Skip Navigation

Cardiovascular Research 1999 42(3):557-564; doi:10.1016/S0008-6363(99)00050-4
© 1999 by European Society of Cardiology
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sasayama, S.
Right arrow Articles by Kihara, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sasayama, S.
Right arrow Articles by Kihara, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1999, European Society of Cardiology

New insights into the pathophysiological role for cytokines in heart failure

Shigetake Sasayama*, Akira Matsumori and Yasuki Kihara

Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

sasayama{at}kuhp.kyoto-u.ac.jp

* Corresponding author. Tel.: +81-75-751-3185; Fax:+81-75-752-0856

Received 28 October 1998; accepted 1 February 1999

The syndrome of heart failure may be produced by a variety of disease states. These include dilated cardiomyopathy, mechanically overloaded hypertrophy or ischemic heart disease. We developed experimental models of these cardiac diseases. In the murine model of myocarditis, inflammatory cytokines were induced rapidly in the myocardium and continued to express during the chronic stage when the heart assumed the typical pattern of dilated cardiomyopathy in the absence of inflammatory processes. In the pressure overloaded ventricle, the myocardium first developed adaptive hypertrophy but in the later stage this pattern of hypertrophy underwent a transition to heart failure. Cytokines appeared to play a significant role in this process by accelerating myocyte growth and down-modulating cardiac function. In the ischemic heart, the non-ischemic myocardium developed hypertrophy associated with the progression of scarring in the ischemic area. This remodelling process initially exerts an important compensatory mechanism for ventricular function but later results in the development of heart failure. During this stage of healing from acute ischemic insult, inflammatory cytokines were upregulated continuously in the non-ischemic myocardium. Thus, we postulated that some aspects of heart failure may be mediated by non-lethal alteration of cardiac function and structural changes of the ventricle induced by cytokines. In this connection, many drugs used routinely in clinical practice have been proved to have anticytokine effects. Immunomodulating or anticytokine therapy could pave a new road in the management of heart failure.

There is a growing body of evidence that immunologic responses mediated by cytokines may play an important pathogenic role in the development of heart failure. A number of clinical studies have demonstrated that patients with congestive heart failure (CHF) express excessive levels of cytokines in plasma [1–4]. Cytokines are soluble peptides which mediate cell-to-cell interactions via specific cell surface receptors and regulates the activation, differentiation, growth, death or aquisition of effector functions of immune cells. Most cytokines act as local autocrine or paracrine mediators and do not act in endocrine fashion. Therefore, systemic elevation of cytokines produces a series of pathologic reactions. A continuous infusion of cytokine in rat was shown to provoke a time-dependent depression in left ventricular (LV) function and structure [5]. Injection of recombinant cytokine increased mortality in the murine model of myocarditis [6]. It has been reported that serum levels of cytokines may correlate with the severity of heart failure, but the net biologic effect of cytokines seems to be determined primarily by the body compartment in which they are produced and not by the ambient serum level [7–9].

Recent observations suggest that proinflammatory cytokines are capable of modulating cardiovascular functions by a variety of mechanisms. Potential biological mechanisms underlying this cardiodepressant effect of inflammatory cytokines include an uncoupling of the beta-receptor from adenylate cyclase by an alteration in the inhibitory guanine regulatory protein [10], an increase in inducible nitric oxide synthase (NOS) activity in cardiac muscle associated with release of nitric oxide (NO) [11,12], direct negative inotropic response mediated by enhanced NO production by a constitutive NOS [13], direct negative effect mediated by alterations in intracellular calcium homeostasis [14] or by activation of the neutral sphingomyelinase pathway [15], or induction of apoptosis in cardiac myocytes [16]. In view of existing knowledge on the biological effect of cytokines, ’cytokine hypothesis’ for heart failure has now attracted a lot of attention.

The syndrome of heart failure may be produced by a variety of causes which produce either intrinsic impairment of myocardial contractility, an increase in mechanical stress, or a loss of contractile myocytes. Thus, we developed animal models which mimic these clinical disorders and assessed the pathogenesis of development of heart failure from the immunological point of view.


   1. Cardiomyopathy
Top
 1. Cardiomyopathy
2. Mechanical overload
 3. Ischemic heart disease
 4. Anticytokine therapy for...
 References
 
Dilated cardiomyopathy (DCM) constitutes a most common cause of heart failure. DCM has been considered to occur as an end result of preceding myocarditis. Recent development of molecular biology techniques have allowed direct detection of viral RNA sequences in myocardium of patients with DCM, even when signs of inflammatory process are completely absent [17].

On the bases of the presence of viral genome in heart tissue, we assessed a causal relationship between DCM and myocarditis in murine models [18,19]. When mice were inoculated with the myocardiotropic variant of encephalomyocarditis (EMC) virus, the virus invaded the heart tissue and directly caused myocarditis during the first 7 days. Congestive heart failure then became apparent from 7 to 10 days after infection ensued, by which time most of the culturable virus had been eliminated, however the viral genome was detectable in the myocardial tissue by the polymerase chain reaction gene amplification technique [19] (Fig. 1). Over the following 3-month period, hypertrophy and myocardial fibrosis proceeded with further dilation of the left ventricular (LV) cavity and the heart assumed the characteristic pattern of DCM. Thereby, no acute inflammatory process was observed but viral genomes were still detected at the site of myocardial damage. In this model, the proinflammatory cytokines, interleukin (IL)-1 β and tumor necrosis factor (TNF)-{alpha} were induced rapidly within 3 days after infection presumably by intrinsic cells in the heart tissue (Fig 1). The immunoregulatory cytokines, interferon (IFN)-{gamma} and IL-2 mRNAs started to be detected from 3 to 7 days after innoculation. TNF-{alpha} mRNA and protein have been shown to be present with the resultant downregulation of its receptors in the failing human heart, suggesting that the heart is capable of synthesizing TNF-{alpha} [20]. However, expression of these cytokines was similar to temporal changes in T cell infiltration in the myocardium in our experiments and infiltrating cells rather than resident heart cells appeared to be responsible for the upregulation of these cytokines [19] (Fig. 1).


Figure 1
View larger version (61K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Representative autoradiograms for PCR products from the murine myocarditis. RNA was extracted from the noninfected control hearts, and infected hearts at the indicated time intervals. The cDNA was synthesized and then amplified by PCR and subjected southern hybridization. Viral genome RNA (top) was detectable immediately after infection, increased rapidly, reaching the peak level on day 7. Then it decreased gradually but was still detectable on day 80. The expressions of IL-1 and TNF-{alpha} were upregulated within 3 days after infection, when cellular infiltration was not apparent. IL-2 and IFN mRNA began to be detected from day 7, with substantial cellular infiltration. The expressions of all of these cytokines peaked on day 7 but persisted for 80 days after virus infection, even when infectious virus was serologically no longer detectable. These persistent expressions of cytokines could greatly affect cardiac function and importantly modify the outcome of the disease process.

 
Gene expressions of these cytokines continued for 3 months after virus inoculation particularly in the absence of inflammatory process (Fig 1). IL-1 β gene expression in the later stage positively correlated with ventricular mass and with the extent of fibrosis. In patients undergoing cardiac transplantation for DCM, IL-1 β mRNA was shown to be elevated in coronary arteries and myocardium, suggesting that IL-1 β may play a part in the pathogenesis of heart failure [21]. Time course of IL-2 and IFN-{gamma} mRNA throughout the disease process correlated well with the amount of the myocardial virus genome RNA, suggesting the persistent virus as the prime inducer of these cytokines. The fundamental process involved in the viral infection leading to DCM is the initial activation of protective immune responses followed by an immune-mediated destructive responses against the heart in the later stage [22–24]. In the murine model of myocarditis and heart failure, administration of recombinant human IL-2 in the acute stage increased survival rate with less intense pathologic changes of myocardium, whereas the same amount of IL-2 exacerbated the severity of the disease and reduced survival rate in the later stage [24]. Thus, the same cytokine may modulate different stages and disease types in different ways and the net effects of the host response may ultimately depend on a balance between the beneficial and injurious effects of cytokines.


   2. Mechanical overload
Top
 1. Cardiomyopathy
 2. Mechanical overload
3. Ischemic heart disease
 4. Anticytokine therapy for...
 References
 
The left ventricle responds to an excessive mechanical load by chamber dilation and myocardial hypertrophy. Initially, these changes provide important compensatory mechanisms permitting to normalize chamber wall stress and to restore relatively normal pumping ability. However, heart failure may ensue as a direct consequence of the limited ability and ultimate failure of these compensatory remodelings. Recently, we have developed an experimental model which permits a proper evaluation of sequence of events occuring during the transition from adaptive LV hypertrophy to cardiac failure [25]. When Dahl salt-sensitive rats were fed with a high-salt diet, they developed rapidly characteristic LV hypertrophy but developed severe impairment of myocardial function associated with chamber dilation within several weeks. In this model, we observed the increased expression of IL-1 β in the hypertrophied heart which was further increased with the development of CHF [26]. Immunohistochemical studies revieled that IL-1 β protein localized in the endothelial cells of the arteriols and the infiltrating macrophages in the hypertrophied myocardium. The amount of IL-1 β mRNA correlated with the ventricular mass. The expression of monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCAF/MCP-1), a potent chemotactic factor for macrophages was also increased together with an increased number of macrophages in the interstitium. In fact, it has been suggested that activated monocytes and macrophages recruited and activated by chemokines are important cellular sources for the increased levels of circulating proinflammatory cytokines [27].

Elevated circulating levels of C-C chemokines have been demonstrated in patients with CHF [28] as well as in those with acute myocardial infarction [29]. In vitro studies on isolated peripheral blood suggested that a platelet-monocyte interaction may contribute to the enhanced chemokine levels in CHF, and serum from CHF patients enhanced O2- generation in monocytes. This effect was inhibited by neutralizing antibodies against MCP-1, reflecting increased monocyte activity [28].

When cyclic mechanical stretch was applied to the endothelial cells (ECs) of human umbilical veins which are cultured on flexible silicone membranes, the levels of MCAF/MCP-1 in the culture medium were significantly elevated [30]. Northern blot analysis indicated that mRNA levels of MCAF/MCP-1 were upregulated by cyclic stretch as a function of intensity. Oscillatory shear stress in cultured human endothelium upregulates adhesion molecules associated with enhanced monocyte adherence [31]. The pattern of adhesion molecule induction with oscillatory flow stress was similar to that seen after cytokine stimulation, being associated with recruitment of macrophages. When focal adhesion was formed by integrin receptor engagement and clustering, integrins link to intracellular cytoskeletal complexes and bundles of actin filaments [30]. Both integrins and the actin cytoskeleton have been considered as mechanochemical transducers which convert mechanical force into gene induction of chemokines [32]. In the human ECs with cyclic stretch, the actin cytoskeleton disruption abolished the stretch induced gene expression of chemokines [33]. Analysis with specific enzyme inhibitors indicated that phospholipase C, protein kinase C and tyrosin kinase were also involved in this chemokine induction [30]. Taken together it can be postulated that mechanical stretch induces gene expression of chemotactic factors for macrophages. Recruited macrophages are the main source of production of cytokines, notably IL-1 β. A continuous infusion of TNF-{alpha} into peritoneal cavity of rats has been shown to lead to a time-dependent depression of LV function together with LV dilation, suggesting that TNF-{alpha} promotes remodeling of the failing heart [5]. However, in our model IL-1 β appeared to play a major role. The transition of compensated hypertrophy to heart failure may be a result of a combination of multiple factors, structure and function of myocyte being modulated not only by loading conditions but also by systemic or local neurohumoral processes (Fig. 2). Myocyte stretch by mechanical overload activates multiple second messenger system and directly induces protooncogene expression and protein synthesis. Mechanical stretch also stimulates the autocrine release of angiotensin (Ang) II in the myocardium from the early stage of hypertrophy which synergistically activates intracellular protein kinase cascades and induces various growth factor genes [34]. Endothelin (ET)-1 also has mitogenic properties but upregulation of ET-1 gene expression in the myocardium was observed only after overt heart failure had ensued [35]. Therefore, ET-1 does not appear to have contributed to the development of hypertrophy but to be responsible directly for deterioration of cardiac function. In conjunction with these factors, cytokines may play a significant role in this transition by accelerating the growth of myocyte and LV remodeling and are responsible for nonlethal downmodulation of cardiac function. There may be interrelated and interlocking positive feedback loops by which cytokines promote the release of ET-1 from cardiac myocytes [36].


Figure 2
View larger version (27K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Stretch activates multiple second messenger systems and directly induces protooncogene expression and protein synthesis and stimulates the autocrine release of angiotensin (Ang). Ang also promotes release of endothelin (ET)-1 from cardiac myocytes. Hypertrophied myocardium undergoes various physiological and biochemical changes leading to depression of contractility and finally overt heart failure ensues. Renin-angiotensin-aldosterone system is markedly activated with the development of heart failure in an attempt to maintain circulatory homeostasis. Ang is a potent arteriolar constrictor and further facilitates an increase in afterload. Mechanical stretch, on the other hand, induces gene expression of chemotactic factors for macrophages. Recruited macrophages are the main source of production of cytokines, notably IL-1. Cytokines also accelerate the growth of myocyte and LV remodeling and are responsible for nonlethal downmodulation of cardiac function. IL-1 which is induced in relatively large amount stimulates ET-1 production. ET-1 expressed here directly contributes to the deterioration of cardiac function but does not play a major role in growth-promotion.

 

   3. Ischemic heart disease
Top
 1. Cardiomyopathy
 2. Mechanical overload
 3. Ischemic heart disease
4. Anticytokine therapy for...
 References
 
With acute coronary occlusion, systolic shortening of the ischemic myocardium is rapidly replaced by a paradoxical systolic expansion with elongation of segment length. In the chronic stage, the scarring process of the infarcted area proceeds with only minimal restoration of function. In the non-infarcted area, there is continuous increases in end-diastolic length and extent of shortening, similarly as observed with chronic volume overload. This remodeling process initially exerts an important compensatory mechanisms for ventricular pump function, however may lead to the later development of heart failure [37].

In a rat model of myocardial infarction, progressive dilation of the LV cavity with impaired systolic shortening was documented by transthoracic echocardiography [38]. In this experimental model, gene expression of TNF-{alpha}, IL-1 β and IL-6 rose sharply in the infarcted region at 1 week after coronary occlusion but decreased gradually thereafter being back to baseline values at 20 weeks. While in the noninfarcted region, the upregulations of the expression of these cytokines were moderate at 1 week but remained elevated significantly throughout the study period. The levels of these cytokines in the noninfarcted region correlated with LV end-diastolic diameter measured at 8 and 20 weeks, after infarction. Among these cytokines, IL-1 β expression was most prominent and its level correlated well with collagen deposition in the noninfarcted myocardium at chronic stages [38].

In addition to a mediator of inflammation, IL-1 β exerts many other divergent biological effets. In the experiments with cell culture, IL-1 β was shown to induce myocyte growth and modulate phenotype [39,40]. A number of signaling pathways and second messengers has been postulated for this growth stimulating effect of IL-1 β. Although IL-1 β induces iNOS gene in cardiac myocytes [41] and the IL-1 β stimulated NO production is modulated by chronic hypoxia [42], it promotes cardiac myocyte growth via an NO independent mechanism [39,40]. Some investigators indicated that IL-1 β reinitiates myocyte DNA synthesis without stimulating the fatal/neonatal transcriptional program [40], while the others demonstrated that IL-1 β caused myocardial hypertrophy in the absence of DNA synthesis associated with induction of fatal genes [39].

IL-1 β has been regarded as a potential regulator of fibroblast proliferation as evidenced by the clear correlation between an extent of IL-1 β gene expression and the cardiac collagen density we have shown in the noninfarcted myocardium of the rat model of pressure overload hypertrophy [38]. While differential growth regulation of IL-1 β in cardiac myocytes and fibroblasts has been demonstrated; fibroblast proliferation being repressed by IL-1 β together with the proliferative effect on myocyte [40]. Myocyte RNA and protein synthesis can be inhibited indirectly through paracrine action of a soluble factor made by the nonmyocytes [43]. Thus, though IL-1 β could affect the structure and function of the myocardium, there still exists a considerable contradiction with respect to mechanisms involved in its biological effects.


   4. Anticytokine therapy for chronic heart failure
Top
 1. Cardiomyopathy
 2. Mechanical overload
 3. Ischemic heart disease
 4. Anticytokine therapy for...
References
 
On the basis of the intriguing possibility that some aspects of heart failure may be caused by alteration of myocyte function induced by cell-mediated immune responses, an intensive interest has been generated in the novel therapies to modulate cytokines [44]. Cytokines are characterized by their pleiotropy and redundancy. A single cytokine carries out multiple functions in disparate organ systems and different cytokines perform seemingly identical activities. Most cytokines induce the production of other mediators of the cytokine family and form a complex cascade or network of interactions between different cytokines. Therefore, elimination of a single cytokine from the biologic system by targeted gene disruption or neutralization with antibodies often fails to have major consequences. Recently, we have demonstrated that some agents which had been proved to improve survival in patients with CHF have the inhibitory effects on cytokines.

During the search for orally effective inotropic agents, one quinolinone derivative, vesnarinone was synthesized. This agent exerts cardiotonic effects through increasing intracellular cyclic adenosine monophosphate (cAMP) by inhibition of a specific isoform of phosphodiesterase. Initial several studies have shown that vesnarinone have the potential to improve the clinical outcome of severe heart failure patients [45,46]. However, treatment of patients with chronic heart failure with this agent was associated with a frequent occurrence of reversible neutropenia. These findings led us to speculate that a mechanism other than a cardiotonic action might be related to this clinical effect [47]. In the murine model of myocarditis, the survival rate was enhanced by vesnarinone in a dose dependent manner [48]. In vitro experiments using several human cell lines, vesnarinone reduced the production of multiple cytokines simultaneously [49]. All agents that lead to an increase in intracellular cAMP and modify protein kinase A suppress cytokine gene expression at the transcriptional level [50], but the effect of amrinone was not the same as that of vesnarinone [48]. Therefore, action of vesnarinone was considered to be related more to its inhibitory action of K+ channels rather than the augmentation of cAMP because the voltage gated K+ channels regulate Ca2+ associated signal transduction pathways and play a substantial role in T-cell activation [51,52]. Recently, it was reported that adenosine can inhibit lipopolysaccharide (LPS) induced expression of TNF-{alpha} in the heart, presumably being mediated by A2 receptor and transduced through a G protein-adenylyl cyclase pathway [53]. Vesnarinone was also shown to exert cardioprotective effects in sustained ischemia and reperfusion via adenosine-dependent mechanism [54]. Thus, we had placed our hope on vesnarinone as a potential cytokine inhibitor, however, the recent large scale multicenter mortality study of vesnarinone has shown that long-term administration of this agent was associated with no overall clinical benefit and an increased risk of sudden death by the predominated action as a phosphodiesterase inhibitor [55]. Nevertheless, this experience with vesnarinone led us to assess the immunomodulating or anticytokine effects of many other drugs used in the treatment of heart failure.

The role of digitalis in the long-term treatment of heart failure has been controversial, however, the recent large scale clinical trial has ironically proved that digoxin reduced the rate of hospitalization both overall and for worsening heart failure [56]. Induction of cytokines following LPS stimulation was suppressed by the cardiac glycoside ouabain both in vitro (human peripheral blood mononuclear cells [PBMC]) and in vivo (mice). While ouabain induced proinflammatory cytokines in the unstimulated cells, both mortality and circulating cytokine levels of the LPS-treated mice were reduced in a dose dependent fashion [57]. This may explain why the clinical response to digitalis in normal circulation is opposite to the one in heart failing subjects.

Amiodarone is now widely used to prevent life-threatening ventricular arrhythmia in patients with CHF. Although amiodalone did not reduce mortality in the large scale clinical trials, the substantial reduction in the combined end point of cardiac death and worsening heart failure was shown in patients with nonischemic heart failure [58]. When human PBMCs were cultured with amiodarone in the presence of LPS, cytokine levels in the culture supernatants were significantly reduced [59]. Because amiodarone blocks the inward rectifier K+ channel, the inhibition of the K+ current mediated T cell activation [51,52] could be involved for this effect.

Treatment of patients with CHF with Ca antagonist has generally been considered to increase morbidity and mortality. However, the results of PRAISE trial have demonstrated that a new Ca antagonist, amlodipine could prolong survival in patients with severe heart failure due to nonischemic DCM [60]. In the murine model of myocarditis and heart failure, amlodipine increased survival with markedly attenuated histopathological changes [61]. In vitro, NO production in the monocyte/macrophage cell line induced by EMC virus was also inhibited by amlodipine [61]. These data again support the view that a cytokine-mediated increase in NO plays an important role in the pathogenesis of heart failure and the therapeutic effect of amlodipine may be related, in part, to an inhibition of overproduction of NO.

In the PRAISE trial, plasma levels of cytokines were actually measured by ELISA in the selected groups of patients. Mean levels of TNF-{alpha} and IL-6 at baseline for the recruited patients were significantly higher compared to healthy control subjects. Though a statistically significant reduction in TNF-{alpha} levels was not observed, patients treated with amlodipine had lower levels of IL-6 than those treated with placebo after 26 weeks of therapy. Cardiac events were also shown to have occurred more commonly in patients with higher IL-6 levels [62]. These observations definitively support our hypothesis for the mechanism of action of this agent.

A xanthine derivative, pentoxifylline which has been used for more than 20 years in patients with peripheral vascular disease has recently been shown to improve symptoms and left ventricular systolic function in patients with DCM. This effect was associated with an inhibition of TNF-{alpha} production at the transcriptional level [63].

The syndrome of heart failure still remains an obscure clinical entity and even its definition has been disputed. Half a century ago, heart failure was viewed as an edematous state due to cardiorenal disorder and physicians were encouraged to use diuretics for the alleviation of edema. Thirty years ago, heart failure was regarded as hemodynamic disorder as a pump, thereby vasodilators and inotropic agents were the main stay of the treatment to regulate cardiocirculatory system. More recently, it has become increasingly apparent that heart failure may relate not only to cardiac dysfunction but also to neurohormonal disturbance [64]. Based on the evidence provided by numerous clinical trials, angiotensin converting enzyme (ACE) inhibitors are now being used in an increasing proportion of patients with CHF. However, the actual magnitude of its survival advantage is still limited. Many more patients than those benefited by the treatment are still dying. It has been emphasized that heart failure is a physiologically complex syndrome and all the three approaches are useful but not sufficient when used alone. On the bases of the observed evidence for immune mechanisms of myocardial injury as a pathogenesis of heart failure, we now propose an additional therapeutic challenge with immunomodulating or anticytokine therapy. Although ACE inhibitor captopril and the Ang II receptor antagonist valsartan was shown to have potent inhibitory effects on the LPS-stimulated production of TNF-{alpha} and IL-1 β in vitro, their efficacy as the anticytokine drug in the clinical settings has not been proved [65]. Because cytokines are pleiotropic and redundant in nature, we need to develop the therapy which exerts inhibitory effect on the orchestrated action of a network of cytokines. Within the framework of the fundamental therapeutic approach that combination of the complementary actions of many different drugs is needed to accomplish goals, anticytokine therapy may represents a new frontier for the management of heart failure.

Time for primary review 29 days.


   References
Top
 1. Cardiomyopathy
 2. Mechanical overload
 3. Ischemic heart disease
 4. Anticytokine therapy for...
 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. N Engl J Med (1990) 323:236–241.[Abstract]
  2. 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]
  3. Kubota T., McNamara D.M., Wang J.J., et al. For the VEST Investigators for TNF Genotype Analysis: Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. Circulation (1998) 97:2499–2501.[Abstract/Free Full Text]
  4. MacGowan G.A., Mann D.L., Kormos R.L., Feldman A.M., Murali S. Circulating interleukin-6 in severe heart failure. Am J Cardiol (1997) 79:1128–1131.[CrossRef][Web of Science][Medline]
  5. Bozkurt B., Kribbs S.B., Clubb F.J., Michael L.H., Didenko V.V., Hornsby P.J., Seta Y., Oral H., Spinale F.G., Mann D.L. Pathophysiologically relevant concentrations of tumor necrosis factor-{alpha} promote progressive left ventricular dysfunction and remodeling in rats. Circulation (1998) 97:1382–1391.[Abstract/Free Full Text]
  6. Yamada T., Matsumori A., Sasayama S. Therapeutic effect of anti-tumor necrosis factor-{alpha} antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus. Circulation (1994) 89:846–851.[Abstract/Free Full Text]
  7. Kubota T., McTiernan C.F., Frye C.S., Slawson S.E., Lemster B.H., Koretsky A.P., Demetris A.J., Feldman A.M. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-{alpha}. Circ Res (1997) 81:627–635.[Abstract/Free Full Text]
  8. Bryant D., Becker L., Richardson J., Shelton J., Franco F., Peshock R., Thompson M., Giroir B. Cardiac function in transgenic mice with myocardial expression of tumor necrosis factor-{alpha}. Circulation (1998) 97:1375–1381.[Abstract/Free Full Text]
  9. Kapadia S.R., Oral H., Lee J., Nakano M., Taffet G.E., Mann D.L. Hemodynamic regulation of tumor necrosis factor-{alpha} gene and protein expression in adult feline myocardium. Circ Res (1997) 81:187–195.[Abstract/Free Full Text]
  10. Gulick T., Chung M.K., Pieper S.J., Lange L.G., Schreiner G.F. Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte β-adrenergic responsiveness. Proc Natl Acad Sci USA (1989) 86:6753–6757.[Abstract/Free Full Text]
  11. Balligand J.L., Ungureanu-Longrois D., Simmons W.W., Pimental D., Malinski T.A., Kapturczak M., Taha Z., Lowenstein C.J., Davidoff A.J., Kelly R.A., Smith T.W., Michel T. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes: characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem (1994) 269:27580–27588.[Abstract/Free Full Text]
  12. Oyama J., Shimokawa H., Momii H., Cheng X., Fukuyama N., Arai Y., Egashira K., Nakazawa H., Tekeshita A. Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dysfunction in dogs in vivo. J Clin Invest (1998) 101:2207–2214.[Web of Science][Medline]
  13. Finkel M.S., Oddis C.V., Jacob T.D., Watkins S.C., Hattler B.G., Simmons R.L. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science (1992) 257:387–389.[Abstract/Free Full Text]
  14. Yokoyama T., Vaca L., Rossen R.D., Durante W., Hazarika P., Mann D.L. Cellular basis for the negative inotropic effects of tumor necrosis factor-{alpha} in the adult mammalian heart. J Clin Invest (1993) 92:2303–2312.[Web of Science][Medline]
  15. Oral H., Mann D.L. 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]
  16. Krown K.A., Page M.T., Nguyen C., Zechner D., Gutierrez V., Comstock K.L., Glembotski C.C., Quintana P.J.E., Sabbadini R.A. 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]
  17. Matsumori A., Matoba Y., Sasayama S. Dilated cardiomyopathy associated with hepatitis C virus infection. Circulation (1995) 92:2519–2525.[Abstract/Free Full Text]
  18. Matsumori A. Viral Infections of the Heart. Banatvala J.E., ed. (1993) London: Edward Arnold. 110–137.
  19. Shioi T., Matsumori A., Sasayama S. Persistent expression of cytokine in the chronic stage of viral myocarditis in mice. Circulation (1996) 94:2930–2937.[Abstract/Free Full Text]
  20. Torre-Amione G., Kapadia S., Lee J., Durand J.-B., Bies R.D., Young J.B., Mann D.L. Tumor necrosis factor-{alpha} and tumor necrosis factor receptors in the failing human heart. Circulation (1996) 93:704–711.[Abstract/Free Full Text]
  21. Francis S.E., Holden H., Holt C.M., Duff G.W. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol (1998) 30:215–223.[CrossRef][Web of Science][Medline]
  22. Lodge P.A., Herzum M., Olszewski J., Huber S.A. Coxsackievirus B-3 myocarditis: acute and chronic forms of the disease caused by different immunopathogenic mechanisms. Am J Pathol (1987) 128:455–463.[Abstract]
  23. Yokoyama T., Nakano M., Bednarczyk J.L., McIntyre B.W., Entman M., Mann D.L. Tumor necrosis factor-{alpha} provokes a hypertrophic growth response in adult cardiac myocytes. Circulation (1997) 95:1247–1252.[Abstract/Free Full Text]
  24. Kishimoto C., Kuroki Y., Hiraoka Y., Ochiai H., Kurokawa M., Sasayama S. Cytokine and murine coxsackievirus B3 myocarditis: interleukin-2 suppressed myocarditis in the acute stage but enhanced the condition in the subsequent stage. Circulation (1994) 89:2836–2842.[Abstract/Free Full Text]
  25. Inoko M., Kihara Y., Morii I., Fujiwara H., Sasayama S. Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats. Am J Physiol (1994) 267:H2471–H2482.[Web of Science][Medline]
  26. Shioi T., Matsumori A., Kihara Y., Inoko M., Ono K., Iwanaga Y., Yamada T., Iwasaki A., Matushima K., Sasayama S. Increased expression of interleukin-1 β and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the hypertrophied and failing heart with pressure overload. Circ Res (1997) 81:664–671.[Abstract/Free Full Text]
  27. Arai K.I., Lee F., Miyajima A., Miyatake S., Arai N., Yokota T. Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem (1990) 59:783–836.[CrossRef][Web of Science][Medline]
  28. Aukrust P., Ueland T., Müller F., Andreassen A.K., Nordøy I., Aas H., Kjekshus J., Simonsen S., Frøland S.S., Gullestad L. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation (1998) 97:1136–1143.[Abstract/Free Full Text]
  29. Matsumori A., Furukawa Y., Hashimoto T., Yoshida A., Ono K., Shioi T., Okada M., Iwasaki A., Nishio R., Matsushima K., Sasayama S. Plasma levels of the monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 are elevated in patients with acute myocardial infarction. J Mol Cell Cardiol (1997) 29:419–423.[CrossRef][Web of Science][Medline]
  30. Okada M., Matsumori A., Ono K., Furukawa Y., Shioi T., Iwasaki A., Matsushima K., Sasayama S. Cyclic stretch upregulates production of interleukin-8 and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in human endothelial cells. Arterioscler Thromb Vasc Biol (1998) 18:894–901.[Abstract/Free Full Text]
  31. Chappell D.C., Varner S.E., Nerem R.M., Medford R.M., Alexander R.W. Oscillatory shear stress stimulates adhesion molecule expression in cultured human endothelium. Circ Res (1998) 82:532–539.[Abstract/Free Full Text]
  32. Vandenburgh H.H. Mechanical forces and their second messengers in stimulating cell growth in vitro. Am J Physiol (1992) 262:R350–R355.[Web of Science][Medline]
  33. Clark E.A., Brugge J.S. Integrins and signal transduction pathways: the road taken. Science (1995) 268:233–239.[Abstract/Free Full Text]
  34. Yamazaki T., Komuro I., Kudoh S., Inagaki K., Yoneda T., Kaburagi S., Araki M., Sasayama S. Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy. Circ Res (1995) 77:258–265.[Abstract/Free Full Text]
  35. Iwanaga Y., Kihara Y., Hasegawa K. Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation (1998) 98:2065–2073.[Abstract/Free Full Text]
  36. Vemulapalli S., Chiu P.J.S., Griscti K., Brown A., Kurowski S., Sybertz E.J. Phosphoramidon does not inhibit endogenous endothelin-1 release stimulated by hemorrhage, cytokines and hypoxia in rats. Eur J Pharmacol (1994) 257:95–102.[CrossRef][Web of Science][Medline]
  37. McDonald K.M. Prevention of ventricular remodeling. J Lab Clin Med (1998) 131:124–129.[CrossRef][Web of Science][Medline]
  38. Ono K., Matsumori A., Shioi T., Furukawa Y., Sasayama S. Cytokine gene expression after myocardial infarction in rat hearts. Possible implication in left ventricular remodeling. Circulation (1998) 98:149–156.[Abstract/Free Full Text]
  39. Thaik C.M., Calderone A., Takahashi N., Colucci W.S. Interleukin-1 β modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest (1995) 96:1093–1099.[Web of Science][Medline]
  40. Palmer J.N., Hartogensis W.E., Patten M., Fortuin F.D., Long C.S. Interleukin-1 β induces cardiac myocyte growth but inhibits cardiac fibroblast proliferation in culture. J Clin Invest (1995) 95:2555–2564.[Web of Science][Medline]
  41. Tsujino M., Hirata Y., Imai T., Kanno K., Eguchi S., Ito H., Marumo F. Induction of nitric oxide synthase gene by interleukin-1 β in cultured rat cardiocytes. Circulation (1994) 90:375–383.[Abstract/Free Full Text]
  42. Kacimi R., Long C.S., Karliner J.S. Chronic hypoxia modulates the interleukin-1 β stimulated inducible nitric oxide synthase pathway in cardiac myocytes. Circulation (1997) 96:1937–1943.[Abstract/Free Full Text]
  43. Hosenpud J.D., Campbell S.M., Pan G. Indirect inhibition of myocyte RNA and protein synthesis by interleukin-1. J Mol Cell Cardiol (1990) 22:213–225.[CrossRef][Web of Science][Medline]
  44. Sasayama S. Immune modulation of cardiac function: a new frontier. Role of the immune system in cardiac dysfunction. J Cardiac Fail (1995) 1:331–335.[CrossRef][Medline]
  45. Sasayama S. For OPC-8212 multicenter Research Group: A placebo-controlled, randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure. Cardiovasc Drugs Ther (1990) 4:419–426.[CrossRef][Web of Science][Medline]
  46. Feldman A.M., Bristow M.R., Parmley W.W., et al. For the Vesnarinone Study Group: Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med (1993) 329:149–155.[Abstract/Free Full Text]
  47. Sasayama S., Matsumori A. Vesnarinone: a potential cytokine inhibitor. J Cardiac Fail (1996) 2:251–258.[CrossRef][Medline]
  48. Matsui S., Matsumori A., Matoba Y., Uchida A., Sasayama S. Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. J Clin Invest (1994) 94:1212–1217.[Web of Science][Medline]
  49. 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:PL11–16.[CrossRef][Web of Science][Medline]
  50. Nishio R., Matsumori A., Shioi T., Wang W., Yamada T., Ono K., Sasayama S. Denopamine, a β1-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-{alpha} production in the heart. J Am Coll Cardiol (1998) 32:808–815.[Abstract/Free Full Text]
  51. Lin C.S., Boltz R.C., Blake J.T., Nguyen M., Talento A., Fischer P.A., Springer M.S., Sigal N.H., Slaughter R.S., Garcia M.L., Kaczorowski G.J., Koo G.C. Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. J Exp Med (1993) 177:637–645.[Abstract/Free Full Text]
  52. Felzen B., Lavy R., Garcia M., Berke G., Gardner P., Binah O. Interaction of cytotoxic T lymphocytes and guinea pig ventricular myocytes: pharmacological modulation by blocking K+ currents in cytotoxic T lymphocytes. Circ Res (1996) 78:253–261.[Abstract/Free Full Text]
  53. Wagner D.R., Combes A., McTiernan C., Sanders V.J., Lemster B., Feldman A.M. Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-{alpha}. Circ Res (1998) 82:47–56.[Abstract/Free Full Text]
  54. Kitakaze M., Minamino T., Funaya H., Node K., Shinozaki Y., Mori H., Hori M. Vesnarinone limits infarct size via adenosine-dependent mechanisms in the canine heart. Circulation (1997) 95:2108–2114.[Abstract/Free Full Text]
  55. Feldman A. et al. for the VesT Investigators: Mechanism of increased mortality from vesnarinone in the severe heart failure trial (VesT). J Am Coll Cardiol 2,64A, 1997 (Abstract).
  56. The Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336,525-533, 1997.
  57. Matsumori A., Ono K., Nishio R., Igata H., Shioi T., Matsui S., Furukawa Y., Iwasaki A., Nose Y., Sasayama S. Modulation of cytokine production and protection against lethal endotoxemia by the cardiac glycoside ouabain. Circulation (1997) 96:1501–1506.[Abstract/Free Full Text]
  58. Massie B.M., Fisher S.G., Deedwania P.C., et al. For the CHF-STAT Investigators: Effect of amiodarone on clinical status and left ventricular function in patients with congestive heart failure. Circulation (1996) 93:2128–2134.[Abstract/Free Full Text]
  59. 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]
  60. Packer M., O’Connor C.M., Ghali J.K., Shioi T., Okada I., Matsui S., Sato Y., Suzuki H., Shiota K., Sasayama S. For the PRAISE Study Group: Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med (1996) 335:1107–1114.[Abstract/Free Full Text]
  61. Wang W.Z., Matsumori A., Yamada T., et al. Beneficial effects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis. A possible mechanism through inhibition of nitric oxide production. Circulation (1997) 95:245–251.[Abstract/Free Full Text]
  62. Mohler E.R. III, Sorensen L.C., Ghali J.K., Schocken D.D., Willis P.W., Bowers J.A., Cropp A.B., Pressler M.L. Role of cytokines in the mechanism of action of amlodipine: the PRAISE heart failure trial. J Am Coll Cardiol (1997) 30:35–41.[Abstract]
  63. Sliwa K., Skudicky D., Candy G., Wisenbaugh T., Sareli P. Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet (1998) 351:1091–1093.[CrossRef][Web of Science][Medline]
  64. Packer M. How should physicians view heart failure? The philosophical and physiological evolution of three conceptual models of the disease. Am J Cardiol (1993) 71:3C–11C.[CrossRef][Medline]
  65. Peeters A.C.T.M., Netea M.G., Kullberg B.J., Thien T., Van der Meer J.W.M. The effect of renin-angiotensin system inhibitors on pro- and anti-inflammatory cytokine production. Immunology (1998) 94:376–379.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Innate ImmunityHome page
H. Loppnow, K. Werdan, and M. Buerke
Invited review: Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms
Innate Immunity, April 1, 2008; 14(2): 63 - 87.
[Abstract] [PDF]

Home page
 Eur J Heart FailHome page
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]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sasayama, S.
Right arrow Articles by Kihara, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sasayama, S.
Right arrow Articles by Kihara, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?