kong xiao-mu zhang jing-jie li nan
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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2006-11-22
Kong Xiao-mu
Zhang Jing-jie
Li Nan
Chu Ming
Mu Xun
Ma Yue
03 basic medical science
2006-11-22
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Congestive Heart Failure (CHF)
BACKGROUD
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Clinical Feature of CHF
progressive dyspnea with exertion
paroxysmal nocturnal dyspnea
orthopnea
nocturnal and dry cough
nocturia
generalized fatigue
peripheral edema
BACKGROUD
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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
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NYHA Classification System for CHF
New York Heart Association (NYHA)
I. asymptomatic
II. symptoms with above average activity
III. symptoms with normal activity
IV. symptoms at rest or with minimal activity
BACKGROUD
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2006-11-22
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Association between inflammation and CHF
Inflammatory processes in CHF
Anti-inflammation therapy in CHF
Outlines
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2006-11-22Agnoletti, L. et al. European society of cardiology. 2004;6:F22-F29.
Clinical & epidemiological study shows
Association between Inflammation and CHF
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Theories explain the cause of inflammatory immune activation in CHF.
Anker, S.D. et al. Heart. 2004;90:464-470.
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Inflammatory Processes in CHF
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Macrophages Lymphocytes
Monocytes
Endothelial cells
Cardiomyocytes
……
Anker, S.D. et al. Heart. 2004;90:464-470.
Immune Cells Activation and Other Cells Involved
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Main Effects that Inflammation Causes in CHF
Direct toxic effect on heart
Structural adaptation
Effect on hormone and nervous system
Extracardial compensation
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• TNFα
• IL: IL-6, IL-1, …
IL-10 (opposite role in inflammation)
• CRP
• NO
• Adhesion molecules: selectin, integrin, VCAM, ICAM, …
Molecules Involved
Co-operation
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2006-11-22Anker, S.D. et al. Heart. 2004;90:464-470.
The effects of TNF-α and IL-6
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TNFα & IL-6 associated with NYHA
Kosar, F. et al. Eur J Heart Failure. 2006;8:270-274.
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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.
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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.
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Signal Transduction of TNFα
Horssen, R.V. et al. Oncologist. 2006;11:397-408.
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TNFα associated with NYHA
TNF α
In heart failure
StressPressure
Volume overload
Feldman, A.M. et al. J Am Coll Cardiol. 2000;35:537-544.
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The effects of TNFα in CHF
Direct toxic effect on heart
Cell injury
Oxidative stress
TNFα
Myocytes & endothelial cells ap
optosis
IL-10
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The effects of TNFα in CHF
Direct toxic effect on heartFunctional change
Decreased contractility
TNFα Ca2+
NO iNOS Contractility
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TN
Fα
ind
uced
Decreased
con
tractility
Feldman, A.M. et al. J Am Coll Cardiol. 2000;35:537-544.
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The effects of TNFα in CHF
Structural adaptationMyocyte remodeling
TNFα Aggradation of collagen
MMP
TIMP
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• Mainly secreted by macrophages.
• IL-6 receptor– IL-6Rα: the ligand bonding
chain– gp130: the signal transmitti
ng chain
Interleukin-6 (IL-6)
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IL-6 extracellular signaling
Mitsuyama, K. et al. Cytokine & Growth Factor Reviews. 2006;in press.
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IL-6 in
tracellular sig
nalin
g
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StressROS
Inflammatory factorsAutonomic nervous system
IL-6
In heart failure
IL-6 associated with NYHA
Kosar, F. et al. Eur J Heart Failure. 2006;8:270-274.
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The effects of IL-6 in CHF
Direct toxic effects on the heart
IL-6
ICAM-1
ROS
Respiratoty burst of neutrophils
Adhesion of myocytes and neutrophils
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Direct toxic effects on heartFunctional change
Decreased contractility
The effects of IL-6 in CHF
IL-6 cGMP Ca2+
NO
Sensitivity of myofilaments to Ca2+
Contractility
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Structural adaptationMyocardial remodeling: hypertrophy
CHF
IL-6
Phosphorylate gp130
Phosphorylate STAT3
Myocyte hypertrophy
Phosphorylate STAT3
The effects of IL-6 in CHF
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The Mechanism of Myocardial Hypertrophy
Kleiner, D.H. et al. J Am Coll Cardiol. 2006;48:A56-66.
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Structural adaptationChanges in non-myocytes
IL-6 Over-aggradation of collagen
Myocardial fibrosis
The effects of IL-6 in CHF
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Effects on hormone and nervous system
IL-6
Cardionatrin
Brain Natriuretic Peptide
Affecting the function of autonomic nervous system
The effects of IL-6 in CHF
β-adrenaline receptor sensitivity
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• Secreted by many kinds of cells.• By cardiac myocytes under hypoxic stress.
C Reactive Protein (CRP)
Anand, I.S. et al. Circulation. 2005;112:1428-1434.
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The effects of CRP in CHF
CRP
Activate the classical complement pathway and opsonises ligands for phagocytosis
Augment IL-1β induced production of iNOS
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• Small gaseous molecule
• Mainly secreted by endothelial cell.
• Forms:– Neuronal (NOSI)– Inducible (NOSII) – Endothelial (NOSIII)
Nitric Oxide (NO)
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The effects of NO in CHF
Direct toxic effects on heart
NO ONOO- (no cytotoxicity)
NO2 and OH- (with high cytotoxicity)
Cytotoxicity
Proliferation inhibition
ATP decrease
DNA disruption cell death
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NO GCs activation
Diastole vascular
The effects of NO in CHF
cGMP
Ca2+
Inflammatory cells Infiltration
Endotoxin and cytotokine
iNOS activation
Induce vascular dilation
PKG activation
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The effects of NO in CHF
Induced vascular contraction
NO Endothelin Vascular contraction
Vascular dilationEndothelial cell shed and death
Enhanced inflammation
Endothelial cell proliferation
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• Families
• Interactions
Adhesion Molecules
leucocyte
leucocyte
Endothelial cell
Extracellular matrix
Intracellular adhesion molecules: ICAM-1~3, VCAM-1
Integrins: LFA-1,glycoprotein IIb/IIIa Selectin: L,P,E selectin
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Adhesion molecules play a role in inflammation.
Anker, S.D. et al. Heart. 2004;90:464-470.
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Anti-Inflammation therapy in CHF
Cardiac glycosides Anti-rheumatic drugs Nonsteroidal anti-inflammatory drugs Glucocorticoids
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Contractility
Cardiac glycosides
Mainstay in CHF treatment
Potassium lossHeart rate
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Anti-rheumatic drugs (DMARDs)
CHF is an complication associated with RA.
DMARDs CHF
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Nonsteroidal anti-inflammatory drugs (NSAID)
PGs
Block the biosynthesis of prostaglandins
COX2 inhibitor
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Glucocorticoids
IL-1、 IL-2、 TNF、 IFN-r、 IL-10…
Block the biosynthesis of prostaglandins
PG and LT
NOS
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• 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.
Conclusion
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• 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 (Mos
c). 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 ni
tric 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 a
nd 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
References
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Thank you for attention!Thank you for attention!