REVIEW ARTICLES
The role of tumor necrosis factor in the pathophysiology of heart failure
Arthur M. Feldman, MD, PhD, FACCa,
Alain Combes, MDa,
Daniel Wagner, MDa,
Toshiaki Kadakomi, MDa,
Toru Kubota, MD, PhDa,
Yun You Li, PhDa and
Charles McTiernan, PhDa
a Cardiovascular Institute of the UPMC Health System, Pittsburgh, Pennsylvania, USA
Manuscript received July 2, 1999;
revised manuscript received October 5, 1999,
accepted November 18, 1999.
Reprint requests and correspondence: Dr. Arthur M. Feldman, Cardiovascular Institute of the UPMC Health System, 200 Lothrop Street, S-572 Scaife Hall, Pittsburgh, Pennsylvania 15213
feldmanam{at}msx.upmc.edu
 |
Abstract
|
|---|
Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors and cachexia, it is now recognized that TNF participates in the pathophysiology of a group of inflammatory diseases including rheumatoid arthritis and Crohn’s disease. The normal heart does not express TNF; however, the failing heart produces robust quantities. Furthermore, there is a direct relationship between the level of TNF expression and the severity of disease. In addition, both in vivo and in vitro studies demonstrate that TNF effects cellular and biochemical changes that mirror those seen in patients with congestive heart failure. Furthermore, in animal models, the development of the heart failure phenotype can be abrogated at least in part by anticytokine therapy. Based on information from experimental studies, investigators are now evaluating the clinical efficacy of novel anticytokine and anti-TNF strategies in patients with heart failure; one such strategy is the use of a recombinantly produced chimeric TNF alpha soluble receptor. Thus, in view of the emerging importance of proinflammatory cytokines in the pathogenesis of heart disease, we review the biology of TNF, its role in inflammatory diseases, the effects of TNF on the physiology of the heart and the development of clinical strategies that target the cytokine pathways.
|
Abbreviations and Acronyms
| | alpha-MHC | = alpha myosin heavy chain | | AMP | = adenosine monophosphate | | beta-MHC | = beta myosin heavy chain | | CHF | = congestive heart failure | | ELAMS | = endothelial leukocyte adhesion molecules | | ICAMS | = intracellular adhesion molecules | | IL-1 | = interleukin-1 | | LPS | = lipopolysaccharide | | MCP | = monocyte chemoattractant protein | | mRNA | = messenger RNA | | NYHA | = New York Heart Association | | SERCA | = sarcoplasmic reticulum Ca2+ ATPase | | TNF | = tumor necrosis factor | | TNFR | = soluble tumor necrosis factor receptor |
|
Dilated cardiomyopathy is a disease of epidemic proportion in the U.S. Although more prevalent in the elderly, it affects patients of all ages, races and genders. Heart failure is generally believed to begin with myocyte damage secondary to a variety of insults including ischemia, toxins such as alcohol or immune mechanisms. However, in many cases the etiology remains undefined. Initially the heart compensates by dilatation and cellular hypertrophy; however, over a period of time, the heart eventually decompensates and patients present with signs and symptoms of heart failure. It is the transition from compensation to decompensation that has been the focus of clinical and basic research over the past two decades and the role of the neurohormones, norepinephrine and angiotensin II, in the development of symptomatic heart failure. However, investigators have recently focused their attention on the proinflammatory cytokine, tumor necrosis factor (TNF). This manuscript reviews the investigational data supporting the role of TNF in the pathogenesis of heart failure and its usefulness as a therapeutic target.
|
The proinflammatory cytokine TNF
|
|---|
In 1975, Carswell et al. (1) first identified tumor necrosis factor (TNF), an endotoxin-induced serum factor that caused necrosis of tumors. A decade later, investigators isolated a protein from endotoxin-treated cells that was named cachectin because of its presumed role in the molecular basis of cachexia (2,3). The subsequent cloning of the genes encoding cachectin and TNF alpha confirmed that these two molecules were identical (4,5). Produced as a prohormone of 233 amino acids, TNF alpha is anchored in the cell membrane and then processed to a 157 residue mature protein by cleavage of a 76 residue signal peptide. In response to a wide variety of infectious or inflammatory stimuli (e.g., lipopolysaccharide, viruses, fungal or parasitic antigens, interleukin-1 [IL-1], TNF alpha), both transcription and translation of TNF precursor is increased, and large amounts of mature protein are rapidly released into the circulation. However, not all of the TNF alpha is released as some remains cell-associated in a transmembrane form (6). Tumor necrosis factor regulates the expression of a variety of peptide regulatory factors including IL-1, IL-6, platelet derived growth factor, transforming growth factor-beta, as well as a group of eicosanoids and hormones including platelet-activating factor and adrenaline (7). In addition, TNF alpha (and IL-1beta) contains a 33 nucleotide 3'-untranslated sequence that shortens messenger RNA (mRNA) half-life and, in so doing, limits the production of large quantities of this potent peptide (4).
|
TNF receptors
|
|---|
Once released from the cell, TNF alpha interacts with one of two TNF alpha receptors—a 55 kd high affinity receptor, soluble tumor necrosis factor receptor 1 (TNFR-1), and a 75 kd low affinity receptor (TNFR-2) (8,9). Intracellular signaling occurs as a result of TNF alpha-induced cross-linking of the receptors. The extracellular portions of these two proteins form a receptor family containing four characteristic domains with regularly spaced cystine residues; however, no significant homology exists between the intracytoplasmic portions of the two TNF alpha receptors (10). Thus, investigators have proposed that these receptors may be coupled to distinct signaling pathways (11). In the presence of noxious stimulants including TNF alpha, lipopolysaccharide (LPS), okadaic acid and phorbol esters, TNF alpha receptors are "shed" into the circulation (12–14). These TNFR receptor proteins appear to be truncated fragments of the extracellular regions of the type 1 and type 2 membrane-bound receptors for TNF alpha (13,15). Although TNF receptors do not possess intrinsic protein kinase activity, within minutes of exposure to TNF alpha, phosphorylation of several distinct proteins occurs, which is likely due to activation of cellular kinases (16). The soluble receptors are able to bind ligand and inhibit the cytotoxic activities of TNF alpha (15). Thus, the shedding of soluble binding proteins might serve as a "biological buffer" that can rapidly neutralize the activities of TNF alpha.
|
Pleiotropic effects of TNF alpha
|
|---|
The cellular effects of TNF alpha are highly pleiotropic. At low concentrations, TNF alpha effects paracrine or autocrine regulation of leukocytes and endothelial cells and, thus, serves as an important regulator of the inflammatory response. Indeed, mice lacking the p55 TNF alpha receptor are highly sensitive to some types of bacterial infections (17). Tumor necrosis factor alpha enhances chemotaxis of macrophages and neutrophils, increases their phagocytic and cytotoxic activity (18) and promotes leucostasis by inducing increased expression of intracellular adhesion molecules (ICAMS) and endothelial leukocyte adhesion molecules (ELAMS) at sites of inflammation. At higher concentrations, TNF alpha production exceeds the number of TNF alpha receptors located on the cell surface with excess TNF alpha being released into the circulation. Once released, TNF alpha exerts endocrine or exocrine effects including initiation of metabolic wasting, microvascular coagulation, hypotension and fever (19,20). Paradoxically, TNF alpha also appears to modulate both tissue destruction and rebuilding. Tumor necrosis factor alpha stimulates fibroblast and mesenchymal cell proliferation directly and induces the biosynthesis of other growth factors. By contrast, it is directly cytotoxic to endothelial cells and can induce the biosynthesis of collagenases, proteases, reactive oxygen intermediates and arachidonic acid metabolites (7). Tumor necrosis factor alpha has also been shown to have an important role in cell death through a variety of mechanisms including second messenger pathways, arachidonate metabolism, protein kinases, oxygen free radicals, nitric oxide, transcription of a variety of cytotoxic genes, regulation of nuclear regulatory factors, ADP-ribosylation and, potentially, DNA fragmentation (21). Under normal situations, these cytotoxic effects are important in host defense by initiating antitumor activity (1,22) and modulating cell growth and differentiation. However, the role of TNF alpha in the pathogenesis of malignancies remains controversial. While therapy with TNF improved survival in tumor-bearing mice, it also promoted tumor cell adhesion, nodule development (23) and metastasis (24). In addition, a direct relationship exists between the level of TNF expression and tumor grade in ovarian cancer (25). By contrast, excessive activation of TNF alpha or nontissue specific expression leads to tissue necrosis and apoptosis. Indeed, recent studies have demonstrated a causative role for TNF alpha in a group of diseases including: septic shock, rheumatoid arthritis (26), preeclampsia (27), hemolytic uremic syndrome (28), allograft rejection (29) and regional enteritis (30).
|
Proinflammatory cytokines and the heart
|
|---|
The first recognition that TNF alpha might participate in the development of congestive heart failure (CHF) came in 1990 when Levine et al. (31) demonstrated that circulating levels of TNF alpha were elevated in patients with end stage heart failure and cachexia. Subsequent studies demonstrated comparable elevations in IL-6 and IL-1beta (32) and a direct relationship between TNF alpha levels and functional heart failure classification (Fig. 1 [33]). Furthermore, direct relationships were identified between circulating levels of TNF alpha and neurohumoral activation and the degree of anemia; however, there was no relationship between cytokine levels and the degree of cachexia (34,35). Cytokine levels were also elevated in patients with heart failure due to myocarditis (36). That the observed increases were of physiologic significance was demonstrated by studies in which injections of endotoxin into humans resulted in TNF alpha elevations, depressed left ventricular function and decreases in mean arterial pressure (37). Parenthetically, it should be noted that the different assay techniques, for example bioassays or ELISA measurements, used by various investigators provide varying values, thus obfuscating the literature to some extent.
View larger version (12K):
[in this window]
[in a new window]
|
Figure 1 Circulating levels of tumor necrosis factor alpha (TNF alpha) in normal subjects and patients with New York Heart Association (NYHA) functional class I to III heart failure. Adapted after Torre-Amione et al. (33) with permission of the authors.
|
|
The increase in circulating TNF alpha in patients with CHF was associated with a substantial decrease in myocardial TNF alpha receptors and an increase in soluble TNF alpha receptors; however, the stoichiometry favored free TNF alpha (38). Perhaps of greatest importance was the demonstration by Mann and colleagues (38) in 1996 that the nonfailing human heart does not express TNF alpha, whereas the end stage failing human heart reexpresses robust amounts of protein (Fig. 2).
View larger version (13K):
[in this window]
[in a new window]
|
Figure 2 Immunodetectable TNF alpha (picograms of TNF alpha per g of cystolic protein) in nonfailing and failing myocardium. Adapted after Torre-Amione et al. (38) with permission of the authors.
|
|
|
Biologic effects of TNF alpha on the myocardium
|
|---|
Beginning with the observation that TNF alpha could inhibit contractility of isolated hamster papillary muscles in a concentration-dependent and reversible manner (39), a series of in vivo and in vitro basic science studies were performed, which paralleled the clinical studies assessing TNF alpha levels in patients with CHF (Fig. 3). First, it was demonstrated that the negative inotropic effects of TNF alpha are virtually immediate (40,41) and appear to be completely reversible upon removal of the cytokine. How-ever, not only does TNF alpha have immediate negative inotropic properties, but it can recapitulate the cellular and biochemical abnormalities that characterize the failing human heart. For example, IL-1beta induces a down regulation of the expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA) and phospholamban at both the mRNA and protein level in neonatal myocytes (42), which is associated with a depression and prolongation of the Ca2+ transient, effects that may be initiated by TNF alpha (40). In addition, TNF alpha effectively uncouples the beta-adrenergic receptors from adenylyl cyclase via an effect on the G inhibitory protein (43,44). Furthermore, TNF alpha activates metalloproteinases and inhibits the expression of inhibitors of metalloproteinases in vivo—effects that would be expected to activate extracellular matrix remodeling (45). Although initial studies suggested that the negative inotropic properties of TNF alpha were attributable to the ability of cytokines to induce nitric oxide synthase, subsequent investigations demonstrated that the induction of inducible nitric oxide synthase could not in and of itself induce contractile dysfunction in cardiac myocytes and that alterations in calcium homeostasis played an important role (40). Tumor necrosis factor alpha also provokes a hypertrophic growth response in cardiac myocytes, which may be an adaptive response to hemodynamic or environmental stress (46). Furthermore, a recent study suggested that the immediate negative inotropic effects of TNF alpha may be mediated by sphingosine (47). Finally, chronic infusion of TNF alpha produces a reversible dilated cardiomyopathy in a rat model—without evidence of inflammatory infiltrate or myocyte necrosis (48).
View larger version (15K):
[in this window]
[in a new window]
|
Figure 3 Tumor necrosis factor alpha acutely depresses contractile activity and calcium transients of isolated adult rat cardiomyocytes. Cells were loaded with the calcium sensitive dye, fura-2, and exposed to 200 U/ml rat TNF alpha or diluent (control) for 30 min. Cells were then electrically stimulated to contract (1 HZ) and a video edge-detection system used to record diastolic cell length and contraction to determine fractional shortening. Cells were alternately illuminated at 340- and 380-nm light and emission of the fura-2 measured at 520-nm. The ratio of light emission from the two illuminating wavelengths was used to follow intracellular free calcium transients. (A) Fractional shortening (n = 30 each group). (B) Mean calcium transient amplitude (difference between peak systolic and peak diastolic 340/380 nm ratio; n = 40 per group). (Wagner, Combes, Janczewski, McTiernan and Feldman; unpublished data). Open square = control; solid square = TNF alpha 200 U/ml.
|
|
|
TNF alpha transgenic mice—a model of dilated cardiomyopathy
|
|---|
To pursue further studies of the role of cytokines in the development of CHF and to provide additional support for the "cytokine hypothesis," a series of mice that harbored a transgene effecting cardiac-specific overexpression of TNF alpha were generated using the cardiac-specific alpha myosin heavy chain (alpha-MHC) promoter. Robust overexpression proved lethal due to (49) fulminant myocarditis; however, lower levels of TNF alpha expression allowed the production of viable founders (50). These mice recapitulate heart failure in humans as they demonstrate: 1) four-chamber dilatation, 2) myocyte hypertrophy, 3) interstitial infiltrates, 4) extracellular matrix remodeling with fibrosis, 5) diminished beta-adrenergic responsiveness; and 6) premature death with a six-month mortality of 25% (Fig. 4). The development of a heart failure phenotype secondary to overexpression of TNF alpha has recently been confirmed by a second laboratory (51). Taken together, the existing TNF alpha transgenic studies suggest that there is a direct relationship between transgene copy number and the degree of inflammation (52). Recent studies suggest that mortality in these animals is due, in part, to an arrhythmogenic event since continuous holter monitoring of transgenic mice demonstrates high grade ventricular ectopy with frequent runs of nonsustained ventricular tachycardia (53). At the cellular and molecular level, the TNF alpha transgenics are characterized by: 1) reexpression of the fetal gene program (e.g., atrial natriuretic factor and beta-MHC), 2) reexpression of downstream TNF alpha responsive cytokines and chemokines including IL-1beta, monocyte chemoattractant protein (MCP), and regulated upon activation, normal T-cell expressed and secreted, 3) increased activity of the metalloproteinases and diminished expression of inhibitors of metalloproteinases (54), 4) activation of both pro- and antiapoptotic pathways (55), 5) down-regulation of phospholamban and SERCA expression, and 6) a decrease in the alpha- and beta-myosin heavy chain mRNA ratio (56,57). Furthermore, the transgenic mice demonstrated reduced ejection fractions and fractional shortening and diminished ventricular compliance. The TNF alpha transgenic also demonstrated a substantial amount of apoptosis; however, this was largely isolated to the interstitium, and myocyte apoptosis was rare (55). Thus, the TNF alpha overexpressing transgenic recapitulates both the pathologic, cellular and molecular phenotype of the human failing heart and, therefore, provides an ideal model in which to study the pathobiology of progressive CHF and to test therapeutic strategies.
View larger version (73K):
[in this window]
[in a new window]
|
Figure 4 Transgenic mice with cardiac-specific overexpression of TNF alpha (TNF1.6) develop dilated cardiomyopathy. Representative magnetic resonance image (MRI, coronal view) from 24 week-old wild type (A) and TNF1.6 transgenic mice (B) at equivalent stage of cardiac cycle. (C) Transgenic animals demonstrate significant cardiac hypertrophy with chamber dilation and decreased ejection fraction as determined from MRI data (short-axis images). Adapted after Kubota et al. (50) with author’s permission. BW = body weight; EDV = end-diastolic volume; ESV = end-systolic volume; HW = heart weight. Open square = wild type; solid square = TNF1.6. *p < 0.05.
|
|
|
"rescuing" the TNF alpha transgenic with TNFR
|
|---|
That there was a direct relationship between TNF alpha expression and negative inotropic effects was first shown by Kapadia et al. (58) using soluble TNF alpha binding proteins. However, to "prove" that overexpression of TNF alpha is a critical step in the development of end stage CHF (52), transgenic and wild type mice were injected with an adenoviral vector encoding a chimeric soluble TNF alpha protein consisting of two moieties of the human 55-kDa TNF alpha receptor extracellular domain fused to a mouse IgG heavy chain (59). Inoculation of mice with 109 plaques forming units resulted in inhibitor production and release by hepatocytes and marked elevations in serum and myocardial TNF alpha receptor levels for as long as six weeks (57). These levels of soluble receptor were several orders of magnitude greater than the levels of myocardial TNF alpha, suggesting a favorable stoichiometry for TNF alpha inhibition. After both two and six weeks of treatment, TNFR completely abrogated the presence of interstitial infiltrates and normalized the expression of alpha-MHC, SERCA, and phospholamban. In addition, the reexpression of downstream cytokines and chemokines including IL-1beta, MCP-1 and rantes was completely inhibited by TNFR therapy. By contrast, there was continued activation of beta-MHC expression, which was consistent with the finding of persistent ventricular hypertrophy in these TNFR treated mice. Finally, there was normalization of matrix metalloproteinase and tissue inhibitor of metalloproteinase expression and stabilization of the degree of interstitial fibrosis, suggesting that extracellular matrix remodeling had abated. Thus, these studies suggest that some, although not all, of the phenotypic characteristics of CHF can be abated by anticytokine strategies. However, both hypertrophy and fibrosis persist despite therapeutic intervention, suggesting early, but not late, therapy using anticytokine approaches might benefit patients with CHF.
|
The molecular genetics of TNF alpha
|
|---|
Genetic polymorphisms in the TNF locus have been associated with higher levels of TNF alpha production (60,61) and are known to be related to several autoimmune, infectious and neoplastic diseases (62,63). These polymorphisms include a G to A transition at position –308 in the promoter region of the TNF alpha gene (TNF alpha2) (64) and a G to A transition at position +252 in the first intron of the TNFbeta gene (65). The frequency of the TNF alpha2 allele, the allele associated with increased TNF expression, is increased in patients with rheumatoid arthritis and systemic lupus erythematosus (66). Similarly, people homozygous for the TNF alpha2 allele have a higher risk for death due to cerebral malaria (67) while homozygous for the TNFbeta2 allele have a higher mortality with sepsis (61). To date, investigators have been unable to demonstrate an association between either the TNF alpha or TNFbeta polymorphisms and the presence of CHF (68); however, these studies had an inherent bias, i.e., that patients with a potentially unfavorable polymorphism might have died prior to receiving medical attention (69). Therefore, further evaluation of this possibility is warranted. An additionally important, but as yet unanswered, question is how myocardial TNF alpha expression is regulated at the molecular level. However, interactions of nuclear proteins with an Ap-1/CRE-like (cis-acting regulatory site) promoter sequence in the human TNF alpha gene (70) and the marked sensitivity of TNF alpha expression to corticosteroids (and possibly cyclic adenosine monophosphate [AMP]) suggest the importance of transcriptional regulation in modifying TNF alpha expression (71–73).
|
Clinical strategies for anticytokine therapy
|
|---|
Based on the basic science and clinical observations regarding the role of proinflammatory cytokines in the development of CHF, efforts have been directed towards developing anticytokine strategies that might be useful in the therapy of patients. Yoshimura et al. (74) suggested that beta-adrenergic agonists could inhibit the production of both TNF alpha and IL-1beta by elevating intracellular cyclic AMP levels. Similarly, pretreatment with isoproterenol blunted the ability of LPS to induce TNF alpha production in conscious mice (75), whereas short-term, but not long-term preexposure of mononuclear cells to adrenergic agonists inhibited LPS-induced production of TNF alpha (76). Phosphodiesterase inhibitors can also serve as potent inhibitors to TNF alpha production (77,78). Indeed, the phosphodiesterase inhibitor, pentoxyfilline, demonstrates salutorius effects on heart failure signs and symptoms while substantially lowering circulating TNF alpha levels (79,80). However, other studies have failed to show an effect of cyclic AMP, cyclic AMP derivatives or beta-adrenergic agonists on TNF alpha production (81). Other inhibitors of cytokine expression include: amiodarone (82), ouabain (83) and thalidomide (84). In addition, a recent report suggests that estrogen may constitutively down-regulate TNF alpha expression (85).
Recently, studies have demonstrated that adenosine is a potent inhibitor of TNF alpha expression by both neonatal myocytes, adult myocytes, rodent papillary muscle preparations and adult human heart via activation of the adenosine A2 receptor (86,87). This effect appears to be partially selective for the heart as adenosine’s anticytokine effects in white cells is mediated via the A3 adenosine receptor (88). That adenosine may have an important role in regulating myocardial cytokine expression was further supported by a recent study by Loh et al. (89) demonstrating improved survival in heart failure patients having a common mutation in at least one allele of the AMP deaminase gene. In the peripheral muscle, and presumably in the heart, patients with this mutation have diminished AMP deaminase activity resulting in decreased metabolism of AMP to inosine and enhanced production of adenosine, leading us to hypothesize that adenosine agonists might have therapeutic utility in the management of patients with CHF (69).
Effective blockade of TNF alpha activity has also been effected using passive immunization. Monoclonal antibodies against TNF alpha have proved successful in ameliorating the effects of sepsis (in animal models) (90,91), cancer (92), synovial inflammation (93), inflammatory bowel disease (94,95) and chronic bacterial infection (96,97). While immunotherapy is effective for investigation studies in animal models, it has limitations in long-term disease therapy as the antibodies serve as immunogens and, therefore, can only be used for a limited period of time. To abrogate the immunogenicity of the antibody, several groups have proposed using monoclonal antibodies in combination with an immunosuppressive such as methotrexate. However, the rationale for using a potent immunosuppressive in a patient with a chronic disease such as heart failure remains questionable.
Perhaps the most exciting strategy that has recently been developed for inhibiting the effects of myocardial TNF alpha production is the use of a recombinantly produced chimeric TNF alpha soluble receptor (Etanercept; Immunex, Seattle, Washington) consisting of the p75 receptor linked to the Fc portion of human IgG (TNFR:Fc). Unlike synthetic pharmacologic agents that can have multiple cellular effects, recombinant proteins have the theoretical benefit of being highly specific. First used in the treatment of rheumatoid arthritis, Etanercept was associated with dose-related reductions in disease activity without dose-limiting toxicity or the development of antibodies to the recombinant receptor protein (98). Based on the salutorious effects of Etanercept in clinical trials of patients with rheumatoid arthritis, the agent was recently approved by the Food and Drug Administration. However, postmarketing surveillance has raised cautions regarding the use of the agent in patients with serious infections.
In a Phase I study assessing the safety of soluble TNF alpha receptor therapy in patients with CHF, a single intravenous dose of Etanercept was well tolerated, suppressed circulating levels of biologically active TNF alpha between 70% and 85% for at least 14 days and improved functional status and quality of life (99). More recently, 47 patients with New York Heart Association (NYHA) class III–IV heart failure symptoms were randomized to receive either biweekly subcutaneous Etanercept or placebo for three months. Etanercept effected dose-related trends in improvements in NYHA classification and quality of life and decreased cytokine expression (100). However, to assess the long-term effects of Etanercept, a randomized, double-blind and placebo-controlled clinical trial, RENAISSANCE, is presently enrolling patients with NYHA class II–IV heart failure symptoms in the U.S., and a companion study is underway in Europe and Australia.
|
Conclusions
|
|---|
In summary, both basic and clinical studies strongly support the hypothesis that myocardial expression of TNF alpha is an important step in the pathophysiologic pathway leading to progressive cardiac dilatation and failure. However, important questions remain to be answered: 1) What is the signal responsible for activating cardiac TNF alpha expression? 2) Why does the heart express TNF alpha? 3) Can we selectively attenuate cardiac TNF alpha expression? 4) What are the clinical benefits of TNF alpha inhibition? 5) When during the transition from compensated to decompensated heart failure is TNF alpha expressed? 6) What role is played by other proinflammatory cytokines such as IL-1beta? By addressing these important questions, it is hoped that investigators will be able to better understand the pathobiology of CHF while at the same time develop new and exciting therapeutic strategies.
|
Acknowledgments
|
|---|
The authors thank Tracey Barry for preparation of the manuscript.
|
Footnotes
|
|---|
This study was supported, in part, by NIH grant 1 P50 HL 6348A5-01.
|
References
|
|---|
1. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 1975;72:3666–3670[Abstract/Free Full Text]
2. Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone, secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985;161:984–995[Abstract/Free Full Text]
3. Evans RD, Argiles JM, Williamson DH. Metabolic effects of tumor necrosis factor-alpha (cachectin) and interleukin-1. Clin Sci. 1989;77:357–364[Medline]
4. Caput D, Beutler B, Hartog K, Thayer R, Brown-Shimer S, Cerami A. Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci USA. 1986;83:1670–1674[Abstract/Free Full Text]
5. Pennica D, Hayflick JS, Bringham TS, Palladino MA, Goeddal DV. Cloning and expression in E coli of the cDNA for murine tumor necrosis factor. Proc Natl Acad Sci USA. 1985;82:6060–6064[Abstract/Free Full Text]
6. Kriegier M, Perez C, DeFay K, Albert I, Lu SD. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988;53:45–53[CrossRef][Medline]
7. Tracey KJ, Vlassara H, Cerami A. Cachectin/tumor necrosis factor. Lancet. 1989;1:1122–1126[Medline]
8. Beutler B, van Huffel C. Unraveling function in the TNF ligand and receptor families. Science. 1994;264:667–668[Free Full Text]
9. Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411–452[CrossRef][Medline]
10. Dembic Z, Loetscher H, Gubler U, et al. Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine. 1990;2:231–237[CrossRef][Medline]
11. Bachmaier K, Pummerer C, Kozieradzki I, et al. Low-molecular-weight tumor necrosis factor receptor p55 controls induction of autoimmune heart disease. Circulation. 1997;95:655–661[Abstract/Free Full Text]
12. Olsson I, Lantz M, Nilsson E, et al. Isolation and characterization of a tumor necrosis factor binding protein from urine. Eur J Haematol. 1989;42:270–275[Medline]
13. Engelmann H, Novick D, Wallach D. Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem. 1990;265:1531–1536[Abstract/Free Full Text]
14. Brakebusch C, Nophar Y, Kemper O, Engelmann H. Cytoplasmic truncation of the p55 tumour necrosis factor (TNF) receptor abolishes signalling, but not induced shedding of the receptor. EMBO J. 1992;11:943–950[Medline]
15. Seckinger P, Isaaz S, Dayer JM. A human inhibitor of tumor necrosis factor alpha. J Exp Med. 1988;167:1511–1516[Abstract/Free Full Text]
16. Vilcek J, Lee TH. Tumor necrosis factor. J Biol Chem. 1991;266:7313–7316[Free Full Text]
17. Pfeffer K, Matsuyama T, Kuendig TM, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to monocytogenes infection. Cell. 1993;73:457–467[CrossRef][Medline]
18. Djeu JY, Blanchard DK, Richards AL, Friedman H. Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes. J Exp Med. 1988;141:4047–4052
19. Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem. 1995;270:15285–15293[Abstract/Free Full Text]
20. Dinarello CA, Cannon JG, Wolff SM, et al. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986;163:1433–1450[Abstract/Free Full Text]
21. Larrick JW, Wright SC. Cytotoxic mechanism of tumor necrosis factor-alpha. FASEB J. 1990;4:3215–3223[Abstract]
22. Old LJ. Tumor necrosis factor (TNF). Science. 1985;230:630–632[Free Full Text]
23. Malik STA, Griffin DB, Fiers W, Balkwill FR. Paradoxical effects of tumor necrosis factor in experimental ovarian cancer. Int J Cancer. 1989;44:918–925[Medline]
24. Malik STA, Naylor MS, East N, Oliff A, Balkwill FR. Cells secreting tumour necrosis factor show enhanced metastasis in nude mice. Eur J Cancer. 1990;26:1031–1034[Medline]
25. Naylor MS, Stamp GWH, Foulkes WD, Eccles D, Balkwill FR. Tumor necrosis factor and its receptors in human ovarian cancer. J Clin Invest. 1993;91:2194–2206[Medline]
26. Manicourt DH, Triki R, Fukuda K, Devogelaer JP, Nagant de Deuxchaisnes C, Thonar EJ. Levels of circulating tumor necrosis factor alpha and interleukin-6 in patients with rheumatoid arthritis. Relationship to serum levels of hyaluronan and antigenic keratan sulfate. Arthritis Rheum. 1993;36:490–499[Medline]
27. Kupferminc MJ, Peaceman AM, Wigton TR, Rehnberg KA, Socol ML. Tumor necrosis factor-alpha is elevated in plasma and amniotic fluid of patients with severe preeclampsia. Am J Obstet Gynecol. 1994;170:1752–1757[Medline]
28. Harel Y, Silva M, Giroir B, Weinberg A, Cleary TB, Beutler B. A reporter transgene indicates renal-specific induction of tumor necrosis factor (TNF) by shiga-like toxin. Possible involvement of TNF in hemolytic uremic syndrome. J Clin Invest. 1992;92:2110–2116
29. Wu CJ, Lovett M, Wong-Lee J, et al. Cytokine gene expression in rejecting cardiac allografts. Transplantation. 1992;54:326–332[Medline]
30. Sandborn WJ. A controlled trial of antitumor necrosis factor alpha antibody for Crohn’s disease. Gastroenterology. 1997;113:1042–1043[CrossRef][Medline]
31. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236–241[Medline]
32. 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]
33. Torre-Amione G, Kapadia S, Benedict C, Oral Y, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol. 1996;27:1201–1206[Abstract]
34. Ferrari R, Bachetti T, Confortini R, et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation. 1995;92:1479–1486[Abstract/Free Full Text]
35. MacGowan G, Mann DL, Kormos RL, Feldman AM, Murali S. Circulating interleukin-6 in severe congestive heart failure. Am J Cardiol. 1997;79:1128–1131[CrossRef][Medline]
36. 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]
37. Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989;321:280–287[Medline]
38. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JBMDL. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation. 1996;93:704–711[Abstract/Free Full Text]
39. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992;257:387–389[Abstract/Free Full Text]
40. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest. 1993;92:2303–2312[Medline]
41. Eichenholz PW, Eichacker PQ, Hoffman WD, Banks SM, Parrillo JEDR, Natanson C. Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction. Am J Physiol. 1992;263:H668–H675[Medline]
42. McTiernan CF, Lemster BH, Frye CS, Combes A, Feldman AM. Interleukin-1B phospholamban gene expression in cultured cardiomyocytes. Circulation Res. 1997;81:493–503[Abstract/Free Full Text]
43. Gulick T, Chung MK, Pieper SJ, Lange LG, Schreiner GF. Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci USA. 1989;86:6753–6757[Abstract/Free Full Text]
44. Chung MK, Gulick TS, Rotondo RE, Schreiner GF, Lange LG. Mechanism of cytokine inhibition of beta-adrenergic agonist stimulation of cyclic AMP in rat cardiac myocytes. Impairment of signal transduction. Circ Res. 1990;67:753–763[Abstract/Free Full Text]
45. Li YY, McTiernan CF, Feldman AM. Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells. Cardiovasc Res. 1999;42:162–172[Abstract/Free Full Text]
46. Yokoyama T, Nakano M, Bednarczyk J, McIntyre BW, Entman M, Mann DL. Tumor Necrosis Factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation. 1996;95:1247–1252
47. Oral H, Dorn GW, Mann DL. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem. 1997;272:4836–4842[Abstract/Free Full Text]
48. 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;97:1382–1391
49. Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM. Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J Cardiac Failure. 1997;3:117–124[CrossRef][Medline]
50. Kubota T, McTiernan CF, Frye CS, 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]
51. Bryant D, Becker L, Richardson J, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation. 1997;97:1375–1381
52. Bristow MR. Tumor necrosis factor-alpha and cardiomyopathy. Circulation. 1998;97:1340–1341[Free Full Text]
53. London B, Baker LC, Kubota T, et al. Slow conduction of premature beats leads to ventricular tachycardia in a TNF alpha transgenic model of congestive heart failure (abstr). Circulation 1999; In press.
54. Li YY, Feng YQ, Kadokami T, McTiernan CF, Feldman AM. Modulation of matrix metalloproteinase activities remodels myocardial extracellular matrix in TNF alpha transgenic mice (abstr). Circulation 1999. In press.
55. Kubota T, Miyagishima M, Bounoutas GS, McTiernan CF, Feldman AM. Overexpression of tumor necrosis factor-alpha activates the expression of multiple members of the apoptosis pathway in transgenic mice. Circulation. 1998;98:I462
56. Kubota T, Bounoutas GS, Miyagishima M, McTiernan CF, Feldman AM. Development of myocarditis in transgenic mice overexpressing tumor necrosis factor alpha is mediated in part by the selective induction of downstream proinflammatory cytokines and beta-chemokines. Circulation. 1998;98:I345
57. Bounoutas GS, Kubota T, Miyagishima M, et al. Adenoviral-directed overexpression of soluble tumor necrosis factor receptors reverses myocarditis in transgenic mice with congestive heart failure (abstr. ). Circulation. 1998;98:I737
58. Kapadia S, Torre-Amione G, Yokoyama T, Mann DL. Soluble TNF binding proteins modulate the negative inotropic properties of TNF-alpha in vitro. Am J Physiol. 1995;268:H517–H525[Medline]
59. Kolls J, Peppel K, Silva M, Beutler B. Prolonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer. Proc Natl Acad Sci USA. 1994;91:215–219[Abstract/Free Full Text]
60. Wilson AG, Symons JA, McDowell TL, di Giovine FS, Duff GW. Effects of a tumor necrosis factor (TNF alpha) promoter base transition on transcriptional activity. Br J Rheum. 1994;33:89[Free Full Text]
61. Stuber F, Petersen M, Bokelmann F, Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med. 1996;24:381–384[CrossRef][Medline]
62. Wilson AG, di Giovine FS, Duff GW. Genetics of tumor necrosis factor-alpha in autoimmune, infectious and neoplastic diseases. J Inflamm. 1995;45:1–12[Medline]
63. Kaijzel EL, van Krugten MV, Brinkman BM, et al. Functional analysis of a human tumor necrosis factor alpha (TNF-alpha) promoter polymorphism related to joint damage in rheumatoid arthritis. Mol Med. 1998;4:724–733[Medline]
64. Wilson AG, di Giovine FS, Blakemore AIF, Duff GW. Single base polymorphism in the human tumor necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genetics. 1992;1:353[Free Full Text]
65. Messer G, Spengler U, Jung MC, et al. Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced levels of TNF-beta production. J Exp Med. 1991;173:209–219[Abstract/Free Full Text]
66. Danis VA, Millington M, Hyland V, Lawford R, Huang Q, Grennan D. Increased frequency of the uncommon allele of a tumor necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Dis Markers. 1994;12:127–133
67. McGuire W, Hill AVS, Allsopp CEM, Greenwood BM, Kwjatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994;371:508–511[CrossRef][Medline]
68. Kubota T, McNamara DM, McTiernan CF, et al. Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. Circulation. 1998;97:2499–2501[Abstract/Free Full Text]
69. Feldman AM, McNamara DM, Wagner DR. AMPD1 gene mutation in congestive heart failure: new insights into the pathobiology of disease progression. Circulation. 1998;99:1397–1399
70. Newell C, Deisseroth A, Lopez-Berestein G. Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF alpha gene. J Leukoc Biol. 1994;56:27–35[Abstract]
71. Snyder DS, Unanue ER. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J Immunol. 1982;129:1803–1805[Abstract]
72. Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986;232:977–980[Abstract/Free Full Text]
73. Arzt E, Sauer T, Pollmacher T, et al. Glucocorticoids suppress interleukin-1 receptor antagonist synthesis following induction by endotoxin. Endocrinology. 1994;134:672–677[Abstract/Free Full Text]
74. Yoshimura T, Kurita C, Nagoa T, et al. Inhibition of tumor necrosis factor-alpha and interleukin-1 beta production by beta-adrenoceptor agonists from lipopolysaccharide-stimulated human peripheral blood mononuclear cells. Pharmacology. 1997;54:144–152[Medline]
75. Szabo C, Hasko G, Zingarelli B, et al. Isoproterenol regulates tumor necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxemia. Immunology. 1997;90:95–100[CrossRef][Medline]
76. Vanderpoll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest. 1996;97:713–719[Medline]
77. Shioi T, Matsumori A, Matsui S, Sasayama S. Inhibition of cytokine production by a new inotropic agent, vesnarinone, in human lymphocytes, T cell line, and monocytic cell line. Life Sci 1994;54:PL11–6.
78. Matsumori A, Shioi T, Yamada T, Matsui S, Sasayama S. Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure. Circulation. 1994;89:955–958[Abstract/Free Full Text]
79. Sliwa K, Skudicky D, Candy G, Wisenbaugh T, Sareli P. Randomized investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet. 1998;351:1091–1093[CrossRef][Medline]
80. Zabel P, Wolter DT, Schonharting MM, Schade UF. Oxpentifylline in endotoxaemia. Lancet. 1989;23:1474–1477
81. Bergman MR, Holycross BJ. Pharmacological modulation of myocardial tumor necrosis factor alpha production by phosphodiesterase inhibitors [published erratum appears in J Pharmacol Exp Ther 1997;280:520]. J Pharmacol Exp Ther. 1996;:247–254
82. Matsumori A, Ono K, Nishio R, Nose Y, Sasayama S. Amiodarone inhibits production of tumor necrosis factor-alpha by human mononuclear cells. A possible mechanism for its effect in heart failure. Circulation. 1997;96:1386–1389[Abstract/Free Full Text]
83. Matsumori A, Ono K, Nishio R, et al. Modulation of cytokine production and protection against lethal endotoxemia by the cardiac glycoside ouabain. Circulation. 1997;96:1501–1506[Abstract/Free Full Text]
84. Corral LG, Muller GW, Moreira AL, et al. Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med. 1996;2:506–515[Medline]
85. Ammann P, Rizzoli R, Bonjour JP. Transgenic mice expressing soluble tumor necrosis factor are protected against bone loss caused by estrogen deficiency. J Clin Invest. 1997;99:1699–1703[Medline]
86. Wagner DR, Combes A, McTiernan CF, Sanders VJ, Feldman AM. Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-alpha. Circ Res. 1998;82:47–56[Abstract/Free Full Text]
87. Wagner DR, McTiernan CF, Frye CS, Lemster BH, Feldman AM. Adenosine inhibits lipopolysaccharide-induced secretion of tumor necrosis factor-alpha in the failing human heart. Circulation. 1998;97:521–524[Abstract/Free Full Text]
88. Sajjadi FG, Takabayashi K, Foster AC, Domingo RC, Firestein GS. Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors. J Immunol. 1996;156:3435–3442[Abstract]
89. Loh E, Rebbeck TR, Mahoney PD, DeNofrio D, Swain JL, Holmes EW. Common variant in the AMPD1 gene predicts improved clinical outcome in patients with heart failure. Circulation. 1998;99:1422–1425
90. Beutler B, Milsark IW, Cerami AC. Passive immunization against cachetin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985;229:869–871[Abstract/Free Full Text]
91. Opal SM, Cross AS, Kelly NM, et al. Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa. J Infect Dis. 1990;161:1148–1152[Abstract/Free Full Text]
92. Sherry BA, Gelin J, Fong Y, et al. Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models. FASEB J. 1989;3:1956–1962[Abstract]
93. Piguet PF, Grau GE, Vesin C, Loetscher H, Gentz R, Lesslauer W. Evolution of collagen arthritis in mice is arrested by treatment with antitumor necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology. 1997;77:510–514
94. Stokkers PC, Camoglio L, van Deventer SJ. Tumor necrosis factor (TNF) in inflammatory bowel disease: gene polymorphisms, animal models and potential for anti-TNF therapy. J Inflamm. 1996;47:97–103
95. Kojouharoff G, Hans W, Obermeier F, et al. Neutralization of tumor necrosis factor (TNF), but not of IL-1, reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin Exp Immunol. 1997;107:353–358[CrossRef][Medline]
96. Havell EA. Evidence that tumor necrosis factor has an important role in antibacterial resistance. J Immunol. 1989;143:2894–2899[Abstract]
97. Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989;56:731–740[CrossRef][Medline]
98. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337:141–147[CrossRef][Medline]
99. Deswal A, Seta Y, Blosch CM, Mann DL. A phase I trial of tumor necrosis factor receptor (p75) fusion protein (TNPF:Fc) in patients with advanced heart failure [abstract]. Circulation. 1998;:I323
100. Bozkurt B, Torre-Amione G, Soran O, et al. Results of a multidose phase I trial with tumor necrosis factor receptor (p75) fusion protein (Etanercept) in patients with heart failure [abstract]. J Am Coll Cardiol. 1999;:184A–185A
This article has been cited by other articles:
|
|
|
|
 
P. S. Petkova-Kirova, B. London, G. Salama, R. L. Rasmusson, and V. E. Bondarenko
Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-{alpha}
Am J Physiol Heart Circ Physiol,
February 1, 2012;
302(4):
H934 - H952.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. B. Aggarwal, S. C. Gupta, and J. H. Kim
Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey
Blood,
January 19, 2012;
119(3):
651 - 665.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Coggins and A. Rosenzweig
The Fire Within: Cardiac Inflammatory Signaling in Health and Disease
Circ. Res.,
January 6, 2012;
110(1):
116 - 125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Lourenco, F. Vasques-Novoa, D. Fontoura, C. Bras-Silva, R. Roncon-Albuquerque Jr, and A. F. Leite-Moreira
A Western-Type Diet Attenuates Pulmonary Hypertension with Heart Failure and Cardiac Cachexia in Rats
J. Nutr.,
November 1, 2011;
141(11):
1954 - 1960.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. B. Maxwell and A. T. Jenkins
Drug-induced heart failure
Am. J. Health Syst. Pharm.,
October 1, 2011;
68(19):
1791 - 1804.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Nilsson, P. Hedberg, and J. Ohrvik
Survival of the fattest: unexpected findings about hyperglycaemia and obesity in a population based study of 75-year-olds
BMJ Open,
September 2, 2011;
1(1):
e000012 - e000012.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. L. Walker and A. McEntegart
35 Arthritis
Oxford Textbook of Heart Failure,
January 1, 2011;
1(1):
med-9780199577729-chapter - med-9780199577729-chapter.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
C. Andersson, M. L. Norgaard, P. R. Hansen, E. L. Fosbol, M. Schmiegelow, P. Weeke, J. B. Olesen, J. Raunso, C. H. Jorgensen, A. Vaag, et al.
Heart failure severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction: a nationwide cohort study
Eur J Heart Fail,
December 1, 2010;
12(12):
1333 - 1338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. E. Hastie, S. Padmanabhan, R. Slack, A. C.H. Pell, K. G. Oldroyd, A. D. Flapan, K. P. Jennings, J. Irving, H. Eteiba, A. F. Dominiczak, et al.
Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention
Eur. Heart J.,
January 2, 2010;
31(2):
222 - 226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. V. McMurray, J. Kjekshus, L. Gullestad, P. Dunselman, A. Hjalmarson, H. Wedel, M. Lindberg, F. Waagstein, P. Grande, J. Hradec, 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,
December 1, 2009;
120(22):
2188 - 2196.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Hylek, L. Frison, L. E. Henault, and A. Cupples
Disparate Stroke Rates on Warfarin Among Contemporaneous Cohorts With Atrial Fibrillation: Potential Insights Into Risk From a Comparative Analysis of SPORTIF III Versus SPORTIF V
Stroke,
November 1, 2008;
39(11):
3009 - 3014.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Panagopoulou, C. H. Davos, D. J. Milner, E. Varela, J. Cameron, D. L. Mann, and Y. Capetanaki
Desmin mediates TNF-{alpha}-induced aggregate formation and intercalated disk reorganization in heart failure
J. Cell Biol.,
October 20, 2008;
181(5):
761 - 775.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Elliott
Relevance of platelet activation in obstructive hypertrophic cardiomyopathy
Heart,
June 1, 2008;
94(6):
688 - 689.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Knuefermann, M. Schwederski, M. Velten, P. Krings, H. Ehrentraut, M. Rudiger, O. Boehm, K. Fink, U. Dreiner, C. Grohe, et al.
Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of Toll-like receptor 9
Cardiovasc Res,
April 1, 2008;
78(1):
26 - 35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Chakir, S. K. Daya, R. S. Tunin, R. H. Helm, M. J. Byrne, V. L. Dimaano, A. C. Lardo, T. P. Abraham, G. F. Tomaselli, and D. A. Kass
Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization
Circulation,
March 18, 2008;
117(11):
1369 - 1377.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. D. Laoutaris, A. Dritsas, M. D. Brown, A. Manginas, M. S. Kallistratos, D. Degiannis, A. Chaidaroglou, D. B. Panagiotakos, P. A. Alivizatos, and D. V. Cokkinos
Immune response to inspiratory muscle training in patients with chronic heart failure
European Journal of Cardiovascular Prevention & Rehabilitation,
October 1, 2007;
14(5):
679 - 686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Schoner and G. Scheiner-Bobis
Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth
Am J Physiol Cell Physiol,
August 1, 2007;
293(2):
C509 - C536.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Monden, T. Kubota, T. Inoue, T. Tsutsumi, S. Kawano, T. Ide, H. Tsutsui, and K. Sunagawa
Tumor necrosis factor-{alpha} is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction
Am J Physiol Heart Circ Physiol,
July 1, 2007;
293(1):
H743 - H753.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Smith, N. W. Wilson, A. Louw, and K. H. Myburgh
Illuminating the interrelated immune and endocrine adaptations after multiple exposures to short immobilization stress by in vivo blocking of IL-6
Am J Physiol Regulatory Integrative Comp Physiol,
April 1, 2007;
292(4):
R1439 - R1447.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Westermann, S. Rutschow, S. Jager, A. Linderer, S. Anker, A. Riad, T. Unger, H.-P. Schultheiss, M. Pauschinger, and C. Tschope
Contributions of Inflammation and Cardiac Matrix Metalloproteinase Activity to Cardiac Failure in Diabetic Cardiomyopathy: The Role of Angiotensin Type 1 Receptor Antagonism
Diabetes,
March 1, 2007;
56(3):
641 - 646.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Monden, T. Kubota, T. Tsutsumi, T. Inoue, S. Kawano, N. Kawamura, T. Ide, K. Egashira, H. Tsutsui, and K. Sunagawa
Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction
Cardiovasc Res,
March 1, 2007;
73(4):
794 - 805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Roig
Usefulness of neurohormonal markers in the diagnosis and prognosis of heart failure
Eur. Heart J. Suppl.,
September 1, 2006;
8(suppl_E):
E12 - E17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen
Statins in the treatment of chronic heart failure: Biological and clinical considerations
Cardiovasc Res,
August 1, 2006;
71(3):
443 - 454.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Kosar, Y. Aksoy, G. Ozguntekin, I. Ozerol, and E. Varol
Relationship between cytokines and tumour markers in patients with chronic heart failure
Eur J Heart Fail,
May 1, 2006;
8(3):
270 - 274.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Petkova-Kirova, E. Gursoy, H. Mehdi, C. F. McTiernan, B. London, and G. Salama
Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-{alpha}
Am J Physiol Heart Circ Physiol,
May 1, 2006;
290(5):
H2098 - H2107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Anand, A. N Mooss, and S. M Mohiuddin
Review: Aldosterone Inhibition Reduces the Risk of Sudden Cardiac Death in Patients with Heart Failure
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2006;
7(1):
15 - 19.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. Odeh, E. Sabo, and A. Oliven
Circulating levels of tumor necrosis factor-{alpha} correlate positively with severity of peripheral oedema in patients with right heart failure
Eur J Heart Fail,
March 1, 2006;
8(2):
141 - 146.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Higuchi, T. O. Chan, M. A. Brown, J. Zhang, B. R. DeGeorge Jr., H. Funakoshi, G. Gibson, C. F. McTiernan, T. Kubota, W. K. Jones, et al.
Cardioprotection afforded by NF-{kappa}B ablation is associated with activation of Akt in mice overexpressing TNF-{alpha}
Am J Physiol Heart Circ Physiol,
February 1, 2006;
290(2):
H590 - H598.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Matsusaka, M. Ikeuchi, S. Matsushima, T. Ide, T. Kubota, A. M. Feldman, A. Takeshita, K. Sunagawa, and H. Tsutsui
Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy
Am J Physiol Heart Circ Physiol,
November 1, 2005;
289(5):
H1858 - H1864.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Hall, I. S. Singh, L. Hester, J. D. Hasday, and T. B. Rogers
Inhibitor-{kappa}B kinase-{beta} regulates LPS-induced TNF-{alpha} production in cardiac myocytes through modulation of NF-{kappa}B p65 subunit phosphorylation
Am J Physiol Heart Circ Physiol,
November 1, 2005;
289(5):
H2103 - H2111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Quenot, G. Le Teuff, C. Quantin, J.-M. Doise, M. Abrahamowicz, D. Masson, and B. Blettery
Myocardial Injury in Critically Ill Patients: Relation to Increased Cardiac Troponin I and Hospital Mortality
Chest,
October 1, 2005;
128(4):
2758 - 2764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Kassiri, G. Y. Oudit, O. Sanchez, F. Dawood, F. F. Mohammed, R. K. Nuttall, D. R. Edwards, P. P. Liu, P. H. Backx, and R. Khokha
Combination of Tumor Necrosis Factor-{alpha} Ablation and Matrix Metalloproteinase Inhibition Prevents Heart Failure After Pressure Overload in Tissue Inhibitor of Metalloproteinase-3 Knock-Out Mice
Circ. Res.,
August 19, 2005;
97(4):
380 - 390.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Avgeropoulou, I. Andreadou, S. Markantonis-Kyroudis, M. Demopoulou, P. Missovoulos, A. Androulakis, and I. Kallikazaros
The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and pro-inflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine
Eur J Heart Fail,
August 1, 2005;
7(5):
882 - 887.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Li, D. Georgakopoulos, G. Lu, L. Hester, D. A. Kass, J. Hasday, and Y. Wang
p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart
Circulation,
May 17, 2005;
111(19):
2494 - 2502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kalantar-Zadeh, K. C Abbott, A. K Salahudeen, R. D Kilpatrick, and T. B Horwich
Survival advantages of obesity in dialysis patients
Am J Clin Nutr,
March 1, 2005;
81(3):
543 - 554.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Munroe and G. A. Bishop
Role of Tumor Necrosis Factor (TNF) Receptor-associated Factor 2 (TRAF2) in Distinct and Overlapping CD40 and TNF Receptor 2/CD120b-mediated B Lymphocyte Activation
J. Biol. Chem.,
December 17, 2004;
279(51):
53222 - 53231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. W. Moe, J. Marin-Garcia, A. Konig, M. Goldenthal, X. Lu, and Q. Feng
In vivo TNF-{alpha} inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure
Am J Physiol Heart Circ Physiol,
October 1, 2004;
287(4):
H1813 - H1820.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Morley and R. N. Baumgartner
Cytokine-Related Aging Process
J Gerontol A Biol Sci Med Sci,
September 1, 2004;
59(9):
M924 - M929.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Morita, G. Stamp, P. Robins, A. Dulic, I. Rosewell, G. Hrivnak, G. Daly, T. Lindahl, and D. E. Barnes
Gene-Targeted Mice Lacking the Trex1 (DNase III) 3'->5' DNA Exonuclease Develop Inflammatory Myocarditis
Mol. Cell. Biol.,
August 1, 2004;
24(15):
6719 - 6727.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M Janczewski, M. Zahid, B. H Lemster, C. S Frye, G. Gibson, Y. Higuchi, E. G Kranias, A. M Feldman, and C. F McTiernan
Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model
Cardiovasc Res,
June 1, 2004;
62(3):
468 - 480.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Higuchi, C. F. McTiernan, C. B. Frye, B. S. McGowan, T. O. Chan, and A. M. Feldman
Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-{alpha}-Induced Cardiomyopathy
Circulation,
April 20, 2004;
109(15):
1892 - 1897.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Horwich, W. R. MacLellan, and G. C. Fonarow
Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure
J. Am. Coll. Cardiol.,
February 18, 2004;
43(4):
642 - 648.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Jortani, S. D. Prabhu, and R. Valdes Jr
Strategies for Developing Biomarkers of Heart Failure
Clin. Chem.,
February 1, 2004;
50(2):
265 - 278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F.-X. Blanc, O. Langeron, C. Coirault, S. Salmeron, F. Lambert, B. Riou, and Y. Lecarpentier
Mechanical Properties of Tracheal Smooth Muscle Are Impaired in the Rabbit With Experimental Cardiac Pressure Overload
Chest,
January 1, 2004;
125(1):
236 - 242.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. C. Fonarow and T. B. Horwich
Cholesterol and mortality in heart failure: the bad gone good?
J. Am. Coll. Cardiol.,
December 3, 2003;
42(11):
1941 - 1943.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Adamopoulos, J. T. Parissis, I. Paraskevaidis, D. Karatzas, E. Livanis, M. Georgiadis, G. Karavolias, D. Mitropoulos, D. Degiannis, and D. Th. Kremastinos
Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy
Eur. Heart J.,
December 2, 2003;
24(24):
2186 - 2196.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Ahokas, K. J. Warrington, I. C. Gerling, Y. Sun, L. A. Wodi, P. A. Herring, L. Lu, S. K. Bhattacharya, A. E. Postlethwaite, and K. T. Weber
Aldosteronism and Peripheral Blood Mononuclear Cell Activation: A Neuroendocrine-Immune Interface
Circ. Res.,
November 14, 2003;
93(10):
e124 - e135.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D B McKenzie and A J Cowley
Drug therapy in chronic heart failure
Postgrad. Med. J.,
November 1, 2003;
79(937):
634 - 642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Horwich, J. Patel, W. R. MacLellan, and G. C. Fonarow
Cardiac Troponin I Is Associated With Impaired Hemodynamics, Progressive Left Ventricular Dysfunction, and Increased Mortality Rates in Advanced Heart Failure
Circulation,
August 19, 2003;
108(7):
833 - 838.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Nakamura, S. Umemoto, G. Naik, G. Moe, S. Takata, P. Liu, and M. Matsuzaki
Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation rat model
J. Am. Coll. Cardiol.,
July 2, 2003;
42(1):
173 - 181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Stenvinkel, R. Pecoits-Filho, and B. Lindholm
Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem
J. Am. Soc. Nephrol.,
July 1, 2003;
14(7):
1927 - 1939.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Kwon, T. R. Cote, M. S. Cuffe, J. M. Kramer, and M M. Braun
Case Reports of Heart Failure after Therapy with a Tumor Necrosis Factor Antagonist
Ann Intern Med,
May 20, 2003;
138(10):
807 - 811.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Francis, R. M. Weiss, A. K. Johnson, and R. B. Felder
Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats
Am J Physiol Regulatory Integrative Comp Physiol,
February 1, 2003;
284(2):
R328 - R335.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Abbate, E. Vecile, N. Fiotti, C. Giansante, G. Guarnieri, G. Di Sciascio, and A. Dobrina
Plasma concentrations of interleukin-2 soluble receptor in mild ischaemic left ventricular dysfunction
Eur J Heart Fail,
January 1, 2003;
5(1):
23 - 25.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V.M. Conraads, P. Beckers, J. Bosmans, L.S. De Clerck, W.J. Stevens, C.J. Vrints, and D.L. Brutsaert
Combined endurance/resistance training reduces plasma TNF-{alpha} receptor levels in patients with chronic heart failure and coronary artery disease
Eur. Heart J.,
December 1, 2002;
23(23):
1854 - 1860.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Page, D. Assouline, O. Brun, D. Coeffic, D. Fric, P. Winckel, A. D. Seidman, M. K. Pierri, and C. Hudis
Cardiac Dysfunction in Clinical Trials of Trastuzumab
J. Clin. Oncol.,
October 1, 2002;
20(19):
4119 - 4120.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J J V McMurray
Heart failure in 10 years time: focus on pharmacological treatment
Heart,
October 1, 2002;
88(90002):
ii40 - 46.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. N. Witherow, P. Dawson, C. A. Ludlam, K. A. A. Fox, and D. E. Newby
Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy
J. Am. Coll. Cardiol.,
September 4, 2002;
40(5):
961 - 966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Funakoshi, T. Kubota, Y. Machida, N. Kawamura, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita
Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha
Am J Physiol Heart Circ Physiol,
June 1, 2002;
282(6):
H2159 - H2166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Funakoshi, T. Kubota, N. Kawamura, Y. Machida, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita
Disruption of Inducible Nitric Oxide Synthase Improves {beta}-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced Cardiomyopathy
Circ. Res.,
May 17, 2002;
90(9):
959 - 965.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Yndestad, J. Kristian Damas, H. Geir Eiken, T. Holm, T. Haug, S. Simonsen, S. S. Froland, L. Gullestad, and P. Aukrust
Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure
Cardiovasc Res,
April 1, 2002;
54(1):
175 - 182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Adamopoulos, J. T. Parissis, and D. Th. Kremastinos
A glossary of circulating cytokines in chronic heart failure
Eur J Heart Fail,
October 1, 2001;
3(5):
517 - 526.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Horwich, G. C. Fonarow, M. A. Hamilton, W. R. MacLellan, M. A. Woo, and J. H. Tillisch
The relationship between obesity and mortality in patients with heart failure
J. Am. Coll. Cardiol.,
September 1, 2001;
38(3):
789 - 795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K S Channer and P J Pugh
Interfering with healing: the benefits of intervention during acute myocardial infarction
Heart,
June 1, 2001;
85(6):
620 - 622.
[Full Text]
|
|
|
|
|
|
|
W. W. Parmley
How Many Medicines Do Patients With Heart Failure Need?
Circulation,
March 27, 2001;
103(12):
1611 - 1612.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Clark
Perioperative Treatment of Congestive Heart Failure
Seminars in Cardiothoracic and Vascular Anesthesia,
November 1, 2000;
4(4):
223 - 235.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. H. MacLean, R. Louie, B. Leake, D. F. McCaffrey, H. E. Paulus, R. H. Brook, and P. G. Shekelle
Quality of Care for Patients With Rheumatoid Arthritis
JAMA,
August 23, 2000;
284(8):
984 - 992.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Feldman, B. H. Lorell, and S. E. Reis
Trastuzumab in the Treatment of Metastatic Breast Cancer : Anticancer Therapy Versus Cardiotoxicity
Circulation,
July 18, 2000;
102(3):
272 - 274.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Funakoshi, T. Kubota, Y. Machida, N. Kawamura, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita
Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha
Am J Physiol Heart Circ Physiol,
June 1, 2002;
282(6):
H2159 - H2166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
The proinflammatory cytokine TNF