Cardiovascular Research

Cardiovascular Research 2002 53(4):822-830; doi:10.1016/S0008-6363(01)00503-X
© 2002 by European Society of Cardiology

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Copyright © 2002, European Society of Cardiology

Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective

William S. Bradham^a, Biykem Bozkurt^b, Himali Gunasinghe^a, Douglas Mann^b and Francis G. Spinale^a,*

^aMedical University of South Carolina, Charleston, SC, USA
^bWinters Center for Heart Failure Research, Section of Cardiology, Houston VAMC and Baylor College of Medicine, Houston, TX, USA

^* Corresponding author. Cardiothoracic Surgery, Room 625, Strom Thurmond Research Building, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, USA. Tel.: +1-843-876-5184; fax: +1-843-876-5187

Received 12 July 2001; accepted 5 October 2001

	Abstract

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. Recent clinical and experimental studies have noted that increased release of tumor necrosis factor alpha (TNF-) can contribute to LV myocardial remodeling. Experimental studies have noted that the induction of TNF- can result in LV dilation and proceed to LV pump dysfunction. The biological effects of TNF- are mediated through TNF receptors that are present on all nucleated cells in the heart. TNF receptor activation can induce a number of cellular and molecular events which contribute to LV remodeling in CHF, and include changes in myocyte size and viability and alterations in myocardial structure/composition. In vitro studies have demonstrated that TNF receptor activation can cause the induction of a proteolytic system. This proteolytic system, the matrix metalloproteinases (MMPs), is upregulated in models of LV dysfunction and possesses the capacity to degrade a wide variety of extracellular matrix components. Therefore, one pathway by which TNF- can influence LV myocardial remodeling is through the induction of a specific portfolio of MMP species. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling will provide new insight into this disease process and future therapeutic modalities.

KEYWORDS AP-1, Activating protein 1; CHF, Congestive heart failure; ECM, Extracellular matrix; LV, Left ventricle; LVEF, Left ventricular ejection fraction; MMP, Matrix metalloproteinase; MRI, Magnetic resonance imaging; NF-B, Nuclear factor kappa B; NYHA, New York Heart Association; TNF-, Tumor necrosis factor alpha; TNFR1, Tumor necrosis factor alpha receptor type 1; TNFR2, Tumor necrosis factor alpha receptor type 2

	1. Introduction

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
Congestive heart failure (CHF) is a major cause of mortality and morbidity worldwide. While the fundamental definition of CHF is based upon signs and symptoms, the functional basis for this disease is left ventricular (LV) pump dysfunction. LV pump dysfunction can arise from a number of different etiologies which include myocardial infarction, hypertension and severe hypertrophy, valvular disorders, and the cardiomyopathies. Despite a multitude of causes for CHF, a milestone in the progression of the disease process is myocardial remodeling. Recent clinical and experimental studies have provided evidence to suggest that increased release of tumor necrosis factor alpha (TNF-) can contribute to the progression of LV pump dysfunction and CHF [1–27]. Experimental studies have documented that increased TNF- levels can cause LV remodeling and the development of LV dysfunction [21–23,25–27]. The purpose of this review is to examine the LV myocardial remodeling process with respect to the relationship of TNF- expression and the development of CHF.

	2. Heart failure and myocardial remodeling

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
The development and progression of LV dysfunction and ultimately the pathophysiological manifestation of CHF, is due to the summation of a number of systemic, cellular and molecular abnormalities [28]. The specific constellation of abnormalities which contribute to the progression of CHF are disease dependent, but likely include neurohormonal system activation, changes in LV loading conditions, defects in myocardial perfusion and metabolism, and alterations in excitation–contraction coupling [28]. One common structural feature in the progression of the CHF process is LV myocardial remodeling [28–31]. Myocardial remodeling can be defined as molecular, cellular, and interstitial changes within the myocardium that result in changes in LV size and function [28–30]. One of the predominant geometric features of myocardial remodeling is LV dilation [30–32]. In patients with CHF, the progression of LV dilation is associated with increased incidence of morbidity and mortality [30–32]. Within the cellular compartment, changes in myocyte structure occur which can include hypertrophy [28,30]. Myocyte loss by either necrosis or apoptosis is also a likely determinant of myocardial remodeling in CHF [28,33]. Changes in myocyte shape and alignment with the progression of LV remodeling are accompanied by alterations in the structure and function of the extracellular matrix (ECM). Comprised of a fibrillar collagen network, basement membrane, and proteoglycans; the ECM serves as a vital supporting scaffold providing structural integrity to adjoining myocytes and translating myocyte shortening to overall LV pump performance. The ECM has also been postulated to function in maintaining the alignment of myofibrils within the myocytes via a collagen–integrin–cytoskeletal–myofibril relationship [29]. The development of LV dilation has been shown to be associated with discontinuity and disruptions of this supporting fibrillar collagen network, reductions in the degree of collagen strut crosslinking, and disruptions in myocyte adhesion capacity to the basement membrane [34,35]. These observations have led to the hypothesis that a loss of myocyte extracellular support can facilitate the progression of LV dilation in patients with CHF [29,30].

	3. TNF- biology and signaling

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
In order to place the cytokine TNF- in the context of being a determinant of LV myocardial remodeling, then a brief review of the synthesis and signaling of this cytokine would be appropriate. Excellent in-depth reviews of this highly complex cytokine system have been published [36,37]. TNF- is synthesized as a nonglycosylated transmembrane protein of approximately 26 kDa, of which a soluble 17 kDa fragment is proteolytically cleaved from the plasma membrane by TNF- converting enzyme. Soluble TNF- is generally regarded to be an endogenous mediator of inflammation and associated phenomena, modulating a wide spectrum of cellular responses including activation of genes involved in inflammatory and immunoregulatory responses, cell proliferation, antiviral responses, growth inhibition, and cell death [36,37]. In the soluble form, three TNF- monomers assemble and circulate as a stable, 51 kDa homotrimer. The biological actions of TNF- result from the response of the target cell, which is mediated by two distinct surface receptor subtypes, TNFR1 (p55) and TNFR2 (p75) with molecular weights of 55–60 kDa and 70–80 kDa, respectively. TNFR1 is the main receptor subtype in most cell types including the myocardium, and the signal transduction for this receptor has been extensively studied. The transduction of signals from TNFR2 and its role in TNF- signaling have been less well characterized [38]. Inflammatory signals may result in the release of cytokine receptors from the cell membrane, a process referred to as receptor ‘shedding’ [39]. Shed TNF receptor complexes are thought to serve a beneficial physiologic role as a buffer against the potentially damaging acute effects of TNF-, but may also effect a detrimental impact as a source of prolonged cytokine activation. Due to the difficulty of directly measuring TNF- in the myocardial compartment, clinical studies have utilized the measurement of circulating TNF receptor as a relative index of local tissue TNF- activation [16].

TNF- binding to cell surface receptors results in the formation of signal transduction complexes that can rapidly activate several divergent downstream signaling pathways [40,41]. Signaling cascades initiated by TNF receptors include mitogen-activated protein kinases (ERK, JNK, p38) which can result in a diverse number of intracellular events including alterations in gene expression [36,37,40]. TNF receptor activation can induce transcription factors such as nuclear factor-kappa B (NF-kB), and activating protein-1 (AP-1) [40,41]. These pathways can induce a number of responses including cell growth, cell death, and of particular relevance to this discussion, the induction of biological processes that can directly affect LV structure and function in the heart failure process.

	4. TNF- and heart failure

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
Since the first observation by Levine noting increased levels of circulating TNF- occurring in patients with severe symptomatic heart failure, further clinical studies have supported the potential importance of TNF- in the pathogenesis of this disease process [1–5]. These initial observations provided the stimuli for more comprehensive studies aimed at defining the relationship between TNF- and the progression of heart failure [6–9]. Torre-Amione and colleagues, for example, reported elevated levels of circulating TNF- in patients with symptomatic LV dysfunction [12]. In this study, an eight-fold increase in circulating levels of TNF- was observed when compared to age-matched normal controls [12]. Torre-Amione and colleagues went on to demonstrate that elevated TNF- levels occurred in patients with progressive clinical signs and symptoms of heart failure [12]. These past observations would suggest that increased plasma TNF- levels would most likely be present only in those patients in which both LV dysfunction and significant manifestations of this disease process occur. However, a more recent study demonstrated that circulating plasma TNF- levels were equally elevated in patients with severe heart failure (NYHA class III) and more advanced heart failure (NYHA IV) [19]. These observations would suggest that increased plasma TNF- is not limited to those patients with extremely advanced CHF and attendant end-organ dysfunction. Several problematic issues surround the interpretation of these past studies regarding circulating plasma TNF- in CHF patients. First, the analytical assays used to measure TNF- levels differed between laboratories and therefore make comparisons between patients and studies difficult. Second, since TNF- can be synthesized within local tissue compartments, then circulating levels of TNF- may represent ‘spillover’ of TNF- produced within the tissue and may not accurately reflect local TNF- activity [17].

TNF- receptors can be ‘she’ from the myocardium following activation by TNF- and be detected in the plasma. Thus, relative plasma levels of TNF- receptors have been used as biomarkers to relate TNF- to the progression of heart failure [7,9,14,16,18,19]. In a recent study analyzing circulating plasma levels of TNF- and TNF- receptors in over 1000 patients with advanced heart failure [19], a significant relationship was observed between levels of soluble TNF- receptors and the heart failure disease process [19]. Furthermore, there was a direct relationship between soluble TNF- receptors and survival rates (Fig. 1). Using statistical modeling, the increases in soluble TNF- receptor subtypes were identified as independent predictors of mortality. In fact, the highest mortality rates occurred in patients with circulating TNFR1 levels greater than the 75^th percentile, and circulating levels of soluble TNFR2 greater than the 50^th percentile. Thus, the presence of increased plasma soluble TNF receptors in patients with CHF are likely indicative of local myocardial TNF- activation and a harbinger of poor prognosis.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Circulating levels of soluble tumor necrosis factor alpha receptor 1 (sTNFR1) were examined in relation to patient survival for 1169 patients (maximum duration, 78 weeks). There was a direct relationship between sTNFR1 and survival rates. The highest mortality rates occurred in patients with circulating TNFR1 levels greater than the 75th percentile. (Data reproduced from Deswal et al., 2001) [19].

 
In addition to circulating TNF-, myocardial TNF- has also been demonstrated to be elevated in the end-stage failing myocardium [13–15]. Clinical reports have shown persistent myocardial TNF- mRNA and protein levels in patients with cardiomyopathic disease [13]. However, it is important to recognize that myocardial TNF- levels are increased in severe heart failure, but do not appear increased in patients with mild heart failure. These findings underscore that increased levels of TNF- within the myocardium is not necessarily a primary event, but rather part of a cascade of events which likely contribute to the progression and exacerbation of the disease process [17].

Most cell types have the capacity to synthesize and release TNF-, including resident cells of the myocardium such as neutrophils, fibroblasts, vascular smooth muscle cells, and cardiac myocytes. Moreover, the synthesis and release of TNF- has been demonstrated both in vivo and in vitro following specific biological stimuli [20,21]. Kapadia and colleagues demonstrated that both TNF- mRNA and protein are rapidly synthesized in response to a pressure overload stimulus [22]. It has been reported that a regional distribution of TNF- within the failing myocardium exists that may be related to regional myocardial wall stress patterns [42]. This past study demonstrated that mechanical unloading of the LV in heart failure patients reduced myocardial TNF- levels [42]. Thus, while the causes for increased TNF- and subsequent TNF receptor activation are likely multifactorial, alterations in wall stress, which is a common structural and geometric manifestation of LV dysfunction, may be an important regulatory determinant of this cytokine system.

In animal model systems, a more precise cause and effect relationship has been described relating TNF- and LV dysfunction. Specifically, increased TNF- exposure to the myocardium either through osmotic infusion pump delivery or by transgenic over-expression has been demonstrated to reduce LV systolic function [23,27,43]. In an in vivo experiment by Bozkurt and colleagues, adult rats were surgically implanted with an osmotic minipump and infused with TNF- in order to reach plasma levels comparable to those reported in clinical heart failure [23]. In this model, a decrease in LV fractional shortening occurred after 5 days of TNF- infusion [23]. Removal of the TNF- pump resulted in the LV fractional shortening returning to control values (Fig. 2). Furthermore, in this past study, injection of a soluble TNF- neutralizing protein abrogated the effects of TNF- infusion on ejection performance. In another study using transgenic mice with specific myocardial overexpression of TNF-, LV ejection performance was reduced compared to wild-type mice [27]. Specifically, Kubota and colleagues documented reduced LV ejection fractions in the transgenic mice compared to age-matched wild-type mice based on magnetic resonance imaging methods [43]. In these model systems, a likely contributory factor for the reduced LV pump function is inherent defects in myocyte contractility [23]. For example, Bozkurt and colleagues demonstrated that contractile function in isolated myocytes was impaired following chronic exposure to elevated levels of TNF- [23].

View larger version (27K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Effect of continuous TNF- infusion in rats on LV geometry in vivo. LV dimensions were studied for 15 days following implantation of an intraperitoneal osmotic infusion that contained either diluent (n=20) or TNF- (2.5 µg/kg/min, n=38). LV dimensions increased with TNF- infusion indicative of LV remodeling induced by TNF-. (From Bozkurt et al., 1998 with permission from Futura Press and the American Heart Association) [23].

 
Another important observation from past studies is that TNF- can cause LV dilation [23,27,43]. Specifically, in the study by Bozkurt and colleagues, TNF- infusion induced a time-dependent increase in LV end diastolic dimension [23]. In this model, LV end diastolic dimension increased following 5 days of TNF- infusion by over 25% when compared to time-matched controls (Fig. 2). In a transgenic mouse model, myocardial TNF- overexpression caused increased systolic and diastolic LV volumes [27,43]. Using magnetic resonance imaging, myocardial TNF- overexpression caused a dilated and globoid LV phenotype (Fig. 3) [43].

View larger version (200K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 A transgenic mouse model with specific myocardial TNF- overexpression was developed. Magnetic resonance imaging was used at 24 weeks. In the TNF- transgenic group the long axis LV MRI images demonstrated a more dilated, globoid shape (TNF-, top left) compared to wild-type (WT, bottom left). In the TNF- transgenic group, the midventricular short-axis view of the heart in end diastole demonstrated a more dilated left ventricle (TNF-, top right) compared to wild-type controls (WT, bottom right). (From Kubota et al., 1997 with permission from Futura Press and the American Heart Association) [43].

 
The changes in LV geometry that have been documented to occur with increased TNF- levels are likely indicative of myocardial structural remodeling. Important determinants of myocardial wall remodeling include changes in myocyte size and number, alignment of myocytes in the myocardial wall, and changes in myocardial extracellular matrix. Increased levels of TNF- have been demonstrated to cause changes in each of these determinants of remodeling [23–25,27]. In transgenic mice overexpressing myocardial TNF-, a number of changes with respect to myocyte viability have been documented. Kubota and colleagues documented myocyte injury and cellular and molecular signs consistent with myocyte apoptosis [43]. Other studies have noted that a consequence of cardiac-specific overexpression of TNF- is an increase in the number of infiltrating cells in the myocardium [25,26]. Thus one mechanism for TNF--mediated myocyte injury and cell loss may be an immune-related cytotoxicity.

In a rat model of TNF- infusion, Bozkurt and colleagues observed a small increase in the average LV myocyte cross-sectional area and a decrease in the calculated number of myocytes across the transmural thickness of the LV wall [23]. These observations led to the conclusion that increased TNF- levels may have resulted in alterations in the spatial alignment of myocytes within the LV wall [23]. A contributory factor for myocyte alignment in the myocardial free wall is the extracellular matrix [44–46]. Increased TNF- in animal models has been demonstrated to cause significant changes in the extracellular matrix [23,27]. For example, chronic TNF- infusion in rats reduced the degree of histological staining for fibrillar collagen by 50% when compared to control [23]. Scanning electron micrographs of myocardial sections performed in TNF- animals revealed disruptions in the myocardial extracellular fibrillar collagen network (Fig. 4). Transgenic mice overexpressing myocardial TNF- demonstrate increased soluble myocardial collagen, which is suggestive of reduced collagen crosslinking [27]. Reduced collagen crosslinking may be due to poorly formed nascent collagen fibrils or because of enhanced turnover. Therefore in animal models of increased TNF- expression, defects in extracellular fibrillar collagen structure and composition occur, which suggests that an extracellular proteolytic system has been induced.

View larger version (144K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Rats were infused with diluent or TNF- for 15 days (2.5 µg/kg/min). Representative scanning electron micrographs of LV myocardial sections were taken. In myocardial samples from diluent-treated animals (control), a fine weave of collagen around the myocytes was observed. In myocardial samples from TNF--infused animals (TNF-), the collagen weave appeared to be significantly disrupted. (From Bozkurt et al., 1998 with permission from Futura Press and the American Heart Association) [23].

 

	5. Matrix metalloproteinases and myocardial remodeling

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
The matrix metalloproteinases (MMPs) have been demonstrated to cause tissue remodeling in normal physiologic processes such as tissue morphogenesis, trophoblast migration, wound healing, and mammary development [47]. MMPs have a high specificity for components of the ECM, such as fibrillar collagen, and the degradative functions of the MMPs are thought to impact a number of disease processes. Increased MMP expression has been identified in pathological processes such as tumor angiogenesis and metastasis, rheumatoid arthritis, atheroma formation, and plaque rupture [48,49]. The MMPs constitute a family of zinc-dependent enzymes that currently number over 20 species [50–52]. There are two principle types of MMPs; the membrane-bound type and those secreted into the extracellular space. The secreted MMPs comprise the majority of known MMP species and are released into the extracellular space in a latent or proenzyme state. Activation of these latent MMPs is required for proteolytic activity. MMPs, both latent and active, bind with a second class of biological molecules, the tissue inhibitors of matrix metalloproteinases (TIMPs). Therefore, overall MMP activity is determined by three important mechanisms; transcription, activation, and inhibition.

Increased MMP zymographic activity has been reported in myocardial samples from patients with end-stage CHF [53–57]. Furthermore, increased levels of certain MMP species have been identified which include MMP-9, MMP-3, and MMP-13 [54,55]. Thus a number of MMP species have been characterized within the failing human myocardium which possesses the capacity to degrade a wide spectrum of extracellular matrix components. In a pacing LV failure animal model, a time-dependent increase in myocardial MMP levels has been demonstrated to accompany LV dilation and dysfunction [58]. This animal study and others have demonstrated a strong association between LV remodeling and MMP induction [59–62].

A clear cause–effect relationship between MMPs and the LV remodeling process has been demonstrated through the use of transgenic models or through the use of pharmacologic MMP inhibitors [63–66]. A loss of MMP inhibitory control through TIMP-1 gene deletion has been shown to cause LV dilation in mice [67]. The deletion of the MMP-9 gene in mice alters the course of LV remodeling post myocardial infarction (MI) [64]. Pharmacologic MMP inhibition has been used in several animal models of LV dysfunction [65,66]. For example, in animal experiments, MMP inhibitor treatment with chronic rapid pacing attenuated the degree of LV dilation that invariably occurs in this model [66]. In the spontaneously hypertensive heart failure rat model, MMP inhibition resulted in attenuation of LV dilation [63]. In the mouse MI model, MMP inhibition has also been shown to reduce the degree of post MI LV dilation [65]. Taken together, past clinical reports of end-stage heart failure and animal models of LV dysfunction have provided compelling evidence to implicate MMPs in the myocardial remodeling process. Thus, defining the upstream signaling events that induce myocardial MMP expression would provide unique insight into the pathogenesis of the myocardial remodeling process.

In past clinical studies differential MMP species abundance has been observed within the failing human myocardium [54,55]. This observation implies differential transcriptional regulation of MMPs likely exists within the myocardium [52]. An important determinant of overall transcription is the production of transcription factors that bind to the gene. The specific promoter sequences present in MMP genes are beginning to be identified, and appear to be variable among MMP species [52]. Common promoter binding regions also exist on MMP genes for transcription factors such as AP-1 or NF-B [68,69]. For example, MMP-9 and MMP-13 contain the promoter region sequence for AP-1 and NF-B [70–72]. A number of in vitro studies have provided evidence that TNF- may induce MMPs through formation of these transcription factors (Fig. 5; [73–78]). In mouse osteoblastic cells, TNF- stimulation was found to result in increased levels of MMP-3, MMP-9, and MMP-13 [76]. Additional studies treating human skin fibroblasts with TNF- have demonstrated the induction of MMP-1, MMP-3, and MMP13; an effect abrogated by simultaneous inhibition of the NF-B transcription pathway [75]. Human endothelial cells treated with TNF- had increased levels of MMP mRNA and demonstrated increased MMP activation [77]. Furthermore, human smooth muscle cells stimulated with TNF- demonstrated increased MMP activity and de novo synthesis and secretion of MMP-1 [78]. Finally, adult rat cardiac fibroblasts stimulated with TNF- have demonstrated increased MMP activity [74]. Therefore, one molecular trigger for the induction of myocardial MMPs in LV remodeling may be increased TNF- release and subsequent activation of TNF receptors (Fig. 5).

View larger version (45K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 5 The activation of TNF- receptors by circulating TNF- results in the activation of a number of cell signaling pathways. Specific genomic pathways include those that result in the production of activator protein-1 (AP-1) and nuclear factor kappa B (NF-B) transcription factors. Activation of cell surface TNF- receptors may therefore result in increased transcription factor production and enhanced MMP gene transcription.

 

	6. TNF- and MMPS: a causal link to myocardial remodeling?

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
In order to provide clinical evidence to support a relationship between TNF receptor activation and MMP induction, a study was undertaken in which soluble TNF receptors and plasma MMP levels were examined in patients with CHF [80]. The CHF patient cohort was a subset of a larger study which has recently been described [19]. Indices of cytokine activation were quantified by plasma levels of soluble TNFR1 and TNFR2. Plasma levels of MMP-9 and MMP-8 were serially examined at baseline and up to 12 months. For means of comparison with respect to MMP levels, age-matched non-failing subjects were used for normal reference values. MMP-9 plasma levels were increased in CHF patients by over three-fold when compared to age-matched controls. During follow-up, an absolute reduction in plasma TNFR1 or TNFR2 from baseline was accompanied by reduced MMP-9 levels whereas stable or increased plasma TNFR1 or TNFR2 resulted in persistently elevated MMP-9 levels. The relationship between TNF receptor levels and MMP-9 levels is demonstrated in Fig. 6. These preliminary results demonstrated that plasma MMP levels are increased in CHF patients and related to temporal changes in TNF receptor activation. While this clinical study only provides associative data, these results support the hypothesis that TNF receptor activation can contribute to detectable changes in MMP plasma levels.

View larger version (18K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 6 Plasma levels of MMP-9 and soluble TNF receptors 1 and 2 (TNFR1 and TNFR2) were serially examined by enzyme-linked immunosorbent assay (ELISA) in CHF patients at study entry and up to 6 months of follow-up (n=24: age 61±3 years). An absolute increase in plasma TNFR1 from baseline was accompanied by increased MMP-9 levels. An increase in TNFR2 plasma levels from baseline was associated with a relative increase in MMP-9 plasma levels in CHF patients. (data extracted from Gunasinghe et al., 2000) [80].

 

	7. Summary and future directions

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 
As outlined in the preceding sections, compelling results exist which have demonstrated that increased TNF receptor activation within the myocardium can induce LV myocardial remodeling. Furthermore, a molecular trigger for TNF--mediated LV remodeling may exist through MMP induction. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling would be warranted. Approaches for modulating TNF- expression within the myocardium may include inhibiting the synthesis and release of TNF- or blocking TNF- signaling. A number of pharmacological agents are available to block the biological effects of TNF- [81,82]. In animal models of LV remodeling, blocking TNF receptor activation can attenuate the degree of LV dilation [23,83] Only two pharmacologic constructs, however, have been used in patients with CHF. The first is pentoxyfilline, a non-specific agent suppressing TNF- production. The second is etanercept, a recombinant human TNF receptor fusion protein consisting of two recombinant p75 TNF- receptors and the Fc portion of human IgG1 [82]. This fusion protein binds biologically soluble TNF-, and thereby would attenuate ligand–receptor complex formation and subsequent signal transduction. This fusion protein has been used in placebo controlled trials of heart failure. In these initial studies, patients receiving etanercept exhibited decreases in biologically active TNF- and improvements in LV function [84]. However, a large-scale clinical trial in which etanercept was being evaluated in CHF was terminated. Specifically, the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE) trial was closed due to failure to meet pre-established clinical end-points [85]. The clinical end-points of this large-scale study were morbidity and mortality. The underlying reasons for the closure of this clinical trial remain to be established. However, it must be recognized that TNF- exerts multiple biological effects and globally reducing TNFR1 and TNFR2 receptor activity may result in a number of downstream cellular and molecular events. Thus while TNF- likely contributes to LV remodeling and to the progression of heart failure, a means by which to selectively target this cytokine system with respect to modulating downstream biological responses such as MMP activation remains to be developed.

Time for primary review 22 days.

	References

Top Abstract 1. Introduction 2. Heart failure and... 3. TNF-{alpha} biology and... 4. TNF-{alpha} and heart... 5. Matrix metalloproteinases and... 6. TNF-{alpha} and MMPS:... 7. Summary and future... References

 

1. Levine B., Kalman J., Mayer L., Fillit H.M., Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. New Engl J Med (1990) 323:236–241.[Abstract]
2. McMurray J., Abdullah I., Dargie H.J., Shapiro D. Increased concentrations of tumour necrosis factor in ‘cachectic’ patients with severe chronic heart failure. Br Heart J (1991) 66:356–358.[Abstract/Free Full Text]
3. Wiedermann C.J., Beimpold H., Knapp H.M., Braunsteiner H. Increased levels of serum neopterin and decreased production of neutrophil superoxide anions in chronic heart failure with elevated levels of tumor necrosis factor-alpha. J Am Coll Cardiol (1993) 22:1897–1901.[Abstract]
4. Matsumori A., Yamada T., Suzuki H., Matoba Y., Sasayama S. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J (1994) 72:561–566.[Abstract/Free Full Text]
5. Katz S.D., Rao R., Berman J.W., 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) 90:12–16.[Abstract/Free Full Text]
6. Kapadia S., Dibbs Z., Kurrelmeyer K., et al. The role of cytokines in the failing human heart. Cardiol Clinics (1998) 16:645–656.[CrossRef][Medline]
7. Ferrari R., Bachetti T., Confortini R., et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive failure. Circulation (1995) 92:1479–1486.[Abstract/Free Full Text]
8. 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) 28:964–971.[Abstract]
9. Koller-Strametz J., Pacher R., Frey B., et al. Circulating tumor necrosis factor-alpha levels in chronic heart failure: relation to its soluble receptor. II. Interleukin-6, and neurohumoral variables. J Heart Lung Transplant (1998) 17:356–362.[Web of Science][Medline]
10. SOLVD Investigators. Effect of enalapril on survival of patients with reduced left ventricular ejection fractions and congestive heart failure. New Engl J Med (1991) 325:293–302.[Abstract]
11. Seta Y., Shan K., Bozkurt B., Oral H., Mann D.L. Basic mechanisms in heart failure: the cytokine hypothesis. J Card Failure (1996) 2:243–249.[CrossRef][Medline]
12. Torre-Amione G., Kapadia S., Benedict C., et al. 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) 27:1201–1206.[Abstract]
13. Birks E.J., Burton P.B., Owen V., et al. Elevated tumor necrosis factor-alpha and interleukin-6 in myocardium and serum of malfunctioning donor hearts. Circulation (2000) 102(III):352–358.
14. Torre-Amione G., Kapadia S., Lee J., et al. Tumor necrosis factor- and tumor necrosis factor receptors in the failing human heart. Circulation (1996) 93:704–711.[Abstract/Free Full Text]
15. Habib F.M., Springall D.R., Davies G.J., et al. Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet (1996) 347:1151–1155.[CrossRef][Web of Science][Medline]
16. Dibbs Z., Thornby J., White B.G., Mann D.L. Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials. J Am Coll Cardiol (1999) 33:1935–1942.[Abstract/Free Full Text]
17. Kapadia S., Dibbs Z., Kurrelmeyer K., et al. The role of cytokines in the failing human heart. Cardiol Clinics (1998) 16:645–656.[CrossRef][Medline]
18. Rauchhaus M., Doehner W., Francis D.P., et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation (2000) 102:3060–3067.[Abstract/Free Full Text]
19. Deswal A., Petersen N.J., Feldman A.M., et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation (2001) 103:2055–2059.[Abstract/Free Full Text]
20. Giroir B.P., Horton J.W., White J.D., McIntyre K.L., Lin C.Q. Inhibition of tumor necrosis factor prevents myocardial dysfunction during burn shock. Am J Physiol (1994) 267:H118–H124.[Web of Science][Medline]
21. Kapadia S., Lee J.R., Torre-Amione G., et al. Tumor necrosis factor gene and protein expression in adult feline myocardium following endotoxin administration. J Clin Invest (1995) 96:1042–1052.[Web of Science][Medline]
22. Kapadia S.R., Oral H., Lee J., et al. Hemodynamic regulation of tumor necrosis factor- gene and protein expression in adult feline myocardium. Circulation Res (1997) 81:187–195.[Abstract/Free Full Text]
23. Bozkurt B., Kribbs S.B., Clubb F.J., et al. Pathophysiologically relevant concentrations of tumor necrosis factor- promote progressive left ventricular dysfunction and remodeling in rats. Circulation (1998) 97:1382–1391.[Abstract/Free Full Text]
24. Krown K.A., Page M.T., Nguyen C., et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes; involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest (1996) 98:2854–2865.[Web of Science][Medline]
25. Bryant D., Becker L., Richardson J., et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-. Circulation (1998) 97:1375–1381.[Abstract/Free Full Text]
26. Kadokami T., McTiernan C.F., Kubota T., Frye C.S., Feldman A.M. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest (2000) 106:589–597.[Web of Science][Medline]
27. Li Y.Y., Feng Y.Q., Kadokami T., et al. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor can be modulated by anti-tumor necrosis factor therapy. Proc Natl Acad Sci USA (2000) 97:12746–12751.[Abstract/Free Full Text]
28. Braunwald E., Bristow M.R. Congestive heart failure; fifty years of progress. Circulation (2000) 102:IV14–IV23.[Medline]
29. Mann D.L., Spinale F.G. Activation of matrix metalloproteinases in the failing human heart; breaking the tie that binds. Circulation (1998) 98:1699–1702.[Free Full Text]
30. Cohn J.N., Ferrari R., Sharpe N. For the International Forum on Cardiac Remodeling. Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Journal of the American College of Cardiology (2000) 35:569–582.[Abstract/Free Full Text]
31. Parmley W.W. Pathophysiology of congestive heart failure. Am J Cardiol (1985) 56:7A–11A.[CrossRef][Medline]
32. Cintron G., Johnson G., Francis G., Cobb F., Cohn J.N. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation (1993) 87:VII7–VI23.
33. Rayment N.B., Haven A.J., Madden B. Myocyte loss in chronic heart failure. J Pathol (1999) 188:213–219.[CrossRef][Web of Science][Medline]
34. Coker M.L., Spinale F.G. Myocardial extracellular matrix remodeling with the development of pacing induced congestive heart failure: contributory mechanisms. Cardiovasc Pathol (1998) 7:161–168.[CrossRef][Web of Science]
35. Spinale F.G., Zellner J.L., Johnson W.S., Emble D.M., Munyer P.D. Cellular and extracellular remodeling with the development and recovery from tachycardia-induced cardiomyopathy: changes in fibrillar collagen, myocyte adhesion capacity and proteoglycans. J Mol Cell Cardiol (1996) 28:1591–1608.[CrossRef][Web of Science][Medline]
36. Leong K.G., Karsan A. Signaling pathways mediated by tumor necrosis factor alpha. Histol Histopathol (2000) 15(4):1303–1325.[Web of Science][Medline]
37. Ledgerwood E.C., Pober J.S., Bradley J.R. Recent advances in the molecular basis of TNF signal transduction. Lab Invest (1999) 79(9):1041–1050.[Web of Science][Medline]
38. Sack M., Smith R., Opie L. Tumor necrosis factor in myocardial hypertrophy and ischaemia – an anti-apoptotic perspective. Cardiovasc Res (2000) 45:688–695.[Free Full Text]
39. Joyce D.A., Steer J.H. Tumor necrosis factor alpha and interleuking-1 alpha stimulate late shedding of p75 TNF receptors but not p55 TNF receptors from human monocytes. J Interfer Cytokine Res (1995) 15:947–954.[Web of Science][Medline]
40. Darnay B.G., Aggarwal B.B. Signal transduction by tumour necrosis factor and tumour necrosis factor related ligands and their receptors. Ann Rheum Dis (1999) 58:I2–I3.[CrossRef][Medline]
41. Westwick J.K., Weitzel C., Minden A., Karin M., Brenner D.A. Tumor necrosis factor stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem (1994) 269(42):26396–26401.[Abstract/Free Full Text]
42. Torre-Amione G., Stetson S.J., Youker K.A., et al. Decreased expression of tumor necrosis factor- in failing human myocardium after mechanical circulatory support, a potential mechanism for cardiac recovery. Circulation (1999) 100:1189–1193.[Abstract/Free Full Text]
43. Kubota T., McTiernan C.F., Frye C.S., et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circulation Res (1997) 81:627–635.[Abstract/Free Full Text]
44. Robinson T.F., Cohen-Gould L., Factor S.M. Skeletal framework of mammalian heart muscle. Arrangement of inter- and pericellular connective tissue structures. Lab Invest (1983) 49:482–498.[Web of Science][Medline]
45. Factor S.M. Role of extracellular matrix in dilated cardiomyopathy. Heart Failure (1994) 9:260–268.
46. Libby P., Lee R.T. Matrix matters. Circulation (2000) 102:1874–1876.[Free Full Text]
47. Vu T.H., Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Devel (2000) 14:2123–2133.[Free Full Text]
48. Dollery C.M., McEwan J.R., Henney A.M. Matrix metalloproteinases and cardiovascular disease. Circulation Res (1995) 77:863–868.[Free Full Text]
49. Galis Z.S., Sukhova G.K., Larck M.W., Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest (1994) 94:2493–2503.[Web of Science][Medline]
50. Rees R.C., Cottam D.W. Regulation of the matrix metalloproteinases: their role in tumor invasion and metastasis. Int J Oncol (1993) 2:861–872.[Web of Science]
51. Nagase H. Activational mechanisms of matrix metalloproteinases. Biol Chem (1997) 378:151–160.[Web of Science][Medline]
52. Fini M.E., Cook J.R., Mohan R., Brinckerhoff C.E. Matrix Metalloproteinases. Parks W.C., Mecham R.P., eds. (1998) San Diego: Academic. 299–356.
53. Feldman A.M., Li Y.Y., McTiernan C.F. Matrix metalloproteinases in pathophysiology and treatment of heart failure. Lancet (2001) 357:654–655.[CrossRef][Web of Science][Medline]
54. Spinale F.G., Coker M.L., Heung L.J., et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation (2000) 102:1944–1949.[Abstract/Free Full Text]
55. Thomas C.V., Coker M.L., Zellner J.L., et al. Increased matrix metalloproteinases activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation (1998) 97:1708–1715.[Abstract/Free Full Text]
56. Gunja-Smith Z., Morales A.R., Romanelli R., Woessner J.F. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Role of metalloproteinases and pyridinoline cross links. Am J Pathol (1996) 148:1345–1350.[Web of Science][Medline]
57. Tyagi S.C., Campbell S.E., Reddy H.K., Tjahaja E., Voelker D.J. Matrix metalloproteinases activity expression in infracted, noninfarcted, and dilated cardiomyopathic human hearts. Mol Cell Biochem (1996) 155:13–21.[CrossRef][Web of Science][Medline]
58. Spinale F.G., Coker M.L., Thomas C.V., et al. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure; relation to ventricular and myocyte function. Circulation Res (1998) 82:482–495.[Abstract/Free Full Text]
59. Nagatomo Y., Carabello B.A., Coker M.L., et al. Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control. Am J Physiol: Heart Circulat Physiol (2000) 278:H151–H161.
60. Coker M.L., Thomas C.V., Clair M.J., et al. Myocardial matrix metalloproteinase activity and abundance with congestive heart failure. Am J Physiol: Heart Circul Physiol (1998) 274:H1516–H1523.[Abstract/Free Full Text]
61. Armstrong P.W., Moe G.W., Howard R.J., Grima E.A., Cruz T.F. Structural remodeling in heart failure: gelatinase induction. Can J Cardiol (1994) 10:214–220.[Web of Science][Medline]
62. Heymans S., Luttun A., Nuyens D., et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med (1999) 5:1122–1123.[CrossRef][Web of Science][Medline]
63. Peterson J.T., Hallak H., Johnson L., et al. Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation (2001) 103:2303–2309.[Abstract/Free Full Text]
64. Ducharme A., Frantz S., Aikawa M., et al. Targeted deletion of matrix metalloproteinase-9 attenuated left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest (2000) 106:55–62.[Web of Science][Medline]
65. Rohde L.E., Ducharme A., Arroyo L.H., et al. Matrix metalloproteinases inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation (1999) 99:3063–3070.[Abstract/Free Full Text]
66. Spinale F.G., Coker M.L., Krombach S.R., et al. Matrix metalloproteinase inhibition during the development of congestive heart failure; effects on left ventricular dimensions and function. Circulation Res (1999) 85:364–376.[Abstract/Free Full Text]
67. Roten L., Nemoto S., Simsic J., et al. Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice. J Mol Cell Cardiol (2000) 32:109–120.[CrossRef][Web of Science][Medline]
68. Birkedal-Hansen H., Moore W.G.I., Bodden M.K., et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med (1993) 4:197–250.[Abstract/Free Full Text]
69. Benbow U., Brinckerhoff C.D. The AP-1 site and MMP gene regulation: what is all the fuss about? Matrix Biol (1997) 15:519–526.[CrossRef][Web of Science][Medline]
70. Sato H., Kita M., Seiki M. v-Src activates the expression of the 92-kDa type IV collagenase gene through the AP-1 site and the GT box homologous to retinoblastoma control elements: a mechanism regulating gene expression independent of that by inflammatory cytokines. J Biol Chem (1993) 268:23460–23468.[Abstract/Free Full Text]
71. Sato H., Seiki M. Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells. Oncogene (1993) 8:395–405.[Web of Science][Medline]
72. Yokoo T., Kitamura M. Dual regulation of IL-1 beta-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kappa B and AP-1. Am J Physiol (1996) 270:F123–F130.[Web of Science][Medline]
73. Bond M., Chase A.J., Baker A.H., Newby A.C. Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3, and -9 production by vascular smooth muscle cells. Cardiovasc Res (2001) 50:556–565.[Abstract/Free Full Text]
74. Siwik D.A., Chang D.L.F., Colucci W.S. Interleukin-1β and tumor necrosis factor- decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circulation Res (2000) 86:1259–1265.[Abstract/Free Full Text]
75. Bondeson J., Brennan F., Foxwell B., Feldman M. Effective adenoviral transfer of IB into human fibroblasts and chondrosarcoma cells reveals that the induction of matrix metalloproteinases and proinflammatory cytokines is nuclear factor-B dependent. J Rheumatol (2000) 27:2078–2089.[Web of Science][Medline]
76. Uchida M., Shima M., Shimoaka T., et al. Regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by bone resorptive factors in osteoblastic cells. J Cell Physiol (2000) 185:207–214.[CrossRef][Web of Science][Medline]
77. Rajavashisth T.B., Liao J.K., Galis Z.S., et al. Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type-1 matrix metalloproteinase. J Biol Chem (1999) 274:11924–11929.[Abstract/Free Full Text]
78. Galis Z.S., Muszynski M., Sukhova G.K., et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circulation Res (1994) 75:181–189.[Abstract/Free Full Text]
80. Gunasinghe H.R., Coker M.L., Thorp A.J., et al. Increased matrix metalloproteinase plasma levels in patients with congestive heart failure: relation to cytokine activation. Circulation (2000) 102:II403.
81. Bozkurt B., Torre-Amione G., Soram O.Z., et al. Results of a multidose phase I trial with tumor necrosis factor receptor (p75) fusion protein (Etanercept) in patients with heart failure. J Am Coll Cardiol (1999) 184:5A.
82. Deswal A., Bozkurt B., Seta Y. Safety and efficacy of a soluble p75 TNF receptor (Enbrel, Etanercept) in patients with advanced heart failure. Circulation (1999) 99:3224–3226.[Abstract/Free Full Text]
83. Kubota T., Bounoutas G.S., Miyagishima M., et al. Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy. Circulation (2000) 101:2518–2525.[Abstract/Free Full Text]
84. Bozkurt B., Torre-Amione G., Warren M.S., et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation (2001) 103:1044–1047.[Abstract/Free Full Text]
85. Immunex press release. www.immunex.com/investor/pressreleases/pr010322c.html.

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