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GROUP 4
2
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
2
3
Introduction
3
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
232223
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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