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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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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 • paroxysmal nocturnal dyspnea • orthopnea • nocturnal and dry cough • nocturia • generalized fatigue • peripheral edema
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
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
Inflammation and Congestive Heart Failure 2006-11-22
Outlines • Association between inflammation and CHF • Inflammatory processes in CHF • Anti-inflammation therapy in CHF
Association between Inflammation and CHF Clinical & epidemiological study shows Agnoletti, L. et al. European society of cardiology. 2004;6:F22-F29.
Theories explain the cause of inflammatory immune activation in CHF. Anker, S.D. et al. Heart. 2004;90:464-470.
Inflammatory Processes in CHF Cells Effects Molecules
Immune Cells Activation and Other Cells Involved Macrophages Lymphocytes Monocytes Endothelial cells Cardiomyocytes …… Anker, S.D. et al. Heart. 2004;90:464-470.
Main Effects that Inflammation Causes in CHF • Direct toxic effect on heart • Structural adaptation • Effect on hormone and nervous system • Extracardial compensation
Molecules Involved • TNFα • IL: IL-6, IL-1, … IL-10 (opposite role in inflammation) • CRP • NO • Adhesion molecules: selectin, integrin, VCAM, ICAM, … Co-operation
The effects of TNF-α and IL-6 Anker, S.D. et al. Heart. 2004;90:464-470.
TNFα & IL-6 associated with NYHA Kosar, F. et al. Eur J Heart Failure. 2006;8:270-274.
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.
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.
Signal Transduction of TNFα Horssen, R.V. et al. Oncologist. 2006;11:397-408.
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.
The effects of TNFα in CHF • Direct toxic effect on heart IL-10 Oxidative stress Cell injury TNFα Myocytes & endothelial cells apoptosis
The effects of TNFα in CHF • Direct toxic effect on heart • Functional change • Decreased contractility TNFα Ca2+ NO Contractility iNOS
TNFα induced Decreased contractility Feldman, A.M. et al. J Am Coll Cardiol. 2000;35:537-544.
The effects of TNFα in CHF • Structural adaptation • Myocyte remodeling MMP TNFα Aggradation of collagen TIMP
Interleukin-6 (IL-6) • Mainly secreted by macrophages. • IL-6 receptor • IL-6Rα: the ligand bonding chain • gp130: the signal transmitting chain
IL-6 extracellular signaling Mitsuyama, K. et al. Cytokine & Growth Factor Reviews. 2006;in press.
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
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
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+
The effects of IL-6 in CHF • Structural adaptation • Myocardial remodeling: hypertrophy CHF Phosphorylate STAT3 IL-6 Myocyte hypertrophy Phosphorylate gp130 Phosphorylate STAT3
The Mechanism of Myocardial Hypertrophy Kleiner, D.H. et al. J Am Coll Cardiol. 2006;48:A56-66.
The effects of IL-6 in CHF • Structural adaptation • Changes in non-myocytes Over-aggradation of collagen IL-6 Myocardial fibrosis
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
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.
The effects of CRP in CHF Activate the classical complement pathway and opsonises ligands for phagocytosis CRP Augment IL-1β induced production of iNOS
Nitric Oxide (NO) • Small gaseous molecule • Mainly secreted by endothelial cell. • Forms: • Neuronal (NOSI) • Inducible (NOSII) • Endothelial (NOSIII)
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
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
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
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
Adhesion molecules play a role in inflammation. Anker, S.D. et al. Heart. 2004;90:464-470.
Anti-Inflammation therapy in CHF • Cardiac glycosides • Anti-rheumatic drugs • Nonsteroidalanti-inflammatorydrugs • Glucocorticoids
Cardiac glycosides Mainstay in CHF treatment Contractility Potassium loss Heart rate
Anti-rheumatic drugs (DMARDs) CHF is an complication associated with RA. DMARDs CHF
Nonsteroidalanti-inflammatorydrugs (NSAID) Block the biosynthesis of prostaglandins COX2 inhibitor PGs
Glucocorticoids Block the biosynthesis of prostaglandins PG and LT IL-1、IL-2、TNF、IFN-r、IL-10… NOS
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.
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