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(Circulation. 1997;95:778-781.)
© 1997 American Heart Association, Inc.

Articles

Cytokines and Cardiac Contractile Function

Ralph A. Kelly, MD; Thomas W. Smith, MD

the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Ralph A. Kelly, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail rakelly@bics.bwh.harvard.edu.

Key Words: Editorials • heart failure • cytokines • nitric oxide • myocarditis

	Introduction

Top Introduction References

 
A working understanding of the molecular and cell biology of inflammatory cytokines is of growing importance to both cardiovascular scientists and practicing clinicians. Accumulating evidence indicates that these locally acting polypeptide mediators, or "autacoids," play a role not only in the pathogenesis of atherosclerosis and in the cardiac dysfunction that accompanies systemic sepsis, viral myocarditis, and cardiac allograft rejection but also in advanced heart failure syndromes resulting from diverse pathogenic insults. ("Autacoid" is derived from the Greek words autos ["self"] and akos ["remedy"]; autacoids are locally acting, biologically active agents [both peptides and nonpeptides] that are distinct from neurotransmitters and hormones in the circulation.¹ ) More than 25 years ago, Lefer and Rovetto² reported that the sera of septic patients and experimental animals contained a "myocardial depressant factor," the molecular nature of which has eluded definitive identification in the intervening years. During the past decade, Parrillo and colleagues^{3 4} used intact animals and in vitro isolated heart cell preparations to systematically investigate the factors that contribute to myocardial depression in systemic sepsis (ie, the systemic inflammatory response syndrome) and concluded that TNF- and IL-1ß were shown to be present in the sera of septic patients and are responsible for most, if not all, of the reversible cardiac depression often seen with this syndrome. These data are consistent with earlier reports (reviewed in Levine et al⁵ ) that soluble inflammatory mediators in medium conditioned by activated immunocytes altered the contractile responsiveness of beating cardiac muscle cells to ß-adrenergic agonists, an effect that could be mimicked in this in vitro preparation by recombinant TNF- or IL-1ß. Interest in these findings has been amplified by reports of elevated circulating as well as intracardiac TNF- levels in patients with heart failure.^{6 7 8 9 10}

Systemic infusions of one or more recombinant cytokines such as TNF- and IL-1ß in intact animal preparations have yielded varying results. Although some studies^{11 12} have observed a gradual decline in cardiac contractile function in dogs injected with recombinant human TNF-, Murray and Freeman¹³ identified a biphasic effect in a conscious, chronically instrumented dog model. In this preparation, recombinant human TNF- increased left ventricular contractile function within minutes, followed by a gradual, profound decline in ventricular systolic function that took several hours to manifest. Many of the differences in the reported effects of recombinant cytokines in both intact animals and in vitro models are likely due to differences in the specific experimental models and procedures that were used. It is relevant, as emphasized by Nathan and Sporn,¹⁴ that in most physiological contexts, inflammatory cytokines such as TNF- and IL-1ß are locally acting autocrine (acting on the cell of origin), paracrine (acting on neighboring cells), or juxtacrine (acting on adjacent cells) agents whose biological activity is determined not only by the specific target cell type but also the intracellular milieu or biological context in which a cytokine acts. Thus, results obtained with systemic or in vitro administration of a specific recombinant cytokine must be interpreted cautiously and with this caveat in mind.

Several reports over the past 5 years have shown an increase in plasma as well as myocardial TNF- in patients with advanced heart failure caused by ischemic or idiopathic cardiomyopathies.^{6 7 8 9 10} There is a concomitant increase in patients with heart failure in plasma levels of soluble TNF- receptors (ie, sTNF-RI[p55] and sTNF-RII[p75]), which appear to bind and neutralize most, if not all, circulating TNF-.^{15 16 17} However, as emphasized above, it is the effect of locally synthesized myocardial TNF- acting within a pathophysiological context that likely includes additional cytokines and other peptide autacoids that may contribute to ongoing myocardial injury and dysfunction in the chronic heart failure syndrome.

Those cytokines directly implicated to date in mediating myocardial depression in systemic sepsis and other forms of cardiac dysfunction include, in addition to TNF- and IL-1ß, IL-2, IL-6, and IFN- (see Figure). Recent research has begun to clarify some of the intracellular signaling mechanisms that contribute to cardiac myocyte contractile dysfunction. IL-1ß has been shown to rapidly suppress voltage-dependent Ca²⁺ current (I_Ca-L) in adult rat ventricular myocytes.¹⁸ Consistent with these data, Mann and colleagues¹⁹ demonstrated that low-to-moderate concentrations of recombinant human TNF- (ie, 200 U/mL) resulted in a rapid, reversible decrease in peak systolic intracellular calcium that was unaffected by inhibitors of NO or eicosanoid-dependent signaling pathways. Additional data from this laboratory have implicated a TNF-RI receptor activation of a neutral sphingomyelinase pathway in cardiac myocytes,²⁰ analogous to activation of this signaling pathway by TNF- in adipocytes.²¹

View larger version (25K): [in this window] [in a new window]   Figure 1. Potential mechanisms and mediators by which cytokines may contribute to cardiac myocyte contractile dysfunction. Inflammatory mediators, including bacterial cell wall components such as lipopolysaccharide (endotoxin), can induce generation of specific cytokines and expression of iNOS in macrophages and endothelial cells. These cells, as well as activated T cells and natural killer (NK) cells, subsequently generate additional cytokines that induce contractile dysfunction in cardiac myocytes by both NO-dependent and NO-independent mechanisms. Recent evidence (see text) has also implicated these cytokines and increased iNOS expression in the pathogenesis of heart failure.

In contrast, substantially higher concentrations of recombinant human TNF- (1000 U/mL) have been shown by Finkel et al²² and by Goldhaber et al²³ to result in rapid and reversible declines in contractile function of isolated hamster papillary muscles or of adult guinea pig and rabbit ventricular myocytes, respectively, a decline that could be abrogated in both preparations by NOS inhibitors. In both experimental models, the effect of recombinant human TNF- was apparent within minutes, implicating activation of the constitutively expressed NOS isoform in cardiac myocytes (ie, eNOS or NOS3; for a review, see Kelly et al²⁴ ). This decline in velocity of shortening with high concentrations of TNF- in isolated myocytes was unaccompanied by a significant change in diastolic or systolic [Ca²⁺]_i activity, implicating a NO-mediated decrease in the sensitivity of the myofilaments to [Ca²⁺]_i.²³ This proposed mechanism is consistent with data reported by Shah et al²⁵ and with preliminary data from our laboratory (D.M. Kaye, S. Wiviott, X. Han, L. Belhassen, R.A. Kelly, T.W. Smith, unpublished data, 1997) that demonstrate that either activation of eNOS in cardiac myocytes or agents that mimic selected components of signal transduction cascades downstream of NO appear to desensitize cardiac myofilaments to [Ca²⁺]_i, an effect that may be due at least in part to phosphorylation of troponin I. Although of considerable mechanistic interest, the physiological or clinical relevance of the high concentrations of cytokines used in some studies^{22 23} remains to be determined.

After several hours of exposure to inflammatory cytokines and/or to cell wall components of Gram-positive or -negative bacteria, cellular constituents with the heart, including the microvascular and endocardial endothelium, vascular smooth muscle, and cardiac myocytes, express a cytokine-inducible "high output" isoform of NOS (iNOS or NOS2; for a review, see Kelly et al²⁴ ). The cytokines most closely associated with iNOS induction (ie, TNF-, IL-1ß, and IL-6) are also known to be mediators of "innate" immunity, whereas IFN-, a T cell–derived cytokine, accelerates iNOS induction in many cell types, including cardiac myocytes and the endothelium of the microvasculature.^{26 27} In addition to induction of iNOS itself, these cytokines also enhance or initiate the expression of proteins essential for maximal iNOS activity in cardiac myocytes and cardiac microvascular endothelium, including cationic amino acid transporters necessary for uptake of the NO precursor L-arginine and enzymes necessary for the production of tetrahydrobiopterin, a cofactor essential for iNOS dimerization and activation.^{28 29 30}

The induction of this NOS isoform in the heart, as in most other tissues, has been included by Nathan³¹ in the category of innate immune responses, a phylogenetically primitive but rapidly activated form of host defense that can be mounted more quickly than the highly selective "adaptive" immune response that requires clonal amplification of antigen-specific lymphocytes. iNOS induction by cytokines within the heart, as in other tissues, undoubtedly plays an important role in host defense to some pathogens. Lowenstein et al³² demonstrated that mice infected with coxsackievirus B3 and concurrently administered drugs that inhibit NOS activity had higher viral titers and mortality than similarly infected mice not receiving these agents. In addition, mice lacking a functional iNOS gene (ie, iNOS "knockout" mice) were much more susceptible than wild-type animals to lethal injection with facultative intracellular and opportunistic pathogens.^{33 34} However, these iNOS knockout animals were less likely to develop a fatal septic shock–like syndrome after an intraperitoneal injection of lipopolysaccharide, supporting the view that iNOS induction plays an important role in the hemodynamic and metabolic sequelae of systemic sepsis.

These data are consistent with a number of recent reports (reviewed in References 24, 35, and 36) that increased iNOS expression in cardiac myocytes and in microvascular and endocardial endothelial cells, which combined with infiltrating inflammatory cells account for most NO production after regional or global iNOS induction in the heart, markedly suppresses basal and ß-adrenergic agonist–stimulated myocardial inotropic responsiveness. The decline in myocardial contractile function after iNOS induction by cytokines is likely due to both NO-dependent activation of guanylyl cyclase and increased intracellular cGMP, as well as to non–cGMP-dependent effects of NO. As in other cell types, NO may either directly or indirectly alter formation of S-nitrosothiols affect cardiac myocyte energetics and the function of specific sarcolemmal ion channels.^{37 38 39} Finally, not all physiological sequelae of iNOS activation may be reversible. In response to IL-1ß, TNF-, and IFN-, Pinsky et al⁴⁰ documented that iNOS induction by these cytokines in adult rat ventricular myocytes resulted in an increase in myocyte death. Subsequent reports from this laboratory have implicated induction by these cytokines of a NO-dependent apoptotic pathway in these cells.^{41 42}

A pathophysiological role for iNOS may not be limited to conditions characterized by systemic or intracardiac iNOS induction, such as systemic sepsis, inflammatory myocarditis, or cardiac allograft rejection. Two recent reports^{43 44} indicate that iNOS expression is increased in the myocardium of patients with advanced heart failure, whether caused by ischemic heart disease, idiopathic cardiomyopathy, or valvular disease, confirming and extending the results of an earlier study.⁴⁵ These data from humans with heart failure have appeared concurrently with reports that induction of iNOS by cytokines in cardiac myocytes is enhanced and sustained by increases in intracellular cAMP and activation of diacylglycerol-regulated protein kinase C after exposure to catecholamines or peptide autacoids such as angiotensin II and arginine vasopressin, all of which are agents that are known to be important components of the neurohumoral activation characteristic of heart failure.^{46 47 48 49 50}

Despite the weight of circumstantial evidence reviewed above, there are no data that firmly establish an important role for iNOS induction in the pathophysiology of clinical heart failure. Nevertheless, the documentation of high intramyocardial and plasma levels of TNF- in humans with heart failure, in combination with catecholamines and peptide autacoids known to enhance iNOS expression and activity in cardiac myocytes, indicates that this is an important hypothesis to be tested. The substantial mortality associated both with systemic sepsis and chronic heart failure reminds clinicians as well as basic and clinical investigators that the stakes are high.

	Selected Abbreviations and Acronyms

 

[Ca2+]i = intracellular calcium concentration IFN- = interferon- IL = interleukin iNOS = inducible nitric oxide synthase NOS = nitric oxide synthase TNF- = tumor necrosis factor-

	Acknowledgments

 
This work was supported by a grant from the National Heart, Lung, and Blood Institute (HL-52320). The authors thank Drs Abul K. Abbas and Daniel I. Simon for their thoughtful reviews of the manuscript.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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				R. S. Vasan, L. M. Sullivan, R. Roubenoff, C. A. Dinarello, T. Harris, E. J. Benjamin, D. B. Sawyer, D. Levy, P. W.F. Wilson, and R. B. D'Agostino Inflammatory Markers and Risk of Heart Failure in Elderly Subjects Without Prior Myocardial Infarction: The Framingham Heart Study Circulation, March 25, 2003; 107(11): 1486 - 1491. [Abstract] [Full Text] [PDF]

				B. Chandrasekar, P. C. Melby, H. M. Sarau, M. Raveendran, R. P. Perla, F. M. Marelli-Berg, N. O. Dulin, and I. S. Singh Chemokine-Cytokine Cross-talk. THE ELR+ CXC CHEMOKINE LIX (CXCL5) AMPLIFIES A PROINFLAMMATORY CYTOKINE RESPONSE VIA A PHOSPHATIDYLINOSITOL 3-KINASE-NF-kappa B PATHWAY J. Biol. Chem., February 7, 2003; 278(7): 4675 - 4686. [Abstract] [Full Text] [PDF]

				Z Mallat, P Henry, R Fressonnet, S Alouani, A Scoazec, P Beaufils, Y Chvatchko, and A Tedgui Increased plasma concentrations of interleukin-18 in acute coronary syndromes Heart, December 1, 2002; 88(5): 467 - 469. [Abstract] [Full Text] [PDF]

				S. Zeuke, A. J Ulmer, S. Kusumoto, H. A Katus, and H. Heine TLR4-mediated inflammatory activation of human coronary artery endothelial cells by LPS Cardiovasc Res, October 1, 2002; 56(1): 126 - 134. [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]

				C A Dinarello Novel targets for interleukin 18 binding protein Ann Rheum Dis, November 1, 2001; 60(90003): iii18 - 24. [Abstract] [Full Text] [PDF]

				F. N. Witherow, A. Helmy, D. J. Webb, K. A.A. Fox, and D. E. Newby Bradykinin Contributes to the Vasodilator Effects of Chronic Angiotensin-Converting Enzyme Inhibition in Patients With Heart Failure Circulation, October 30, 2001; 104(18): 2177 - 2181. [Abstract] [Full Text] [PDF]

				J. F. Vazquez-Jimenez, M. Qing, B. Hermanns, B. Klosterhalfen, M. Woltje, R. Chakupurakal, K. Schumacher, B. J. Messmer, G.o. von Bernuth, and M.-C. Seghaye Moderate hypothermia during cardiopulmonary bypass reduces myocardial cell damage and myocardial cell death related to cardiac surgery J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1216 - 1223. [Abstract] [Full Text] [PDF]

				G. E. Hill The Inflammatory Response to Cardiopulmonary Bypass-- Should It Be Treated? Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 229 - 235. [Abstract] [PDF]

				B. Chandrasekar, J. F. Nelson, J. T. Colston, and G. L. Freeman Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2094 - H2102. [Abstract] [Full Text] [PDF]

				A. A. IONESCU, A.-A. IONESCU, N. PAYNE, I. OBIETA-FRESNEDO, A. G. FRASER, and D. J. SHALE Subclinical Right Ventricular Dysfunction in Cystic Fibrosis . A Study Using Tissue Doppler Echocardiography Am. J. Respir. Crit. Care Med., April 1, 2001; 163(5): 1212 - 1218. [Abstract] [Full Text]

				C. Li, R. L. Kao, T. Ha, J. Kelley, I. W. Browder, and D. L. Williams Early activation of IKK{beta} during in vivo myocardial ischemia Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1264 - H1271. [Abstract] [Full Text] [PDF]

				B. J. Pomerantz, L. L. Reznikov, A. H. Harken, and C. A. Dinarello Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta PNAS, February 27, 2001; 98(5): 2871 - 2876. [Abstract] [Full Text] [PDF]

				L. M. MALBOUISSON, C. J. BUSCH, L. PUYBASSET, Q. LU, P. CLUZEL, J.-J. ROUBY, and the CT Scan ARDS Study Gr Role of the Heart in the Loss of Aeration Characterizing Lower Lobes in Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med., June 1, 2000; 161(6): 2005 - 2012. [Abstract] [Full Text]

				A. Heim, S. Zeuke, S. Weiss, W. Ruschewski, and I. M. Grumbach Transient Induction of Cytokine Production in Human Myocardial Fibroblasts by Coxsackievirus B3 Circ. Res., April 14, 2000; 86(7): 753 - 759. [Abstract] [Full Text] [PDF]

				A. J. Spanier and K. H. McDonough Dexamethasone Blocks Sepsis-Induced Protection of the Heart from Ischemia Reperfusion Injury Experimental Biology and Medicine, January 1, 2000; 223(1): 82 - 87. [Abstract] [Full Text]

				S. M. Wildhirt, S. Weismueller, C. Schulze, N. Conrad, A. Kornberg, and B. Reichart Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury Cardiovasc Res, August 15, 1999; 43(3): 698 - 711. [Abstract] [Full Text] [PDF]

				S. Ishiyama, M. Hiroe, T. Nishikawa, T. Shimojo, T. Hosokawa, I. Ikeda, T. Toyozaki, T. Kasajima, and F. Marumo Inhibitory effects of vesnarinone in the progression of myocardial damage in experimental autoimmune myocarditis in rats Cardiovasc Res, August 1, 1999; 43(2): 389 - 397. [Abstract] [Full Text] [PDF]

				G. Kojda and K. Kottenberg Regulation of basal myocardial function by NO Cardiovasc Res, March 1, 1999; 41(3): 514 - 523. [Full Text] [PDF]