Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Nitric oxide, other hormones, cytokines, and chemokines in heart failure

Wilson S Colucci, MD
Section Editor
Stephen S Gottlieb, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


The signs and symptoms of heart failure (HF) are in part due to compensatory mechanisms utilized by the body in an attempt to repair the primary deficit in the cardiac output. Well-recognized neurohumoral adaptations, such as activation of the renin-angiotensin-aldosterone and sympathetic nervous systems and antidiuretic hormone (vasopressin) by the low output state, can contribute to maintenance of perfusion of vital organs in two ways:

Maintenance of systemic pressure by vasoconstriction, resulting in redistribution of blood flow to vital organs.

Restoration of cardiac output by increasing myocardial contractility and heart rate and by expansion of the extracellular fluid volume.

(See "Pathophysiology of heart failure: Neurohumoral adaptations".)

As discussed below, HF is also associated with alterations in a host of cellular, autocrine, and paracrine signaling systems that are involved in mediating inflammation and oxidative stress, and may manifest as alterations in the levels of nitric oxide, inflammatory cytokines, and other chemokines that can be measured as biomarkers. The physiologic and clinical significance of these changes is not well understood.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: May 31, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
  1. Förstermann U, Closs EI, Pollock JS, et al. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension 1994; 23:1121.
  2. Katz SD, Khan T, Zeballos GA, et al. Decreased activity of the L-arginine-nitric oxide metabolic pathway in patients with congestive heart failure. Circulation 1999; 99:2113.
  3. Kubo SH, Rector TS, Bank AJ, et al. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991; 84:1589.
  4. Katz SD, Krum H, Khan T, Knecht M. Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure: role of endothelium-derived nitric oxide. J Am Coll Cardiol 1996; 28:585.
  5. Nightingale AK, Blackman DJ, Ellis GR, et al. Preservation of venous endothelial function in the forearm venous capacitance bed of patients with chronic heart failure despite arterial endothelial dysfunction. J Am Coll Cardiol 2001; 37:1062.
  6. Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998; 97:363.
  7. Stein B, Eschenhagen T, Rüdiger J, et al. Increased expression of constitutive nitric oxide synthase III, but not inducible nitric oxide synthase II, in human heart failure. J Am Coll Cardiol 1998; 32:1179.
  8. Damy T, Ratajczak P, Shah AM, et al. Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet 2004; 363:1365.
  9. Haywood GA, Tsao PS, von der Leyen HE, et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation 1996; 93:1087.
  10. Drexler H, Kästner S, Strobel A, et al. Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart. J Am Coll Cardiol 1998; 32:955.
  11. Comini L, Bachetti T, Agnoletti L, et al. Induction of functional inducible nitric oxide synthase in monocytes of patients with congestive heart failure. Link with tumour necrosis factor-alpha. Eur Heart J 1999; 20:1503.
  12. Scherrer-Crosbie M, Ullrich R, Bloch KD, et al. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 2001; 104:1286.
  13. Tatsumi T, Matoba S, Kawahara A, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes. J Am Coll Cardiol 2000; 35:1338.
  14. Hare JM, Loh E, Creager MA, Colucci WS. Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction. Circulation 1995; 92:2198.
  15. Yamamoto S, Tsutsui H, Tagawa H, et al. Role of myocyte nitric oxide in beta-adrenergic hyporesponsiveness in heart failure. Circulation 1997; 95:1111.
  16. Hare JM, Givertz MM, Creager MA, Colucci WS. Increased sensitivity to nitric oxide synthase inhibition in patients with heart failure: potentiation of beta-adrenergic inotropic responsiveness. Circulation 1998; 97:161.
  17. Shinke T, Takaoka H, Takeuchi M, et al. Nitric oxide spares myocardial oxygen consumption through attenuation of contractile response to beta-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy. Circulation 2000; 101:1925.
  18. Hare JM. Spatial confinement of isoforms of cardiac nitric-oxide synthase: unravelling the complexities of nitric oxide's cardiobiology. Lancet 2004; 363:1338.
  19. Riede UN, Förstermann U, Drexler H. Inducible nitric oxide synthase in skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol 1998; 32:964.
  20. Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27:1201.
  21. 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.
  22. Mohler ER 3rd, Sorensen LC, Ghali JK, et al. Role of cytokines in the mechanism of action of amlodipine: the PRAISE Heart Failure Trial. Prospective Randomized Amlodipine Survival Evaluation. J Am Coll Cardiol 1997; 30:35.
  23. Deswal A, Petersen NJ, Feldman AM, et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 2001; 103:2055.
  24. 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.
  25. Rauchhaus M, Doehner W, Francis DP, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 2000; 102:3060.
  26. Vasan RS, Sullivan LM, Roubenoff R, et al. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 2003; 107:1486.
  27. Murray DR, Freeman GL. Proinflammatory cytokines: predictors of a failing heart? Circulation 2003; 107:1460.
  28. Kelly RA, Smith TW. Cytokines and cardiac contractile function. Circulation 1997; 95:778.
  29. Kapadia SR, Yakoob K, Nader S, et al. Elevated circulating levels of serum tumor necrosis factor-alpha in patients with hemodynamically significant pressure and volume overload. J Am Coll Cardiol 2000; 36:208.
  30. Feldman AM, Combes A, Wagner D, et al. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol 2000; 35:537.
  31. Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996; 93:704.
  32. Kapadia SR, Oral H, Lee J, et al. Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res 1997; 81:187.
  33. Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 1999; 353:1838.
  34. Bryant D, Becker L, Richardson J, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 1998; 97:1375.
  35. Franco F, Thomas GD, Giroir B, et al. Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 1999; 99:448.
  36. Kadokami T, Frye C, Lemster B, et al. Anti-tumor necrosis factor-alpha antibody limits heart failure in a transgenic model. Circulation 2001; 104:1094.
  37. Kubota T, Bounoutas GS, Miyagishima M, et al. Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy. Circulation 2000; 101:2518.
  38. 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.
  39. Nakamura K, Fushimi K, Kouchi H, et al. Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation 1998; 98:794.
  40. Birks EJ, Owen VJ, Burton PB, et al. Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation. Circulation 2000; 102:326.
  41. Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 1998; 31:391.
  42. Maeda K, Tsutamoto T, Wada A, et al. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol 2000; 36:1587.
  43. Wollert KC, Drexler H. The role of interleukin-6 in the failing heart. Heart Fail Rev 2001; 6:95.
  44. Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol 1994; 55:97.
  45. Aukrust P, Ueland T, Müller F, et al. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation 1998; 97:1136.
  46. Damås JK, Gullestad L, Ueland T, et al. CXC-chemokines, a new group of cytokines in congestive heart failure--possible role of platelets and monocytes. Cardiovasc Res 2000; 45:428.
  47. Damås JK, Gullestad L, Aass H, et al. Enhanced gene expression of chemokines and their corresponding receptors in mononuclear blood cells in chronic heart failure--modulatory effect of intravenous immunoglobulin. J Am Coll Cardiol 2001; 38:187.
  48. Wong SC, Fukuchi M, Melnyk P, et al. Induction of cyclooxygenase-2 and activation of nuclear factor-kappaB in myocardium of patients with congestive heart failure. Circulation 1998; 98:100.
  49. Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005; 25:1102.
  50. Galijasevic S, Saed GM, Diamond MP, Abu-Soud HM. Myeloperoxidase up-regulates the catalytic activity of inducible nitric oxide synthase by preventing nitric oxide feedback inhibition. Proc Natl Acad Sci U S A 2003; 100:14766.
  51. Ng LL, Pathik B, Loke IW, et al. Myeloperoxidase and C-reactive protein augment the specificity of B-type natriuretic peptide in community screening for systolic heart failure. Am Heart J 2006; 152:94.
  52. Tang WH, Tong W, Troughton RW, et al. Prognostic value and echocardiographic determinants of plasma myeloperoxidase levels in chronic heart failure. J Am Coll Cardiol 2007; 49:2364.
  53. Kitamura K, Kangawa K, Kawamoto M, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993; 192:553.
  54. Szokodi I, Kinnunen P, Tavi P, et al. Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide. Circulation 1998; 97:1062.
  55. Nishikimi T, Saito Y, Kitamura K, et al. Increased plasma levels of adrenomedullin in patients with heart failure. J Am Coll Cardiol 1995; 26:1424.
  56. Yu CM, Cheung BM, Leung R, et al. Increase in plasma adrenomedullin in patients with heart failure characterised by diastolic dysfunction. Heart 2001; 86:155.
  57. Nakamura M, Yoshida H, Makita S, et al. Potent and long-lasting vasodilatory effects of adrenomedullin in humans. Comparisons between normal subjects and patients with chronic heart failure. Circulation 1997; 95:1214.
  58. Nagaya N, Satoh T, Nishikimi T, et al. Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure. Circulation 2000; 101:498.
  59. Richards AM, Doughty R, Nicholls MG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol 2001; 37:1781.