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Kong Xiao-mu Zhang Jing-jie Li Nan

Inflammation and Congestive Heart Failure. 03 basic medical science. Kong Xiao-mu Zhang Jing-jie Li Nan. Chu Ming Mu Xun Ma Yue. 2006-11-22. BACKGROUD. Congestive Heart Failure (CHF). BACKGROUD. Clinical Feature of CHF. progressive dyspnea with exertion

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Kong Xiao-mu Zhang Jing-jie Li Nan

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  1. Inflammation and Congestive Heart Failure 03 basic medical science Kong Xiao-mu Zhang Jing-jie Li Nan Chu Ming Mu Xun Ma Yue 2006-11-22

  2. BACKGROUD Congestive Heart Failure (CHF)

  3. BACKGROUD Clinical Feature of CHF • progressive dyspnea with exertion • paroxysmal nocturnal dyspnea • orthopnea • nocturnal and dry cough • nocturia • generalized fatigue • peripheral edema

  4. BACKGROUD A History of Causes of CHF • chest pain, coronary artery disease, myocardial infarction (MI), hypertension, acute chest congestion A History of Cardiovascular Risk Factors • diabetes, smoking, obesity, heart enlargement, elevated cholesterol

  5. BACKGROUD NYHA Classification System for CHF New York Heart Association (NYHA) • asymptomatic • symptoms with above average activity • symptoms with normal activity • symptoms at rest or with minimal activity

  6. Inflammation and Congestive Heart Failure 2006-11-22

  7. Outlines • Association between inflammation and CHF • Inflammatory processes in CHF • Anti-inflammation therapy in CHF

  8. Association between Inflammation and CHF Clinical & epidemiological study shows Agnoletti, L. et al. European society of cardiology. 2004;6:F22-F29.

  9. Theories explain the cause of inflammatory immune activation in CHF. Anker, S.D. et al. Heart. 2004;90:464-470.

  10. Inflammatory Processes in CHF Cells Effects Molecules

  11. Immune Cells Activation and Other Cells Involved Macrophages Lymphocytes Monocytes Endothelial cells Cardiomyocytes …… Anker, S.D. et al. Heart. 2004;90:464-470.

  12. Main Effects that Inflammation Causes in CHF • Direct toxic effect on heart • Structural adaptation • Effect on hormone and nervous system • Extracardial compensation

  13. Molecules Involved • TNFα • IL: IL-6, IL-1, … IL-10 (opposite role in inflammation) • CRP • NO • Adhesion molecules: selectin, integrin, VCAM, ICAM, … Co-operation

  14. The effects of TNF-α and IL-6 Anker, S.D. et al. Heart. 2004;90:464-470.

  15. TNFα & IL-6 associated with NYHA Kosar, F. et al. Eur J Heart Failure. 2006;8:270-274.

  16. Tumor Necrosis Factor (TNFα) • Mainly secreted by macrophages. • Only in failing heart. Feldman, A.M. et al. J Am Coll Cardiol. 2000;35:537-544.

  17. TNFα Receptor (TNFR) • TNFRI • Main signaling receptor • TNFRII • Protective role • Both of them present in non-failing and failing heart Murali, R. et al. Proc Natl Acad Sci. 2005;102:10970-10975.

  18. Signal Transduction of TNFα Horssen, R.V. et al. Oncologist. 2006;11:397-408.

  19. TNFα associated with NYHA Stress Pressure Volume overload TNF α In heart failure Feldman, A.M. et al. J Am Coll Cardiol. 2000;35:537-544.

  20. The effects of TNFα in CHF • Direct toxic effect on heart IL-10 Oxidative stress Cell injury TNFα Myocytes & endothelial cells apoptosis

  21. The effects of TNFα in CHF • Direct toxic effect on heart • Functional change • Decreased contractility TNFα Ca2+ NO Contractility iNOS

  22. TNFα induced Decreased contractility Feldman, A.M. et al. J Am Coll Cardiol. 2000;35:537-544.

  23. The effects of TNFα in CHF • Structural adaptation • Myocyte remodeling MMP TNFα Aggradation of collagen TIMP

  24. Interleukin-6 (IL-6) • Mainly secreted by macrophages. • IL-6 receptor • IL-6Rα: the ligand bonding chain • gp130: the signal transmitting chain

  25. IL-6 extracellular signaling Mitsuyama, K. et al. Cytokine & Growth Factor Reviews. 2006;in press.

  26. IL-6 intracellular signaling

  27. IL-6 associated with NYHA Kosar, F. et al. Eur J Heart Failure. 2006;8:270-274. Stress ROS Inflammatory factors Autonomic nervous system IL-6 In heart failure

  28. The effects of IL-6 in CHF • Direct toxic effects on the heart IL-6 Respiratoty burst of neutrophils ROS ICAM-1 Adhesion of myocytes and neutrophils

  29. The effects of IL-6 in CHF • Direct toxic effects on heart • Functional change • Decreased contractility IL-6 cGMP Ca2+ NO Contractility Sensitivity of myofilaments to Ca2+

  30. The effects of IL-6 in CHF • Structural adaptation • Myocardial remodeling: hypertrophy CHF Phosphorylate STAT3 IL-6 Myocyte hypertrophy Phosphorylate gp130 Phosphorylate STAT3

  31. The Mechanism of Myocardial Hypertrophy Kleiner, D.H. et al. J Am Coll Cardiol. 2006;48:A56-66.

  32. The effects of IL-6 in CHF • Structural adaptation • Changes in non-myocytes Over-aggradation of collagen IL-6 Myocardial fibrosis

  33. The effects of IL-6 in CHF • Effects on hormone and nervous system Cardionatrin Brain Natriuretic Peptide IL-6 Affecting the function of autonomic nervous system β-adrenaline receptor sensitivity

  34. C Reactive Protein (CRP) • Secreted by many kinds of cells. • By cardiac myocytes under hypoxic stress. Anand, I.S. et al. Circulation. 2005;112:1428-1434.

  35. The effects of CRP in CHF Activate the classical complement pathway and opsonises ligands for phagocytosis CRP Augment IL-1β induced production of iNOS

  36. Nitric Oxide (NO) • Small gaseous molecule • Mainly secreted by endothelial cell. • Forms: • Neuronal (NOSI) • Inducible (NOSII) • Endothelial (NOSIII)

  37. The effects of NO in CHF • Direct toxic effects on heart NO ONOO- (no cytotoxicity) NO2 and OH- (with high cytotoxicity) Cytotoxicity ATP decrease Proliferation inhibition DNA disruption cell death

  38. The effects of NO in CHF • Induce vascular dilation NO GCs activation cGMP PKG activation iNOS activation Ca2+ Endotoxin and cytotokine Diastole vascular Inflammatory cells Infiltration

  39. The effects of NO in CHF • Induced vascular contraction NO Endothelin Vascular contraction Endothelial cell proliferation Vascular dilation Endothelial cell shed and death Enhanced inflammation

  40. Adhesion Molecules • Families • Interactions Intracellular adhesion molecules: ICAM-1~3, VCAM-1 Integrins: LFA-1,glycoprotein IIb/IIIa Selectin: L,P,E selectin leucocyte leucocyte Endothelial cell Extracellular matrix

  41. Adhesion molecules play a role in inflammation. Anker, S.D. et al. Heart. 2004;90:464-470.

  42. Anti-Inflammation therapy in CHF • Cardiac glycosides • Anti-rheumatic drugs • Nonsteroidalanti-inflammatorydrugs • Glucocorticoids

  43. Cardiac glycosides Mainstay in CHF treatment Contractility Potassium loss Heart rate

  44. Anti-rheumatic drugs (DMARDs) CHF is an complication associated with RA. DMARDs CHF

  45. Nonsteroidalanti-inflammatorydrugs (NSAID) Block the biosynthesis of prostaglandins COX2 inhibitor PGs

  46. Glucocorticoids Block the biosynthesis of prostaglandins PG and LT IL-1、IL-2、TNF、IFN-r、IL-10… NOS

  47. Conclusion • Congestive heart failure (CHF) is a state of immune activation. • Inflammation process in CHF and molecules involved provide anti-inflammation therapy as a new sight to CHF treatment. • The detailed mechanisms still need further investigation.

  48. References • Burnett AL,et al. Nitric oxide:a physiologic mediator of penile erection. Science, 1992,257:401 • Moncada S,et al. Nitric oxide: physiology, pathophyiology and Pharmacology. Pharmacol Rev, 1991, 43:109 • Maede H, Akaike T. Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc). 1998, 63:854-865 • Vila-Petroff MG, Younes A, Egan J, et al. Activation of distinct cAMP dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. Circ Res. 1999;84:1020–1031. • He Y, Yu W, Baas PW. Microtubule reconfiguration during axonal retraction induced by nitric oxide. J Neurosci. 2002;22:5982–5991. • Jaffrey SR, Erdjument-Bromage H, Ferris CD, et al. Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol. 2001;3:193–197. • Cross SS , Wolin MS . Nitric oxide pathophysiological mechanisms[J ]. Annu Rev Physiol ,1995 ,57∶737～769. • Bonfoco E , Krainc D , Ankarcrona M. Apoptosis and necrosis :tow distinct events induced respectively by mild and intense insult with N - methyl - D - aspartate or nitric oxide/ superoxide in cortical cell cultures [ J ] . ProcNatl Acad Sci USA ,1995 ,92∶7162～7166. • Brown GC. Nitric oxide regulates mitochondrial respira2tion and cell functions by inhibiting cytochrome oxidase [J ] . FEBS Lett ,1995 ,369∶136～139. • de Belder AJ, Radomski MW, Why HJ, et al. Nitric oxide synthase activities in human myocardium. Lancet. 1993;341:84–85. • Heineke J, Kempf T, Kraft T, et al. Downregulation of cytoskeletal muscle LIM protein by nitric oxide: impact on cardiac myocyte hypertrophy. Circulation. 2003;107:1424–1431. • Patten RD, DeNofrio D, El-Zaru M, et al. Ventricular assist device therapy normalizes inducible nitric oxide synthase expression and reduces cardiomyocyte apoptosis in the failing human heart. J Am Coll Cardiol 2005;45:1419 –24. • Clzel M ,Breu V ,Burri K,et al. Pathphysiological role of endothelin revealed by the first orally active endothelin receptor antagonist . Nature ,1993 ,365 :759

  49. Thank you for attention!

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