart failure: novel therapeutic approaches. Int J Clin Pract 2007;61:611–21. McAllen RM, Salo LM, Paton JF, Pickering AE. Processing of central and reflex vagal drives by rat cardiac ganglion neurones: an intracellular analysis. J Physiol 2011;589:5801–18. Vanhoutte PM, Levy MN. Prejunctional cholinergic modulation of adrenergic neurotransmission in the cardiovascular system. Am J Physiol 1980;238:H275–81. Chapleau MW, Sabharwal R. Methods of assessing vagus nerve activity and reflexes. Heart Fail Rev 2011;16:109–27. McAllen RM, Spyer KM. Two types of vagal preganglionic motoneurones projecting to the heart and lungs. J Physiol 1978;282:353–64. Nosaka S, Yasunaga K, Tamai S. Vagal cardiac preganglionic neurons: distribution, cell types, and reflex discharges. Am J Physiol 1982;243:R92–8. Bibevski S, Dunlap ME. Evidence for impaired vagus nerve activity in heart failure. Heart Fail Rev 2011;16:129–35. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 1971;285:877–83. Porter TR, Eckberg DL, Fritsch JM, et al. Autonomic pathophysiology in heart failure patients. Sympathetic-cholinergic interrelations. J Clin Invest 1990;85:1362–71.

T

[16]

[17] [18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31] [32]

[33]

[34]

R E N D S I N

C

A R D I O V A S C U L A R

Azevedo ER, Parker JD. Parasympathetic control of cardiac sympathetic activity: normal ventricular function versus congestive heart failure. Circulation 1999;100:274–9. Levy MN. Sympathetic–parasympathetic interactions in the heart. Circ Res 1971;29:437–45. Dunlap ME, Bibevski S, Rosenberry TL, Ernsberger P. Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity. Am J Physiol Heart Circ Physiol 2003;285:H1632–40. Gimenez LE, Hernandez CC, Mattos EC, et al. DNA immunizations with M2 muscarinic and beta1 adrenergic receptor coding plasmids impair cardiac function in mice. J Mol Cell Cardiol 2005;38:703–14. Pei J, Li N, Chen J, et al. The predictive values of beta1adrenergic and M2 muscarinic receptor autoantibodies for sudden cardiac death in patients with chronic heart failure. Eur J Heart Fail 2012;14:887–94. Talvani A, Rocha MO, Ribeiro AL, Borda E, Sterin-Borda L, Teixeira MM. Levels of anti-M2 and anti-beta1 autoantibodies do not correlate with the degree of heart dysfunction in Chagas' heart disease. Microbes Infect 2006;8: 2459–64. Shi H, Wang H, Li D, Nattel S, Wang Z. Differential alterations of receptor densities of three muscarinic acetylcholine receptor subtypes and current densities of the corresponding Kþ channels in canine atria with atrial fibrillation induced by experimental congestive heart failure. Cell Physiol Biochem 2004;14:31–40. Li W, Olshansky B. Inflammatory cytokines and nitric oxide in heart failure and potential modulation by vagus nerve stimulation. Heart Fail Rev 2011;16:137–45. Lu B, Kwan K, Levine YA, et al. Alpha 7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release. Mol Med 2014;20:350–8. Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002;966:290–303. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458–62. Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med 2011;269:45–53. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384–8. de Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol 2007;151:915–29. Lu B, Kwan K, Levine YA, et al. α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release. Mol Med 2014; 20:350–8. Metz CN, Tracey KJ. It takes nerve to dampen inflammation. Nat Immunol 2005;6:756–7. de Jonge WJ, van der Zanden EP, The FO, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 2005;6:844–51. Liu H, Yao YM, Dong YQ, Yu Y, Sheng ZY. The role of Janus kinase-signal transducer and transcription activator pathway in the regulation of synthesis and release of lipopolysaccharide-induced high mobility group box-1 protein. Zhonghua Shao Shang Za Zhi 2005;21:414–7. Oke SL, Tracey KJ. From CNI-1493 to the immunological homunculus: physiology of the inflammatory reflex. J Leukoc Biol 2008;83:512–7.

ME

D I C I N E

[35] [36] [37]

[38]

[39] [40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

26 (2016) 1–11

9

Tracey KJ. The inflammatory reflex. Nature 2002;420:853–9. Sternberg EM. Neural–immune interactions in health and disease. J Clin Invest 1997;100:2641–7. Bernik TR, Friedman SG, Ochani M, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med 2002;195:781–8. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol 2012;8:743–54. Nathan C. Points of control in inflammation. Nature 2002; 420:846–52. Orr-Urtreger A, Goldner FM, Saeki M, et al. Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents. J Neurosci 1997;17:9165–71. Li T, Zuo X, Zhou Y, et al. The vagus nerve and nicotinic receptors involve inhibition of HMGB1 release and early pro-inflammatory cytokines function in collagen-induced arthritis. J Clin Immunol 2010;30:213–20. Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004;10:1216–21. Pavlov VA, Parrish WR, Rosas-Ballina M, et al. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun 2009;23:41–5. Huston JM, Ochani M, Rosas-Ballina M, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 2006;203:1623–8. Rosas-Ballina M, Ochani M, Parrish WR, et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A 2008;105:11008–13. Martelli D, McKinley MJ, McAllen RM. The cholinergic antiinflammatory pathway: a critical review. Auton Neurosci 2014;182:65–9. Martelli D, Yao ST, McKinley MJ, McAllen RM. Reflex control of inflammation by sympathetic nerves, not the vagus. J Physiol 2014;592:1677–86. Bratton BO, Martelli D, McKinley MJ, Trevaks D, Anderson CR, McAllen RM. Neural regulation of inflammation: no neural connection from the vagus to splenic sympathetic neurons. Exp Physiol 2012;97:1180–5. Rosas-Ballina M, Valdes-Ferrer SI, Dancho ME, et al. Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. Brain Behav Immun 2015;44:19–27. Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J Exp Med 2014;211:1037–48. Prather AA, Carroll JE, Fury JM, McDade KK, Ross D, Marsland AL. Gender differences in stimulated cytokine production following acute psychological stress. Brain Behav Immun 2009;23:622–8. Ostermann S, Herbsleb M, Schulz S, et al. Exercise reveals the interrelation of physical fitness, inflammatory response, psychopathology, and autonomic function in patients with schizophrenia. Schizophr Bull 2013;39: 1139–49. O’Donnell K, Brydon L, Wright CE, Steptoe A. Self-esteem levels and cardiovascular and inflammatory responses to acute stress. Brain Behav Immun 2008;22:1241–7. Lujan HL, DiCarlo SE. Physical activity, by enhancing parasympathetic tone and activating the cholinergic antiinflammatory pathway, is a therapeutic strategy to

10

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

T

R E N D S I N

C

A R D I O V A S C U L A R

restrain chronic inflammation and prevent many chronic diseases. Med Hypotheses 2013;80:548–52. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68:1471–81. Mioni C, Bazzani C, Giuliani D, et al. Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats. Crit Care Med 2005;33:2621–8. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 2004;109:120–4. Calvillo L, Vanoli E, Andreoli E, et al. Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion. J Cardiovasc Pharmacol 2011;58:500–7. Shinlapawittayatorn K, Chinda K, Palee S, et al. Vagus nerve stimulation initiated late during ischemia, but not reperfusion, exerts cardioprotection via amelioration of cardiac mitochondrial dysfunction. Heart Rhythm 2014;11: 2278–87. Zhao M, He X, Bi XY, Yu XJ, Gil Wier W, Zang WJ. Vagal stimulation triggers peripheral vascular protection through the cholinergic anti-inflammatory pathway in a rat model of myocardial ischemia/reperfusion. Basic Res Cardiol 2013;108:345. Bernik TR, Friedman SG, Ochani M, et al. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J Vasc Surg 2002; 36:1231–6. Kong SS, Liu JJ, Hwang TC, Yu XJ, Lu Y, Zang WJ. Tumour necrosis factor-α and its receptors in the beneficial effects of vagal stimulation after myocardial infarction in rats. Clin Exp Pharmacol Physiol 2011;38:300–6. Katare RG, Ando M, Kakinuma Y, Arikawa M, Yamasaki F, Sato T. Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury. J Mol Cell Cardiol 2010;49:234–44. Shinlapawittayatorn K, Chinda K, Palee S, et al. Lowamplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury. Heart Rhythm 2013;10: 1700–7. Zhuo W, Lilei Y, Songyun W, et al. Chronic intermittent low-level transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction. Circ Heart Fail 2014. Zhang C, Chen H, Xie HH, Shu H, Yuan WJ, Su DF. Inflammation is involved in the organ damage induced by sinoaortic denervation in rats. J Hypertens 2003;21: 2141–8. Yu JG, Song SW, Shu H, et al. Baroreflex deficiency hampers angiogenesis after myocardial infarction via acetylcholineα7-nicotinic ACh receptor in rats. Eur Heart J 2013;34: 2412–20. Sabbah HN, Ilsar I, Zaretsky A, Rastogi S, Wang M, Gupta RC. Vagus nerve stimulation in experimental heart failure. Heart Fail Rev 2011;16:171–8. Sabbah HN. Electrical vagus nerve stimulation for the treatment of chronic heart failure. Cleve Clin J Med 2011; 78:S24–9. Ruble SB, Hamann JJ, Gupta RC, Mishra S, Sabbah HN. Chronic vagus nerve stimulation impacts biomarkers of heart failure in canines. J Am Coll Cardiol 2010;55:A16.

ME

D I C I N E

[71]

[72]

[73]

[74] [75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87] [88]

26 (2016) 1–11

Hamann JJ, Ruble SB, Stolen C, et al. Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure. Eur J Heart Fail 2013;15: 1319–26. Yu H, Tang M, Yu J, Zhou X, Zeng L, Zhang S. Chronic vagus nerve stimulation improves left ventricular function in a canine model of chronic mitral regurgitation. J Transl Med 2014;12:302. Ismahil MA, Hamid T, Bansal SS, Patel B, Kingery JR, Prabhu SD. Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ Res 2014;114:266–82. Blum A, Miller H. Pathophysiological role of cytokines in congestive heart failure. Annu Rev Med 2001;52:15–27. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002; 91:988–98. Chen D, Assad-Kottner C, Orrego C, Torre-Amione G. Cytokines and acute heart failure. Crit Care Med 2008;36: S9–16. Vistnes M, Waehre A, Nygard S, et al. Circulating cytokine levels in mice with heart failure are etiology-dependent. J Appl Physiol 2010;108:1357–64. Aukrust P, Ueland T, Muller F, et al. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation 1998;97:1136–43. Aukrust P, Ueland T, Lien E, et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999;83: 376–82. Testa M, Yeh M, Lee P, et al. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol 1996;28:964–71. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201–6. Yan AT, Yan RT, Cushman M, et al. Relationship of interleukin-6 with regional and global left-ventricular function in asymptomatic individuals without clinical cardiovascular disease: insights from the Multi-Ethnic Study of Atherosclerosis. Eur Heart J 2010;31:875-82. Wirtz PH, Redwine LS, Linke S, et al. Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) independently predict depressive symptom severity after 12 months in heart failure patients. Brain Behav Immun 2010; 24:366–9. Alvarez-Guardia D, Palomer X, Coll T, et al. The p65 subunit of NF-{kappa}B binds to PGC-1{alpha} linking inflammation and metabolic disturbances in cardiac cells. Cardiovasc Res 2010;87:449–58. von Haehling S, Schefold JC, Lainscak M, Doehner W, Anker SD. Inflammatory biomarkers in heart failure revisited: much more than innocent bystanders. Heart Fail Clin 2009;5:549–60. Matsumori A. Treatment options in myocarditis: what we know from experimental data and how it translates to clinical trials. Herz 2007;32:452–6. Vallejo J, Mann DL. Antiinflammatory therapy in myocarditis. Curr Opin Cardiol 2003;18:189–93. Smeets PJ, Teunissen BE, Planavila A, et al. Inflammatory pathways are activated during cardiomyocyte hypertrophy and attenuated by peroxisome proliferator-activated receptors PPARalpha and PPARdelta. J Biol Chem 2008;283: 29109–18.

T

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96] [97]

[98]

R E N D S I N

C

A R D I O V A S C U L A R

Kang YM, Zhang ZH, Xue B, Weiss RM, Felder RB. Inhibition of brain proinflammatory cytokine synthesis reduces hypothalamic excitation in rats with ischemia-induced heart failure. Am J Physiol Heart Circ Physiol 2008;295: H227–36. Dinh W, Futh R, Nickl W, et al. Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders. Cardiovasc Diabetol 2009;8:58. Mehta JL, Li DY. Inflammation in ischemic heart disease: response to tissue injury or a pathogenetic villain? Cardiovasc Res 1999;43:291–9. Hamid T, Gu Y, Ortines RV, et al. Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation 2009;119:1386–97. Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 2001;103:2055–9. Kubota T, McTiernan CF, Frye CS, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81:627–35. Liaquat A, Shauket U, Ahmad W, Javed Q. The tumor necrosis factor-alpha-238G/A and IL-6-572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls. Clin Chem Lab Med 2015;53:307–18. Yang Y, Zhang F, Skrip L, et al. IL-6 gene polymorphisms and CAD risk: a meta-analysis. Mol Biol Rep 2013;40:2589–98. Ishikawa C, Tsutamoto T, Fujii M, Sakai H, Tanaka T, Horie M. Prediction of mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in patients with dilated cardiomyopathy. Circ J 2006;70:857–63. Danesh J, Kaptoge S, Mann AG, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008;5:e78.

ME

D I C I N E

[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

26 (2016) 1–11

11

Bibek SB, Xie Y, Gao JJ, Wang Z, Wang JF, Geng DF. Role of pre-procedural c-reactive protein level in the prediction of major adverse cardiac events in patients undergoing percutaneous coronary intervention: a meta-analysisof longitudinal studies. Inflammation 2015;38:159-69. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594–602. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003; 107:3133–40. Anker SD, Coats AJ. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 2002;86:123–30. Torre-Amione G, Anker SD, Bourge RC, et al. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial. Lancet 2008;371:228–36. Heymans S, Hirsch E, Anker SD, et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2009;11:119–29. Sloan RP, McCreath H, Tracey KJ, Sidney S, Liu K, Seeman T. RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol Med 2007;13:178–84. Zannad F, De Ferrari GM, Tuinenburg AE, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy for Heart Failure (NECTAR-HF) randomized controlled trial. Eur Heart J 2015;36:425–33.