GROUP 4

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Introduction

The myocardium comprises many different cells. Cardiac myocytes (cardiocytes), The largest of these cells, occupy 75%.

25% include 1) Endothelial

cells2) Vascular

smooth muscle cells

3) Cardiac fibroblasts

4) Macrophages and mast cells

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3

Introduction

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Blood pressure / volume overload

Adaptation- Size of cardiomyocyte- Cardiac muscle mass

CARDIAC HYPERTROPHY

4

Introduction

4

CARDIAC HYPERTROPHY

Physiological hypertrophy

(Athlete’s Heart)

Pathological hypertrophy (Cardiovascular disease)

Finding animal study

Identified key signaling mechanisms

To diagnosis, New Therapeutic

Increased heart mass Normal or Enhanced cardiac function Reversible

Increased heart mass Reduced cardiac function Irreversible Cell death and fibrosis Increased mortality

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What induced hypertrophy?

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Pressure overload

Systolic wall stress

Mechanical transducers

Eccentric hypertrophy

Volume overload

Diastolic wall stress

Concentric hypertrophy

Responses to hemodynamic overload

Ventricular hypertrophy

Extracellular and intracellular signals

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Cardiac Hypertrophy in the Athlete’s Heart

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Resistance training

Endurance training

Eccentric

Concentric

Combination

training

Eccentric+Concentric

Exercise

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Cardiac Hypertrophy in the Athlete’s Heart

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ENDURANCE TRAININGEndurance training Sedentary Resistance training

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Cardiac Hypertrophy in the Athlete’s Heart

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Endurance training

Resistance training

• Increase blood flow• Increase preload• Increasing LV internal diameter • LV wall thickness • Increase cardiac output (HR SV )

Eccentric hypertrop

hy

Concentric hypertrop

hy• Increase blood pressure• Increased afterload• Slightly increase LV internal diameter • LV wall thickness • Increase cardiac output (HR SV )

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Cardiac Hypertrophy in the Athlete’s Heart

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» Physiological Changes with Exercise

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Signaling pathway in Physiological Cardiac Hypertrophy

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PI3K (p110α)

Akt1Angiogenesis

Contractility Heart

growth

Anti-apoptosis

Anti-fibrosis

Pathological pathway

IGF-1

IGF-1 Receptor

Cell membrane Cell membrane

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Signaling pathway in Physiological Cardiac Hypertrophy

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• mTOR dependent pathway

• mTOR independent pathway

» Regulation of protein synthesis and cell size

Akt1

mTOR

Protein synthesis Protein degradation

Cell size

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Signaling pathway in Physiological Cardiac Hypertrophy

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» Improve contractile function

Control Ca2+ cycling by increase the density of :

• L-type Ca2+ channel

• SERCA2 protein

» AngiogenesisStimulate cardiomyocytes to secrete 2 growth

factors :• Vascular Endothelial growth factor

(VEGF)

• Angiopoietin-2

SRCa2+

Ca2+

Ca2+

L-Type Ca2+ channel

SERCA2Ca2+

Ca2+Ca2+

Cell membrane Cell membrane

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Signaling pathway in Physiological Cardiac Hypertrophy

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» Anti-apoptosis

Cardioprotection» Anti-fibrosis

Control

PI3K activity (dnPI3K)

PI3K activity

(caPI3K)

Stimulated by Aortic banding (pressure overload)

Akt1

Cytochrome c releasing

Program cell death

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Cardiac Hypertrophy in the Failing Heart

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Concentric

Eccentric

Etiology: Mutation

Dilated cardiomyopathy (DCM)

chronic chronic chronic

Etiology: Volume overload

- Valvular heart disease - Myocarditis- Myocardial infarction

Etiology: Pressure overload

- Hypertension- Aortic stenosis- Chronic renal failure

- MYBP3 mutation gene effect

- Sarcomere act as “calcium trapping”- Sudden cardiac death

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Cardiac Hypertrophy in the Failing Heart

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Cardiac remodeling

Pressure/volumeoverload Concentric

/Eccentric HT

CO ↓

Systolic /

Diastolic wall stress

chronic

Com

pens

ated

Irre

vers

ible

Dec

ompe

nsat

ed

chronic

Renin Angiotensin Aldosterone system

(RAAS)

Sympathetic activation

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Cardiac Hypertrophy in the Failing Heart

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CO ↓Sympathetic activation

RAAS

Cardiac filling pressure ↑

Cardiac remodleing

↑ Aldosterone↑ ADH

Decompensatory stage

ChronicEarly

- Peripheral Vasoconstriction- Heart rate ↑- Contractility ↑

↑ Ang II production

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Cardiac Hypertrophy in the Failing Heart

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Dilated cardiomyopathy

Cardiomyocyte death

Heart failure

Enlarged left atrium

WeakenedMuscle wall

Enlargedleft ventricle

Thin cardiac wall

Fibrosis

Chamber dilatation

Sarcomere dysfunction

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Signaling pathway in Pathological Cardiac Hypertrophy

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Pathological hypertrophic signaling pathway

G protein couple receptor pathway(GPCR pathway)

Mitogen-activated protein kinase pathway

(MAPKs pathway)

AngII, ET-1

Stress

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Signaling pathway in Pathological Cardiac Hypertrophy

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Gαq

GPCR

PLC

IP3

MAPKs (ERK, p38, JNK)

- Fetal genes expression- Apoptosis- Hypertrophy

» Excessive Ang II, ET-1

DAG

PI3K (p110γ)

Akt*

Gβγ

Transcriptional factors

Cell membrane Cell membrane

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Signaling pathway in Pathological Cardiac Hypertrophy

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Stress (e.g. ischmia, overload)

MAPK pathway

ERK JNK, P38

Transcriptional factors- Fetal genes expression- Apoptosis - Hypertrophy

Anti-apoptosis

Transcriptional factors

Cell membrane Cell membrane

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Signaling pathway in Pathological Cardiac Hypertrophy

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• Fetal gene expression

- MHC isoform shift (α → β) - SERCA2 protein ↓ - L-type Ca2+ channel ↓

• Cardiomyocyte death →

• Pathological cardiac hypertrophy

Outcomes from these pathways?

} Contractility ↓

Fibrosis

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Endurance exerciseResistance exerciseCombination exercise

HypertensionDilated cardiomyopathy(DCM)

Hypertrophic cardiomyopathy

(HCM)

Pressure overload

Volume overload

Distinct characteristics of physiological and pathological cardiac hypertrophy

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PI3K (p110α)

Akt1

Gαq

PLC

IP3

MAPKs (ERK, p38, JNK)

DAG

PI3K (p110γ)

Gβγ

Akt*

GPCR

New therapeutic strategyactivate reguletors of

PI3K (p110α) pathway,i.e. ‘PI3K–regulated microRNAs’

IGF-1

IGF-1 Receptor

Cell membrane

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Thank you for your kind attention. Any questions are welcome.

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