03 basic medical science
Kong Xiao-mu
Zhang Jing-jie
Li Nan
2006-11-22
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Chu Ming
Mu Xun
Ma Yue
2006-11-22
BACKGROUD
Congestive Heart Failure (CHF)
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BACKGROUD
Clinical Feature of CHF
progressive dyspnea with exertion
paroxysmal nocturnal dyspnea
orthopnea
nocturnal and dry cough
nocturia
generalized fatigue
peripheral edema
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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
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BACKGROUD
NYHA Classification System for CHF
New York Heart Association (NYHA)
I.
II.
III.
IV.
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asymptomatic
symptoms with above average activity
symptoms with normal activity
symptoms at rest or with minimal activity
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Outlines
Association between inflammation
and CHF
Inflammatory processes in CHF
Anti-inflammation therapy in CHF
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Association between Inflammation and CHF
Clinical & epidemiological study shows
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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.
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Inflammatory Processes in CHF
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Immune Cells Activation and Other Cells
Involved
Macrophages
Lymphocytes
Monocytes
Endothelial cells
Cardiomyocytes
……
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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
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Molecules Involved
• TNFα
Co-operation
• IL: IL-6, IL-1, …
IL-10 (opposite role in inflammation)
• CRP
• NO
• Adhesion molecules: selectin, integrin,
VCAM, ICAM, …
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The effects of TNF-α and IL-6
Anker, S.D. et al. Heart. 2004;90:464-470.
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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
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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.
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The effects of TNFα in CHF
Direct toxic effect on heart
IL-10
Oxidative stress
TNFα
Cell injury
Myocytes &
endothelial cells
apoptosis
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The effects of TNFα in CHF
Direct toxic effect on heart
Functional change
Decreased contractility
TNFα
iNOS
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Ca2+
NO
Contractility
TNFα induced Decreased contractility
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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
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Interleukin-6 (IL-6)
• Mainly secreted by
macrophages.
• IL-6 receptor
– IL-6Rα: the ligand bonding
chain
– gp130: the signal
transmitting chain
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IL-6 extracellular signaling
Mitsuyama, K. et al. Cytokine & Growth Factor Reviews. 2006;in press.
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IL6
intracellular signaling
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IL-6 associated with NYHA
Kosar, F. et al. Eur J Heart Failure. 2006;8:270-274.
Stress
ROS
Inflammatory factors
Autonomic nervous system
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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
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Adhesion of myocytes
and neutrophils
The effects of IL-6 in CHF
Direct toxic effects on heart
Functional change
Decreased contractility
IL-6
NO
Ca2+
cGMP
Contractility
Sensitivity of myofilaments to Ca2+
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The effects of IL-6 in CHF
Structural adaptation
Myocardial remodeling: hypertrophy
CHF
Phosphorylate STAT3
IL-6
Myocyte hypertrophy
Phosphorylate gp130
Phosphorylate STAT3
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The Mechanism of Myocardial Hypertrophy
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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
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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
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C Reactive Protein (CRP)
• Secreted by many kinds of cells.
• By cardiac myocytes under hypoxic stress.
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Anand, I.S. et al. Circulation. 2005;112:1428-1434.
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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Nitric Oxide (NO)
• Small gaseous molecule
• Mainly secreted by endothelial cell.
• Forms:
– Neuronal
– Inducible
– Endothelial
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(NOSI)
(NOSII)
(NOSIII)
The effects of NO in CHF
Direct toxic effects on heart
NO
ONOO- (no cytotoxicity)
NO2 and OH- (with high cytotoxicity)
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Cytotoxicity
ATP decrease
Proliferation inhibition
DNA disruption cell death
The effects of NO in CHF
Induce vascular dilation
NO
GCs activation
iNOS activation
Endotoxin and cytotokine
Inflammatory cells Infiltration
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cGMP
PKG activation
Ca2+
Diastole vascular
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
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Adhesion Molecules
• Families
Intracellular adhesion molecules: ICAM-1~3, VCAM-1
Integrins: LFA-1,glycoprotein IIb/IIIa Selectin: L,P,E selectin
• Interactions
leucocyte
leucocyte
Endothelial cell
Extracellular matrix
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Adhesion molecules play a role in inflammation.
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Anker, S.D. et al. Heart. 2004;90:464-470.
Anti-Inflammation therapy in CHF
Cardiac glycosides
Anti-rheumatic drugs
Nonsteroidal anti-inflammatory drugs
Glucocorticoids
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Cardiac glycosides
Mainstay in CHF treatment
Contractility
Heart rate
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Potassium loss
Anti-rheumatic drugs (DMARDs)
CHF is an complication associated with RA.
DMARDs
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CHF
Nonsteroidal anti-inflammatory drugs (NSAID)
Block the biosynthesis of prostaglandins
COX2 inhibitor
PGs
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Glucocorticoids
Block the biosynthesis of prostaglandins
PG and LT
IL-1、IL-2、TNF、IFN-r、IL-10…
NOS
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Conclusion
• Congestive heart failure (CHF) is a state
of immune activation.
• Inflammation process in CHF and
molecules involved provide antiinflammation therapy as a new sight to
CHF treatment.
• The detailed mechanisms still need
further investigation.
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References
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Thank you for attention!
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