Immune Modulation in Heart Failure - Springer Link

4 downloads 0 Views 358KB Size Report
... Failure: Past Challenges and Future Hopes. Jose H. Flores-Arredondo & Gerardo García-Rivas &. Guillermo Torre-Amione. Published online: 8 January 2011.
Curr Heart Fail Rep (2011) 8:28–37 DOI 10.1007/s11897-010-0044-2

Immune Modulation in Heart Failure: Past Challenges and Future Hopes Jose H. Flores-Arredondo & Gerardo García-Rivas & Guillermo Torre-Amione

Published online: 8 January 2011 # Springer Science+Business Media, LLC 2011

Abstract Immune-modulation therapy has had great success in various inflammatory diseases. Despite the promising results of preliminary studies in anti-tumor necrosis factor-α therapies, large randomized studies have lacked positive clinical outcomes in patients with heart failure. These results have led to the idea that therapies directed toward specific inflammatory mediators may not be the answer and lead us toward the development of novel anti-inflammatory strategies that may involve a broader spectrum of inflammatory mediators. Therapeutic plasma exchange has been demonstrated as a safe treatment, and preliminary outcomes led us to develop new treatment schemes. Keywords Neurohormonal . Heart failure . Interleukin-1 . Interleukin-6 . Tumor necrosis factor-α . Immune modulation . Therapeutic plasma exchange . Intravenous immunoglobulin . Cytokines Clinical Trial Acronyms ACCLAIM Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy ATTACH Anti-TNF-α Therapy against Chronic Heart Failure J. H. Flores-Arredondo : G. Torre-Amione (*) Methodist DeBakey Heart Center, The Methodist Hospital, 6550 Fannin Street, Suite 1901, Houston, TX 77030, USA e-mail: [email protected] G. García-Rivas : G. Torre-Amione Instituto de Cardiología y Medicina Vascular del Tecnológico de Monterrey, Av. Morones Prieto #3000 Pte. Col. Los Doctores, Monterrey, Nuevo León, Mexico CP 64710

CORONA GISSI-HF

RECOVER RENAISSANCE

SOLVD

Controlled Rosuvastatin in Multinational Trial in Heart Failure Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (Italian Group for the Study of Survival in Myocardial Infarction) Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction Randomized Etanercept North American Strategy to Study Antagonism of Cytokines Studies of Left Ventricular Dysfunction

Introduction It has become clear that the mechanisms that contribute to the progression of heart failure (HF) involve a variety of compensatory mechanisms that are triggered in response to the failing heart. The most relevant ones are the reninangiotensin system and the β-adrenergic system. These two systems are important not only because they are known to be upregulated and capable of inducing cardiac dysfunction in experimental animals, but also, more importantly, because pharmacological interventions aimed to modulate their activation are associated with amelioration of disease progression and increased survival. This general concept has led to the notion that persistent activation of systems that are initially compensatory may lead to long-term cardiac injury, and that proper manipulation of those systems may lead to improved survival. Unfortunately, clinical studies that block other neurohormonal pathways (e.g., endothelin 1) have not demonstrated clinical benefit in addition to the clinical benefit observed with

Curr Heart Fail Rep (2011) 8:28–37

angiotensin-converting enzyme–inhibitors and β-blockers. This observation has raised the question as to whether it is possible to further improve clinical outcomes in patients with HF treated with maximal medical therapy by modulating other neurohormonal pathways. Among patients with HF, there is significant activation of a variety of inflammatory molecules and pathways. These include increases in proinflammatory cytokines, activation of T cells, the formation of autoantibodies, and the activation of the complement system. For the most part, these elements of the inflammatory cascade are secreted in response to injury, specifically cardiac or vascular injury, and exert effects in the local microenvironment. These inflammatory components represent a system response to injury that is somewhat different to the conventional neurohormonal response. The inflammatory response constitutes a basic response to injury; it is active in the local microenvironment, is redundant, and expands easily. Modulation of inflammatory pathways has led to a number of clinical benefits in conditions wherein the immune system is overactive and partly responsible for tissue injury. Therefore, understanding the response of the immune system to cardiac injury and attempts to regulate such a response may provide a therapeutic opportunity different than the one observed with neurohormonal intervention.

Cytokines and Heart Failure Cytokines are polypeptide or glycoprotein factors that signal a vast array of physiologic responses via specific membrane-bound receptors. The most studied cytokines in cardiology are tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, and IL-10. Proinflammatory cytokines can be secreted from many types of nucleated cells, including the myocardium, endothelium, and adipose tissue [1–3], and can modulate cardiac function via effects on contractile cells and the extracellular matrix. The response evoked may be either stimulatory or depressant depending on the redox state of the cell [4]. These effects are elicited by the interaction of cytokines, and their receptors are dependent on the exposure time. The immediate contractile effects result from nitric oxide (NO) derived from constitutive nitric oxide synthase (NOS) from endothelial cells, sphingolipid mediators, arachidonic acid, and alterations in intracellular Ca2+. The delayed response is due to NO from inducible NOS, reactive oxygen species, and β-adrenergic receptor (β-AR) modulation [3]. Tumor Necrosis Factor-α TNF-α is a proinflammatory cytokine initially identified by its ability to induce necrosis in experimental tumors, but

29

also was a mediator of cachexia [5]. Early observations in patients with advanced HF, suggest that in cachectic patients with HF, there were increased levels of TNF-α that may in part explain the syndrome of cardiac cachexia [6, 7]. Subsequently, TNF-α was found to be released during endotoxemia and was found to induce reversible inotropic effects in vitro and in vivo [8]; thus, the hypothesis was put forth that TNF-α was present in patients with HF, and may contribute to the progression of HF. However, to further strengthen this hypothesis, it is necessary to demonstrate that TNF-α receptors were present in the human heart and understand how these are regulated. Studies from various laboratories demonstrated that TNF-α was produced not only in immune cells in the periphery, but also in the failing human heart in response to hemodynamic stimuli, and that the human heart expressed both TNF-α receptors. Importantly, it was found the TNF-α receptors were downregulated in patients with HF [9]. With this information as the experimental basis to further pursue the hypothesis of TNF-α as a major pathogenetic mediator of HF, initial clinical trials that demonstrated early safety and a potential for clinical benefit were conducted. Animal experiments with TNF-α have shown that the immediate effects on contractile function are reversible when the concentrations are lowered [10]. A single infusion of recombinant TNF-α can elicit contractile dysfunction, slow ventricular relaxation, and cause left ventricular (LV) dilation and diastolic stiffness. These effects are reversible if the stimulus lasts only up to a couple of days. Further studies revealed that before the dysfunction was present, there was a short-lasting positive inotropic and lusitropic effect. The conclusion of the immediate effect of cytokinereceptor interaction is a biphasic effect, suggesting initial mechanisms with no gene expression followed by a delayed onset and prolonged duration response suggestive of de novo gene expression and protein synthesis, and activation of secondary mediators [11, 12]. The main TNF-α production site is the activated macrophage, but many other cell types, such as fibroblasts, neutrophils, endothelial cells, vascular smooth muscle, mast cells, adipocytes, and cardiomyocytes themselves also have been implicated as sources under stimuli of hypoxia, mechanical stress and endotoxins [2, 13]. Experimental evidence of local TNF-α synthesis in feline myocardium was initially observed when correlated in a directly proportional manner with the degree of distension of the LV cavity1,9. This data was confirmed by Ferrari et al. [14] observing the presence of mRNA and cytokine receptors in human myocytes isolated from necropsy hearts. Based on these observations, it was clear that cardiac myocytes, when stimulated by pressure or volume load, were capable of producing TNF-α. In turn, local production would lead to

30

spill over into the circulation, and contribute to the immune activation and systemic inflammatory status. Patients with HF have increased levels of serum TNF-α and IL-6, which are directly correlated with a worsening prognosis. Patients from the SOLVD trial had higher TNF-α and IL-6 levels in comparison to the control patients and were directly correlated with the New York Heart Association (NYHA) functional class [15]. The effects of TNF-α are mediated through two different receptors. The type 1 receptor regulates the negative inotropic effect of TNF-α, even though both receptors are expressed in similar proportions and have equal affinity for its ligand. Two soluble proteins bind TNF-α [16, 17], both of which are fragments resembling the extracellular regions of the membrane-bound receptors. The binding of TNF-α with a soluble receptor causes an inactivation of the protein and is perceived as a buffering system. However, it still is unknown if these soluble receptors in the periphery are capable of neutralizing the effects of TNF-α synthesized centrally within the myocardium, or if they stabilize TNF-α in the circulation and act as a reservoir with a slow release of active cytokines into the circulation. Hasper et al. [18] hypothesize that the inefficient vasodilatory response and the reduced aerobic enzyme activity characteristic of the multiorgan involvement of HF would be sufficient stimuli to cause a systemic cytokine overexpression. Tissue hypoxia and free radical generation are potent stimuli for the synthesis of nuclear factor (NF) ĸβ-associated cytokines in immunocompetent cells of the whole body [19]. As the disease progresses, the elevated levels of cytokines would worsen the endothelial dysfunction, tissue hypoxia, and skeletal muscle apoptosis even more, and serve as a stimulus for the systemic synthesis of cytokines and oxidative stress, creating a vicious cycle of the disease and promotion of cachexia that mimics systemic progression of HF. NFĸ-β is a transcription factor that regulates several proinflammatory molecules and may be activated by multiple stimuli such as hypoxia, ROS, and cytokines among others [20•, 21•]. The myocardial tissue of patients with HF of different etiologies exhibits overexpression of this molecule and of the genes that it regulates, such as those associated with the synthesis of TNF-α, NO, leukocyte-adhesion molecules, and metalloproteinases. It has been demonstrated in vitro that many types of cells such as endothelial cells, macrophages, leukocytes, and cardiomyocytes synthesize NFĸ-β in response to some cytokine stimuli in a positive feedback pattern that sustains the inflammatory activation [21•]. Interleukin-6 IL-6 is a multifunctional cytokine that has been linked to the progression of cardiac dysfunction [22••]. IL-6 promotes

Curr Heart Fail Rep (2011) 8:28–37

lymphocyte proliferation and maturation, promotes cardiomyocyte hypertrophy, and stimulates the synthesis of caspases and hepatic mediators of the acute response, such as C-reactive protein (CRP). IL-6, along with other cytokines (e.g., TNF-α, IL-1β), has proven to induce muscle proteolysis, leading to cachexia and weight loss [7]. Recently, Plenz et al. [23] studied the hearts of patients with advanced HF at the moment of organ explantation for transplant and found a messenger RNA (mRNA) expression for IL-6 and its receptor on myocardial tissue significantly greater than that found in biopsy specimens of individuals with no structural disease undergoing electrophysiologic study. Although myocardial production of IL-6 is significant, it also may be produced in the periphery. For example, one study showed that not only were peripheral IL-6 levels significantly increased in femoral arteries and veins of patients with HF, but also that there was an increased difference of arteriovenous concentrations of IL-6 that correlated with disease severity [24]. Munger et al. [25] conducted a retrospective study in 78 patients with NYHA class III and IV HF and found a significant increase in IL-6 levels in patients with advanced disease and progression, regardless of the etiology. Lommi et al. [26] observed that IL6 levels are directly related to filling pressures and inversely related to cardiac output, thus apparently reflecting a hemodynamic impact mediated by the concentration of IL-6. In their study, Kell et al. [27] analyzed plasma concentrations of IL-1, IL-6, IL-10, IL-12, TNF-α, and soluble CD14 in 91 patients with NYHA class III HF and ejection fraction (EF) less than 40%. After a mean follow-up of 22 months, IL-6 proved to be the prognostic marker of survival with the greatest independent predictive power in 1 year. Interleukin-1 In humans, most cell types can produce IL-1 under varying physiologic conditions [6]. The mechanism through which IL-1 triggers its proinflammatory effects seems to involve prostaglandin synthesis and, perhaps, a direct action on βAR uncoupling [3]. Thaik et al. [28] studied rat cardiomyocyte cultures and observed that the IL-1β stimulus is able to cause hypertrophy via a NO-independent mechanism, with induction of fetal gene synthesis and downregulation of genes that regulate intramyocytic Ca2+ dynamics. The negative inotropic effect of IL-1 is mediated by directly stimulating NO synthesis [29•]. IL-1—soluble receptors have been considered the most sensitive and reliable markers of activation of the IL-1 loop and have a strong correlation with the severity of several diseases such as HF or sepsis, where peripheral levels of IL-1 are usually low [30]. Recently, peripheral detection of a soluble form of IL-1 membrane receptor called ST2 has been reported as predictive of events in patients with HF [29•, 31••].

Curr Heart Fail Rep (2011) 8:28–37

31

Pathways of Immune Activation in Cardiac Injury The activation of inflammatory components may occur by at least two distinct pathways: 1) by direct stimulation of an antigen expressed in the normal myocyte that leads to an immune attack resulting in cardiac injury; and 2) by the result of neo-expression of a protein in the cell surface that triggers an immune response. Acute myocarditis and acute cardiac allograft rejection are two classic examples of immune activation by direct antigenic stimulation. In acute myocarditis, a cardiotrophic virus infects the cardiomyocyte and triggers a variety of immune responses orchestrated by T helper type 1 lymphocytes. These responses activate the inflammatory cascade as well as mononuclear and B cells. These cells are capable of producing proinflammatory cytokines such as TNF-α, IL-6, IL-1B, IL-2, and can release toxic oxygen species that may affect cardiac function [32–35]. Similarly, when the myocardium of an allograft transplant recipient undergoes rejection, differences in major histocompatibility complex elicit a T cell—mediated response that also activates the inflammatory cascade. While the initial insult differs in both scenarios, histological evaluation of endomyocardial biopsies in both settings show equal infiltrates of mononuclear, B, and T cells, as well as increased levels of certain proinflammatory cytokines (TNF-α, IL-1 and IL-6) [36–38]. The proinflammatory and anti-inflammatory cytokines as well as their pathogenic potential can be seen in Table 1. On the other hand, immune activation secondary to cardiac injury occurs when new antigenic peptides are present in the myocardium, which triggers an immune response. For example, after a myocardial infarction, inflammatory cells populate the area and autoantibodies directed against cardiac specific proteins such as myosin become present. These antimyosin antibodies are found in patients with HF, and animal models have shown that immunization with myosin leads to the development of

myocarditis. Also, antibodies against the β-AR are found in patients with advanced nonischemic cardiomyopathy. In dilated cardiomyopathy, there are detectable autoantibodies directed against certain cellular proteins such as the sarcolemmal Na-K-adenosine triphosphate (ATP) or the mitochondrial adenosine diphosphate/ATP carrier [39•, 40, 41, 42•, 43]. In addition to the presence of autoantibodies, there is evidence of activation of the complement system, increased expression of class II human leukocyte antigen genes and intracardiac cytokines [44–46]. Therefore, regardless of the initial cardiac insult, myocardial injury leads to activation of the inflammatory cascade. A schematic representation of the inflammatory mediators and cells involved in HF can be seen in Fig. 1. Experimental Evidence of Immune Activation To establish a direct relationship between the activation of the inflammatory cascade in a state of cardiac injury, it is important to define the type of hemodynamic insult and isolate possible variables within an experimental mode. To accomplish this, we adapted a HF model, induced by the administration of salt, NG-nitro-L-arginine methyl ester and angiotensin II, that induces hypertension and cardiac dysfunction [47]. Under well-controlled experimental conditions that result from the administration of these agents, the experimental animals developed hypertension, and in association with that hemodynamic change, there is increased production of intracardiac proinflammatory cytokines. In addition, there is decreased expression of anti-inflammatory cytokines, in particular, IL-10. These inflammatory changes are associated with increased hypertrophy and fibrosis and a decrease LVEF. However, the contribution of this expression of inflammatory molecules on cardiac phenotype is unknown. Figure 2 shows the changes that occur at the histological level in mice treated to develop HF and the expression of inflammatory molecules.

Table 1 Cytokines involved in congestive heart failure Cytokine

Proinflammatory?

Anti-inflammatory?

Pathogenic response

TNF-α

Yes

No

IL-1B IL-4

Yes No

No Yes

IL-6

Yes

No

IL-10

No

Yes

IL-18

Yes

No

Known to participate in the progression of heart failure via cellular remodeling and apoptosis Increase in fibrotic response in myocardial tissue Inhibits the production of proinflammatory cytokines while it upregulates the fibrotic response Direct correlation between IL-6 upregulation and risk for CHF; IL-6 also has been known for its NFĸ-β activation Inhibits the secretion of TNF-α; found to be decreased in heart failure and has demonstrated a direct correlation with decreased LVEF Has been found to induce osteopontin and mediate fibrosis

CHF congestive heart failure; IL interleukin; LVEF left ventricular ejection fraction; NF nuclear factor; TNF-α tumor necrosis factor alpha.

32

Fig. 1 Schematic of the interplay between the inflammatory mediators and inflammatory cells and the resulting cardiac abnormalities in heart failure. Cardiac insult activates naïve B-cell activation and T cells through antigen presentation via the CD40L and the T-cell receptors, resulting in isotype switching and antibody deposition. a IgG deposition. Macrophage and T-cell production of inflammatory

Curr Heart Fail Rep (2011) 8:28–37

cytokines lead to activation of B cells in the inflammatory cascade through various proinflammatory cytokines as well as an effect on fibroblasts and cardiac muscle resulting in b collagen accumulation and c cardiac cell hypertrophy, commonly seen in heart failure. Ig immunoglobulin; IL interleukin; TNF-α tumor necrosis factor alpha

Management of Heart Failure as an Inflammatory Illness Most of the work directed to decrease immune activation in HF has centered on the role of TNF-α in chronic HF. The reasons are that TNF-α is the most studied cytokine and there are specific receptors (a variety of those) in clinical practice for other conditions involving TNF-α as a mediator of injury. However, it has become clear that a specific strategy is not sufficient or feasible in the treatment of patients with chronic HF. The various approaches aimed to decrease various aspects of immune activation in patients with HF will be briefly reviewed. The broad category of therapies can be divided into specific or broad-spectrum interventions Specific Immunomodulatory Strategies

Fig. 2 The histological and polymerase chain reaction findings in a nonischemic model of heart failure. In histological sections, a significant amount of collagen deposition (Pink) is observed in a heart failure model in comparison to normal. Pro-inflammatory cytokines related to heart failure as well as collagen are found to be elevated in a heart failure model (four right bands) in comparison to control (four left bands), while anti- inflammatory cytokines such as IL-10 are found to be decreased. Ang II angiotensin II; ET-1 endothelin 1; IL interleukin; Lname NG- nitro-L-arginine methyl ester; MCP-1 monocyte chemotactic protein 1; TNF-α tumor necrosis factor alpha

While evidence of preclinical and preliminary clinical studies support the role of TNF-α in the pathogenesis of congestive heart failure (CHF), large clinical trials demonstrate little effect of anti-TNF-α therapies. In both the RECOVER and RENNAISSANCE trials, no significant differences in all-cause mortality and HF hospitalization were seen in patients with CHF (NYHA class II-IV) after treatment with etanercept [48]. The ATTACH trial demonstrated a dose-related increase in death and hospitalizations using

Curr Heart Fail Rep (2011) 8:28–37

33

infliximab (a humanized murine monoclonal antibody against TNF-α) in patients with NYHA class III and IV HF [49]. Low-dose anti-TNF-α therapy in patients with documented inflammatory/metabolic problems or in cardiac cachexia has not yet been adequately assessed. Given that the immune system is redundant and the heterogeneity in the degree of immune and inflammatory activation in different HF populations, further studies that better profile and select eligible patients for anti-inflammatory therapy are required. A summary of specific immunomodulatory therapies as well as their impact can be found in Table 1. Nonspecific Immunomodulatory Strategies There are a number of strategies with potential immunomodulatory effects; however, the most relevant ones are those that have been conducted that directly diminish the number of autoantibodies, either by using high doses of immunoglobulins or removing them with either immunoadsorption or therapeutic plasma exchange (TPE). Intravenous immunoglobulin (IVIG) therapy is used in certain autoimmune diseases and has effects on neutralization of autoantibodies and inhibition of complement activation. Some clinical studies in patients with CHF suggest significant increases in anti-inflammatory mediators (IL-10), decline in pulmonary wedge pressure, and improvements in NYHA class, but further clinical trials still are required. On the downside, maintenance therapy is required and long-term use appears to enhance complement activation [50, 51]. Autoantibodies are thought to play a role in the pathogenesis of myocarditis and idiopathic dilated cardiomyopathy. In this context, it is logical that immunoadsorption therapy could remove circulating autoanti-

bodies and hopefully improve cardiac function. The few small clinical trials regarding the use of immunoadsorption show promising results, especially in patients with dilated cardiomyopathy; however, large trials still are required [52, 53]. Other Nonspecific Interventions Immune-modulation Therapy Immune-modulation therapy (IMT) consists of autologous blood being exposed ex vivo to oxidative stress at elevated temperatures and administered intramuscularly to patients with CHF, resulting in an increase in anti-inflammatory cytokines. While significant reductions in risk of death, mortality, and hospitalization were observed in patients with CHF treated with IMT in small clinical trials, the phase 3 ACCLAIM trial did not show a significant difference in CHF hospitalization or mortality. However, in patients with no prior history of a myocardial infarction or patients with NYHA class II HF, there was a significant reduction in CHF hospitalization and time to death. These findings further support the need for more detailed immunologic profiling for patients with CHF in future anti-inflammatory clinical trials [54, 55, 56••, 57]. Pentoxifylline Pentoxifylline is a purine derivative that has vasodilatory and anti-inflammatory properties. In patients with dilated cardiomyopathy, small pentoxifylline trials show some significant increase in EF, improved functional status, and increased exercise tolerance. But the long-term effect on mortality or CHF-related hospitalizations remains debatable [58].

Table 2 Specific immunomodulatory strategies Study

Year Patients, Treatment n

Primary end point

Primary end point reached?

Secondary end point

Secondary end point reached?

IMAC I

2001

62

IVIG

Change in LVEF

No

None

N/A

ATTACH [49]

2003

150

Infliximab

Clinical improvement No

No

RECOVER RENAISSANCE RENEWALb [48] ACCLAIM [56••]

2004 2004 2004

1123 925 2048

Etanercept Etanercept Etanercept

Clinical improvement No Clinical improvement No Death/hospitalization No

Change in LVEF or inflammatory markers Overall mortality Overall mortality None

2008

2426

Immunomodulation Overall mortality/CV No hospitalization

Change in LVEF and/or NYHA class

No

a

Group taking etanercept, 25 mg twice weekly (n=300).

b

Combined outcome of death/hospitalization in patients taking higher doses of etanercept in RECOVER and RENAISSANCE.

Yesa No N/A

ACCLAIM Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy; ATTACH Anti-TNF-α Therapy against Chronic Heart Failure; CV cardiovascular; IMAC I Intervention in Myocarditis and Acute Cardiomyopathy; IVIG intravenous immunoglobulin; LVEF left ventricular ejection fraction; N/A not applicable; NYHA New York Heart Association; RECOVER Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction; RENAISSANCE Randomised Etanercept North American Strategy to Study Antagonism of Cytokines; RENEWAL Randomised Etanercept Worldwide Evaluation.

34

Curr Heart Fail Rep (2011) 8:28–37

Table 3 Nonspecific immunomodulatory strategies Study

Year Patients, Treatment n

Primary end point

Primary end Secondary end point Secondary end point reached? point reached?

Intravenous immunoglobulin [50] CORONA [62]

2001

40

IVIG

Change in inflammatory and anti-inflammatory mediators

Yes

Change in LVEF

Yes

2007

5011

Rosuvastatin

Decrease in vascular events or CV death

No

No

GISSI-HF [61]

2008

4574

Rosuvastatin

Time to death or admission to hospital for CV reasons

No

CORONA (subset analysis)

2009

4961

Rosuvastatin

Decrease in vascular events or CV death

Yesa

Therapeutic 2010 plasma exchange [65]

10

IVIG and plasma exchange

Change in LVEF and quality of life

No

Mortality, coronary event, CV death, and hospitalization CV mortality, hospitalizations, sudden cardiac death, hospitalization for CV event, HF, MI, or stroke Mortality, coronary event, CV death, and hospitalization None

a

No

No N/A

Reduced incidence of primary end point in hs-CRP≥2.0 mg/L.

CORONA Controlled Rosuvastatin in Multinational Trial in Heart Failure; CV cardiovascular; GISSI-HF Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (Italian Group for the Study of Survival in Myocardial Infarction); HF heart failure; IVIG intravenous immunoglobulin; LVEF left ventricular ejection fraction; MI myocardial infarction; N/A not applicable.

Statin Therapy Statins, having pleiotropic properties, are known to decrease inflammatory markers. In a simple observational study, we found that the use of statins is associated with decrease expression of intramyocardial TNF-α [59]. The abundance of potential beneficial effects in patients with HF led to a large randomized clinical trial in HF aimed to define an effect in the progression of HF. Unfortunately,

Fig. 3 The histopathologic, clinical, and functional outcomes of patients treated with plasma exchange and IVIG. Staining intensity shows a decrease in a IgG deposition in patients during follow-up as well as a b change in NYHA Classification and c change in left

CORONA and GISSI-HF failed to demonstrate conclusive clinical benefits when statins where used in patients with HF [60, 61]. However, a subset analysis of CORONA demonstrated a reduction in high-sensitivity CRP (hs-CRP), low density lipoprotein cholesterol, and cardiovascular events in patients treated with rosuvastatin, indicating an association of decreased events with anti-inflammatory properties. Furthermore, McMurray et al. [62] found that those patients that had higher hs-CRP (≥2 mg/L) at the

ventricular ejection fraction. IG immunoglobulin; IVIG intravenous immunoglobulin; LVEF left ventricular ejection fraction; NYHA New York Heart Association

Curr Heart Fail Rep (2011) 8:28–37

beginning of the study and who were treated with rosuvastatin had the greatest benefit of statin therapy [62]. This finding was consistent with the hypothesis that statin therapy may have an anti-inflammatory effect. Table 2 presents a summary of various studies of nonspecific immunomodulatory strategies (Table 3). Future Therapies Therapeutic Plasma Exchange It is clear that HF increases a variety of inflammatory molecules, and it would be difficult to imagine that a single intervention may result in a profound benefit. TPE is a strategy whereby large amounts of plasma are removed from the circulation. This results in a reduction of circulating inflammatory cytokines and antibodies as well as complement components [63, 64]. We tested this concept by performing a small nonrandomized clinical study in patients with advanced HF. TPE was performed in five sessions, each consisting in replacing a patient’s plasma with 5% albumin as well as physiologic concentrations of potassium chloride and calcium gluconate. The therapeutic exchange was performed in five 60- to 90-min sessions. Plasma exchange demonstrated to be well tolerated even in patients with compromised cardiac function. After the last session of TPE, IVIG was used to replace the removed proteins at 500 mg/kg−1. Patients treated with therapeutic plasma exchange demonstrated improved LVEF as well as improvements in quality of life as measured by the Minnesota Living with Heart Failure Questionnaire. In addition, a reduction of the presence of immunoglobulin G in myocardium toward normal was demonstrated, as well as a decrease in myocyte hypertrophy [65]. The previously mentioned therapies raise the question of the importance of antigen presentation and immune complex activation of the inflammatory response in HF. It is important to apply these therapies to a higher number of patients to check safety and efficacy. An illustration demonstrating the results of TPE can be seen in Fig. 3.

Conclusions The systemic response to cardiac injury is characterized by mechanisms that are directed to reestablish hemodynamic stability and, subsequently, to improve and repair tissue injury. The components of the inflammatory cascade that are active in response to cardiac injury are inflammatory peptides and cytokines; T cells and B cells; and components of the complement cascade. Perhaps the most widely studied of these is the cytokine network and, in particular, TNF-α (a cytokine released in response to cardiac injury

35

and capable of inducing cardiac dysfunction). Experimental and clinical studies link TNF-α with the pathogenesis of HF, but large randomized clinical trials did not show clinical improvement in patients with symptomatic HF, giving rise to a serious question on whether therapeutic strategies directed to decrease inflammation are of any value. It is clear that active inflammatory components exist in patients with HF in the periphery as well as in the local microenvironment, and that multiple mechanisms do not operate as single molecules. Therefore, recent studies are directed to modulate an activation of the inflammatory cascade in a broad range. Pharmacologic treatment of HF is faced with a unique challenge. The fact that we have a number of drugs that incrementally improve HF means that new clinical studies must surpass current medical therapy to demonstrate clinical improvement. This concept is important because the absence of a clinical response with antiinflammatory strategies does not negate a pathogenic role of chronic inflammation in HF, but indicates that in the setting of the best current therapy, it is not possible to demonstrate additional clinical benefit. Future investigation in this area will define the role of autoantibodies in patients with HF, particularly among those with dilated cardiomyopathies. These strategies likely will involve broad spectrum interventions. We currently are developing new modalities of TPE, which may provide a novel anti-inflammatory strategy.

Disclosures No potential conflicts of interest relevant to this article were reported.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. Torre-Amione G, Kapadia S, Lee J, et al.. Tumor necrosis factoralpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93(4):704–11. 2. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548–56. 3. Prabhu SD. Cytokine-induced modulation of cardiac function. Circ Res. 2004;95(12):1140–53. 4. Choudhary G, Dudley SC Jr. Heart failure, oxidative stress, and ion channel modulation. Congest Heart Fail. 2002;8(3):148–55. 5. Rothstein JL, Schreiber H. Synergy between tumor necrosis factor and bacterial products causes hemorrhagic necrosis and lethal shock in normal mice. Proc Natl Acad Sci USA. 1988;85(2):607–11. 6. Levine B, Kalman J, Mayer L et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323(4):236–41.

36 7. Pajak B, Orzechowska S, Pijet B, et al. Crossroads of cytokine signaling—the chase to stop muscle cachexia. J Physiol Pharmacol. 2008;59(Suppl 9):251–64. 8. Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257(5068):387–9. 9. Torre-Amione G, Kapadia S, Lee J, et al. Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation 1995; 92(6):1487–93. 10. Bozkurt B, Kribbs SB, Clubb FJ Jr., et al. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998; 97(14):1382–91. 11. Wagner DR, Combes A, McTiernan C, et al. Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-alpha. Circ Res. 1998; 82(1):47–56. 12. Palmieri EA, Benincasa G, Di RF, et al. Differential expression of TNF-alpha, IL-6, and IGF-1 by graded mechanical stress in normal rat myocardium. Am J Physiol Heart Circ Physiol. 2002; 282(3):H926–34. 13. Kacimi R, Long CS, Karliner JS. Chronic hypoxia modulates the interleukin-1beta-stimulated inducible nitric oxide synthase pathway in cardiac myocytes. Circulation 1997; 96(6):1937–43. 14. Ferrari R, Bachetti T, Confortini R, et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 1995; 92(6):1479–86. 15. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991;325(5):293–302. 16. Seckinger P, Isaaz S, Dayer JM. A human inhibitor of tumor necrosis factor alpha. J Exp Med. 1988;167(4):1511–6. 17. Engelmann H, Aderka D, Rubinstein M, et al. A tumor necrosis factor-binding protein purified to homogeneity from human urine protects cells from tumor necrosis factor toxicity. J Biol Chem. 1989;264(20):11974–80. 18. Hasper D, Hummel M, Kleber FX, et al. Systemic inflammation in patients with heart failure. Eur Heart J. 1998;19(5):761–5. 19. Henderson BC, Tyagi SC. Oxidative mechanism and homeostasis of proteinase/antiproteinase in congestive heart failure. J Mol Cell Cardiol. 2006;41(6):959–62. 20. • Santos DG, Resende MF, Mill JG, et al. Nuclear Factor (NF) kappaB polymorphism is associated with heart function in patients with heart failure. BMC Med Genet. 2010;11:89. The importance of nuclear factor (NF)-κΒ as a transcription factor in heart failure and the diminished activation of NF-κB1 on the onset and progression of disease in HF demonstrated in this study reiterates the importance of this factor in the disease. 21. • Hamid T, Guo SZ, Kingery JR, et al. Cardiomyocyte NF{kappa}B p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc Res. 2010 September 16. The implication of NF-κB in various pathways of inflammation and its mysterious role in HF have led to studies to better understand this transcription factor, this article describes its possible role in cardiac remodeling via proinflammatory, profibrotic, and proapoptotic events. 22. •• Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol. 2010;55(19):2129–37. Inflammatory markers long have been described in HF and have been targeted in recent years as a means of therapy. The study investigators were able to associate incident HF (n=2610) with an increase in baseline inflammatory cytokines IL-6, TNF-α, and CRP. It previously has been described that IL-6 and TNF-α affect cardiomyocyte contractility as well as being implicated in cardiac remodeling.

Curr Heart Fail Rep (2011) 8:28–37 23. Plenz G, Eschert H, Erren M, et al. The interleukin-6/interleukin6-receptor system is activated in donor hearts. J Am Coll Cardiol. 2002;39(9):1508–12. 24. Plenz G, Song ZF, Tjan TD, et al. Activation of the cardiac interleukin-6 system in advanced heart failure. Eur J Heart Fail 2001;3(4):415–21. 25. Munger MA, Johnson B, Amber IJ, et al. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1996;77(9):723–7. 26. Lommi J, Pulkki K, Koskinen P, et al. Haemodynamic, neuroendocrine and metabolic correlates of circulating cytokine concentrations in congestive heart failure. Eur Heart J. 1997;18 (10):1620–5. 27. Kell R, Haunstetter A, Dengler TJ, et al. Do cytokines enable risk stratification to be improved in NYHA functional class III patients? Comparison with other potential predictors of prognosis. Eur Heart J. 2002;23(1):70–8. 28. Thaik CM, Calderone A, Takahashi N, Colucci WS. Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest. 1995;96(2):1093–9. 29. • Daniels LB, Clopton P, Iqbal N, et al. Association of ST2 levels with cardiac structure and function and mortality in outpatients. Am Heart J. 2010;160(4):721–8. ST2 is upregulated in cases of cardiomyocyte strain. The authors of this study (n=588) correlated right-sided heart size, function, and mortality with ST2 levels. This leads to the question of the prognostic significance that ST2 could have on predictive mortality risk. 30. Katz SD, Rao R, Berman JW, et al. Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive heart failure. Relation to nitric oxide-dependent vasodilation in the forearm circulation. Circulation 1994;90 (1):12–6. 31. •• Pascual-Figal DA, Ordonez-Llanos J, Tornel PL, et al. Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction. J Am Coll Cardiol. 2009;54(23):2174–9. The predictive value of ST2 in HF has gained popularity and has been challenging. Elevated soluble ST2 was found to have a positive predictive value in sudden cardiac death. This study brings to question the impact that ST2 could have in the future in clinical management in patients with HF. 32. Stein B, Frank P, Schmitz W, et al. Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol. 1996;28(8):1631–9. 33. Cunningham MW. T regulatory cells: sentinels against autoimmune heart disease. Circ Res. 2006;99(10):1024–6. 34. Blauwet LA, Cooper LT. Myocarditis. Prog Cardiovasc Dis. 2010;52(4):274–88. 35. Rose NR. Myocarditis: infection versus autoimmunity. J Clin Immunol. 2009;29(6):730–7. 36. Mengel M, Sis B, Kim D, et al. The molecular phenotype of heart transplant biopsies: relationship to histopathological and clinical variables. Am J Transplant. 2010;10(9):2105–15. 37. Moulik M, Breinholt JP, Dreyer WJ, et al. Viral endomyocardial infection is an independent predictor and potentially treatable risk factor for graft loss and coronary vasculopathy in pediatric cardiac transplant recipients. J Am Coll Cardiol. 2010;56(7):582–92. 38. Cunningham KS, Veinot JP, Butany J. An approach to endomyocardial biopsy interpretation. J Clin Pathol. 2006;59(2):121–9. 39. • Kaya Z, Katus HA, Rose NR. Cardiac troponins and autoimmunity: their role in the pathogenesis of myocarditis and of heart failure. Clin Immunol. 2010;134(1):80–8. Cardiac troponin I (cTNI) has been widely used in acute coronary syndrome (ACS) because of its sensitivity and specificity for

Curr Heart Fail Rep (2011) 8:28–37

40. 41. 42.

43.

44. 45. 46.

47.

48.

49.

50. 51. 52.

detecting cardiac lesions. In patients with ACS, cTNI antibodies were found to be present and the authors suggest that cTNI antibodies have an impact on LVEF. Caforio AL, Mahon NJ, Tona F, McKenna WJ. Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance. Eur J Heart Fail. 2002;4(4):411–7. Caforio AL, Mahon NJ, McKenna WJ. Cardiac autoantibodies to myosin and other heart-specific autoantigens in myocarditis and dilated cardiomyopathy. Autoimmunity 2001;34(3):199–204. • Bjerre M, Kistorp C, Hansen TK, et al. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure. Scand Cardiovasc J. 2010 June 7. Diabetes long has been associated with increased risk for cardiovascular disease. The authors hypothesize, based on preliminary evidence, that insulin resistance leads to complement activation and, subsequently, damage of heart tissues. Kohno K, Takagaki Y, Aoyama N, et al. A peptide fragment of beta cardiac myosin heavy chain (beta-CMHC) can provoke autoimmune myocarditis as well as the corresponding alpha cardiac myosin heavy chain (alpha-CMHC) fragment. Autoimmunity 2001;34(3):177–85. Marchant DJ, McManus BM. Regulating viral myocarditis: allografted regulatory T cells decrease immune infiltration and viral load. Circulation 2010;121(24):2609–11. Yajima T, Knowlton KU. Viral myocarditis: from the perspective of the virus. Circulation 2009;119(19):2615–24. Triantafilou K, Orthopoulos G, Vakakis E, et al. Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol. 2005;7(8):1117–26. Oestreicher EM, Martinez-Vasquez D, Stone JR, et al. Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury. Circulation 2003;108(20):2517–23. 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(13):1594–602. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-tosevere heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107 (25):3133–40. Gullestad L, Aass H, Fjeld JG, et al. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation 2001;103(2):220–5. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001;103(18):2254–9. Staudt A, Hummel A, Ruppert J, et al. Immunoadsorption in dilated cardiomyopathy: 6-month results from a randomized study. Am Heart J. 2006;152(4):712–6.

37 53. Staudt A, Staudt Y, Dorr M, et al. Potential role of humoral immunity in cardiac dysfunction of patients suffering from dilated cardiomyopathy. J Am Coll Cardiol. 2004;44(4):829–36. 54. Torre-Amione G, Sestier F, Radovancevic B, Young J. Broad modulation of tissue responses (immune activation) by celacade may favorably influence pathologic processes associated with heart failure progression. Am J Cardiol 2005;95(11A):30C–7C 55. Torre-Amione G, Sestier F, Radovancevic B, Young J. Effects of a novel immune modulation therapy in patients with advanced chronic heart failure: results of a randomized, controlled, phase II trial. J Am Coll Cardiol 2004;44(6):1181–6. 56. •• 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(9608):228–36. ACCLAIM was a double-blind placebocontrolled study in which patients were randomly assigned to immune-modulation therapy (n=1213) or placebo (n=1213). The importance of this study was the nonspecific targeting of inflammatory factors, based on the disappointing results obtained from anti-TNF-α therapy. Although the results of this study did not meet its end points, it leads us to believe that patients in the early stages of HF without myocardial infarctions would benefit from such a therapy. 57. Torre-Amione G, Bourge RC, Colucci WS, et al. A study to assess the effects of a broad-spectrum immune modulatory therapy on mortality and morbidity in patients with chronic heart failure: the ACCLAIM trial rationale and design. Can J Cardiol. 2007;23 (5):369–76. 58. Sliwa K, Woodiwiss A, Kone VN, et al. Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study. Circulation 2004;109(6):750–5. 59. Wallace CK, Stetson SJ, Kucuker SA, et al. Simvastatin decreases myocardial tumor necrosis factor alpha content in heart transplant recipients. J Heart Lung Transplant. 2005;24(1):46–51. 60. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357 (22):2248–61. 61. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1231–9. 62. McMurray JJ, Kjekshus J, Gullestad L, et al. Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis. Circulation 2009;120(22):2188–96. 63. Koo AP. Therapeutic apheresis in autoimmune and rheumatic diseases. J Clin Apher 2000;15(1–2):18–27. 64. Brecher ME. Plasma exchange: why we do what we do. J Clin Apher. 2002;17(4):207–11. 65. Torre-Amione G, Orrego CM, Khalil N, et al. Therapeutic plasma exchange a potential strategy for patients with advanced heart failure. J Clin Apher 2010 September 24.