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GROUP 4
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Vascular smooth muscle cells Cardiac fibroblasts
Introduction The myocardium comprises many different cells. Cardiac myocytes (cardiocytes), The largest of these cells, occupy 75%. 25% include Endothelial cells Vascular smooth muscle cells Cardiac fibroblasts Macrophages and mast cells 2
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Blood pressure / volume overload
Introduction Blood pressure / volume overload Adaptation - Size of cardiomyocyte - Cardiac muscle mass CARDIAC HYPERTROPHY 3
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CARDIAC HYPERTROPHY Introduction Identified key signaling mechanisms
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 4
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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 Eccentric hypertrophy 5
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Eccentric+Concentric
Cardiac Hypertrophy in the Athlete’s Heart Exercise Endurance training Combination training Resistance training Eccentric Eccentric+Concentric Concentric 6
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Endurance training Sedentary Resistance training
Cardiac Hypertrophy in the Athlete’s Heart ENDURANCE TRAINING Endurance training Sedentary Resistance training 7
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Eccentric hypertrophy Concentric hypertrophy
Cardiac Hypertrophy in the Athlete’s Heart Endurance training Resistance training Eccentric hypertrophy Concentric hypertrophy Increase blood flow Increase preload Increasing LV internal diameter LV wall thickness Increase cardiac output (HR SV ) Increase blood pressure Increased afterload Slightly increase LV internal diameter LV wall thickness Increase cardiac output (HR SV ) 8
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Cardiac Hypertrophy in the Athlete’s Heart
» Physiological Changes with Exercise 9
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Akt1 Signaling pathway in Physiological Cardiac Hypertrophy
IGF-1 IGF-1 Receptor Cell membrane Cell membrane Pathological pathway PI3K (p110α) Angiogenesis Akt1 Anti-fibrosis Contractility Anti-apoptosis Heart growth 10
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Akt1 mTOR Protein synthesis Protein degradation
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 11
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» Improve contractile function
Signaling pathway in Physiological Cardiac Hypertrophy » Improve contractile function SR Ca2+ L-Type Ca2+ channel SERCA2 Cell membrane Cell membrane Control Ca2+ cycling by increase the density of : L-type Ca2+ channel SERCA2 protein » Angiogenesis Stimulate cardiomyocytes to secrete 2 growth factors : Vascular Endothelial growth factor (VEGF) Angiopoietin-2 12
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Cytochrome c releasing
Signaling pathway in Physiological Cardiac Hypertrophy » Anti-fibrosis Cardioprotection Stimulated by Aortic banding (pressure overload) » Anti-apoptosis PI3K activity (dnPI3K) PI3K activity (caPI3K) Akt1 Cytochrome c releasing Program cell death Control 13
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Dilated cardiomyopathy
Cardiac Hypertrophy in the Failing Heart Eccentric Concentric Etiology: Volume overload - Valvular heart disease - Myocarditis - Myocardial infarction Etiology: Pressure overload - Hypertension - Aortic stenosis - Chronic renal failure Etiology: Mutation - MYBP3 mutation gene effect - Sarcomere act as “calcium trapping” - Sudden cardiac death chronic chronic chronic Dilated cardiomyopathy (DCM) 14
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CO ↓ Concentric/Eccentric HT chronic chronic Pressure/volume overload
Cardiac Hypertrophy in the Failing Heart Concentric/Eccentric HT Pressure/volume overload Systolic / Diastolic wall stress Compensated chronic CO ↓ Decompensated Sympathetic activation Renin Angiotensin Aldosterone system (RAAS) chronic Cardiac remodeling Irreversible 15
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Cardiac filling pressure ↑
Cardiac Hypertrophy in the Failing Heart Decompensatory stage Cardiac remodleing CO ↓ Sympathetic activation RAAS - Peripheral Vasoconstriction - Heart rate ↑ - Contractility ↑ ↑ Ang II production ↑ ADH ↑ Aldosterone Chronic Cardiac filling pressure ↑ Early 16
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Dilated cardiomyopathy Sarcomere dysfunction
Cardiac Hypertrophy in the Failing Heart Dilated cardiomyopathy Sarcomere dysfunction Cardiomyocyte death Enlarged left atrium Fibrosis Weakened Muscle wall Thin cardiac wall Enlarged left ventricle Chamber dilatation Heart failure 17
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Stress Mitogen-activated protein kinase pathway (MAPKs pathway)
Signaling pathway in Pathological Cardiac Hypertrophy Pathological hypertrophic signaling pathway G protein couple receptor pathway (GPCR pathway) Mitogen-activated protein kinase pathway (MAPKs pathway) AngII, ET-1 Stress 18
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Transcriptional factors
Signaling pathway in Pathological Cardiac Hypertrophy » Excessive Ang II, ET-1 GPCR Cell membrane Cell membrane Gαq Gβγ PLC PI3K (p110γ) MAPKs (ERK, p38, JNK) IP3 DAG - Fetal genes expression - Apoptosis - Hypertrophy Akt* Transcriptional factors 19
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Signaling pathway in Pathological Cardiac Hypertrophy
Stress (e.g. ischmia, overload) Cell membrane Cell membrane MAPK pathway ERK JNK, P38 Transcriptional factors Transcriptional factors - Fetal genes expression - Apoptosis Hypertrophy Anti-apoptosis 20
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Outcomes from these pathways?
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 → Pathological cardiac hypertrophy } Contractility ↓ Fibrosis 21
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Dilated cardiomyopathy (DCM) Hypertrophic cardiomyopathy (HCM)
Endurance exercise Resistance exercise Combination exercise Pressure overload Volume overload Hypertension Dilated cardiomyopathy (DCM) Hypertrophic cardiomyopathy (HCM) 23 23
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Distinct characteristics of physiological and pathological cardiac hypertrophy
IGF-1 GPCR IGF-1 Receptor Cell membrane New therapeutic strategy activate reguletors of PI3K (p110α) pathway, i.e. ‘PI3K–regulated microRNAs’ Gαq Gβγ PLC PI3K (p110α) PI3K (p110γ) IP3 DAG Akt* Akt1 MAPKs (ERK, p38, JNK) 23
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Thank you for your kind attention. Any questions are welcome.
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