2006-11-22

Kong Xiao-mu

Zhang Jing-jie

Li Nan

Chu Ming

Mu Xun

Ma Yue

03 basic medical science

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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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Association between inflammation and CHF

Inflammatory processes in CHF

Anti-inflammation therapy in CHF

Outlines

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

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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References

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Thank you for attention!Thank you for attention!