GROUP 4
Introduction
The myocardium comprises many different
cells. Cardiac myocytes (cardiocytes), The largest
of these cells, occupy 75%.
25% include
1) Endothelial cells
2) Vascular smooth
muscle cells
3) Cardiac
fibroblasts
4) Macrophages
and mast cells
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Introduction
Blood pressure / volume overload
Adaptation
- Size of cardiomyocyte
- Cardiac muscle mass
CARDIAC HYPERTROPHY
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Introduction
CARDIAC HYPERTROPHY
Physiological hypertrophy
(Athlete’s Heart)
Pathological hypertrophy
(Cardiovascular disease)
 Increased heart mass
 Normal or Enhanced cardiac function
 Reversible





Increased heart mass
Reduced cardiac function
Irreversible
Cell death and fibrosis
Increased mortality
Finding animal study
Identified key signaling mechanisms
To diagnosis, New Therapeutic
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What induced hypertrophy?
Responses to hemodynamic overload
Volume overload
Pressure overload
Systolic wall stress
Diastolic wall stress
Mechanical transducers
Extracellular and intracellular signals
Ventricular hypertrophy
Concentric hypertrophy
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Eccentric hypertrophy
Cardiac Hypertrophy in the Athlete’s Heart
Exercise
Endurance
training
Eccentric
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Combination
training
Eccentric+Concentric
Resistance
training
Concentric
Cardiac Hypertrophy in the Athlete’s Heart
ENDURANCE TRAINING
Endurance training
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Sedentary
Resistance training
Cardiac Hypertrophy in the Athlete’s Heart
Endurance training
Eccentric
hypertrophy
• Increase blood flow
• Increase preload
• Increasing LV internal
diameter
• LV wall thickness
• Increase cardiac output
(HR SV
)
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Resistance training
Concentric
hypertrophy
• Increase blood pressure
• Increased afterload
• Slightly increase
LV internal diameter
• LV wall thickness
• Increase cardiac output
(HR SV )
Cardiac Hypertrophy in the Athlete’s Heart
» Physiological Changes with Exercise
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Signaling pathway in Physiological Cardiac Hypertrophy
IGF-1
Cell membrane
Pathological
pathway
Angiogenesis
Contractility
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IGF-1
Receptor
Cell membrane
PI3K
(p110α)
Akt1
Heart growth
Anti-fibrosis
Anti-apoptosis
Signaling pathway in Physiological Cardiac Hypertrophy
» Regulation of protein synthesis and cell size
Akt1
mTOR
Protein synthesis
Protein degradation
Cell size
• mTOR dependent pathway
• mTOR independent pathway
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Signaling pathway in Physiological Cardiac Hypertrophy
» Improve contractile function
L-Type Ca2+ channel
Cell membrane
Cell membrane
Ca2+
Ca2+
Ca2+
SERCA2
Control Ca2+ cycling by
increase the density of :
• L-type Ca2+ channel
Ca2+
Ca2+
• SERCA2 protein
Ca2+ SR
» Angiogenesis
Stimulate cardiomyocytes to secrete 2 growth factors :
• Vascular Endothelial growth factor (VEGF)
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• Angiopoietin-2
Signaling pathway in Physiological Cardiac Hypertrophy
Cardioprotection
» Anti-apoptosis
» Anti-fibrosis
Stimulated by Aortic banding
(pressure overload)
Akt1
Cytochrome c
releasing
Program
cell death
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PI3K activity
(dnPI3K)
PI3K activity
(caPI3K)
Control
Cardiac Hypertrophy in the Failing Heart
Eccentric
Concentric
Etiology: Volume
overload
Etiology: Pressure
overload
- Valvular heart disease
- Myocarditis
- Myocardial infarction
- Hypertension
- Aortic stenosis
- Chronic renal failure
chronic
chronic
Etiology: Mutation
- MYBP3 mutation
gene effect
- Sarcomere act as
chronic
“calcium trapping”
- Sudden cardiac
death
Dilated cardiomyopathy
(DCM)
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Pressure/volume
overload
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Concentric
Diastolic wall stress
/Eccentric
chronic
HT
CO ↓
Sympathetic activation
chronic
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Systolic /
Renin Angiotensin
Aldosterone system (RAAS)
Cardiac
remodeling
Irreversible
Decompensated
Compensated
Cardiac Hypertrophy in the Failing Heart
Cardiac Hypertrophy in the Failing Heart
Decompensatory stage
Cardiac
remodleing
CO ↓
Sympathetic activation
- Peripheral
Vasoconstriction
- Heart rate ↑
- Contractility ↑
Early
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RAAS
↑ Ang II production
↑ ADH
Cardiac filling
pressure ↑
↑ Aldosterone
Chronic
Cardiac Hypertrophy in the Failing Heart
Dilated cardiomyopathy
Sarcomere dysfunction
Enlarged left
atrium
Cardiomyocyte death
Fibrosis
Weakened
Muscle wall
Thin cardiac wall
Enlarged
left ventricle
Chamber dilatation
Heart failure
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Signaling pathway in Pathological Cardiac Hypertrophy
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
» Excessive Ang II, ET-1
GPCR
Cell membrane
Gαq
Cell membrane
Gβγ
PLC
MAPKs (ERK, p38, JNK)
IP3
DAG
Transcriptional
factors
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PI3K
(p110γ)
- Fetal genes
expression
- Apoptosis
- Hypertrophy
Akt*
Signaling pathway in Pathological Cardiac Hypertrophy
Stress (e.g. ischmia, overload)
Cell membrane
Cell membrane
MAPK pathway
ERK
Transcriptional factors
Anti-apoptosis
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JNK, P38
Transcriptional factors
- Fetal genes expression
- Apoptosis
- Hypertrophy
Signaling pathway in Pathological Cardiac Hypertrophy
Outcomes from these pathways?
• Fetal gene expression
}
- MHC isoform shift (α → β)
- SERCA2 protein ↓
- L-type Ca2+ channel ↓
• Cardiomyocyte death →
Contractility ↓
Fibrosis
• Pathological cardiac hypertrophy
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Endurance exercise
Resistance exercise Combination exercise
Volume
overload
Hypertension
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Dilated cardiomyopathy
(DCM)
Hypertrophic
cardiomyopathy
(HCM)
Distinct characteristics of physiological
and pathological cardiac hypertrophy
IGF-1
GPCR
Cell membrane
IGF-1
Receptor
Gαq
PI3K
(p110α)
Gβγ
New
therapeutic
strategy
PLC
PI3K
activate reguletors of(p110γ)
PI3KDAG(p110α) pathway,
IP
Akt*
i.e. ‘PI3K–regulated microRNAs’
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Akt1
MAPKs (ERK, p38, JNK)
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Thank you for your kind attention.
Any questions are welcome.
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