GROUP 4 Introduction The myocardium comprises many different

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 2 2

Introduction Blood pressure / volume overload Adaptation - Size of cardiomyocyte - Cardiac muscle mass CARDIAC HYPERTROPHY 3 3

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 4 4

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 5 5 Eccentric hypertrophy

Cardiac Hypertrophy in the Athlete’s Heart Exercise Endurance training Eccentric 6 6 Combination training Eccentric+Concentric Resistance training Concentric

Cardiac Hypertrophy in the Athlete’s Heart ENDURANCE TRAINING Endurance training 7 7 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 ) 8 8 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 9 9

Signaling pathway in Physiological Cardiac Hypertrophy IGF-1 Cell membrane Pathological pathway Angiogenesis Contractility 10 10 IGF-1 Receptor Cell membrane PI 3 K (p 110α) Akt 1 Heart growth Anti-fibrosis Anti-apoptosis

Signaling pathway in Physiological Cardiac Hypertrophy » Regulation of protein synthesis and cell size Akt 1 m. TOR Protein synthesis Protein degradation Cell size • m. TOR dependent pathway 11 11 • m. TOR independent pathway

Signaling pathway in Physiological Cardiac Hypertrophy » Improve contractile function L-Type Ca 2+ channel Cell membrane Ca 2+ SERCA 2 Control Ca 2+ cycling by increase the density of : • L-type Ca 2+ channel Ca 2+ • SERCA 2 protein Ca 2+ SR » Angiogenesis Stimulate cardiomyocytes to secrete 2 growth factors : • Vascular Endothelial growth factor (VEGF) 12 12 • Angiopoietin-2

Signaling pathway in Physiological Cardiac Hypertrophy Cardioprotection » Anti-apoptosis » Anti-fibrosis Stimulated by Aortic banding (pressure overload) Akt 1 Cytochrome c releasing Program cell death 13 13 PI 3 K activity (dn. PI 3 K) PI 3 K activity (ca. PI 3 K) 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 Etiology: Mutation - MYBP 3 mutation gene effect - Sarcomere act as chronic “calcium trapping” - Sudden cardiac death Dilated cardiomyopathy (DCM) 14 14

Pressure/volume overload 15 Systolic / Concentric Diastolic wall stress /Eccentric chronic HT CO ↓ Sympathetic activation chronic 15 Heart Renin Angiotensin Aldosterone system (RAAS) Cardiac remodeling Irreversible Decompensated Cardiac Hypertrophy in the Failing

Cardiac Hypertrophy in the Failing Heart Decompensatory stage Cardiac remodleing CO ↓ Sympathetic activation - Peripheral Vasoconstriction - Heart rate ↑ - Contractility ↑ Early 16 16 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 Enlarged left ventricle Thin cardiac wall Chamber dilatation Heart failure 17 17

Signaling pathway in Pathological Cardiac Hypertrophy Pathological hypertrophic signaling pathway G protein couple receptor pathway (GPCR pathway) Mitogen-activated protein kinase pathway (MAPKs pathway) Ang. II, ET-1 Stress 18 18

Signaling pathway in Pathological Cardiac Hypertrophy » Excessive Ang II, ET-1 GPCR Cell membrane Gαq G βγ PLC MAPKs (ERK, p 38, JNK) IP 3 DAG Transcriptional factors 19 19 Cell membrane - Fetal genes expression - Apoptosis - Hypertrophy PI 3 K (p 110γ) Akt*

Signaling pathway in Pathological Cardiac Hypertrophy Stress (e. g. ischmia, overload) Cell membrane MAPK pathway ERK Transcriptional factors Anti-apoptosis 20 20 JNK, P 38 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) - SERCA 2 protein ↓ - L-type Ca 2+ channel ↓ • Cardiomyocyte death → Contractility ↓ Fibrosis • Pathological cardiac hypertrophy 21 21

Endurance exercise ure s s Pre Hypertension 23 22 Resistance exercise Combination exercise d oa l r e ov Volume overload Dilated cardiomyopathy (DCM) Hypertrophic cardiomyopathy (HCM)

Distinct characteristics of physiological and pathological cardiac hypertrophy IGF-1 GPCR Cell membrane IGF-1 Receptor Gαq PI 3 K (p 110α) Gβ γ New therapeutic strategy PLC PI 3 K activate reguletors of(p 110γ) PI 3 KDAG(p 110α) pathway, IP Akt* i. e. ‘PI 3 K–regulated micro. RNAs’ 3 Akt 1 MAPKs (ERK, p 38, JNK) 23

Thank you for your kind attention. Any questions are welcome. 24 24