Contents TOC o “1-3” h z u LIST OF FIGURES PAGEREF _Toc508531671 h iiiLIST OF TABLES PAGEREF _Toc508531672 h ivLIST OF ABBREVIATIONS PAGEREF _Toc508531673 h vABSTRACT PAGEREF _Toc508531674 h viiiCHAPTER 1

Contents
TOC o “1-3” h z u LIST OF FIGURES PAGEREF _Toc508531671 h iiiLIST OF TABLES PAGEREF _Toc508531672 h ivLIST OF ABBREVIATIONS PAGEREF _Toc508531673 h vABSTRACT PAGEREF _Toc508531674 h viiiCHAPTER 1: INTRODUCTION PAGEREF _Toc508531675 h 11.1. BACKGROUND PAGEREF _Toc508531676 h 11.2. RESEARCH QUESTION; PAGEREF _Toc508531677 h 21.3. HYPOTHESIS; PAGEREF _Toc508531678 h 21.4. OBJECTIVES; PAGEREF _Toc508531679 h 21.4.1. Overall research aim PAGEREF _Toc508531680 h 21.4.2. Specific objectives PAGEREF _Toc508531681 h 2CHAPTER 2: LITERATURE REVIEW PAGEREF _Toc508531682 h 52.1. HYPERTROPHIC CARDIOMYOPATHY (HCM) PAGEREF _Toc508531683 h 52.2. OXIDATIVE STRESS PAGEREF _Toc508531684 h 102.2.1. OXIDATIVE STRESS AND HCM PAGEREF _Toc508531685 h 152.2.2. ROS, SIGNALING PATHWAYS AND HCM PAGEREF _Toc508531686 h 17CHAPTER 3: METHODOLOGY. PAGEREF _Toc508531687 h 283.1. STUDY DESIGN PAGEREF _Toc508531688 h 283.1.1. Type and site of the study PAGEREF _Toc508531689 h 283.1.2. Study population PAGEREF _Toc508531690 h 283.2. PATIENT’S HISTORY; PAGEREF _Toc508531691 h 283.2.1. Patient 1; PAGEREF _Toc508531692 h 293.2.2. Patient 2; PAGEREF _Toc508531693 h 303.2.3. Patient 3; PAGEREF _Toc508531694 h 323.3. RESEARCH CONCEPT PAGEREF _Toc508531695 h 343.4. MATERIALS PAGEREF _Toc508531696 h 353.5. METHODS PAGEREF _Toc508531697 h 363.5.1. Making PB solution PAGEREF _Toc508531698 h 363.5.2. Making 30% sucrose solution PAGEREF _Toc508531699 h 363.5.3. Making 20% sucrose solution PAGEREF _Toc508531700 h 363.5.4. Making the store solution PAGEREF _Toc508531701 h 363.5.5. Making a working solution PAGEREF _Toc508531702 h 363.5.6. Fixing and slicing the heart samples PAGEREF _Toc508531703 h 373.5.7. Staining of the heart samples and ROS visualization. PAGEREF _Toc508531704 h 373.5.8. Analysis PAGEREF _Toc508531705 h 373.6. ETHICAL CONSIDERATION PAGEREF _Toc508531706 h 38CHAPTER 4: RESULTS PAGEREF _Toc508531707 h 394.1. Microscopy images and Image J analysis PAGEREF _Toc508531708 h 394.2. SPSS statistical analysis. PAGEREF _Toc508531709 h 414.2.1. Analysis of the First heart. PAGEREF _Toc508531710 h 424.2.2. Analysis of the second heart. PAGEREF _Toc508531711 h 444.2.3. Analysis of the Third heart Sample. PAGEREF _Toc508531712 h 47CHAPTER 5: DISCUSSION PAGEREF _Toc508531713 h 525.1. LIMITATION AND STREGHTH OF THE STUDY PAGEREF _Toc508531714 h 54CHAPTER 6: CONCLUSION PAGEREF _Toc508531715 h 55CHAPTER 7: REFERENCES. PAGEREF _Toc508531716 h 56
LIST OF FIGURES TOC h z c “Figure” Figure 1. Histologic subtypes of the heart samples. PAGEREF _Toc508527979 h 4Figure 2. Four steps reduction of oxygen to form water. PAGEREF _Toc508527980 h 9Figure 3. Fenton reaction. PAGEREF _Toc508527981 h 10Figure 4. The MAPK signaling pathway, PAGEREF _Toc508527982 h 16Figure 5. PI3K/Akt/mTOR signaling cascade PAGEREF _Toc508527983 h 19Figure 6. Calcineurin/ NF-AT signaling pathway PAGEREF _Toc508527984 h 22Figure 7. NF-KB signaling pathway activation. PAGEREF _Toc508527985 h 24Figure 8. Fluorescent microscopy images showing ROS in different heart chambers with HCM. PAGEREF _Toc508527986 h 38Figure 9. Image j analysis of the above fluorescent images from figure 8. PAGEREF _Toc508527987 h 39Figure 10. Bar chart showing the mean amount of reactive oxygen species in the heart chambers of the first patient’s heart. PAGEREF _Toc508527988 h 40Figure 11.Bar chart showing the mean value of ROS in different chambers of the second heart. PAGEREF _Toc508527989 h 43Figure 12.Bar chart showing mean value of ROS in different chambers of the third heart. PAGEREF _Toc508527990 h 46Figure 13. Chamber wise comparison of mean ROS in the three hearts. PAGEREF _Toc508527991 h 49
LIST OF TABLES TOC h z c “Table” Table 1: Description statistics of ROS the first heart. PAGEREF _Toc508531187 h 42Table 2: ANOVA of ROS in the first heart PAGEREF _Toc508531188 h 43Table 3: Multiple comparison of ROS in the first heart PAGEREF _Toc508531189 h 43Table 4: Descriptive statistic of ROS in the second heart PAGEREF _Toc508531190 h 45Table 5: ANOVA of ROS in the second heart PAGEREF _Toc508531191 h 46Table 6: Multiple comparison in the mean ROS in the second heart PAGEREF _Toc508531192 h 46Table 7: Descriptive statistic of ROS in the third heart PAGEREF _Toc508531193 h 48Table 8: ANOVA of ROS in the third heart PAGEREF _Toc508531194 h 49Table 9: Multiple comparison of mean ROS from the third heart PAGEREF _Toc508531195 h 49
LIST OF ABBREVIATIONS
HCM Hypertrophic cardiomyopathyROS Reactive oxygen species
DHE DihydroethidiumKCNQ4 Potassium voltage gated channel subfamily KQT member 4
SCD Sudden cardiac death
HMG-COA 3- Hydroxy-3- Methyl- Glutaryl- Co enzyme A
NAC N- Acetyl cysteine?- MyHCBeta myocin heavy chain
MyBPMyocin binding protein
cTnTCardiac troponin T
AF Atrial fibrillation
H&E Hematoxylin and Eosin
ACE Angiotensin converting enzyme
ICD Implantable Cardiovertor Defibrillator
AIDC Automated Implantable Cardiovertor Defibrillator
LVAD Left Ventricular Assisted Device
O-2 Superoxide anions
H2O2 Hydrogen peroxide
HO Hydroxyl radicals
NO Nitric Oxide
ONOO- Peroxy Nitrite Anions
ATP Adenosine TriphosphateNADPH Nicotinamide Adenine Dinucleotide Phosphate
NADH Nicotinamide Adenine DinucleotideHOCL Hypochlorous acid
Fe Iron
Cu Copper
AP-1 Activator protein 1
NF-kBNuclear Factor Kappa – light – chain enhancer of activated B cells
DNA Deoxyribonucleic acid
ALCAT1 Lysocardiolipin Acyltransferase 1
MAPK Mitogen activated protein kinasePI3K-AKT Phosphatidylinositol 3- kinase- protein kinase B
NF-AT Nuclear factor of activated T cell
Ca2+ Calcium ions
Na+ Sodium ions
FADH2 Flavine adenine dinuceotideH+ Hydrogen ions
mTORMammalian target of rapamycinRAF Rapidly accelerated fibrosarcomaERK Extracellular signal regulated kinasesGDP Guanosine 5′- DiphosphateGTP Guanosine 5′- TriphosphateGAPs GTPase activating proteins
JNKs C- Jun N- terminal kinasesUV light Ultraviolet light
TRX1 Theoredoxin 1
RTK Receptor tyrosine kinaseIRS1 Insulin receptor substrate 1
PIP2 Phosphatidylinositol 4,5- BiphoshatePIP3 Phosphatidylinositol 3,4,5- TriphosphateMRNA Messenger ribonucleic acid
PtPn1 Tyrosine protein phosphatase non- receptor type 1
NSML Noonan syndrome with multiple lentiginesPTEN Phosphatase and tensin homolog
NIK NF-kB inducing kinaseTRAF3 Tumor necrosis factor – receptor associated factor 3
TRAF2 Tumor necrosis factor – receptor associated factor 2
CiAPCellular inhibitor of apoptosis
IL Interleukin
PDTC Pyrrolidine dithiocarbamateBP Blood pressure
PR Pulse rate
RR Respiratory rate
EF Ejection fraction
KG Kilogram
HBSS Hank’s balanced salt solution
DMSO Anhydrous dimethyl sulfoxideOCT Optimal cutting temperature
NYHA New york heart association
TNNI3 Troponin I, cardiac muscle
PB solution Phosphate buffer solution
SPSS Statistical package for the social sciences
ANOVA Analysis of variance
HNE 4- hydroxyl- 2- nonenolFK506 Tacrolimus
AKAP 79 A- kinase anchor protein 79
PICOT PKC interacting cousin of thioredoxin
ABSTRACTBackground: Hypertrophic cardiomyopathy (HCM) is a genetic heart disease with an autosomal dominant mode of inheritance but can occur sporadically. It mostly occurs due to mutation in the sarcomeric gene proteins. Despite its genetic factor, only few patients have phenotypic expression of the disease and some do not. Increase in oxidative stress in the heart muscles plays a significant role in the phenotypic expression of the disease. High amount of reactive oxygen species (ROS) plays a significant role in the myocardial hypertrophy, myocardial fibrosis, necrosis of the muscles, apoptosis and have been implicated in heart failure as per many studies that have already been done, features which are also present in HCM patients. Furthermore, oxidative stress (high ROS), plays a significant role in activating important cell signaling pathways which are also activated in patients with HCM. So far the management of HCM is based on relieving symptoms but blocking the oxidative stress could provide a possible means of reversing and even blocking the phenotypic expression of the disease. Few researches have proved the increase in oxidative stress in the HCM animal models but very few if any have proved in humans.

Objective: To observe and prove the increase in the oxidative stress in the human hearts with hypertrophic cardiomyopathy as compared to the normal hearts.

Method: An experimental study was done on four human hearts; three were diseased hearts from patients with hypertrophic cardiomyopathy after heart transplant and one from a normal heart chamber. Amount of ROS was tested in the heart tissues using Dihydroethidium (DHE) staining. Each chamber in each heart was tested separately in order to determine the chamber with the highest amount of ROS and hence a highly destructed chamber.
Results: The mean amount of ROS was significantly high in the hearts with hypertrophic cardiomyopathy as compared to the normal heart with the p value of ;0.0001 in most of the chambers. In chamber wise comparison, the left ventricle had significantly highest amount of ROS in all the hearts followed by the right ventricle then the right atrium and lastly the normal heart. Heart from the third patient with systolic dysfunction had equal increase in oxidative stress as the other two hearts with Diastolic dysfunction.
Conclusion; there is a significant increase in the reactive oxygen species in the hearts of patients with hypertrophic cardiomyopathy.

Key words: Hypertrophic cardiomyopathy, oxidative stress.

CHAPTER 1: INTRODUCTION1.1. BACKGROUNDHypertrophic cardiomyopathy (HCM) is a genetic heart disease with an autosomal dominant mode of inheritance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWNoZWxzPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
UmVjTnVtPjI8L1JlY051bT48RGlzcGxheVRleHQ+WzEsIDJdPC9EaXNwbGF5VGV4dD48cmVjb3Jk
PjxyZWMtbnVtYmVyPjI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi
LWlkPSIwZWRhc3hhZWFyOXowNGV3c2F5djJmcmdlZHhhejlkZXA5MHoiIHRpbWVzdGFtcD0iMTUx
MTk2OTUwOSI+Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy
dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWljaGVs
cywgTS48L2F1dGhvcj48YXV0aG9yPk9saXZvdHRvLCBJLjwvYXV0aG9yPjxhdXRob3I+QXNzZWxi
ZXJncywgRi4gVy48L2F1dGhvcj48YXV0aG9yPnZhbiBkZXIgVmVsZGVuLCBKLjwvYXV0aG9yPjwv
YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlRob3JheGNlbnRlciwgRGVwYXJ0
bWVudCBvZiBDYXJkaW9sb2d5LCBFcmFzbXVzIE1DLCBSb3R0ZXJkYW0sIFRoZSBOZXRoZXJsYW5k
cy4mI3hEO0NhcmVnZ2kgVW5pdmVyc2l0eSBIb3NwaXRhbCwgRmxvcmVuY2UsIEl0YWx5LiYjeEQ7
VW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciBVdHJlY2h0LCBVdHJlY2h0LCBUaGUgTmV0aGVybGFu
ZHMuJiN4RDtWVSBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBBbXN0ZXJkYW0sIFRoZSBOZXRo
ZXJsYW5kcy4gai52YW5kZXJ2ZWxkZW5AdnVtYy5ubC4mI3hEO05ldGhlcmxhbmRzIEhlYXJ0IElu
c3RpdHV0ZSwgVXRyZWNodCwgVGhlIE5ldGhlcmxhbmRzLiBqLnZhbmRlcnZlbGRlbkB2dW1jLm5s
LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkxpZmUtbG9uZyB0YWlsb3Jpbmcgb2YgbWFu
YWdlbWVudCBmb3IgcGF0aWVudHMgd2l0aCBoeXBlcnRyb3BoaWMgY2FyZGlvbXlvcGF0aHkgOiBB
d2FyZW5lc3MgYW5kIGRlY2lzaW9uLW1ha2luZyBpbiBjaGFuZ2luZyBzY2VuYXJpb3M8L3RpdGxl
PjxzZWNvbmRhcnktdGl0bGU+TmV0aCBIZWFydCBKPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRs
ZT5OZXRoZXJsYW5kcyBoZWFydCBqb3VybmFsIDogbW9udGhseSBqb3VybmFsIG9mIHRoZSBOZXRo
ZXJsYW5kcyBTb2NpZXR5IG9mIENhcmRpb2xvZ3kgYW5kIHRoZSBOZXRoZXJsYW5kcyBIZWFydCBG
b3VuZGF0aW9uPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV0
aCBIZWFydCBKPC9mdWxsLXRpdGxlPjxhYmJyLTE+TmV0aGVybGFuZHMgaGVhcnQgam91cm5hbCA6
IG1vbnRobHkgam91cm5hbCBvZiB0aGUgTmV0aGVybGFuZHMgU29jaWV0eSBvZiBDYXJkaW9sb2d5
IGFuZCB0aGUgTmV0aGVybGFuZHMgSGVhcnQgRm91bmRhdGlvbjwvYWJici0xPjwvcGVyaW9kaWNh
bD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV0aCBIZWFydCBKPC9mdWxsLXRpdGxlPjxh
YmJyLTE+TmV0aGVybGFuZHMgaGVhcnQgam91cm5hbCA6IG1vbnRobHkgam91cm5hbCBvZiB0aGUg
TmV0aGVybGFuZHMgU29jaWV0eSBvZiBDYXJkaW9sb2d5IGFuZCB0aGUgTmV0aGVybGFuZHMgSGVh
cnQgRm91bmRhdGlvbjwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjE4Ni0xOTk8L3Bh
Z2VzPjx2b2x1bWU+MjU8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAx
NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp
c2JuPjE1NjgtNTg4OCAoUHJpbnQpJiN4RDsxNTY4LTU4ODggKExpbmtpbmcpPC9pc2JuPjxhY2Nl
c3Npb24tbnVtPjI4MDA1MjMxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy
bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI4MDA1MjMxPC91cmw+PC9yZWxh
dGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjUzMTM0NTE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVz
b3VyY2UtbnVtPjEwLjEwMDcvczEyNDcxLTAxNi0wOTQzLTI8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut
bnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1hcm9uPC9BdXRob3I+PFllYXI+MTk4
NDwvWWVhcj48UmVjTnVtPjEwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMDwvcmVjLW51
bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImRlcmZldDB6azl3eHNyZXRw
MDlwend4cng1MGRmdnhhcjU5MiIgdGltZXN0YW1wPSIxNTE0OTc4NTExIj4xMDwva2V5PjwvZm9y
ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48
Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TWFyb24sIEIuIEouPC9hdXRob3I+PGF1dGhv
cj5OaWNob2xzLCBQLiBGLiwgM3JkPC9hdXRob3I+PGF1dGhvcj5QaWNrbGUsIEwuIFcuPC9hdXRo
b3I+PGF1dGhvcj5XZXNsZXksIFkuIEUuPC9hdXRob3I+PGF1dGhvcj5NdWx2aWhpbGwsIEouIEou
PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlBhdHRlcm5z
IG9mIGluaGVyaXRhbmNlIGluIGh5cGVydHJvcGhpYyBjYXJkaW9teW9wYXRoeTogYXNzZXNzbWVu
dCBieSBNLW1vZGUgYW5kIHR3by1kaW1lbnNpb25hbCBlY2hvY2FyZGlvZ3JhcGh5PC90aXRsZT48
c2Vjb25kYXJ5LXRpdGxlPkFtIEogQ2FyZGlvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+
VGhlIEFtZXJpY2FuIGpvdXJuYWwgb2YgY2FyZGlvbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxw
ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogQ2FyZGlvbDwvZnVsbC10aXRsZT48YWJici0xPlRo
ZSBBbWVyaWNhbiBqb3VybmFsIG9mIGNhcmRpb2xvZ3k8L2FiYnItMT48L3BlcmlvZGljYWw+PGFs
dC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogQ2FyZGlvbDwvZnVsbC10aXRsZT48YWJici0x
PlRoZSBBbWVyaWNhbiBqb3VybmFsIG9mIGNhcmRpb2xvZ3k8L2FiYnItMT48L2FsdC1wZXJpb2Rp
Y2FsPjxwYWdlcz4xMDg3LTk0PC9wYWdlcz48dm9sdW1lPjUzPC92b2x1bWU+PG51bWJlcj44PC9u
dW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkNhcmRpb215b3BhdGh5LCBIeXBlcnRyb3BoaWMvKmdl
bmV0aWNzL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DaHJvbW9zb21lIEFiZXJy
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9tb3NvbWUgRGlzb3JkZXJzPC9rZXl3b3JkPjxr
ZXl3b3JkPkVjaG9jYXJkaW9ncmFwaHkvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPkhlbW9keW5hbWljczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8
L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QZWRpZ3JlZTwva2V5d29y
ZD48a2V5d29yZD5QaGVub3R5cGU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk4
NDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwciAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+
PGlzYm4+MDAwMi05MTQ5IChQcmludCkmI3hEOzAwMDItOTE0OSAoTGlua2luZyk8L2lzYm4+PGFj
Y2Vzc2lvbi1udW0+NjUzODM4NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1
cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC82NTM4Mzg0PC91cmw+PC9yZWxh
dGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWNoZWxzPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48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ADDIN EN.CITE.DATA 1, 2. It is the most common cause of sudden cardiac death in youngPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA 3-5 with the prevalence of 1:500PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWtyb3U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWtyb3U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
ZWNOdW0+MzE8L1JlY051bT48RGlzcGxheVRleHQ+WzYsIDddPC9EaXNwbGF5VGV4dD48cmVjb3Jk
PjxyZWMtbnVtYmVyPjMxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk
Yi1pZD0iMHo5ZWZhNWV4MndkOXJlOXM5dHg5OTJtOTl6ZnRlYXN6eGF6IiB0aW1lc3RhbXA9IjE1
MTkxOTgwNzQiPjMxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg
QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5WYWty
b3UsIFMuPC9hdXRob3I+PGF1dGhvcj5BYnJhaGFtLCBNLiBSLjwvYXV0aG9yPjwvYXV0aG9ycz48
L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIENhcmRpb2xvZ3ksIFNjaG9v
bCBvZiBNZWRpY2luZSwgSm9obnMgSG9wa2lucyBVbml2ZXJzaXR5IEJhbHRpbW9yZSwgTUQsIFVT
QS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5IeXBlcnRyb3BoaWMgY2FyZGlvbXlvcGF0
aHk6IGEgaGVhcnQgaW4gbmVlZCBvZiBhbiBlbmVyZ3kgYmFyPzwvdGl0bGU+PHNlY29uZGFyeS10
aXRsZT5Gcm9udCBQaHlzaW9sPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5Gcm9udGllcnMg
aW4gcGh5c2lvbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl
PkZyb250IFBoeXNpb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5Gcm9udGllcnMgaW4gcGh5c2lvbG9n
eTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+RnJvbnQg
UGh5c2lvbDwvZnVsbC10aXRsZT48YWJici0xPkZyb250aWVycyBpbiBwaHlzaW9sb2d5PC9hYmJy
LTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MzA5PC9wYWdlcz48dm9sdW1lPjU8L3ZvbHVtZT48
ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48L2RhdGVzPjxpc2JuPjE2NjQtMDQyWCAoUHJpbnQpJiN4
RDsxNjY0LTA0MlggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1MTkxMjc1PC9hY2Nl
c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p
aC5nb3YvcHVibWVkLzI1MTkxMjc1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20y
PjQxMzczODY8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMzODkvZnBoeXMu
MjAxNC4wMDMwOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl
PjxBdXRob3I+TWFyb248L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxSZWNOdW0+MTE8L1JlY051
bT48cmVjb3JkPjxyZWMtbnVtYmVyPjExPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh
cHA9IkVOIiBkYi1pZD0iZGVyZmV0MHprOXd4c3JldHAwOXB6d3hyeDUwZGZ2eGFyNTkyIiB0aW1l
c3RhbXA9IjE1MTQ5Nzg2OTMiPjExPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9
IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1
dGhvcj5NYXJvbiwgQi4gSi48L2F1dGhvcj48YXV0aG9yPkdhcmRpbiwgSi4gTS48L2F1dGhvcj48
YXV0aG9yPkZsYWNrLCBKLiBNLjwvYXV0aG9yPjxhdXRob3I+R2lkZGluZywgUy4gUy48L2F1dGhv
cj48YXV0aG9yPkt1cm9zYWtpLCBULiBULjwvYXV0aG9yPjxhdXRob3I+QmlsZCwgRC4gRS48L2F1
dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DYXJkaW92YXNjdWxh
ciBSZXNlYXJjaCBEaXZpc2lvbiwgTWlubmVhcG9saXMgSGVhcnQgSW5zdGl0dXRlIEZvdW5kYXRp
b24sIE1OIDU1NDA3LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UHJldmFsZW5j
ZSBvZiBoeXBlcnRyb3BoaWMgY2FyZGlvbXlvcGF0aHkgaW4gYSBnZW5lcmFsIHBvcHVsYXRpb24g
b2YgeW91bmcgYWR1bHRzLiBFY2hvY2FyZGlvZ3JhcGhpYyBhbmFseXNpcyBvZiA0MTExIHN1Ympl
Y3RzIGluIHRoZSBDQVJESUEgU3R1ZHkuIENvcm9uYXJ5IEFydGVyeSBSaXNrIERldmVsb3BtZW50
IGluIChZb3VuZykgQWR1bHRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNpcmN1bGF0aW9uPC9z
ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5DaXJjdWxhdGlvbjwvYWx0LXRpdGxlPjwvdGl0bGVz
PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNpcmN1bGF0aW9uPC9mdWxsLXRpdGxlPjwvcGVyaW9k
aWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2lyY3VsYXRpb248L2Z1bGwtdGl0bGU+
PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+Nzg1LTk8L3BhZ2VzPjx2b2x1bWU+OTI8L3ZvbHVtZT48
bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48
a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5DYXJkaW9teW9wYXRoeSwgSHlwZXJ0cm9w
aGljLypkaWFnbm9zdGljIGltYWdpbmcvKmVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5D
b2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Db3JvbmFyeSBEaXNlYXNlL2VwaWRlbWlv
bG9neTwva2V5d29yZD48a2V5d29yZD4qRWNob2NhcmRpb2dyYXBoeTwva2V5d29yZD48a2V5d29y
ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVy
dHJvcGh5LCBMZWZ0IFZlbnRyaWN1bGFyL2RpYWdub3N0aWMgaW1hZ2luZzwva2V5d29yZD48a2V5
d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+
UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTU8L3llYXI+
PHB1Yi1kYXRlcz48ZGF0ZT5BdWcgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4w
MDA5LTczMjIgKFByaW50KSYjeEQ7MDAwOS03MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u
LW51bT43NjQxMzU3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw
Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzc2NDEzNTc8L3VybD48L3JlbGF0ZWQtdXJs
cz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA 6, 7 .It is caused by mutation in the contractile sarcomeric protein gene though mutation in non-sarcomeric protein genes like potassium voltage gated channels (KCNQ4) have also been reported.
The management of HCM being either surgical like septal myomectomyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl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ADDIN EN.CITE.DATA 8-10 and Implantable cardioverter defibrillator ADDIN EN.CITE ;EndNote;;Cite;;Author;Mitsui;/Author;;Year;2016;/Year;;RecNum;3;/RecNum;;DisplayText;11;/DisplayText;;record;;rec-number;3;/rec-number;;foreign-keys;;key app=”EN” db-id=”ddpp9at0qefxziese9b5d2pgxt5ssss25e0d” timestamp=”1512192444″;3;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Mitsui, T.;/author;;author;Masuyama, H.;/author;;author;Ejiri, K.;/author;;author;Hayata, K.;/author;;author;Ito, H.;/author;;author;Hiramatsu, Y.;/author;;/authors;;/contributors;;auth-address;Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan. Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan.;/auth-address;;titles;;title;A Pregnancy with Severe Hypertrophic Obstructive Cardiomyopathy after Surgery for an Implantable Cardioverter Defibrillator: A Case Report and Literature Review;/title;;secondary-title;Case Rep Obstet Gynecol;/secondary-title;;alt-title;Case reports in obstetrics and gynecology;/alt-title;;/titles;;periodical;;full-title;Case Rep Obstet Gynecol;/full-title;;abbr-1;Case reports in obstetrics and gynecology;/abbr-1;;/periodical;;alt-periodical;;full-title;Case Rep Obstet Gynecol;/full-title;;abbr-1;Case reports in obstetrics and gynecology;/abbr-1;;/alt-periodical;;pages;4690790;/pages;;volume;2016;/volume;;dates;;year;2016;/year;;/dates;;isbn;2090-6684 (Print) 2090-6692 (Linking);/isbn;;accession-num;27830098;/accession-num;;urls;;related-urls;;url;http://www.ncbi.nlm.nih.gov/pubmed/27830098;/url;;/related-urls;;/urls;;custom2;5088310;/custom2;;electronic-resource-num;10.1155/2016/4690790;/electronic-resource-num;;/record;;/Cite;;/EndNote;11 or medical management like use of Beta- Adrenoceptor blockers, calcium channel blockersPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcG9sYWRvcmU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcG9sYWRvcmU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy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ADDIN EN.CITE.DATA 12 is based on preventing and relieving symptoms of heart failure and preventing sudden cardiac death ADDIN EN.CITE ;EndNote;;Cite;;Author;Collis;/Author;;Year;2017;/Year;;RecNum;6;/RecNum;;DisplayText;13;/DisplayText;;record;;rec-number;6;/rec-number;;foreign-keys;;key app=”EN” db-id=”0edasxaear9z04ewsayv2frgedxaz9dep90z” timestamp=”1511970736″;6;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Collis, R.;/author;;author;Watkinson, O.;/author;;author;Pantazis, A.;/author;;author;Tome-Esteban, M.;/author;;author;Elliott, P. M.;/author;;author;McGregor, C. G. A.;/author;;/authors;;/contributors;;auth-address;Institute of Cardiovascular Science, University College London, London, United Kingdom. Royal Brompton Hospital, Sydney St, Chelsea, London. Cardiology Clinical Academic Group, St George;apos;s University Hospitals NHS Foundation Trust, Tooting, London.;/auth-address;;titles;;title;Early and medium-term outcomes of Alfieri mitral valve repair in the management of systolic anterior motion during septal myectomy;/title;;secondary-title;J Card Surg;/secondary-title;;alt-title;Journal of cardiac surgery;/alt-title;;/titles;;periodical;;full-title;J Card Surg;/full-title;;abbr-1;Journal of cardiac surgery;/abbr-1;;/periodical;;alt-periodical;;full-title;J Card Surg;/full-title;;abbr-1;Journal of cardiac surgery;/abbr-1;;/alt-periodical;;dates;;year;2017;/year;;pub-dates;;date;Nov 23;/date;;/pub-dates;;/dates;;isbn;1540-8191 (Electronic) 0886-0440 (Linking);/isbn;;accession-num;29168204;/accession-num;;urls;;related-urls;;url;http://www.ncbi.nlm.nih.gov/pubmed/29168204;/url;;/related-urls;;/urls;;electronic-resource-num;10.1111/jocs.13239;/electronic-resource-num;;/record;;/Cite;;/EndNote;13. Though they increase survival and improve the quality of life, none of them have made progress in treating and reversing the pathogenesis of the disease. Since cardiac hypertrophy and interstitial fibrosis have prognostic value in this disease, the reversal of the two is expected to improve morbidity as well as decrease the risk of SCD in patients with HCM. Cardiac hypertrophy is thought to be potentially reversible and preventable ADDIN EN.CITE ;EndNote;;Cite;;Author;Marian;/Author;;Year;2000;/Year;;RecNum;4;/RecNum;;DisplayText;14;/DisplayText;;record;;rec-number;4;/rec-number;;foreign-keys;;key app=”EN” db-id=”0edasxaear9z04ewsayv2frgedxaz9dep90z” timestamp=”1511969872″;4;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Marian, A. J.;/author;;/authors;;/contributors;;auth-address;Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. [email protected];/auth-address;;titles;;title;Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy;/title;;secondary-title;Lancet;/secondary-title;;alt-title;Lancet;/alt-title;;/titles;;periodical;;full-title;Lancet;/full-title;;abbr-1;Lancet;/abbr-1;;/periodical;;alt-periodical;;full-title;Lancet;/full-title;;abbr-1;Lancet;/abbr-1;;/alt-periodical;;pages;58-60;/pages;;volume;355;/volume;;number;9197;/number;;keywords;;keyword;Cardiomyopathy, Hypertrophic/*etiology/*genetics</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Myocardial Contraction/*genetics</keyword><keyword>Phenotype</keyword><keyword>Transforming Growth Factors/*genetics</keyword></keywords><dates><year>2000</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>0140-6736 (Print) 0140-6736 (Linking)</isbn><accession-num>10615904</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/10615904</url></related-urls></urls></record></Cite></EndNote>14 if the molecular mechanisms that are involved in the pathogenesis of the phenotype are targetedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
ZWNOdW0+NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTVdPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxy
ZWMtbnVtYmVyPjU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk
PSJhdDBkMmUyMjRyZHpmMWU5ZnBicHQ1OWY5dHhzcHJ4OXd0MDIiPjU8L2tleT48a2V5IGFwcD0i
RU5XZWIiIGRiLWlkPSIiPjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91
cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y
PkxvbWJhcmRpLCBSLjwvYXV0aG9yPjxhdXRob3I+Um9kcmlndWV6LCBHLjwvYXV0aG9yPjxhdXRo
b3I+Q2hlbiwgUy4gTi48L2F1dGhvcj48YXV0aG9yPlJpcHBsaW5nZXIsIEMuIE0uPC9hdXRob3I+
PGF1dGhvcj5MaSwgVy48L2F1dGhvcj48YXV0aG9yPkNoZW4sIEouPC9hdXRob3I+PGF1dGhvcj5X
aWxsZXJzb24sIEouIFQuPC9hdXRob3I+PGF1dGhvcj5CZXRvY2NoaSwgUy48L2F1dGhvcj48YXV0
aG9yPldpY2tsaW5lLCBTLiBBLjwvYXV0aG9yPjxhdXRob3I+RWZpbW92LCBJLiBSLjwvYXV0aG9y
PjxhdXRob3I+TWFyaWFuLCBBLiBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48
YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgQ2FyZGlvdmFzY3VsYXIgR2VuZXRpY3MsIEJyb3duIEZv
dW5kYXRpb24gSW5zdGl0dXRlIG9mIE1vbGVjdWxhciBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBU
ZXhhcyBIZWFsdGggU2NpZW5jZSBDZW50ZXIsIGFuZCBUZXhhcyBIZWFydCBJbnN0aXR1dGUsIEhv
dXN0b24sIFRYLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmVzb2x1dGlvbiBv
ZiBlc3RhYmxpc2hlZCBjYXJkaWFjIGh5cGVydHJvcGh5IGFuZCBmaWJyb3NpcyBhbmQgcHJldmVu
dGlvbiBvZiBzeXN0b2xpYyBkeXNmdW5jdGlvbiBpbiBhIHRyYW5zZ2VuaWMgcmFiYml0IG1vZGVs
IG9mIGh1bWFuIGNhcmRpb215b3BhdGh5IHRocm91Z2ggdGhpb2wtc2Vuc2l0aXZlIG1lY2hhbmlz
bXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2lyY3VsYXRpb248L3NlY29uZGFyeS10aXRsZT48
YWx0LXRpdGxlPkNpcmN1bGF0aW9uPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1
bGwtdGl0bGU+Q2lyY3VsYXRpb248L2Z1bGwtdGl0bGU+PGFiYnItMT5DaXJjdWxhdGlvbjwvYWJi
ci0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2lyY3VsYXRpb248
L2Z1bGwtdGl0bGU+PGFiYnItMT5DaXJjdWxhdGlvbjwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+
PHBhZ2VzPjEzOTgtNDA3PC9wYWdlcz48dm9sdW1lPjExOTwvdm9sdW1lPjxudW1iZXI+MTA8L251
bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWNldHlsY3lzdGVpbmUvKnRoZXJhcGV1dGljIHVzZTwv
a2V5d29yZD48a2V5d29yZD5BY3RpbnMvYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFs
czwva2V5d29yZD48a2V5d29yZD5BbmltYWxzLCBHZW5ldGljYWxseSBNb2RpZmllZDwva2V5d29y
ZD48a2V5d29yZD5BbnRpb3hpZGFudHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29y
ZD5DYXJkaW9teW9wYXRoeSwgSHlwZXJ0cm9waGljL2NvbXBsaWNhdGlvbnMvKmRydWcgdGhlcmFw
eS9nZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBTaXplPC9rZXl3b3Jk
PjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLCBBbmltYWw8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPkZpYnJvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRhdGhpb25l
L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SGVhcnQgRmFpbHVyZSwgU3lzdG9saWMvZXRp
b2xvZ3kvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8
L2tleXdvcmQ+PGtleXdvcmQ+TUFQIEtpbmFzZSBTaWduYWxpbmcgU3lzdGVtL2RydWcgZWZmZWN0
czwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk15b2N5dGVzLCBDYXJk
aWFjL2RydWcgZWZmZWN0cy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TXlvc2luIEhlYXZ5
IENoYWlucy9kZWZpY2llbmN5L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk5GQVRDIFRyYW5z
Y3JpcHRpb24gRmFjdG9ycy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9yeWxh
dGlvbjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIFByb2Nlc3NpbmcsIFBvc3QtVHJhbnNsYXRp
b25hbDwva2V5d29yZD48a2V5d29yZD5SYWJiaXRzPC9rZXl3b3JkPjxrZXl3b3JkPlN1bGZoeWRy
eWwgQ29tcG91bmRzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlZlbnRyaWN1bGFyIEZp
YnJpbGxhdGlvbi9ldGlvbG9neS9wcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtl
eXdvcmQ+cDM4IE1pdG9nZW4tQWN0aXZhdGVkIFByb3RlaW4gS2luYXNlcy9tZXRhYm9saXNtPC9r
ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0
ZT5NYXIgMTc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI0LTQ1MzkgKEVsZWN0
cm9uaWMpJiN4RDswMDA5LTczMjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5MjU1
MzQ2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j
YmkubmxtLm5paC5nb3YvcHVibWVkLzE5MjU1MzQ2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz
PjxjdXN0b20yPjI3NzM4MDE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEx
NjEvQ0lSQ1VMQVRJT05BSEEuMTA4Ljc5MDUwMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9y
ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 15. Many mechanisms are involved in the pathogenesis of the disease, which restricts targeting a specific pathway for its management. An alternative approach for successful management could be targeting mechanisms/pathways that are common to cardiac hypertrophic growth, such as oxidative stress pathways and specific cell signaling pathways, which are common to various forms of cardiac hypertrophy including HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZW50aGlsPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
UmVjTnVtPjI2PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxNi0yMF08L0Rpc3BsYXlUZXh0PjxyZWNv
cmQ+PHJlYy1udW1iZXI+MjY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i
IGRiLWlkPSIwejllZmE1ZXgyd2Q5cmU5czl0eDk5Mm05OXpmdGVhc3p4YXoiIHRpbWVzdGFtcD0i
MTUxODc2MjgwMCI+MjY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h
bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNl
bnRoaWwsIFYuPC9hdXRob3I+PGF1dGhvcj5DaGVuLCBTLiBOLjwvYXV0aG9yPjxhdXRob3I+VHN5
Ym91bGV2YSwgTi48L2F1dGhvcj48YXV0aG9yPkhhbGRlciwgVC48L2F1dGhvcj48YXV0aG9yPk5h
Z3VlaCwgUy4gRi48L2F1dGhvcj48YXV0aG9yPldpbGxlcnNvbiwgSi4gVC48L2F1dGhvcj48YXV0
aG9yPlJvYmVydHMsIFIuPC9hdXRob3I+PGF1dGhvcj5NYXJpYW4sIEEuIEouPC9hdXRob3I+PC9h
dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2lu
ZSwgQmF5bG9yIENvbGxlZ2Ugb2YgTWVkaWNpbmUsIE9uZSBCYXlsb3IgUGxhemEsIDUxOUQsIEhv
dXN0b24sIFRYIDc3MDMwLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UHJldmVu
dGlvbiBvZiBjYXJkaWFjIGh5cGVydHJvcGh5IGJ5IGF0b3J2YXN0YXRpbiBpbiBhIHRyYW5zZ2Vu
aWMgcmFiYml0IG1vZGVsIG9mIGh1bWFuIGh5cGVydHJvcGhpYyBjYXJkaW9teW9wYXRoeTwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5DaXJjIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+
Q2lyY3VsYXRpb24gcmVzZWFyY2g8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs
bC10aXRsZT5DaXJjIFJlczwvZnVsbC10aXRsZT48YWJici0xPkNpcmN1bGF0aW9uIHJlc2VhcmNo
PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaXJjIFJl
czwvZnVsbC10aXRsZT48YWJici0xPkNpcmN1bGF0aW9uIHJlc2VhcmNoPC9hYmJyLTE+PC9hbHQt
cGVyaW9kaWNhbD48cGFnZXM+Mjg1LTkyPC9wYWdlcz48dm9sdW1lPjk3PC92b2x1bWU+PG51bWJl
cj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+
QW5pbWFscywgR2VuZXRpY2FsbHkgTW9kaWZpZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QXBvcHRvc2lz
PC9rZXl3b3JkPjxrZXl3b3JkPkF0b3J2YXN0YXRpbiBDYWxjaXVtPC9rZXl3b3JkPjxrZXl3b3Jk
PkNhcmRpb215b3BhdGh5LCBIeXBlcnRyb3BoaWMvKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwv
a2V5d29yZD48a2V5d29yZD5DaG9sZXN0ZXJvbC9ibG9vZDwva2V5d29yZD48a2V5d29yZD5ETkEs
IE1pdG9jaG9uZHJpYWwvYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMs
IEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5FeHRyYWNlbGx1bGFyIFNpZ25hbC1SZWd1bGF0ZWQg
TUFQIEtpbmFzZXMvYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr
ZXl3b3JkPkhlcHRhbm9pYyBBY2lkcy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh5ZHJveHltZXRoeWxnbHV0YXJ5bC1Db0EgUmVkdWN0YXNlIEluaGliaXRvcnMvKnRoZXJhcGV1
dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5IeXBlcnRyb3BoeSwgTGVmdCBWZW50cmljdWxhci9w
cmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48
a2V5d29yZD5NeW9jeXRlcywgQ2FyZGlhYy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TXlv
c2luIEhlYXZ5IENoYWlucy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBT
dHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+UHlycm9sZXMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29y
ZD48a2V5d29yZD5SYWJiaXRzPC9rZXl3b3JkPjxrZXl3b3JkPlZlbnRyaWN1bGFyIEZ1bmN0aW9u
LCBMZWZ0PC9rZXl3b3JkPjxrZXl3b3JkPnAzOCBNaXRvZ2VuLUFjdGl2YXRlZCBQcm90ZWluIEtp
bmFzZXMvYW5hbHlzaXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNTwveWVh
cj48cHViLWRhdGVzPjxkYXRlPkF1ZyA1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+
MTUyNC00NTcxIChFbGVjdHJvbmljKSYjeEQ7MDAwOS03MzMwIChMaW5raW5nKTwvaXNibj48YWNj
ZXNzaW9uLW51bT4xNjAyMDc1NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1
cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjAyMDc1NjwvdXJsPjwvcmVs
YXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj4xMjAxNDQ5PC9jdXN0b20yPjxlbGVjdHJvbmljLXJl
c291cmNlLW51bT4xMC4xMTYxLzAxLlJFUy4wMDAwMTc3MDkwLjA3Mjk2LmFjPC9lbGVjdHJvbmlj
LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhv
cj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNOdW0+MjU8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy
PjI1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMHo5ZWZh
NWV4MndkOXJlOXM5dHg5OTJtOTl6ZnRlYXN6eGF6IiB0aW1lc3RhbXA9IjE1MTg3NjIwODgiPjI1
PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8
L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJpYW4sIEEuIEouPC9h
dXRob3I+PGF1dGhvcj5TZW50aGlsLCBWLjwvYXV0aG9yPjxhdXRob3I+Q2hlbiwgUy4gTi48L2F1
dGhvcj48YXV0aG9yPkxvbWJhcmRpLCBSLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y
cz48YXV0aC1hZGRyZXNzPlNlY3Rpb24gb2YgQ2FyZGlvbG9neSwgRGVwYXJ0bWVudCBvZiBNZWRp
Y2luZSwgQmF5bG9yIENvbGxlZ2Ugb2YgTWVkaWNpbmUsIEhvdXN0b24sIFRleGFzLCBVU0EuIGFt
YXJpYW5AYmNtLnRtYy5lZHU8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbnRpZmlicm90
aWMgZWZmZWN0cyBvZiBhbnRpb3hpZGFudCBOLWFjZXR5bGN5c3RlaW5lIGluIGEgbW91c2UgbW9k
ZWwgb2YgaHVtYW4gaHlwZXJ0cm9waGljIGNhcmRpb215b3BhdGh5IG11dGF0aW9uPC90aXRsZT48
c2Vjb25kYXJ5LXRpdGxlPkogQW0gQ29sbCBDYXJkaW9sPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10
aXRsZT5Kb3VybmFsIG9mIHRoZSBBbWVyaWNhbiBDb2xsZWdlIG9mIENhcmRpb2xvZ3k8L2FsdC10
aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFtIENvbGwgQ2FyZGlvbDwv
ZnVsbC10aXRsZT48YWJici0xPkpvdXJuYWwgb2YgdGhlIEFtZXJpY2FuIENvbGxlZ2Ugb2YgQ2Fy
ZGlvbG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+
SiBBbSBDb2xsIENhcmRpb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5Kb3VybmFsIG9mIHRoZSBBbWVy
aWNhbiBDb2xsZWdlIG9mIENhcmRpb2xvZ3k8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdl
cz44MjctMzQ8L3BhZ2VzPjx2b2x1bWU+NDc8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5
d29yZHM+PGtleXdvcmQ+QWNldHlsY3lzdGVpbmUvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48
a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlveGlkYW50cy8qdGhlcmFwZXV0
aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNhcmRpb215b3BhdGh5LCBIeXBlcnRyb3BoaWMvZGlh
Z25vc3RpYyBpbWFnaW5nLypkcnVnPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHkvbWV0YWJvbGlz
bS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29sbGFnZW4vYW5hbHlzaXM8L2tleXdvcmQ+
PGtleXdvcmQ+RE5BL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RE5BLCBNaXRvY2hvbmRy
aWFsL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RWNob2NhcmRpb2dyYXBoeTwva2V5d29y
ZD48a2V5d29yZD5GaWJyb3Npczwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb248L2tl
eXdvcmQ+PGtleXdvcmQ+SGVhcnQvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkxpcGlk
IFBlcm94aWRhdGlvbjwva2V5d29yZD48a2V5d29yZD5NYWxvbmRpYWxkZWh5ZGUvYW5hbHlzaXM8
L2tleXdvcmQ+PGtleXdvcmQ+TWF0cml4IE1ldGFsbG9wcm90ZWluYXNlIDEvbWV0YWJvbGlzbTwv
a2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8
L2tleXdvcmQ+PGtleXdvcmQ+TXlvY2FyZGl1bS9tZXRhYm9saXNtL3BhdGhvbG9neTwva2V5d29y
ZD48a2V5d29yZD5Qcm9jb2xsYWdlbi9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3
b3JkPlJldmVyc2UgVHJhbnNjcmlwdGFzZSBQb2x5bWVyYXNlIENoYWluIFJlYWN0aW9uPC9rZXl3
b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5G
ZWIgMjE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTU4LTM1OTcgKEVsZWN0cm9u
aWMpJiN4RDswNzM1LTEwOTcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE2NDg3ODUy
PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku
bmxtLm5paC5nb3YvcHVibWVkLzE2NDg3ODUyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxj
dXN0b20yPjI3NzI4NjU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv
ai5qYWNjLjIwMDUuMTAuMDQxPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np
dGU+PENpdGU+PEF1dGhvcj5UaXJvdXZhbnppYW08L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
ZWNOdW0+NzE3PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj43MTc8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJmeHI1d2FkZHY1YWZhMGVlMGU5eGR2dGVz
ZXZmOXM1NWZ2d2UiIHRpbWVzdGFtcD0iMTQ5MzE5MTY5NCI+NzE3PC9rZXk+PC9mb3JlaWduLWtl
eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli
dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5UaXJvdXZhbnppYW0sIFIuPC9hdXRob3I+PGF1dGhvcj5D
b25yYWQsIEMuIEsuPC9hdXRob3I+PGF1dGhvcj5Cb3R0aWdsaWVyaSwgVC48L2F1dGhvcj48YXV0
aG9yPkhlcnplbmJlcmcsIEwuIEEuPC9hdXRob3I+PGF1dGhvcj5Nb3NzLCBSLiBCLjwvYXV0aG9y
PjxhdXRob3I+SGVyemVuYmVyZywgTC4gQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv
cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEdlbmV0aWNzLCBTdGFuZm9yZCBVbml2ZXJz
aXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU3RhbmZvcmQsIENBIDk0MzA1LCBVU0EuIHRpcm91dmFu
QHN0YW5mb3JkLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkhpZ2gtZG9zZSBvcmFs
IE4tYWNldHlsY3lzdGVpbmUsIGEgZ2x1dGF0aGlvbmUgcHJvZHJ1ZywgbW9kdWxhdGVzIGluZmxh
bW1hdGlvbiBpbiBjeXN0aWMgZmlicm9zaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UHJvYyBO
YXRsIEFjYWQgU2NpIFUgUyBBPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5Qcm9jZWVkaW5n
cyBvZiB0aGUgTmF0aW9uYWwgQWNhZGVteSBvZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRl
cyBvZiBBbWVyaWNhPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+
UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjxhYmJyLTE+UHJvY2VlZGluZ3Mg
b2YgdGhlIE5hdGlvbmFsIEFjYWRlbXkgb2YgU2NpZW5jZXMgb2YgdGhlIFVuaXRlZCBTdGF0ZXMg
b2YgQW1lcmljYTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0
bGU+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBBPC9mdWxsLXRpdGxlPjxhYmJyLTE+UHJvY2VlZGlu
Z3Mgb2YgdGhlIE5hdGlvbmFsIEFjYWRlbXkgb2YgU2NpZW5jZXMgb2YgdGhlIFVuaXRlZCBTdGF0
ZXMgb2YgQW1lcmljYTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjQ2MjgtMzM8L3Bh
Z2VzPjx2b2x1bWU+MTAzPC92b2x1bWU+PG51bWJlcj4xMjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5
d29yZD5BY2V0eWxjeXN0ZWluZS8qYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3Jk
PjxrZXl3b3JkPkFkbWluaXN0cmF0aW9uLCBPcmFsPC9rZXl3b3JkPjxrZXl3b3JkPkFkb2xlc2Nl
bnQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW94aWRhbnRzL21ldGFib2xpc208L2tleXdvcmQ+PGtl
eXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q3lzdGljIEZpYnJvc2lzLypkcnVnIHRoZXJh
cHk8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdsdXRhdGhpb25l
L2FuYWx5c2lzL2NoZW1pc3RyeS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8
L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlscy8qZHJ1
ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlBhbmNyZWF0aWMgRWxhc3Rhc2UvbWV0YWJvbGlz
bTwva2V5d29yZD48a2V5d29yZD5QbmV1bW9uaWEvKmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5
d29yZD5Qcm9kcnVncy8qYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3
b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw
MDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXIgMjE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl
cz48aXNibj4wMDI3LTg0MjQgKFByaW50KSYjeEQ7MDAyNy04NDI0IChMaW5raW5nKTwvaXNibj48
YWNjZXNzaW9uLW51bT4xNjUzNzM3ODwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz
Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNjUzNzM3ODwvdXJsPjwv
cmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj4xNDUwMjIyPC9jdXN0b20yPjxlbGVjdHJvbmlj
LXJlc291cmNlLW51bT4xMC4xMDczL3BuYXMuMDUxMTMwNDEwMzwvZWxlY3Ryb25pYy1yZXNvdXJj
ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VGFraW1vdG8sIEUuOyBLYXNzLCBE
LiBBLjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051bT43MTU8L1JlY051bT48cmVjb3Jk
PjxkYXRhYmFzZSBuYW1lPSJNeSBFbmROb3RlIExpYnJhcnkuZW5sIiBwYXRoPSIvVXNlcnMvbWEv
RG9jdW1lbnRzL015IEVuZE5vdGUgTGlicmFyeS5lbmwiPk15IEVuZE5vdGUgTGlicmFyeS5lbmw8
L2RhdGFiYXNlPjxzb3VyY2UtYXBwIG5hbWU9IkVuZE5vdGUiIHZlcnNpb249IjE3LjAiPkVuZE5v
dGU8L3NvdXJjZS1hcHA+PHJlYy1udW1iZXI+NzE1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+
PGtleSBhcHA9IkVOIiBkYi1pZD0iZnhyNXdhZGR2NWFmYTBlZTBlOXhkdnRlc2V2ZjlzNTVmdndl
Ij43MTU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl
Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPjxzdHlsZSBmYWNl
PSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPlRha2ltb3RvLCBFLjwvc3R5bGU+
PC9hdXRob3I+PGF1dGhvcj48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBzaXpl
PSIxMDAlIj5LYXNzLCBELiBBLjwvc3R5bGU+PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0
b3JzPjxhdXRoLWFkZHJlc3M+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6
ZT0iMTAwJSI+RGl2aXNpb24gb2YgQ2FyZGlvbG9neSwgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwg
Sm9obnMgSG9wa2lucyBNZWRpY2FsIEluc3RpdHV0aW9ucywgQmFsdGltb3JlLCBNRCAyMTIwNSwg
VVNBLjwvc3R5bGU+PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+PHN0eWxlIGZhY2U9Im5v
cm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+Um9sZSBvZiBveGlkYXRpdmUgc3RyZXNz
IGluIGNhcmRpYWMgaHlwZXJ0cm9waHkgYW5kIHJlbW9kZWxpbmc8L3N0eWxlPjwvdGl0bGU+PHNl
Y29uZGFyeS10aXRsZT48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj5IeXBlcnRlbnNpb248L3N0eWxlPjwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+PHN0
eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+SHlwZXJ0ZW5zaW9u
PC9zdHlsZT48L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT48c3R5
bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBzaXplPSIxMDAlIj5IeXBlcnRlbnNpb248
L3N0eWxlPjwvZnVsbC10aXRsZT48YWJici0xPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRl
ZmF1bHQiIHNpemU9IjEwMCUiPkh5cGVydGVuc2lvbjwvc3R5bGU+PC9hYmJyLTE+PC9wZXJpb2Rp
Y2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250
PSJkZWZhdWx0IiBzaXplPSIxMDAlIj5IeXBlcnRlbnNpb248L3N0eWxlPjwvZnVsbC10aXRsZT48
YWJici0xPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPkh5
cGVydGVuc2lvbjwvc3R5bGU+PC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+PHN0eWxl
IGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+MjQxLTg8L3N0eWxlPjwv
cGFnZXM+PHZvbHVtZT48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj40OTwvc3R5bGU+PC92b2x1bWU+PG51bWJlcj48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250
PSJkZWZhdWx0IiBzaXplPSIxMDAlIj4yPC9zdHlsZT48L251bWJlcj48a2V5d29yZHM+PGtleXdv
cmQ+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+QW5pbWFs
czwvc3R5bGU+PC9rZXl3b3JkPjxrZXl3b3JkPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRl
ZmF1bHQiIHNpemU9IjEwMCUiPkNhcmRpb21lZ2FseS9ldGlvbG9neS8qcGh5c2lvcGF0aG9sb2d5
PC9zdHlsZT48L2tleXdvcmQ+PGtleXdvcmQ+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVm
YXVsdCIgc2l6ZT0iMTAwJSI+SHVtYW5zPC9zdHlsZT48L2tleXdvcmQ+PGtleXdvcmQ+PHN0eWxl
IGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+SHlwZXJ0ZW5zaW9uL2Nv
bXBsaWNhdGlvbnM8L3N0eWxlPjwva2V5d29yZD48a2V5d29yZD48c3R5bGUgZmFjZT0ibm9ybWFs
IiBmb250PSJkZWZhdWx0IiBzaXplPSIxMDAlIj5NaXRvY2hvbmRyaWEsIEhlYXJ0L21ldGFib2xp
c208L3N0eWxlPjwva2V5d29yZD48a2V5d29yZD48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJk
ZWZhdWx0IiBzaXplPSIxMDAlIj5OQURQSCBPeGlkYXNlL21ldGFib2xpc208L3N0eWxlPjwva2V5
d29yZD48a2V5d29yZD48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj5OaXRyaWMgT3hpZGUgU3ludGhhc2UgVHlwZSBJSUkvbWV0YWJvbGlzbTwvc3R5bGU+PC9r
ZXl3b3JkPjxrZXl3b3JkPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9
IjEwMCUiPk5pdHJvc28gQ29tcG91bmRzL21ldGFib2xpc208L3N0eWxlPjwva2V5d29yZD48a2V5
d29yZD48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBzaXplPSIxMDAlIj5PeGlk
YXRpb24tUmVkdWN0aW9uPC9zdHlsZT48L2tleXdvcmQ+PGtleXdvcmQ+PHN0eWxlIGZhY2U9Im5v
cm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+Kk94aWRhdGl2ZSBTdHJlc3M8L3N0eWxl
Pjwva2V5d29yZD48a2V5d29yZD48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBz
aXplPSIxMDAlIj5PeGlkb3JlZHVjdGFzZXMvbWV0YWJvbGlzbTwvc3R5bGU+PC9rZXl3b3JkPjxr
ZXl3b3JkPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPlJl
YWN0aXZlIE94eWdlbiBTcGVjaWVzL21ldGFib2xpc208L3N0eWxlPjwva2V5d29yZD48a2V5d29y
ZD48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJkZWZhdWx0IiBzaXplPSIxMDAlIj4qVmVudHJp
Y3VsYXIgUmVtb2RlbGluZzwvc3R5bGU+PC9rZXl3b3JkPjxrZXl3b3JkPjxzdHlsZSBmYWNlPSJu
b3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPlhhbnRoaW5lIE94aWRhc2UvbWV0YWJv
bGlzbTwvc3R5bGU+PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjxzdHlsZSBmYWNl
PSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPjIwMDc8L3N0eWxlPjwveWVhcj48
cHViLWRhdGVzPjxkYXRlPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9
IjEwMCUiPkZlYjwvc3R5bGU+PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+PHN0eWxl
IGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+MTUyNC00NTYzIChFbGVj
dHJvbmljKSAwMTk0LTkxMVggKExpbmtpbmcpPC9zdHlsZT48L2lzYm4+PGFjY2Vzc2lvbi1udW0+
PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+MTcxOTA4Nzg8
L3N0eWxlPjwvYWNjZXNzaW9uLW51bT48bm90ZXM+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0i
ZGVmYXVsdCIgc2l6ZT0iMTAwJSI+VGFraW1vdG8sIEVpa2kgS2FzcywgRGF2aWQgQSBlbmcgQUcx
ODMyNC9BRy9OSUEgTklIIEhIUy8gUDAxSDA3NzE4MC9QSFMgSEhTLyBQMDFITDU5NDA4L0hML05I
TEJJIE5JSCBISFMvIFJlc2VhcmNoIFN1cHBvcnQsIE4uSS5ILiwgRXh0cmFtdXJhbCBSZXNlYXJj
aCBTdXBwb3J0LCBOb24tVS5TLiBHb3YmYXBvczt0IFJldmlldyBEYWxsYXMsIFRleC4gOiAxOTc5
IDIwMDYvMTIvMjggMDk6MDAgSHlwZXJ0ZW5zaW9uLiAyMDA3IEZlYjs0OSgyKToyNDEtOC4gRXB1
YiAyMDA2IERlYyAyNi48L3N0eWxlPjwvbm90ZXM+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPjxz
dHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPmh0dHA6Ly93d3cu
bmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTcxOTA4Nzg8L3N0eWxlPjwvdXJsPjwvcmVsYXRlZC11
cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHN0eWxlIGZhY2U9Im5vcm1hbCIg
Zm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+MTAuMTE2MS8wMS5IWVAuMDAwMDI1NDQxNS4zMTM2
Mi5hNzwvc3R5bGU+PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENp
dGU+PEF1dGhvcj5SPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVjTnVtPjcwOTwvUmVjTnVt
PjxyZWNvcmQ+PHJlYy1udW1iZXI+NzA5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh
cHA9IkVOIiBkYi1pZD0iZnhyNXdhZGR2NWFmYTBlZTBlOXhkdnRlc2V2ZjlzNTVmdndlIiB0aW1l
c3RhbXA9IjE0OTI2ODkzMjIiPjcwOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l
PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh
dXRob3I+TG9tYmFyZGkgUjwvYXV0aG9yPjxhdXRob3I+Um9kcmlndWV6IEc8L2F1dGhvcj48YXV0
aG9yPkNoZW4gU048L2F1dGhvcj48YXV0aG9yPlJpcHBsaW5nZXIgQ008L2F1dGhvcj48YXV0aG9y
PkxpIFc8L2F1dGhvcj48YXV0aG9yPkNoZW4gSjwvYXV0aG9yPjxhdXRob3I+V2lsbGVyc29uLCBK
LiBULjwvYXV0aG9yPjxhdXRob3I+QmV0b2NjaGksIFMuPC9hdXRob3I+PGF1dGhvcj5XaWNrbGlu
ZSBTQTwvYXV0aG9yPjxhdXRob3I+RWZpbW92IElSPC9hdXRob3I+PGF1dGhvcj5NYXJpYW4sIEEu
IEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlJlc29s
dXRpb24gb2YgRXN0YWJsaXNoZWQgQ2FyZGlhYyBIeXBlcnRyb3BoeSBhbmQgRmlicm9zaXMgYW5k
IFByZXZlbnRpb24gb2YgU3lzdG9saWMgRHlzZnVuY3Rpb24gaW4gYSBUcmFuc2dlbmljIFJhYmJp
dCBNb2RlbCBvZiBIdW1hbiBDYXJkaW9teW9wYXRoeSBUaHJvdWdoIFRoaW9sLVNlbnNpdGl2ZSBN
ZWNoYW5pc21zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNpcmN1bGF0aW9uPC9zZWNvbmRhcnkt
dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2lyY3VsYXRpb248L2Z1bGwt
dGl0bGU+PGFiYnItMT5DaXJjdWxhdGlvbjwvYWJici0xPjwvcGVyaW9kaWNhbD48ZWRpdGlvbj4y
MDA5IE1hciAyPC9lZGl0aW9uPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjwvZGF0ZXM+PHVybHM+
PC91cmxzPjxjdXN0b20yPlBNQzI3NzM4MDE8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut
bnVtPjEwLjExNjEvQ0lSQ1VMQVRJT05BSEEuMTA4Ljc5MDUwMTwvZWxlY3Ryb25pYy1yZXNvdXJj
ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZW50aGlsPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE.DATA 16-20.
Various medications that block the oxidative stress pathways have provided wonderful results in experimental animals, like N- Acetyl cysteine (NAC) have shown to reduce fibrosis together with reducing myocardial oxidative stress in mouse modelsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 17, 21. HMG-CoA reductase inhibitors or statins having antioxidant effects PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA 22-25, have been experimented in transgenic rabbit models and have shown to reverse cardiac myocyte hypertrophy and fibrosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRlbDwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRlbDwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl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ADDIN EN.CITE.DATA 16, 26. Cardiac hypertrophy was prevented using Atorvastatin in transgenic Rabbit model PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZW50aGlsPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZW50aGlsPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE.DATA 16. Despite the wonderful results in experimental animals, none of these drugs that block oxidative stress pathways have shown a significant good results in humanPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYW48L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 16, 17. The reason for this could be different cell signaling pathways that are activated by oxidative stress in the pathogenesis of the disease. Targeting cell signaling pathways together with antioxidants working on them could be a reasonable approach in finding a cure for this disease.

We report the importance of Oxidative stress in the phenotypic expression of hypertrophic cardiomyopathy.

1.2. RESEARCH QUESTION;Is there increase in reactive oxygen species (ROS) in the heart of a patient with hypertrophic cardiomyopathy?
1.3. HYPOTHESIS;There is increase in oxidative stress that is high amount of ROS in the human hearts affected by hypertrophic cardiomyopathy.

1.4. OBJECTIVES;1.4.1. Overall research aim
To observe and prove the increase in the oxidative stress in the human hearts with hypertrophic cardiomyopathy as compared to the normal hearts.

1.4.2. Specific objectives- To investigate different amount of ROS in different chambers of the heart.

– To investigate the difference in increase in increase of ROS in the patients with diastolic dysfunction and the ones having systolic dysfunction HCM
CHAPTER 2: LITERATURE REVIEW2.1. HYPERTROPHIC CARDIOMYOPATHY (HCM)It is the most common inherited heart disease that leads to marked hypertrophy of the left ventricle, which cannot be explained by other co morbidities example hypertension. It is the most common cause of sudden cardiac death in young and affects 1 in 500 people in the general population ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27. As said, the heart muscle cells hypertrophy and cause the ventricle walls to thicken. When the thickening blocks the blood flow out of the ventricle, it is known as obstructive hypertrophic cardiomyopathy. Sometimes the disease affects the hearts mitral valve and causes the blood to leak backwards through it. And sometimes the hypertrophied muscles doesn’t block the flow of blood, this is referred to as non-obstructive hypertrophic cardiomyopathy.
As mentioned before HCM is a genetic disease that is caused by mutation in the contractile sarcomeric protein genes in its typical forms but can also be caused by mutation in the non-sarcomeric proteins like mutation in the potassium voltage gated channels (KCNQ4)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3BlczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3BlczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
Y051bT4yPC9SZWNOdW0+PERpc3BsYXlUZXh0PlsyOF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJl
Yy1udW1iZXI+MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9
IjB6OWVmYTVleDJ3ZDlyZTlzOXR4OTkybTk5emZ0ZWFzenhheiIgdGltZXN0YW1wPSIxNTE2MTAz
MDczIj4yPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs
ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3BlcywgTC4g
Ui48L2F1dGhvcj48YXV0aG9yPlpla2F2YXRpLCBBLjwvYXV0aG9yPjxhdXRob3I+U3lycmlzLCBQ
LjwvYXV0aG9yPjxhdXRob3I+SHViYW5rLCBNLjwvYXV0aG9yPjxhdXRob3I+R2lhbWJhcnRvbG9t
ZWksIEMuPC9hdXRob3I+PGF1dGhvcj5EYWxhZ2VvcmdvdSwgQy48L2F1dGhvcj48YXV0aG9yPkpl
bmtpbnMsIFMuPC9hdXRob3I+PGF1dGhvcj5NY0tlbm5hLCBXLjwvYXV0aG9yPjxhdXRob3I+VWsx
MGssIENvbnNvcnRpdW08L2F1dGhvcj48YXV0aG9yPlBsYWdub2wsIFYuPC9hdXRob3I+PGF1dGhv
cj5FbGxpb3R0LCBQLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h
ZGRyZXNzPlRoZSBIZWFydCBIb3NwaXRhbCwgMTYtMTggV2VzdG1vcmVsYW5kIFN0cmVldCwgTG9u
ZG9uIFcxRyA4UEgsIFVLLiBwZXJyeS5lbGxpb3R0QHVjbC5hYy51azwvYXV0aC1hZGRyZXNzPjx0
aXRsZXM+PHRpdGxlPkdlbmV0aWMgY29tcGxleGl0eSBpbiBoeXBlcnRyb3BoaWMgY2FyZGlvbXlv
cGF0aHkgcmV2ZWFsZWQgYnkgaGlnaC10aHJvdWdocHV0IHNlcXVlbmNpbmc8L3RpdGxlPjxzZWNv
bmRhcnktdGl0bGU+SiBNZWQgR2VuZXQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkpvdXJu
YWwgb2YgbWVkaWNhbCBnZW5ldGljczwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm
dWxsLXRpdGxlPkogTWVkIEdlbmV0PC9mdWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBvZiBtZWRp
Y2FsIGdlbmV0aWNzPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10
aXRsZT5KIE1lZCBHZW5ldDwvZnVsbC10aXRsZT48YWJici0xPkpvdXJuYWwgb2YgbWVkaWNhbCBn
ZW5ldGljczwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjIyOC0zOTwvcGFnZXM+PHZv
bHVtZT41MDwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVs
dDwva2V5d29yZD48a2V5d29yZD5BbWlubyBBY2lkIFN1YnN0aXR1dGlvbi9nZW5ldGljczwva2V5
d29yZD48a2V5d29yZD5DYXJkaW9teW9wYXRoeSwgSHlwZXJ0cm9waGljLypnZW5ldGljcy9wYXRo
b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPipIaWdoLVRo
cm91Z2hwdXQgTnVjbGVvdGlkZSBTZXF1ZW5jaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv
a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3
b3JkPjxrZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBlZGlncmVlPC9rZXl3b3Jk
PjxrZXl3b3JkPlBvbHltb3JwaGlzbSwgU2luZ2xlIE51Y2xlb3RpZGU8L2tleXdvcmQ+PGtleXdv
cmQ+U2FyY29tZXJlcy8qZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxk
YXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRh
dGVzPjwvZGF0ZXM+PGlzYm4+MTQ2OC02MjQ0IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0yNTkzIChM
aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzM5Njk4MzwvYWNjZXNzaW9uLW51bT48dXJs
cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y
MzM5Njk4MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj4zNjA3MTEzPC9jdXN0
b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTM2L2ptZWRnZW5ldC0yMDEyLTEwMTI3
MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA 28. Currently over 1500 genetic mutations are implicated in hypertrophic cardiomyopathy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXN3YW5hdGhhbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXN3YW5hdGhhbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll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ADDIN EN.CITE.DATA 29. About 2/3 of cases have familial origin but only 1/3 occur sporadically though still genetic and can be passed to the offspring ADDIN EN.CITE <EndNote><Cite><Author>Marian</Author><Year>2001</Year><RecNum>4</RecNum><DisplayText>3</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516105389″>4</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marian, A. J.</author><author>Roberts, R.</author></authors></contributors><auth-address>Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. [email protected]</auth-address><titles><title>The molecular genetic basis for hypertrophic cardiomyopathy</title><secondary-title>J Mol Cell Cardiol</secondary-title><alt-title>Journal of molecular and cellular cardiology</alt-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></periodical><alt-periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></alt-periodical><pages>655-70</pages><volume>33</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cardiomyopathy, Hypertrophic/*genetics/metabolism/pathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Mice, Transgenic</keyword><keyword>Phenotype</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-2828 (Print) 0022-2828 (Linking)</isbn><accession-num>11273720</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11273720</url></related-urls></urls><custom2>2901497</custom2><electronic-resource-num>10.1006/jmcc.2001.1340</electronic-resource-num></record></Cite></EndNote>3. Common genes responsible for HCM are the beta myocin heavy chain (?-MyHC), myocin-binding protein- C (MyBP-C), cardiac troponin T (cTnT) and these three takes approximately ¾ of the HCM cases. Other rare ones are ?-tropomyocin, cardiac troponin-I, ?-cardiac actin, titin and essential and regulatory light chains ADDIN EN.CITE <EndNote><Cite><Author>Marian</Author><Year>2001</Year><RecNum>4</RecNum><DisplayText>3</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516105389″>4</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marian, A. J.</author><author>Roberts, R.</author></authors></contributors><auth-address>Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. [email protected]</auth-address><titles><title>The molecular genetic basis for hypertrophic cardiomyopathy</title><secondary-title>J Mol Cell Cardiol</secondary-title><alt-title>Journal of molecular and cellular cardiology</alt-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></periodical><alt-periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></alt-periodical><pages>655-70</pages><volume>33</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cardiomyopathy, Hypertrophic/*genetics/metabolism/pathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Mice, Transgenic</keyword><keyword>Phenotype</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-2828 (Print) 0022-2828 (Linking)</isbn><accession-num>11273720</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11273720</url></related-urls></urls><custom2>2901497</custom2><electronic-resource-num>10.1006/jmcc.2001.1340</electronic-resource-num></record></Cite></EndNote>3. According to the previous studies ?-MyHC gene mutation had the largest prevalence of about 50% of cases followed by MyBP-C of about 20% of cases ADDIN EN.CITE <EndNote><Cite><Author>Marian</Author><Year>2001</Year><RecNum>4</RecNum><DisplayText>3</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516105389″>4</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marian, A. J.</author><author>Roberts, R.</author></authors></contributors><auth-address>Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. [email protected]</auth-address><titles><title>The molecular genetic basis for hypertrophic cardiomyopathy</title><secondary-title>J Mol Cell Cardiol</secondary-title><alt-title>Journal of molecular and cellular cardiology</alt-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></periodical><alt-periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></alt-periodical><pages>655-70</pages><volume>33</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cardiomyopathy, Hypertrophic/*genetics/metabolism/pathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Mice, Transgenic</keyword><keyword>Phenotype</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-2828 (Print) 0022-2828 (Linking)</isbn><accession-num>11273720</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11273720</url></related-urls></urls><custom2>2901497</custom2><electronic-resource-num>10.1006/jmcc.2001.1340</electronic-resource-num></record></Cite></EndNote>3, but recent studies have found MyBP-C having the highest amount of mutation of about 51% followed by ?-MyHC of around 24%PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXN3YW5hdGhhbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXN3YW5hdGhhbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll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ADDIN EN.CITE.DATA 29-31.

Patients with HCM can be asymptomatic and some can have severe symptoms like cardiac arrhythmias especially Atrial fibrillation (AF), heart failure, exercise intolerance, syncope and even sudden cardiac death ADDIN EN.CITE <EndNote><Cite><Author>Marian</Author><Year>2001</Year><RecNum>4</RecNum><DisplayText>3</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516105389″>4</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marian, A. J.</author><author>Roberts, R.</author></authors></contributors><auth-address>Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. [email protected]</auth-address><titles><title>The molecular genetic basis for hypertrophic cardiomyopathy</title><secondary-title>J Mol Cell Cardiol</secondary-title><alt-title>Journal of molecular and cellular cardiology</alt-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></periodical><alt-periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></alt-periodical><pages>655-70</pages><volume>33</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cardiomyopathy, Hypertrophic/*genetics/metabolism/pathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Mice, Transgenic</keyword><keyword>Phenotype</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-2828 (Print) 0022-2828 (Linking)</isbn><accession-num>11273720</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11273720</url></related-urls></urls><custom2>2901497</custom2><electronic-resource-num>10.1006/jmcc.2001.1340</electronic-resource-num></record></Cite></EndNote>3. The presentation varies even for individuals carrying the same mutation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXN3YW5hdGhhbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXN3YW5hdGhhbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll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ADDIN EN.CITE.DATA 29. Pathologically, there is occurrence of myocyte hypertrophy, myocyte disarray and interstitial fibrosis. While cardiac hypertrophy and interstitial fibrosis are major determinant of morbidity and mortality, myocyte disarray is considered the pathological hallmark of HCM ADDIN EN.CITE <EndNote><Cite><Author>Marian</Author><Year>2001</Year><RecNum>4</RecNum><DisplayText>3</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516105389″>4</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marian, A. J.</author><author>Roberts, R.</author></authors></contributors><auth-address>Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. [email protected]</auth-address><titles><title>The molecular genetic basis for hypertrophic cardiomyopathy</title><secondary-title>J Mol Cell Cardiol</secondary-title><alt-title>Journal of molecular and cellular cardiology</alt-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></periodical><alt-periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></alt-periodical><pages>655-70</pages><volume>33</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cardiomyopathy, Hypertrophic/*genetics/metabolism/pathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Mice, Transgenic</keyword><keyword>Phenotype</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-2828 (Print) 0022-2828 (Linking)</isbn><accession-num>11273720</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11273720</url></related-urls></urls><custom2>2901497</custom2><electronic-resource-num>10.1006/jmcc.2001.1340</electronic-resource-num></record></Cite></EndNote>3.

Figure SEQ Figure * ARABIC 1; histologic subtypes of the heart samples.A. Is a normal section of myocardium stained with Hematoxylin and Eosin (H& E), B. H&E stained myocardial section of the heart with HCM showing the disorganized Architecture. C. This is the higher magnification of H&E stained heart with HCM that shows myocyte disarray. D. a Masson Trichome stained myocardial section from the heart with HCM that shows interstitial fibrosis
The management of hypertrophic cardiomyopathy is divided into Life style changes, Pharmacologic therapy and Therapy that relieve the symptoms of illness example, therapies for advanced heart failure and therapies for cardiac arrhythmias also surgical therapies to reduce the manifestation of the phenotype.
In life style modification, patient should avoid strenuous exercise because even moderate intense physical activity may lead into syncope or even sudden cardiac death. This is because of systemic hypo perfusion secondary to decrease in systemic vascular resistance and outflow obstruction despite increase in heart contraction and heart rate. Patient should also avoid volume depletion as this can decrease even more the outflow gradient and cause systemic hypo perfusion that can end up into syncope and sudden cardiac death ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27.

In pharmacologic management the following have been described;
Beta-blockers; the beta-adrenergic blocking agents like propranolol, Nadolol Bisoprolol, have been experimented much. Due to their effect of reducing heart rate hence increase diastolic filling time, decreasing heart contraction and reducing ventricular stiffness, they have been shown to reduce symptoms like physiologic outflow obstruction, dyspnea on exertion, ventricular arrhythmias and even Angina. They are used in patients with and without outflow obstruction but the non-vasodilating beta-blockers are preferred for patient with obstructive HCM so as to avoid exacerbating outflow gradient ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27.

Non- dihydropyridine calcium channel blockers; the two most known drugs are verapamil and diltiazem. They function like beta-blockers by reducing heart rate and heart contraction. Though there is improvement is some of the clinical outcome, there is no evidence in improvement in clinical outcome, reduction in sudden cardiac death and heart failure in using these drugs. They are used as optional drugs in patients with severe ouflow obstruction or severe heart failure in non-obstructive disease due to their vasodilatory effect in the peripheral vessels and negative inotropic effects respectively ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27.

Disopyramide; is a class IA antiarrhythmic medication that have been shown to reduce outflow gradients hence improve symptoms in patient with outflow obstruction but no role in patient without obstruction gradient. Despite its anticholinergic side effects and QTc prolongation, it remains an important pharmacologic option for symptomatic patient with high outflow gradient and those without improvement despite the use of above medications ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27.
Angiotensin converting enzyme (ACE) inhibitors, Angiotensin receptor blockers (ARB’s) and aldosterone receptor antagonists, have shown to have important effect in phenotypic expression of HCM (myocyte hypertrophy, myocyte disarray and interstitial fibrosis) rather than improvement in clinical symptoms. These should be used with caution as they tend to reduce the afterload and augment the outflow gradient hence can worsen the symptoms ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27.

Management of Atrial Fibrillation; this has management have two aims, rate versus rhythm control and reducing the risk of thromboembolism. Patient with AF and hemodynamic instability should undergo emergent direct current cardioversion. In ventricular rate control, beta-blockers and non-dihydropyridine calcium channel blockers should be used. In case of poor rate control Amiodarone can successfully restore normal sinus rhythm. Due to proarrythmic properties in patients with hypertrophy, propafenone, 1C antiarrythmic medications and Fleicainide should not be used. All HCM patients having persistent and paroxysmal AF should be treated with oral anticoagulation therapy or rather antiplatelet agents (clopidogrel and Aspirin) though less effective compaired to the former ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27.
Apart from medication, the electrophysiological devices that are used in the management of HCM they help to reduce sudden cardiac death and reduce the need for surgical myomectomy. These are;
Defibrillator therapy, it is called implantable cardiovertor defibrillator (ICD) or automated implantable cardiovertor defibrillator (AICD). It monitors the heart rate and rhythm and delivers therapies in terms of electrical shock. It is implanted inside the body and performs defibrillation and even pacing of the heart and by so doing it is able to correct life threatening arrhythmias PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXJvd3NraTwvQXV0aG9yPjxZZWFyPjE5ODA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXJvd3NraTwvQXV0aG9yPjxZZWFyPjE5ODA8L1llYXI+
PFJlY051bT44PC9SZWNOdW0+PERpc3BsYXlUZXh0PlszMl08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+
PHJlYy1udW1iZXI+ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGIt
aWQ9IjB6OWVmYTVleDJ3ZDlyZTlzOXR4OTkybTk5emZ0ZWFzenhheiIgdGltZXN0YW1wPSIxNTE2
NzYyOTM1Ij44PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0
aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NaXJvd3Nr
aSwgTS48L2F1dGhvcj48YXV0aG9yPlJlaWQsIFAuIFIuPC9hdXRob3I+PGF1dGhvcj5Nb3dlciwg
TS4gTS48L2F1dGhvcj48YXV0aG9yPldhdGtpbnMsIEwuPC9hdXRob3I+PGF1dGhvcj5Hb3R0LCBW
LiBMLjwvYXV0aG9yPjxhdXRob3I+U2NoYXVibGUsIEouIEYuPC9hdXRob3I+PGF1dGhvcj5MYW5n
ZXIsIEEuPC9hdXRob3I+PGF1dGhvcj5IZWlsbWFuLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+S29s
ZW5paywgUy4gQS48L2F1dGhvcj48YXV0aG9yPkZpc2NoZWxsLCBSLiBFLjwvYXV0aG9yPjxhdXRo
b3I+V2Vpc2ZlbGR0LCBNLiBMLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0
bGVzPjx0aXRsZT5UZXJtaW5hdGlvbiBvZiBtYWxpZ25hbnQgdmVudHJpY3VsYXIgYXJyaHl0aG1p
YXMgd2l0aCBhbiBpbXBsYW50ZWQgYXV0b21hdGljIGRlZmlicmlsbGF0b3IgaW4gaHVtYW4gYmVp
bmdzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxl
PjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FsdC10aXRs
ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0
bGU+PGFiYnItMT5UaGUgTmV3IEVuZ2xhbmQgam91cm5hbCBvZiBtZWRpY2luZTwvYWJici0xPjwv
cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9mdWxs
LXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FiYnIt
MT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4zMjItNDwvcGFnZXM+PHZvbHVtZT4zMDM8L3ZvbHVt
ZT48bnVtYmVyPjY8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29y
ZD48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BcnJoeXRobWlhcywgQ2FyZGlhYy8q
dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCBUcmlhbHMgYXMgVG9waWM8L2tleXdv
cmQ+PGtleXdvcmQ+RWxlY3RyaWMgQ291bnRlcnNob2NrLyppbnN0cnVtZW50YXRpb24vbWV0aG9k
czwva2V5d29yZD48a2V5d29yZD5FbGVjdHJvZGVzLCBJbXBsYW50ZWQ8L2tleXdvcmQ+PGtleXdv
cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkhlYXJ0IFZlbnRyaWNsZXMvcGh5c2lvcGF0aG9s
b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3
b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBpbG90IFByb2plY3Rz
PC9rZXl3b3JkPjxrZXl3b3JkPlRhY2h5Y2FyZGlhL3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+
VmVudHJpY3VsYXIgRmlicmlsbGF0aW9uLyp0aGVyYXB5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRh
dGVzPjx5ZWFyPjE5ODA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWcgNzwvZGF0ZT48L3B1Yi1k
YXRlcz48L2RhdGVzPjxpc2JuPjAwMjgtNDc5MyAoUHJpbnQpJiN4RDswMDI4LTQ3OTMgKExpbmtp
bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjY5OTE5NDg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl
bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvNjk5MTk0
ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu
MTA1Ni9ORUpNMTk4MDA4MDczMDMwNjA3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y
ZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE.DATA 32. It protects against sudden cardiac death secondary to ventricular fibrillation, ventricular tachycardia or bradycardia ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2017</Year><RecNum>7</RecNum><DisplayText>33</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516762762″>7</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Wang, N.</author><author>Xie, A.</author><author>Tjahjono, R.</author><author>Tian, D. H.</author><author>Phan, S.</author><author>Yan, T. D.</author><author>Bajona, P.</author><author>Phan, K.</author></authors></contributors><auth-address>Collaborative Research (CORE) Group, Sydney, Australia. Faculty of Medicine, University of Sydney, Sydney, Australia. Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Institute of Life Sciences, Sant&apos;Anna School of Advanced Studies, Pisa, Italy.</auth-address><titles><title>Implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: an updated systematic review and meta-analysis of outcomes and complications</title><secondary-title>Ann Cardiothorac Surg</secondary-title><alt-title>Annals of cardiothoracic surgery</alt-title></titles><periodical><full-title>Ann Cardiothorac Surg</full-title><abbr-1>Annals of cardiothoracic surgery</abbr-1></periodical><alt-periodical><full-title>Ann Cardiothorac Surg</full-title><abbr-1>Annals of cardiothoracic surgery</abbr-1></alt-periodical><pages>298-306</pages><volume>6</volume><number>4</number><dates><year>2017</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>2225-319X (Print) 2225-319X (Linking)</isbn><accession-num>28944170</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/28944170</url></related-urls></urls><custom2>5602202</custom2><electronic-resource-num>10.21037/acs.2017.07.05</electronic-resource-num></record></Cite></EndNote>33.
Dual- chamber pacing, in here electrodes are inserted both in right atrium and right ventricle. The atrial lead can sense the patient’s intrinsic P waves and stimulate the atrium when the atrial rate becomes too slow. The device provides atrial ventricular delay, which is analogous to PR interval seen in normal conduction. It maintains physiologic timing between atrial and ventricular systole. The device can reduce left ventricular outflow tract gradient hence relieve symptoms and regress hypertrophy in some patients ADDIN EN.CITE <EndNote><Cite><Author>Nishimura</Author><Year>1997</Year><RecNum>9</RecNum><DisplayText>34</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516766030″>9</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Nishimura, R. A.</author><author>Symanski, J. D.</author><author>Hurrell, D. G.</author></authors></contributors><auth-address>Department of Internal Medicine, Mayo Clinic, Rochester, Minn, USA.</auth-address><titles><title>Images in cardiovascular medicine. Dual-chamber pacing in a patient with hypertrophic cardiomyopathy</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><alt-periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></alt-periodical><pages>1701</pages><volume>96</volume><number>5</number><keywords><keyword>Cardiac Pacing, Artificial/*methods</keyword><keyword>Cardiomyopathy, Hypertrophic/complications/*therapy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Middle Aged</keyword><keyword>Ventricular Outflow Obstruction/etiology/physiopathology/therapy</keyword></keywords><dates><year>1997</year><pub-dates><date>Sep 2</date></pub-dates></dates><isbn>0009-7322 (Print) 0009-7322 (Linking)</isbn><accession-num>9315567</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/9315567</url></related-urls></urls></record></Cite></EndNote>34. Despite its functioning, some studies have noted no beneficial effect nor relieve of symptoms when using this device PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VzdG9uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VzdG9uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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ADDIN EN.CITE.DATA 27, 35.

Biventricular pacing, in here there are at least two leads, one into the right ventricle to stimulate the septum and another is inserted through the coronary sinus to pace the left ventricular apical wall. For patients with normal sinus rhythm, another lead is placed in the right atrium to facilitate synchrony with atrial contraction. The system is said to reduce outflow tract gradient and some studies have already demonstrated improvement of symptoms PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VzdG9uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VzdG9uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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=
ADDIN EN.CITE.DATA 27, 36.

Despite medical therapy, some patients remain symptomatic with significant outflow obstruction and are symptomatic both during exercise and even at rest. These patients are candidates for septal- reduction technique. These are of two types; Septal ablation and surgical myectomy.

Septal ablation; also known as percutaneous alcohol septal ablation performed by injecting absolute alcohol into the first septal perforator of the left anterior descending artery, which will cause controlled infarction of the hypertrophied septum therefore reduce its contractility and eventually even the thickness of the proximal inter-ventricular septumPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VzdG9uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VzdG9uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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ADDIN EN.CITE.DATA 27, 37. Patient symptomatic despite medical therapy is one of the criteria for alcohol septal ablation; other suggested ones are septal hypertrophy of 18mm or more and resting or provoked gradient of 50 mmHg or more PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl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ADDIN EN.CITE.DATA 38. Surgical myectomy involves resection of the small amount of muscle (2-5) g from the proximal ventricular septum and some have modified it to be more widely and more distally, so as to widen the outflow tract and reduce the gradient ADDIN EN.CITE <EndNote><Cite><Author>Maron</Author><Year>2007</Year><RecNum>14</RecNum><DisplayText>39</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516874015″>14</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Maron, B. J.</author></authors></contributors><auth-address>Minneapolis Heart Institute Foundation, 920 E 28th St, Ste 60, Minneapolis, MN 55407, USA. [email protected]</auth-address><titles><title>Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><alt-periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></alt-periodical><pages>196-206; discussion 206</pages><volume>116</volume><number>2</number><keywords><keyword>Cardiomyopathy, Hypertrophic/pathology/*surgery</keyword><keyword>Heart Failure/surgery</keyword><keyword>Heart Septum/pathology/*surgery</keyword><keyword>Humans</keyword><keyword>Informed Consent</keyword><keyword>Length of Stay</keyword><keyword>Reproducibility of Results</keyword><keyword>Risk Assessment</keyword><keyword>Survivors</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul 10</date></pub-dates></dates><isbn>1524-4539 (Electronic) 0009-7322 (Linking)</isbn><accession-num>17620519</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17620519</url></related-urls></urls><electronic-resource-num>10.1161/CIRCULATIONAHA.107.691378</electronic-resource-num></record></Cite></EndNote>39. Between the two, surgical myectomy have proven to be superior to alcohol septal ablation and the later has been taken as an alternative to the patients unfit for surgery. This might be due to the high risk of ventricular arrhythmias and heart block of septal ablation method PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl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ADDIN EN.CITE.DATA 27, 39.

For patients with advanced heart failure, left ventricular assisted devices (LVAD) have somehow been explored and have been successful in a number of patients especially those who had concurrent septal myectomy to enlarge the left ventricular cavity size so as to accommodate the inflow cannula ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27. Also, heart transplantation have been done for patients with life threatening arrhythmias and refractory heart failure with success ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>2014</Year><RecNum>1</RecNum><DisplayText>27</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1516099875″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Houston, B. A.</author><author>Stevens, G. R.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a review</title><secondary-title>Clin Med Insights Cardiol</secondary-title><alt-title>Clinical Medicine Insights. Cardiology</alt-title></titles><periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></periodical><alt-periodical><full-title>Clin Med Insights Cardiol</full-title><abbr-1>Clinical Medicine Insights. Cardiology</abbr-1></alt-periodical><pages>53-65</pages><volume>8</volume><number>Suppl 1</number><dates><year>2014</year></dates><isbn>1179-5468 (Print) 1179-5468 (Linking)</isbn><accession-num>25657602</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25657602</url></related-urls></urls><custom2>4309724</custom2><electronic-resource-num>10.4137/CMC.S15717</electronic-resource-num></record></Cite></EndNote>27.

2.2. OXIDATIVE STRESSIt is an imbalance between oxidants and antioxidant system in the body. In other words, it is an imbalance between the production of oxygen free radicals and an inability of the body to counteract or neutralize them that leads into their excess in the body. The free radicals are the molecules that contain one or more unpaired electrons that make them highly reactive with other molecules in the body. Examples of free radicals are; Reactive oxygen species (ROS) which includes Superoxide anions (O-2), Hydrogen peroxide (H2O2) and Hydroxyl radicals (HO). Others are Nitric oxide (NO), Peroxynitrite Anions (ONOO-) etc.

The mechanisms in which the free radicals are formed are as follows:
Reduction- Oxidation reaction during metabolic processes; during normal metabolisms cells of the body generates energy, Adenosine triphosphate (ATP) by oxidative process. The end product is water from the combination of oxygen and hydrogen atoms. In this process four electrons are donated in four steps and in each step, partially reduced intermediates, which are free radicals, will be formed. Therefore free radicals will be formed by four steps reduction of oxygen as elaborated from the equation below.

Figure SEQ Figure * ARABIC 2; four steps reduction of oxygen to form water. Note the free radical intermediates which produce increased oxidative stress when the reduction process is not complete.

Radiant energy; absorption of ionizing radiation like ultra violet light and X- rays can cause formation of free radicals. Example water molecule can undergo radiolysis and produce hydroxyl radicals.

Neutrophils function in oxygen dependent pathway or oxygen independent pathway in response to infection. In the oxygen dependent pathway, there is a process called “oxidative burst” in which, under NADPH oxidase, oxygen forms superoxide and then bleach (HOCl). Therefore there is a formation of free radicals.

Transition metals; metals like Iron (Fe) and copper (Cu) do donate or accept free electrons during various intracellular reactions, through this they help to catalyze the formation of free radicals. Good example is the Fenton reaction during which hydroxyl radicals are formed from ferrous iron when combines with hydrogen peroxide.

Figure SEQ Figure * ARABIC 3; Fenton reaction.Enzymatic metabolism of exogenous chemicals and drugs. Example, Acetaminophen that is metabolized by Cytochrome P450 (CP450) enzyme system, generate free radicals during the process. Therefore high doses of Acetaminophen will generate high dose of free radicals so does metabolism of Tetra hydrochloride.

Nitrogen Oxide (NO) generated from endothelial cells, neurons, macrophages etc., combine with superoxide and forms Peroxynitrate (ONOO-).

When the free radicals are formed, systems in the body work to remove and neutralize them and hence prevent oxidative stress caused by their excess. These are,
Antioxidant system; Vitamin A, Vitamin C and Vitamin E, works as antioxidants together with Glutathione, which is found in the cytosol. Glutathione can block the formation of free radicals and can also inactivate them (Scavenger system).

Metal carrier proteins; these are proteins binds, transport and store metals and make them inactive hence cannot for free radicals. These are such as Transferrin, Ferritin and Ceruloplasmin, where the first two are for iron and the last one is for copper.
Free radicals scavenging system; it is a system of enzymes that neutralize the free radicals and hence reduce them in the body. There are three key enzymes in this system where each is responsible largely to a certain type of free radicals, these are, superoxide dismutase, catalase and glutathione peroxidase dealing with superoxide, hydrogen peroxide and hydroxyl radicals respectively.
Catalase is found in peroxisomes and it breakdown hydrogen peroxide into oxygen and water. Superoxide dismutase converts superoxide into hydrogen peroxide. It has been said that, the ratio of oxidized glutathione to reduced glutathione reflects the oxidative state of the cell.
Free radicals are known for their ability to cause cellular injury in the body. It does so in three types of reactions, these are,
Lipid peroxidation in the membranes.

Oxidative modification of proteins.

DNA damage.

In lipid peroxidation, free radicals particularly hydroxyl radicals, target double bonds of unsaturated fatty acids. This result into peroxides, which are unstable and reactive and can result into autocatalytic reaction, this reaction produces more and more free radicals and hence membrane damage.
In oxidative modification of proteins, free radicals enhance oxidation of amino acid side chains of proteins and cause formation of covalent bonds example the disulphide bonds between proteins and form protein to protein cross linking. Oxidation can also occur in the protein backbone. The whole oxidation process tends to disrupt the active sites of enzymes (since they are also proteins) and reduces their functionality or even loss their function. In the structural proteins, the process can disrupt the structure and causes their conformation changes.

The DNA damage is done by breaking down the DNA strands and can even form cross-linking between different strands. This leads to formation of mutant DNA strands that can lead cellular aging and even malignant transformation.

Coming to the reactive oxygen species (ROS) in particular, there are some important functions, which have been noted like, activation of redox-sensitive transcription factors, such as AP-1, p53 and NF-?B and hence expression of pro-inflammatory cytokines ADDIN EN.CITE <EndNote><Cite><Author>Burton</Author><Year>2011</Year><RecNum>15</RecNum><DisplayText>40</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1517218390″>15</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Burton, G. J.</author><author>Jauniaux, E.</author></authors></contributors><auth-address>Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. [email protected]</auth-address><titles><title>Oxidative stress</title><secondary-title>Best Pract Res Clin Obstet Gynaecol</secondary-title><alt-title>Best practice &amp; research. Clinical obstetrics &amp; gynaecology</alt-title></titles><periodical><full-title>Best Pract Res Clin Obstet Gynaecol</full-title><abbr-1>Best practice &amp; research. Clinical obstetrics &amp; gynaecology</abbr-1></periodical><alt-periodical><full-title>Best Pract Res Clin Obstet Gynaecol</full-title><abbr-1>Best practice &amp; research. Clinical obstetrics &amp; gynaecology</abbr-1></alt-periodical><pages>287-99</pages><volume>25</volume><number>3</number><keywords><keyword>Endoplasmic Reticulum/physiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Maternal-Fetal Exchange</keyword><keyword>Oxidative Stress/*physiology</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications/physiopathology</keyword><keyword>*Reactive Oxygen Species</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1532-1932 (Electronic) 1521-6934 (Linking)</isbn><accession-num>21130690</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21130690</url></related-urls></urls><custom2>3101336</custom2><electronic-resource-num>10.1016/j.bpobgyn.2010.10.016</electronic-resource-num></record></Cite></EndNote>40, activation of Protein Kinases hence control cellular functions like cell survival, proliferation and even cellular apoptosis depending on the receptor being activated ADDIN EN.CITE <EndNote><Cite><Author>Burton</Author><Year>2011</Year><RecNum>15</RecNum><DisplayText>40</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1517218390″>15</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Burton, G. J.</author><author>Jauniaux, E.</author></authors></contributors><auth-address>Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. [email protected]</auth-address><titles><title>Oxidative stress</title><secondary-title>Best Pract Res Clin Obstet Gynaecol</secondary-title><alt-title>Best practice &amp; research. Clinical obstetrics &amp; gynaecology</alt-title></titles><periodical><full-title>Best Pract Res Clin Obstet Gynaecol</full-title><abbr-1>Best practice &amp; research. Clinical obstetrics &amp; gynaecology</abbr-1></periodical><alt-periodical><full-title>Best Pract Res Clin Obstet Gynaecol</full-title><abbr-1>Best practice &amp; research. Clinical obstetrics &amp; gynaecology</abbr-1></alt-periodical><pages>287-99</pages><volume>25</volume><number>3</number><keywords><keyword>Endoplasmic Reticulum/physiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Maternal-Fetal Exchange</keyword><keyword>Oxidative Stress/*physiology</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications/physiopathology</keyword><keyword>*Reactive Oxygen Species</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1532-1932 (Electronic) 1521-6934 (Linking)</isbn><accession-num>21130690</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21130690</url></related-urls></urls><custom2>3101336</custom2><electronic-resource-num>10.1016/j.bpobgyn.2010.10.016</electronic-resource-num></record></Cite></EndNote>40 and opening of ion channels particularly calcium release channels in endoplasmic reticulum membrane that leads into activation of calcium sensitive processes in the cell ADDIN EN.CITE <EndNote><Cite><Author>Hool</Author><Year>2007</Year><RecNum>16</RecNum><DisplayText>41</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1517221874″>16</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Hool, L. C.</author><author>Corry, B.</author></authors></contributors><auth-address>Discipline of Physiology, School of Biomedical, Biomolecular, and Chemical Sciences, The University of Western Australia, Crawley, Western Australia. [email protected]</auth-address><titles><title>Redox control of calcium channels: from mechanisms to therapeutic opportunities</title><secondary-title>Antioxid Redox Signal</secondary-title><alt-title>Antioxidants &amp; redox signaling</alt-title></titles><periodical><full-title>Antioxid Redox Signal</full-title><abbr-1>Antioxidants &amp; redox signaling</abbr-1></periodical><alt-periodical><full-title>Antioxid Redox Signal</full-title><abbr-1>Antioxidants &amp; redox signaling</abbr-1></alt-periodical><pages>409-35</pages><volume>9</volume><number>4</number><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Calcium/metabolism/physiology</keyword><keyword>Calcium Channel Blockers/pharmacology</keyword><keyword>Calcium Channels/genetics/*physiology</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Molecular Sequence Data</keyword><keyword>Oxidation-Reduction/drug effects</keyword><keyword>Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1523-0864 (Print) 1523-0864 (Linking)</isbn><accession-num>17280484</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17280484</url></related-urls></urls><electronic-resource-num>10.1089/ars.2006.1446</electronic-resource-num></record></Cite></EndNote>41. Despite its useful functions, ROS have been implicated in a number of diseases like neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease ADDIN EN.CITE <EndNote><Cite><Author>Uttara</Author><Year>2009</Year><RecNum>21</RecNum><DisplayText>42</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app=”EN” db-id=”0edasxaear9z04ewsayv2frgedxaz9dep90z” timestamp=”1512281626″>21</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Uttara, B.</author><author>Singh, A. V.</author><author>Zamboni, P.</author><author>Mahajan, R. T.</author></authors></contributors><auth-address>Department of Biotechnology, M. J. College, M. J. Road, Jalgaon- 425 001, India. [email protected]</auth-address><titles><title>Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options</title><secondary-title>Curr Neuropharmacol</secondary-title><alt-title>Current neuropharmacology</alt-title></titles><periodical><full-title>Curr Neuropharmacol</full-title><abbr-1>Current neuropharmacology</abbr-1></periodical><alt-periodical><full-title>Curr Neuropharmacol</full-title><abbr-1>Current neuropharmacology</abbr-1></alt-periodical><pages>65-74</pages><volume>7</volume><number>1</number><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1570-159X (Print) 1570-159X (Linking)</isbn><accession-num>19721819</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19721819</url></related-urls></urls><custom2>2724665</custom2><electronic-resource-num>10.2174/157015909787602823</electronic-resource-num></record></Cite></EndNote>42, various types of cancers due to destruction of the DNA and hence mutation of genes, various cardiovascular system diseases like in the development of atherosclerosis in the blood vessel walls, cardiomyopathies example diabetic cardiomyopathyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba2hpbGVzaHdhciwgVi47IFBhdGVsLCBTLiBQLjsgS2F0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba2hpbGVzaHdhciwgVi47IFBhdGVsLCBTLiBQLjsgS2F0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ADDIN EN.CITE.DATA 43, 44, and so does hypertrophic cardiomyopathy.
Many researchers have shown the involvement of oxidative stress in hypertrophic cardiomyopathy, example, the expression of ALCAT1 (Acyl-CoA: Lysocardiolipin Acyltransferase-1), a lysocardiolipin acyltransferase that catalyzes the synthesis of cardiolipin important for oxidative phosphorylation in the mitochondrial membrane, was highly unregulated and caused severe oxidative stress in the cardiac cells with hypertrophic cardiomyopathy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 45. Also, Celecoxib, a cyclooxygenase-2 non-steroid anti-inflammatory drug that have antioxidant effect, was shown to prevent cardiac hypertrophy, proved by reduction in Malondialdehyde, an oxidative stress maker during timely treatment with the drug PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl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ADDIN EN.CITE.DATA 46.

Though a straightforward pathway on how it causes hypertrophic cardiomyopathy is not yet clear, its action on different cell signaling pathway responsible for the development of HCM could answer the question. There are soo many cell signaling pathways in the human body cells that are responsible for various physiological pathways, disregulation of these pathway may lead into serious conditions like HCM. The pathways well studied in causing hypertrophic cardiomyopathy are Mitogen activated protein kinase signaling pathway (MAPK pathway), Phosphoinositide 3-kinase (PI3K-AKT) signaling pathway, Ca2+/calcineurin/NF-AT signaling pathway and Nuclear factor kappa- light- chain- enhancer of activated B cell (NF-kB) signaling pathway and all this have been shown to be activated by ROS in their process of causing cardiac hypertrophy.
2.2.1. OXIDATIVE STRESS AND HCMThere has been evidence in the increased amount of reactive oxygen species in the serum and heart muscles of patients with hypertrophic cardiomyopathy. Various theories exist concerning the increase in the oxidative stress in the heart and serum of patient with hypertrophic cardiomyopathy.

The abnormalities in the Ca2+ handling by the mitochondria
During the process of contraction calcium induces calcium release from the endoplasmic reticulum, the calcium influx in the cytoplasm cause the muscle contraction by binding the thin filament regulatory protein troponin C. At the same time, calcium release from the sarcoplasmic reticulum stimulates ATP production from the mitochondria due to their close proximity. The latter is possible through mitochondrial calcium uniporter and the ability of mitochondrial matrix Ca2+ to control enzymes in the TCA (Tricarboxylic acid) cycle that yields reduced NADH that enter the electron transport chain and later converted to NADPH and reduce the oxidative stress in the process, so doing the anti-oxidant function. Mitochondrial Ca2+ also stimulates mitochondrial ATP synthase that eventually produces ATP. The amount of matrix calcium is affected by the amount of sodium in the cytoplasm. In the failing hearts as well as the hearts with HCM, it has been reported to have high amount cytosolic Na+ that increase the activity of mitochondrial Na+ – Ca2+ exchanger and hence a lot of Ca2+ is exported out of the mitochondria impairing the above activities and ultimately increase in the oxidative stress of the heart muscles ADDIN EN.CITE <EndNote><Cite><Author>Vakrou</Author><Year>2014</Year><RecNum>31</RecNum><DisplayText>6</DisplayText><record><rec-number>31</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1519198074″>31</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Vakrou, S.</author><author>Abraham, M. R.</author></authors></contributors><auth-address>Division of Cardiology, School of Medicine, Johns Hopkins University Baltimore, MD, USA.</auth-address><titles><title>Hypertrophic cardiomyopathy: a heart in need of an energy bar?</title><secondary-title>Front Physiol</secondary-title><alt-title>Frontiers in physiology</alt-title></titles><periodical><full-title>Front Physiol</full-title><abbr-1>Frontiers in physiology</abbr-1></periodical><alt-periodical><full-title>Front Physiol</full-title><abbr-1>Frontiers in physiology</abbr-1></alt-periodical><pages>309</pages><volume>5</volume><dates><year>2014</year></dates><isbn>1664-042X (Print) 1664-042X (Linking)</isbn><accession-num>25191275</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25191275</url></related-urls></urls><custom2>4137386</custom2><electronic-resource-num>10.3389/fphys.2014.00309</electronic-resource-num></record></Cite></EndNote>6.

Impaired Mitochondrial Oxidative phosphorylation.

During the normal oxidative phosphorylation that occurs in the inner mitochondrial membrane, electrons are transported in the series of structural protein complexes known as electron transport chain. There are five protein complexes; complex I (NADH dehydrogenase), complex II (Succinate dehydrogenase), complex III (Cytochrome C oxyreductase), Complex IV (Cytochrome oxidase) and Complex V (ATP synthase). The electrons are carried from the glycolysis, Preparatory stapes and the Creb’s cycle in the form of NADH and FADH2. The final electron acceptor in the process is O2, which is reduced to form water. And during the electron transport process, the H+ are being pumped out to the inter-membranous region at the complex proteins, producing the proton gradient, which then enter back the mitochondrial matrix due to their gradient through the complex V (ATP synthase) and harness ATP in the process where 4H+ will produce 1ATP molecule ADDIN EN.CITE <EndNote><Cite><Author>Fosslien</Author><Year>2003</Year><RecNum>35</RecNum><DisplayText>47</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1519224638″>35</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Fosslien, E.</author></authors></contributors><auth-address>Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA. [email protected]</auth-address><titles><title>Review: Mitochondrial medicine–cardiomyopathy caused by defective oxidative phosphorylation</title><secondary-title>Ann Clin Lab Sci</secondary-title><alt-title>Annals of clinical and laboratory science</alt-title></titles><periodical><full-title>Ann Clin Lab Sci</full-title><abbr-1>Annals of clinical and laboratory science</abbr-1></periodical><alt-periodical><full-title>Ann Clin Lab Sci</full-title><abbr-1>Annals of clinical and laboratory science</abbr-1></alt-periodical><pages>371-95</pages><volume>33</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cardiomyopathies/*etiology/therapy</keyword><keyword>Energy Metabolism</keyword><keyword>Humans</keyword><keyword>Mitochondria, Heart/genetics/*metabolism</keyword><keyword>Myocardium/metabolism</keyword><keyword>*Oxidative Phosphorylation</keyword></keywords><dates><year>2003</year><pub-dates><date>Fall</date></pub-dates></dates><isbn>0091-7370 (Print) 0091-7370 (Linking)</isbn><accession-num>14584751</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/14584751</url></related-urls></urls></record></Cite></EndNote>47.
In HCM, there is impairment in the oxidative phosphorylation reported in various studies; the process leads to the increase in the amount of reactive oxygen species in the heart muscles and increase in the oxidative damage PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHJpc3RpYW5zZW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHJpc3RpYW5zZW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z
ZWFyPjxSZWNOdW0+MzI8L1JlY051bT48RGlzcGxheVRleHQ+WzQ4XTwvRGlzcGxheVRleHQ+PHJl
Y29yZD48cmVjLW51bWJlcj4zMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF
TiIgZGItaWQ9IjB6OWVmYTVleDJ3ZDlyZTlzOXR4OTkybTk5emZ0ZWFzenhheiIgdGltZXN0YW1w
PSIxNTE5MjIyNTkyIj4zMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy
bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+
Q2hyaXN0aWFuc2VuLCBMLiBCLjwvYXV0aG9yPjxhdXRob3I+RGVsYSwgRi48L2F1dGhvcj48YXV0
aG9yPktvY2gsIEouPC9hdXRob3I+PGF1dGhvcj5IYW5zZW4sIEMuIE4uPC9hdXRob3I+PGF1dGhv
cj5MZWlmc3NvbiwgUC4gUy48L2F1dGhvcj48YXV0aG9yPllva290YSwgVC48L2F1dGhvcj48L2F1
dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFZldGVyaW5h
cnkgQ2xpbmljYWwgYW5kIEFuaW1hbCBTY2llbmNlcywgRmFjdWx0eSBvZiBIZWFsdGggYW5kIE1l
ZGljYWwgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVu
bWFyazsgRGVwYXJ0bWVudCBvZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBDZW50ZXIgZm9yIEhlYWx0
aHkgQWdpbmcsIFVuaXZlcnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVubWFyazsg
YW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBDZW50ZXIgZm9yIEhl
YWx0aHkgQWdpbmcsIFVuaXZlcnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVubWFy
azsgYW5kLiYjeEQ7RGVwYXJ0bWVudCBvZiBWZXRlcmluYXJ5IENsaW5pY2FsIGFuZCBBbmltYWwg
U2NpZW5jZXMsIEZhY3VsdHkgb2YgSGVhbHRoIGFuZCBNZWRpY2FsIFNjaWVuY2VzLCBVbml2ZXJz
aXR5IG9mIENvcGVuaGFnZW4sIENvcGVuaGFnZW4sIERlbm1hcms7JiN4RDtEZXBhcnRtZW50IG9m
IFZldGVyaW5hcnkgRGlzZWFzZSBCaW9sb2d5LCBGYWN1bHR5IG9mIEhlYWx0aCBhbmQgTWVkaWNh
bCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBDb3BlbmhhZ2VuLCBDb3BlbmhhZ2VuLCBEZW5tYXJr
LiYjeEQ7RGVwYXJ0bWVudCBvZiBCaW9tZWRpY2FsIFNjaWVuY2VzLCBDZW50ZXIgZm9yIEhlYWx0
aHkgQWdpbmcsIFVuaXZlcnNpdHkgb2YgQ29wZW5oYWdlbiwgQ29wZW5oYWdlbiwgRGVubWFyazsg
YW5kIHQteW9rb3RhQG1lZC5ob2t1ZGFpLmFjLmpwLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp
dGxlPkltcGFpcmVkIGNhcmRpYWMgbWl0b2Nob25kcmlhbCBveGlkYXRpdmUgcGhvc3Bob3J5bGF0
aW9uIGFuZCBlbmhhbmNlZCBtaXRvY2hvbmRyaWFsIG94aWRhdGl2ZSBzdHJlc3MgaW4gZmVsaW5l
IGh5cGVydHJvcGhpYyBjYXJkaW9teW9wYXRoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBK
IFBoeXNpb2wgSGVhcnQgQ2lyYyBQaHlzaW9sPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5B
bWVyaWNhbiBqb3VybmFsIG9mIHBoeXNpb2xvZ3kuIEhlYXJ0IGFuZCBjaXJjdWxhdG9yeSBwaHlz
aW9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0gSiBQ
aHlzaW9sIEhlYXJ0IENpcmMgUGh5c2lvbDwvZnVsbC10aXRsZT48YWJici0xPkFtZXJpY2FuIGpv
dXJuYWwgb2YgcGh5c2lvbG9neS4gSGVhcnQgYW5kIGNpcmN1bGF0b3J5IHBoeXNpb2xvZ3k8L2Fi
YnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGh5c2lv
bCBIZWFydCBDaXJjIFBoeXNpb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5BbWVyaWNhbiBqb3VybmFs
IG9mIHBoeXNpb2xvZ3kuIEhlYXJ0IGFuZCBjaXJjdWxhdG9yeSBwaHlzaW9sb2d5PC9hYmJyLTE+
PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+SDEyMzctNDc8L3BhZ2VzPjx2b2x1bWU+MzA4PC92b2x1
bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk
PjxrZXl3b3JkPkNhcmRpb215b3BhdGh5LCBIeXBlcnRyb3BoaWMvKm1ldGFib2xpc208L2tleXdv
cmQ+PGtleXdvcmQ+Q2F0czwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdv
cmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWEsIEhlYXJ0LyptZXRhYm9saXNt
PC9rZXl3b3JkPjxrZXl3b3JkPk11c2NsZSBGaWJlcnMsIFNrZWxldGFsL21ldGFib2xpc208L2tl
eXdvcmQ+PGtleXdvcmQ+TXlvY3l0ZXMsIENhcmRpYWMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5
d29yZD4qT3hpZGF0aXZlIFBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD4qT3hpZGF0
aXZlIFN0cmVzczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxw
dWItZGF0ZXM+PGRhdGU+TWF5IDE1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUy
Mi0xNTM5IChFbGVjdHJvbmljKSYjeEQ7MDM2My02MTM1IChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4yNTc3MDI0MzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+
aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTc3MDI0MzwvdXJsPjwvcmVsYXRl
ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE1Mi9hanBoZWFydC4w
MDcyNy4yMDE0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO
b3RlPn==
ADDIN EN.CITE.DATA 48. Oxidative phosphorylation can be impaired by various causes, common ones reported are the nuclear gene mutation or mitochondrial gene mutation, and these mutations cause abnormalities in the mitochondria and its protein complexes responsible for oxidative phosphorylation. Various patients with HCM have been reported to have defects in the protein complexes in the mitochondria responsible for the oxidative phosphorylation. The common mutations have been mutation in the complex I which takes about 1/3 of cases. And these mutations have been found in the cardiac muscles ADDIN EN.CITE <EndNote><Cite><Author>Holmgren</Author><Year>2003</Year><RecNum>33</RecNum><DisplayText>49</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1519223173″>33</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Holmgren, D.</author><author>Wahlander, H.</author><author>Eriksson, B. O.</author><author>Oldfors, A.</author><author>Holme, E.</author><author>Tulinius, M.</author></authors></contributors><auth-address>Division of Pediatric Cardiology, The Queen Silvia Children&apos;s Hospital, Goteborg, Sweden. [email protected]</auth-address><titles><title>Cardiomyopathy in children with mitochondrial disease; clinical course and cardiological findings</title><secondary-title>Eur Heart J</secondary-title><alt-title>European heart journal</alt-title></titles><periodical><full-title>Eur Heart J</full-title><abbr-1>European heart journal</abbr-1></periodical><alt-periodical><full-title>Eur Heart J</full-title><abbr-1>European heart journal</abbr-1></alt-periodical><pages>280-8</pages><volume>24</volume><number>3</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Cardiomyopathy, Hypertrophic/*etiology/pathology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Echocardiography, Doppler/methods</keyword><keyword>Electrocardiography/methods</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant, Newborn</keyword><keyword>Male</keyword><keyword>Mitochondrial Diseases/*complications/pathology</keyword><keyword>Prognosis</keyword><keyword>Survival Analysis</keyword></keywords><dates><year>2003</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0195-668X (Print) 0195-668X (Linking)</isbn><accession-num>12590906</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/12590906</url></related-urls></urls></record></Cite></EndNote>49 through endocardial biopsies in patients with idiopathic HCM. Mutations that cause complex II abnormalities have also been found in patients with HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmdlbGluaTwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmdlbGluaTwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+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=
ADDIN EN.CITE.DATA 50. Mutation that cause abnormalities in the ATP synthase 6 subunit of complex V have also been found in the patients with HCM and this mutation were present in the heart and not in the other parts of the body like the liver PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHJpc3RpYW5zZW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHJpc3RpYW5zZW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z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ADDIN EN.CITE.DATA 48
Slow generation of anti-oxidant enzymes by the cardiomyocytes, which exposes the heart to high risk of free radical injury. This was proved right by the experiment on exercising mice. The theory have never been proved in human heart, but if so could be a significant cause of increased oxidative stress in the hearts with HCM since mutation in the sarcomere cause increase in their energy cost and hence excessive sarcomere energy use.

Low activity of catalase, as was explained before, catalase is an enzyme that is present in a large number of living cells and acts as antioxidants by reducing the cellular oxidative stress by breaking down hydrogen peroxide into water and oxygen molecules. There has been a report on the reduction on the amount of catalase in the porcine hearts with HCM, which lead into oxidative damage of the heart muscles PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 51.

ROS acts on different signaling pathways to cause the phenotypes present in HCM commonly ones being cardiac hypertrophy and interstitial fibrosis. The common pathways that have been studies thoroughly which are activated by ROS are, MAPK signaling pathway, Akt/mTor signaling pathway, calcineurin/NF-AT signaling pathway and NF-kB signaling pathway. All these are activated in hypertrophic cardiomyopathy and so does ROS plays a great role in activating them already proved in other conditions.
2.2.2. ROS, SIGNALING PATHWAYS AND HCM 2.2.2.1. MAPK signaling pathway
Mitogen-activated protein kinase (MAPK) also called Ras-Raf-MEK-ERK signaling pathways; belong to a family of Serine-Threonine protein kinases. It consist of a small G-protein (RAS) and three protein kinases (RAF, MEK, ERK) ADDIN EN.CITE <EndNote><Cite><Author>McCain</Author><Year>2013</Year><RecNum>78</RecNum><DisplayText>52</DisplayText><record><rec-number>78</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1515761591″>78</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>McCain, J.</author></authors></contributors><titles><title>The MAPK (ERK) Pathway: Investigational Combinations for the Treatment Of BRAF-Mutated Metastatic Melanoma</title><secondary-title>P T</secondary-title><alt-title>P &amp; T : a peer-reviewed journal for formulary management</alt-title></titles><periodical><full-title>P T</full-title><abbr-1>P &amp; T : a peer-reviewed journal for formulary management</abbr-1></periodical><alt-periodical><full-title>P T</full-title><abbr-1>P &amp; T : a peer-reviewed journal for formulary management</abbr-1></alt-periodical><pages>96-108</pages><volume>38</volume><number>2</number><dates><year>2013</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1052-1372 (Print) 1052-1372 (Linking)</isbn><accession-num>23599677</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23599677</url></related-urls></urls><custom2>3628180</custom2></record></Cite></EndNote>52 which sequentially phosphorylates each other in response to a particular stimuli like growth factors, cellular stress and cytokines. Upon ligand binding on the cell membrane receptors like tyrosine kinase or G-protein coupled receptors, the receptor signaling complex is formed that activates RAS by converting GDP bound RAS into GTP. RAS activates c-RAF, which phosphorylate and activate MEK1/2. The latter activate ERK1/2. ERKs do a lot of activities in the cytoplasm and nucleus and one most important is phosphorylation of transcription factors like Myc and regulates gene expression. By so doing the pathway is able to regulate a vast amount of processes in the body like cell growth and development, differentiation and cellular adaptations ADDIN EN.CITE <EndNote><Cite><Author>Orton</Author><Year>2005</Year><RecNum>79</RecNum><DisplayText>53</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1515761722″>79</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Orton, R. J.</author><author>Sturm, O. E.</author><author>Vyshemirsky, V.</author><author>Calder, M.</author><author>Gilbert, D. R.</author><author>Kolch, W.</author></authors></contributors><auth-address>Bioinformatics Research Centre, Department of Computing Science, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.</auth-address><titles><title>Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>249-61</pages><volume>392</volume><number>Pt 2</number><keywords><keyword>Animals</keyword><keyword>*Computer Simulation</keyword><keyword>*MAP Kinase Signaling System</keyword><keyword>Mitogen-Activated Protein Kinase Kinases/*metabolism</keyword><keyword>*Models, Biological</keyword><keyword>Receptor Protein-Tyrosine Kinases/*metabolism</keyword></keywords><dates><year>2005</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1470-8728 (Electronic) 0264-6021 (Linking)</isbn><accession-num>16293107</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16293107</url></related-urls></urls><custom2>1316260</custom2><electronic-resource-num>10.1042/BJ20050908</electronic-resource-num></record></Cite></EndNote>53. The pathway is deactivated by deactivating RAS through GTpase activating proteins (GAPs), these convert GTP of RAS back to GDP which is its inactive form. MAPK superfamily is divided in subfamilies known as extracellular responsive kinases (ERKs) and the two “stress-responsive” MAPK subfamilies, namely, the c-Jun N-terminal kinases (JNKs) and the p38-MAPKs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JjZTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
Y051bT4yNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNTQtNTZdPC9EaXNwbGF5VGV4dD48cmVjb3Jk
PjxyZWMtbnVtYmVyPjI0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk
Yi1pZD0iMGVkYXN4YWVhcjl6MDRld3NheXYyZnJnZWR4YXo5ZGVwOTB6IiB0aW1lc3RhbXA9IjE1
MTIzMDk1MjUiPjI0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg
QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Gb3Jj
ZSwgVC48L2F1dGhvcj48YXV0aG9yPlBvbWJvLCBDLiBNLjwvYXV0aG9yPjxhdXRob3I+QXZydWNo
LCBKLiBBLjwvYXV0aG9yPjxhdXRob3I+Qm9udmVudHJlLCBKLiBWLjwvYXV0aG9yPjxhdXRob3I+
S3lyaWFraXMsIEouIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk
ZHJlc3M+Q2FyZGlhYyBVbml0LCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIENoYXJs
ZXN0b3duIDAyMTI5LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U3RyZXNzLWFj
dGl2YXRlZCBwcm90ZWluIGtpbmFzZXMgaW4gY2FyZGlvdmFzY3VsYXIgZGlzZWFzZTwvdGl0bGU+
PHNlY29uZGFyeS10aXRsZT5DaXJjIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q2ly
Y3VsYXRpb24gcmVzZWFyY2g8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10
aXRsZT5DaXJjIFJlczwvZnVsbC10aXRsZT48YWJici0xPkNpcmN1bGF0aW9uIHJlc2VhcmNoPC9h
YmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaXJjIFJlczwv
ZnVsbC10aXRsZT48YWJici0xPkNpcmN1bGF0aW9uIHJlc2VhcmNoPC9hYmJyLTE+PC9hbHQtcGVy
aW9kaWNhbD48cGFnZXM+OTQ3LTUzPC9wYWdlcz48dm9sdW1lPjc4PC92b2x1bWU+PG51bWJlcj42
PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2Fy
ZGlvdmFzY3VsYXIgRGlzZWFzZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+R1RQLUJp
bmRpbmcgUHJvdGVpbnMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv
cmQ+PGtleXdvcmQ+SW5mbGFtbWF0aW9uL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SXNj
aGVtaWEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qSk5LIE1pdG9nZW4tQWN0aXZhdGVk
IFByb3RlaW4gS2luYXNlczwva2V5d29yZD48a2V5d29yZD5NQVAgS2luYXNlIEtpbmFzZSA0PC9r
ZXl3b3JkPjxrZXl3b3JkPipNaXRvZ2VuLUFjdGl2YXRlZCBQcm90ZWluIEtpbmFzZSBLaW5hc2Vz
PC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4gS2luYXNlcy8qcGh5c2lvbG9neTwva2V5d29yZD48
a2V5d29yZD5UcmFuc2NyaXB0aW9uIEZhY3RvcnMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29y
ZD5UdW1vciBOZWNyb3NpcyBGYWN0b3ItYWxwaGEvcGh5c2lvbG9neTwva2V5d29yZD48L2tleXdv
cmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwv
cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwOS03MzMwIChQcmludCkmI3hEOzAwMDktNzMzMCAo
TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+ODYzNTI0NDwvYWNjZXNzaW9uLW51bT48dXJs
cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC84
NjM1MjQ0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48
QXV0aG9yPkt5cmlha2lzPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVjTnVtPjI1PC9SZWNO
dW0+PHJlY29yZD48cmVjLW51bWJlcj4yNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9IjBlZGFzeGFlYXI5ejA0ZXdzYXl2MmZyZ2VkeGF6OWRlcDkweiIgdGlt
ZXN0YW1wPSIxNTEyMzA5NzA5Ij4yNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l
PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh
dXRob3I+S3lyaWFraXMsIEouIE0uPC9hdXRob3I+PGF1dGhvcj5BdnJ1Y2gsIEouPC9hdXRob3I+
PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGlhYmV0ZXMgVW5pdCwgTWFz
c2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBDaGFybGVzdG93biwgVVNBLjwvYXV0aC1hZGRy
ZXNzPjx0aXRsZXM+PHRpdGxlPlByb3RlaW4ga2luYXNlIGNhc2NhZGVzIGFjdGl2YXRlZCBieSBz
dHJlc3MgYW5kIGluZmxhbW1hdG9yeSBjeXRva2luZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+
QmlvZXNzYXlzPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5CaW9Fc3NheXMgOiBuZXdzIGFu
ZCByZXZpZXdzIGluIG1vbGVjdWxhciwgY2VsbHVsYXIgYW5kIGRldmVsb3BtZW50YWwgYmlvbG9n
eTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJpb2Vzc2F5czwv
ZnVsbC10aXRsZT48YWJici0xPkJpb0Vzc2F5cyA6IG5ld3MgYW5kIHJldmlld3MgaW4gbW9sZWN1
bGFyLCBjZWxsdWxhciBhbmQgZGV2ZWxvcG1lbnRhbCBiaW9sb2d5PC9hYmJyLTE+PC9wZXJpb2Rp
Y2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CaW9lc3NheXM8L2Z1bGwtdGl0bGU+PGFi
YnItMT5CaW9Fc3NheXMgOiBuZXdzIGFuZCByZXZpZXdzIGluIG1vbGVjdWxhciwgY2VsbHVsYXIg
YW5kIGRldmVsb3BtZW50YWwgYmlvbG9neTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2Vz
PjU2Ny03NzwvcGFnZXM+PHZvbHVtZT4xODwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxrZXl3
b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkNhbGNpdW0tQ2FsbW9kdWxp
bi1EZXBlbmRlbnQgUHJvdGVpbiBLaW5hc2VzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+
Q3l0b2tpbmVzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWF0aW9uLypt
ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1hbW1hbHMvbWV0YWJvbGlzbTwva2V5d29yZD48
a2V5d29yZD5Qcm90ZWluIEtpbmFzZXMvY2hlbWlzdHJ5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxr
ZXl3b3JkPlNhY2NoYXJvbXljZXMgY2VyZXZpc2lhZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3
b3JkPlNpZ25hbCBUcmFuc2R1Y3Rpb24vcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5TdHJl
c3MsIFBoeXNpb2xvZ2ljYWw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5Njwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjAyNjUtOTI0NyAoUHJpbnQpJiN4RDswMjY1LTkyNDcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np
b24tbnVtPjg3NTc5MzU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0
dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODc1NzkzNTwvdXJsPjwvcmVsYXRlZC11
cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9iaWVzLjk1MDE4MDcw
ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+
Um9iaW5zb248L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxSZWNOdW0+MjY8L1JlY051bT48cmVj
b3JkPjxyZWMtbnVtYmVyPjI2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0iMGVkYXN4YWVhcjl6MDRld3NheXYyZnJnZWR4YXo5ZGVwOTB6IiB0aW1lc3RhbXA9
IjE1MTIzMDk4NjciPjI2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5S
b2JpbnNvbiwgTS4gSi48L2F1dGhvcj48YXV0aG9yPkNvYmIsIE0uIEguPC9hdXRob3I+PC9hdXRo
b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0eSBvZiBUZXhhcyBTb3V0
aHdlc3Rlcm4gTWVkaWNhbCBDZW50ZXIsIDUzMjMgSGFycnkgSGluZXMgQm91bGV2YXJkLCBEYWxs
YXMsIFRYIDc1MjM1LTkwNCwxIFVTQS4gbWVnYW5AaG93aWUuc3dtZWQuZWR1PC9hdXRoLWFkZHJl
c3M+PHRpdGxlcz48dGl0bGU+TWl0b2dlbi1hY3RpdmF0ZWQgcHJvdGVpbiBraW5hc2UgcGF0aHdh
eXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q3VyciBPcGluIENlbGwgQmlvbDwvc2Vjb25kYXJ5
LXRpdGxlPjxhbHQtdGl0bGU+Q3VycmVudCBvcGluaW9uIGluIGNlbGwgYmlvbG9neTwvYWx0LXRp
dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkN1cnIgT3BpbiBDZWxsIEJpb2w8
L2Z1bGwtdGl0bGU+PGFiYnItMT5DdXJyZW50IG9waW5pb24gaW4gY2VsbCBiaW9sb2d5PC9hYmJy
LTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DdXJyIE9waW4gQ2Vs
bCBCaW9sPC9mdWxsLXRpdGxlPjxhYmJyLTE+Q3VycmVudCBvcGluaW9uIGluIGNlbGwgYmlvbG9n
eTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjE4MC02PC9wYWdlcz48dm9sdW1lPjk8
L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5
d29yZD48a2V5d29yZD5DYWxjaXVtLUNhbG1vZHVsaW4tRGVwZW5kZW50IFByb3RlaW4gS2luYXNl
cy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+
TUFQIEtpbmFzZSBLaW5hc2UgMTwva2V5d29yZD48a2V5d29yZD4qTUFQIEtpbmFzZSBLaW5hc2Ug
S2luYXNlIDE8L2tleXdvcmQ+PGtleXdvcmQ+TWFtbWFsczwva2V5d29yZD48a2V5d29yZD4qTWl0
b2dlbi1BY3RpdmF0ZWQgUHJvdGVpbiBLaW5hc2UgS2luYXNlczwva2V5d29yZD48a2V5d29yZD5Q
cm90ZWluLVNlcmluZS1UaHJlb25pbmUgS2luYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3
b3JkPlByb3RlaW4tVHlyb3NpbmUgS2luYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk
PlByb3RvLU9uY29nZW5lIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UHJv
dG8tT25jb2dlbmUgUHJvdGVpbnMgYy1yYWY8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5z
ZHVjdGlvbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk3PC95ZWFyPjxwdWIt
ZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDk1NS0wNjc0
IChQcmludCkmI3hEOzA5NTUtMDY3NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+OTA2
OTI1NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u
Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC85MDY5MjU1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz
PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JjZTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl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ADDIN EN.CITE.DATA 54-56. These are named so due to their induction by physical, chemical and physiological stressors such as ultraviolet (UV) light, oxidative stress, osmotic shock, infection, and cytokines ADDIN EN.CITE <EndNote><Cite><Author>Kyriakis</Author><Year>2001</Year><RecNum>877</RecNum><DisplayText>57</DisplayText><record><rec-number>877</rec-number><foreign-keys><key app=”EN” db-id=”fxr5waddv5afa0ee0e9xdvtesevf9s55fvwe” timestamp=”1497058557″>877</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Kyriakis, J. M.</author><author>Avruch, J.</author></authors></contributors><auth-address>Diabetes Research Laboratory, Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02129, USA. [email protected]</auth-address><titles><title>Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation</title><secondary-title>Physiol Rev</secondary-title><alt-title>Physiological reviews</alt-title></titles><periodical><full-title>Physiol Rev</full-title><abbr-1>Physiological reviews</abbr-1></periodical><alt-periodical><full-title>Physiol Rev</full-title><abbr-1>Physiological reviews</abbr-1></alt-periodical><pages>807-69</pages><volume>81</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Cytokines/physiology</keyword><keyword>Humans</keyword><keyword>Inflammation/*physiopathology</keyword><keyword>MAP Kinase Signaling System/*physiology</keyword><keyword>Mammals</keyword><keyword>Mitogen-Activated Protein Kinases/*metabolism</keyword><keyword>Stress, Physiological/*physiopathology</keyword><keyword>p38 Mitogen-Activated Protein Kinases</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0031-9333 (Print) 0031-9333 (Linking)</isbn><accession-num>11274345</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11274345</url></related-urls></urls></record></Cite></EndNote>57.

Figure SEQ Figure * ARABIC 4; The MAPK signaling pathway,.Figure shows the intermediary downstream effectors and the end action produced by the pathway.

Involvement of MAPK signaling in the pathogenesis of HCM have largely been proven and the majority of disease happen due to mutation of genes coding for RAS and RAF proteins as described well by Bruce et al who explained RAS and RAF 1 mutation in HCM. Most of these mutations cause over activation of ERK1/2 that later lead into HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZWxiPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZWxiPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA 58, 59. In these cases gene therapy or blocking the over activated pathway could be a proper way forward, this was well demonstrated by Bruce and colleague, where MEK inhibitors prevented and even reversed the development of HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZWxiPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZWxiPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA 58. In a transgenic rabbit model of ?-MyHC HCM, ERK1/2 were highly activated, upon treatment with simvastatin, cardiac hypertrophy and interstitial fibrosis were reduced and the cardiac function improved significantly compared to the control groups. Simvastatin acted by reducing the level of activated ERK1/2 and no effect was reported on RAS, while in the same type of model, Atorvastatin had the same effect but through inhibition of RAS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRlbDwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRlbDwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl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ADDIN EN.CITE.DATA 16, 26. MAPK signaling has been reported to participate largely in the cardiac hypertrophy even in cases, which are not classical HCM, this was proved by resultant inhibition of cardiac hypertrophy by MEK inhibitors and RAF inhibitors after giving hypertrophic agonists (Endothelin 1 and Phenyephrine) which activated MAPK signaling firstPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZdWU8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZdWU8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 60.

On the other hand, ROS (oxidative stress) have been reported to play a greater role in the activation of MAPK signaling pathway. The activation is done mostly through RAS protein. RAS contains six cysteine residues four of which are on the surface and are the active ones ADDIN EN.CITE <EndNote><Cite><Author>Mallis</Author><Year>2001</Year><RecNum>5</RecNum><DisplayText>61</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1512316477″>5</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Mallis, R. J.</author><author>Buss, J. E.</author><author>Thomas, J. A.</author></authors></contributors><auth-address>Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, U.S.A.</auth-address><titles><title>Oxidative modification of H-ras: S-thiolation and S-nitrosylation of reactive cysteines</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>145-53</pages><volume>355</volume><number>Pt 1</number><keywords><keyword>3T3 Cells</keyword><keyword>Animals</keyword><keyword>Cysteine/*metabolism</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Mice</keyword><keyword>Nitroso Compounds/*metabolism</keyword><keyword>Oncogene Protein p21(ras)/chemistry/*metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Precipitin Tests</keyword><keyword>Sulfhydryl Compounds/*metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr 1</date></pub-dates></dates><isbn>0264-6021 (Print) 0264-6021 (Linking)</isbn><accession-num>11256959</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11256959</url></related-urls></urls><custom2>1221722</custom2></record></Cite></EndNote>61. These four cysteines have reactive thiol groups, which can undergo oxidative modification like S-Nitrosylation or S-Glutathiolation during normal or pathological cellular events ADDIN EN.CITE <EndNote><Cite><Author>Gabriela M. Kuster</Author><Year>2005</Year><RecNum>6</RecNum><DisplayText>62</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1512318507″>6</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Gabriela M. Kuster, MD</author><author>David R. Pimentel, MD</author><author>Takeshi Adachi, MD, PhD</author><author>Yasuo Ido, MD, PhD</author><author>Daniel A. Brenner, MA</author><author>Richard A. Cohen, MD</author><author>Ronglih Liao, PhD</author><author>Deborah A. Siwik, PhD</author><author>Wilson S. Colucci, MD</author></authors></contributors><titles><title>Alpha-Adrenergic Receptor–Stimulated Hypertrophy in Adult Rat Ventricular Myocytes Is Mediated via Thioredoxin-1–Sensitive Oxidative Modification of Thiols on Ras</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><dates><year>2005</year></dates><urls><related-urls><url>http://www.circulationaha.or</url></related-urls></urls><electronic-resource-num>10.1161/01.CIR.0000157148.59308.F5</electronic-resource-num></record></Cite></EndNote>62. When they undergo oxidative modification, the GTP/GDP ratio is affected and changes its activities ADDIN EN.CITE <EndNote><Cite><Author>Mallis</Author><Year>2001</Year><RecNum>5</RecNum><DisplayText>61</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1512316477″>5</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Mallis, R. J.</author><author>Buss, J. E.</author><author>Thomas, J. A.</author></authors></contributors><auth-address>Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, U.S.A.</auth-address><titles><title>Oxidative modification of H-ras: S-thiolation and S-nitrosylation of reactive cysteines</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>145-53</pages><volume>355</volume><number>Pt 1</number><keywords><keyword>3T3 Cells</keyword><keyword>Animals</keyword><keyword>Cysteine/*metabolism</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Mice</keyword><keyword>Nitroso Compounds/*metabolism</keyword><keyword>Oncogene Protein p21(ras)/chemistry/*metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Precipitin Tests</keyword><keyword>Sulfhydryl Compounds/*metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr 1</date></pub-dates></dates><isbn>0264-6021 (Print) 0264-6021 (Linking)</isbn><accession-num>11256959</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11256959</url></related-urls></urls><custom2>1221722</custom2></record></Cite></EndNote>61 which mostly is activation of the cell signaling pathway. In cell cultures, H202 activated different members of MAPK superfamily and cause ERK activity to increase about 25 folds while other members like JNK and P38 activities increased in about 3-5 folds than the controlsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXl0b248L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXl0b248L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 63 and this activation was largely inhibited by an antioxidant NACPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV2ZW5zb248L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV2ZW5zb248L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFy
PjxSZWNOdW0+ODY8L1JlY051bT48RGlzcGxheVRleHQ+WzY0XTwvRGlzcGxheVRleHQ+PHJlY29y
ZD48cmVjLW51bWJlcj44NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg
ZGItaWQ9ImRlcmZldDB6azl3eHNyZXRwMDlwend4cng1MGRmdnhhcjU5MiIgdGltZXN0YW1wPSIx
NTE5NzE0NDM2Ij44Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFs
IEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3Rl
dmVuc29uLCBNLiBBLjwvYXV0aG9yPjxhdXRob3I+UG9sbG9jaywgUy4gUy48L2F1dGhvcj48YXV0
aG9yPkNvbGVtYW4sIEMuIE4uPC9hdXRob3I+PGF1dGhvcj5DYWxkZXJ3b29kLCBTLiBLLjwvYXV0
aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRhbmEgRmFyYmVyIENh
bmNlciBJbnN0aXR1dGUsIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTWFzc2FjaHVz
ZXR0cyAwMjExNS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5YLWlycmFkaWF0aW9uLCBw
aG9yYm9sIGVzdGVycywgYW5kIEgyTzIgc3RpbXVsYXRlIG1pdG9nZW4tYWN0aXZhdGVkIHByb3Rl
aW4ga2luYXNlIGFjdGl2aXR5IGluIE5JSC0zVDMgY2VsbHMgdGhyb3VnaCB0aGUgZm9ybWF0aW9u
IG9mIHJlYWN0aXZlIG94eWdlbiBpbnRlcm1lZGlhdGVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl
PkNhbmNlciBSZXM8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkNhbmNlciByZXNlYXJjaDwv
YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNhbmNlciBSZXM8L2Z1
bGwtdGl0bGU+PGFiYnItMT5DYW5jZXIgcmVzZWFyY2g8L2FiYnItMT48L3BlcmlvZGljYWw+PGFs
dC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNhbmNlciBSZXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5D
YW5jZXIgcmVzZWFyY2g8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4xMi01PC9wYWdl
cz48dm9sdW1lPjU0PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk
PjNUMyBDZWxsczwva2V5d29yZD48a2V5d29yZD5BY2V0eWxjeXN0ZWluZS9waGFybWFjb2xvZ3k8
L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtLUNhbG1v
ZHVsaW4tRGVwZW5kZW50IFByb3RlaW4gS2luYXNlcy9kcnVnIGVmZmVjdHMvKm1ldGFib2xpc20v
cmFkaWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+RG93
bi1SZWd1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZSBBY3RpdmF0aW9uL2RydWcgZWZm
ZWN0cy9yYWRpYXRpb24gZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5IeWRyb2dlbiBQZXJveGlk
ZS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5P
eGlkYXRpb24tUmVkdWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5
d29yZD48a2V5d29yZD5Qcm90ZWluIEtpbmFzZSBDL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv
cmQ+UmVhY3RpdmUgT3h5Z2VuIFNwZWNpZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+
VGV0cmFkZWNhbm95bHBob3Jib2wgQWNldGF0ZS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PC9rZXl3
b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbiAxPC9kYXRl
PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwOC01NDcyIChQcmludCkmI3hEOzAwMDgtNTQ3
MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+ODI2MTQzMTwvYWNjZXNzaW9uLW51bT48
dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l
ZC84MjYxNDMxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu
ZE5vdGU+
ADDIN EN.CITE.DATA 64. Inhibiting rise in H2O2 inhibited MAPK pathway activation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kYXJlc2FuPC9BdXRob3I+PFllYXI+MTk5NjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kYXJlc2FuPC9BdXRob3I+PFllYXI+MTk5NjwvWWVh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ADDIN EN.CITE.DATA 65. All these emphasize on the importance of ROS in MAPK signaling. Growth factors have been known to activate MAPK pathway, this activation depends on the production ROS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JcmFuaTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JcmFuaTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJl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ADDIN EN.CITE.DATA 66.

ROS activating MAPK pathway have largely been reported in causing myocardial hypertrophy. The ?-Adrenoceptor causes cellular hypertrophy by increasing protein synthesis and sarcomere organization. In adult rat, ventricular myocyte hypertrophy by ? -Adrenoceptor stimulation, was through activation of MAPK signaling pathway, the activation was highly inhibited by TRX 1 (Theoredoxin-1) which is an oxidoreductase that maintains intracellular thiols in a reduced state, by so doing it prevents oxidation of RAS thiols and prevents activation of MAPK signaling. TRX 1 over expression inhibited cardiac hypertrophy and sarcomere organization in rat’s ventricular myocytes ADDIN EN.CITE <EndNote><Cite><Author>Gabriela M. Kuster</Author><Year>2005</Year><RecNum>6</RecNum><DisplayText>62</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1512318507″>6</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Gabriela M. Kuster, MD</author><author>David R. Pimentel, MD</author><author>Takeshi Adachi, MD, PhD</author><author>Yasuo Ido, MD, PhD</author><author>Daniel A. Brenner, MA</author><author>Richard A. Cohen, MD</author><author>Ronglih Liao, PhD</author><author>Deborah A. Siwik, PhD</author><author>Wilson S. Colucci, MD</author></authors></contributors><titles><title>Alpha-Adrenergic Receptor–Stimulated Hypertrophy in Adult Rat Ventricular Myocytes Is Mediated via Thioredoxin-1–Sensitive Oxidative Modification of Thiols on Ras</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><dates><year>2005</year></dates><urls><related-urls><url>http://www.circulationaha.or</url></related-urls></urls><electronic-resource-num>10.1161/01.CIR.0000157148.59308.F5</electronic-resource-num></record></Cite></EndNote>62. Left ventricular hypertrophy due to pressure overload is also reported to be due to ROS activation of MAPK signaling, in here ROS was due o increase in the activity of NADPH oxidase ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2002</Year><RecNum>89</RecNum><DisplayText>67</DisplayText><record><rec-number>89</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1519724848″>89</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Li, J. M.</author><author>Gall, N. P.</author><author>Grieve, D. J.</author><author>Chen, M.</author><author>Shah, A. M.</author></authors></contributors><auth-address>Department of Cardiology, Guy&apos;s King&apos;s &amp; St Thomas&apos; School of Medicine (Denmark Hill Campus), King&apos;s College London, London, United Kingdom.</auth-address><titles><title>Activation of NADPH oxidase during progression of cardiac hypertrophy to failure</title><secondary-title>Hypertension</secondary-title><alt-title>Hypertension</alt-title></titles><periodical><full-title>Hypertension</full-title><abbr-1>Hypertension</abbr-1></periodical><alt-periodical><full-title>Hypertension</full-title><abbr-1>Hypertension</abbr-1></alt-periodical><pages>477-84</pages><volume>40</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Disease Progression</keyword><keyword>Enzyme Activation</keyword><keyword>Guinea Pigs</keyword><keyword>Heart Failure/*enzymology/etiology</keyword><keyword>Hypertrophy, Left Ventricular/*enzymology/etiology</keyword><keyword>Male</keyword><keyword>Mitogen-Activated Protein Kinases/metabolism</keyword><keyword>Myocardium/enzymology</keyword><keyword>NADPH Oxidases/*metabolism</keyword><keyword>Phosphorylation</keyword><keyword>Protein Subunits</keyword><keyword>Reactive Oxygen Species/metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1524-4563 (Electronic) 0194-911X (Linking)</isbn><accession-num>12364350</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/12364350</url></related-urls></urls></record></Cite></EndNote>67.

Having high oxidative stress in patients with HCM and the activation of MAPK pathway in the disease pathogenesis makes oxidative stress a possible activator of MAPK pathway, which leads into development of the cardiac hypertrophy and other phenotypes in patients with HCM. There is few if any research done on the activation of MAPK by ROS as a possible mechanism that leads into expression of the phenotypes present in HCM. Further research need to be done on this pathway to widen the options for possible disease cure.

2.2.2.2. PI3K- AKT- mTOR signaling pathway;
This is an intracellular signaling pathway which does many of cellular functions and most importantly it controls the cell cycle, by so doing it is directly involved in cellular quiescence, cellular proliferation and even in cancers. The pathway is activated by various factors like growth factors, hormones, and cytokines. In the process of activation, the ligand binds the membranous embedded receptor tyrosine kinase (RTK) and cause receptor phosphorylation, the Insulin receptor substrate 1 (IRS1) binds the phosphorylated site and act as an anchor and activator of Phosphotidylinositol-3- kinase (PI3K), the PI3K can also bind directly on the phosphorylated receptor and becomes activated. The third mechanism in which PI3K is activated is by binding the activated RAS-GTP. The activated PI3K migrates to the inner side of the membrane and binds PIP2, which is a regular component in the cell membrane and phosphorylate it to form (Phosphatidylinositol- 3,4,5 -triphosphate) PIP3. PIP3 activate AKT, a protooncoprotein with a vast amount of substrates in its downstream. Through its action on various substrates, AKT inhibits Apoptosis and activates protein synthesis. One of the most important downstream effectors of AKT is MTOR (Mammalian target of Rapamycin), which is activated by AKT through Rheb protein. MTOR activates a translation factor S6K that binds the large ribosomal subunit and activates translation of MRNA into proteins PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZW1taW5nczwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZW1taW5nczwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+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==
ADDIN EN.CITE.DATA 68, 69.

Figure SEQ Figure * ARABIC 5; PI3K/Akt/mTOR signaling cascadeSignaling through a trans-membrane receptor activates the PI3K signaling which phosphorylate Akt and exerts its functions like promoting cell proliferation through mTOR. There are multiple feedback loops that have been shown which are currently the target for many therapies including cancer therapy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWw8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWw8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 70.

PI3K/AKT pathway plays an important role in cardiac functions and diseases. It regulates different cardiac functions like metabolism, protein synthesis and inhibition of apoptosis hence cardiac adaptation ADDIN EN.CITE <EndNote><Cite><Author>Harvey</Author><Year>2011</Year><RecNum>13</RecNum><DisplayText>71</DisplayText><record><rec-number>13</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1514979867″>13</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Harvey, P. A.</author><author>Leinwand, L. A.</author></authors></contributors><auth-address>Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, USA.</auth-address><titles><title>The cell biology of disease: cellular mechanisms of cardiomyopathy</title><secondary-title>J Cell Biol</secondary-title><alt-title>The Journal of cell biology</alt-title></titles><periodical><full-title>J Cell Biol</full-title><abbr-1>The Journal of cell biology</abbr-1></periodical><alt-periodical><full-title>J Cell Biol</full-title><abbr-1>The Journal of cell biology</abbr-1></alt-periodical><pages>355-65</pages><volume>194</volume><number>3</number><keywords><keyword>Apoptosis</keyword><keyword>Cardiomyopathies/genetics/*pathology/*physiopathology</keyword><keyword>Heart/*physiopathology</keyword><keyword>Humans</keyword><keyword>Myocardium/metabolism/*pathology</keyword><keyword>Necrosis</keyword><keyword>Phosphatidylinositol 3-Kinases/metabolism</keyword><keyword>Proto-Oncogene Proteins c-akt/metabolism</keyword><keyword>Signal Transduction/genetics</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug 8</date></pub-dates></dates><isbn>1540-8140 (Electronic) 0021-9525 (Linking)</isbn><accession-num>21825071</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21825071</url></related-urls></urls><custom2>3153638</custom2><electronic-resource-num>10.1083/jcb.201101100</electronic-resource-num></record></Cite></EndNote>71. MTOR exerts its action through two distinct multiprotein complexes, MTOR complex 1 (mTORC1) and MTOR complex 2 (MTORC2) ADDIN EN.CITE <EndNote><Cite><Author>Sciarretta</Author><Year>2014</Year><RecNum>18</RecNum><DisplayText>72</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1514988635″>18</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Sciarretta, S.</author><author>Volpe, M.</author><author>Sadoshima, J.</author></authors></contributors><auth-address>From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ (S.S., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S., M.V.); and Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University Sapienza, Rome, Italy (M.V.).</auth-address><titles><title>Mammalian target of rapamycin signaling in cardiac physiology and disease</title><secondary-title>Circ Res</secondary-title><alt-title>Circulation research</alt-title></titles><periodical><full-title>Circ Res</full-title><abbr-1>Circulation research</abbr-1></periodical><alt-periodical><full-title>Circ Res</full-title><abbr-1>Circulation research</abbr-1></alt-periodical><pages>549-64</pages><volume>114</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Heart Diseases/*metabolism/pathology/*physiopathology</keyword><keyword>Humans</keyword><keyword>Myocardium/cytology/metabolism/pathology</keyword><keyword>Signal Transduction/*physiology</keyword><keyword>TOR Serine-Threonine Kinases/*physiology</keyword></keywords><dates><year>2014</year><pub-dates><date>Jan 31</date></pub-dates></dates><isbn>1524-4571 (Electronic) 0009-7330 (Linking)</isbn><accession-num>24481845</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/24481845</url></related-urls></urls><custom2>3995130</custom2><electronic-resource-num>10.1161/CIRCRESAHA.114.302022</electronic-resource-num></record></Cite></EndNote>72. MTORC1 regulates cellular functions like protein synthesis, cell growth and proliferation, cell metabolism, autophagy, and stress responses, and MTORC2 seems to regulate cell survival and polarity ADDIN EN.CITE <EndNote><Cite><Author>Sciarretta</Author><Year>2014</Year><RecNum>18</RecNum><DisplayText>72</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1514988635″>18</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Sciarretta, S.</author><author>Volpe, M.</author><author>Sadoshima, J.</author></authors></contributors><auth-address>From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ (S.S., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S., M.V.); and Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University Sapienza, Rome, Italy (M.V.).</auth-address><titles><title>Mammalian target of rapamycin signaling in cardiac physiology and disease</title><secondary-title>Circ Res</secondary-title><alt-title>Circulation research</alt-title></titles><periodical><full-title>Circ Res</full-title><abbr-1>Circulation research</abbr-1></periodical><alt-periodical><full-title>Circ Res</full-title><abbr-1>Circulation research</abbr-1></alt-periodical><pages>549-64</pages><volume>114</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Heart Diseases/*metabolism/pathology/*physiopathology</keyword><keyword>Humans</keyword><keyword>Myocardium/cytology/metabolism/pathology</keyword><keyword>Signal Transduction/*physiology</keyword><keyword>TOR Serine-Threonine Kinases/*physiology</keyword></keywords><dates><year>2014</year><pub-dates><date>Jan 31</date></pub-dates></dates><isbn>1524-4571 (Electronic) 0009-7330 (Linking)</isbn><accession-num>24481845</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/24481845</url></related-urls></urls><custom2>3995130</custom2><electronic-resource-num>10.1161/CIRCRESAHA.114.302022</electronic-resource-num></record></Cite></EndNote>72.
mTor pathway have been reported to participate in the pathogenesis of HCM. In mutant mice with Ptpn 11 mutation having Leopards syndrome and concurrent HCM, the Akt/mTor pathway was hyper activated in the heart muscles. Other pathways like MAPK pathways were also activated. Upon a short-term treatment with Rapamycin, all the cardiac phenotypes disappeared which showed the potential involvement of Akt/mTor pathway in inducing HCM phenotypes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
Y051bT4yMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNzNdPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxy
ZWMtbnVtYmVyPjIzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p
ZD0iZGVyZmV0MHprOXd4c3JldHAwOXB6d3hyeDUwZGZ2eGFyNTkyIiB0aW1lc3RhbXA9IjE1MTQ5
ODk0NTkiPjIzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0
aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5NYXJpbiwg
VC4gTS48L2F1dGhvcj48YXV0aG9yPktlaXRoLCBLLjwvYXV0aG9yPjxhdXRob3I+RGF2aWVzLCBC
LjwvYXV0aG9yPjxhdXRob3I+Q29ubmVyLCBELiBBLjwvYXV0aG9yPjxhdXRob3I+R3VoYSwgUC48
L2F1dGhvcj48YXV0aG9yPkthbGFpdHppZGlzLCBELjwvYXV0aG9yPjxhdXRob3I+V3UsIFguPC9h
dXRob3I+PGF1dGhvcj5MYXVyaW9sLCBKLjwvYXV0aG9yPjxhdXRob3I+V2FuZywgQi48L2F1dGhv
cj48YXV0aG9yPkJhdWVyLCBNLjwvYXV0aG9yPjxhdXRob3I+QnJvbnNvbiwgUi48L2F1dGhvcj48
YXV0aG9yPkZyYW5jaGluaSwgSy4gRy48L2F1dGhvcj48YXV0aG9yPk5lZWwsIEIuIEcuPC9hdXRo
b3I+PGF1dGhvcj5Lb250YXJpZGlzLCBNLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1
dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTWVkaWNpbmUsIERpdmlzaW9uIG9mIENh
cmRpb2xvZ3ksIEJldGggSXNyYWVsIERlYWNvbmVzcyBNZWRpY2FsIENlbnRlciwgQm9zdG9uLCBN
YXNzYWNodXNldHRzIDAyMTE1LCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmFw
YW15Y2luIHJldmVyc2VzIGh5cGVydHJvcGhpYyBjYXJkaW9teW9wYXRoeSBpbiBhIG1vdXNlIG1v
ZGVsIG9mIExFT1BBUkQgc3luZHJvbWUtYXNzb2NpYXRlZCBQVFBOMTEgbXV0YXRpb248L3RpdGxl
PjxzZWNvbmRhcnktdGl0bGU+SiBDbGluIEludmVzdDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0
bGU+VGhlIEpvdXJuYWwgb2YgY2xpbmljYWwgaW52ZXN0aWdhdGlvbjwvYWx0LXRpdGxlPjwvdGl0
bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQ2xpbiBJbnZlc3Q8L2Z1bGwtdGl0bGU+PGFi
YnItMT5UaGUgSm91cm5hbCBvZiBjbGluaWNhbCBpbnZlc3RpZ2F0aW9uPC9hYmJyLTE+PC9wZXJp
b2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIENsaW4gSW52ZXN0PC9mdWxsLXRp
dGxlPjxhYmJyLTE+VGhlIEpvdXJuYWwgb2YgY2xpbmljYWwgaW52ZXN0aWdhdGlvbjwvYWJici0x
PjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjEwMjYtNDM8L3BhZ2VzPjx2b2x1bWU+MTIxPC92b2x1
bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+
PGtleXdvcmQ+Q2FyZGlvbXlvcGF0aHksIEh5cGVydHJvcGhpYy8qZHJ1ZyB0aGVyYXB5LypnZW5l
dGljczwva2V5d29yZD48a2V5d29yZD5DYXRhbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RWNob2Nh
cmRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVt
YW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1cHByZXNzaXZlIEFnZW50cy8qcGhhcm1hY29s
b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkxFT1BBUkQgU3luZHJvbWUvKmRydWcgdGhlcmFweS8qZ2Vu
ZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3
b3JkPjxrZXl3b3JkPipNdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5QaGVub3R5cGU8L2tleXdv
cmQ+PGtleXdvcmQ+UHJvdGVpbiBUeXJvc2luZSBQaG9zcGhhdGFzZSwgTm9uLVJlY2VwdG9yIFR5
cGUgMTEvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1Y3Rpb248L2tl
eXdvcmQ+PGtleXdvcmQ+U2lyb2xpbXVzLypwaGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+
VE9SIFNlcmluZS1UaHJlb25pbmUgS2luYXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29y
ZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9w
dWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTU4LTgyMzggKEVsZWN0cm9uaWMpJiN4RDswMDIxLTk3
MzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxMzM5NjQzPC9hY2Nlc3Npb24tbnVt
Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi
bWVkLzIxMzM5NjQzPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjMwNDkzNzc8
L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNzIvSkNJNDQ5NzI8L2VsZWN0
cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA 73. Rapamycin is an inhibitor of Akt/mTor pathway, which acts by destabilizing mTor-Raptor complex PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxsb3U8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxsb3U8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 74, 75. While all these reports are from mutant mice, a report of a patient having Noonan syndrome with multiple lentigines (NSML) with a rapid progressive HCM, showed above level activities of Akt/mTor signaling where the cardiac functions were also improved by a Rapamycin analogue EverolimusPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWhuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWhuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA 59. Mutation in the PTEN caused deregulation of PI3K/Akt/mTor pathway that ended up with HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA 76. PTEN is PIP3 inhibitor as it prevents phosphorylation of PIP2 ADDIN EN.CITE <EndNote><Cite><Author>Leslie</Author><Year>2002</Year><RecNum>26</RecNum><DisplayText>77</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1514991404″>26</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Leslie, N. R.</author><author>Downes, C. P.</author></authors></contributors><auth-address>Division of Cell Signalling, School of Life Sciences, Medical Sciences Institute, University of Dundee, DD1 5EH Scotland, Dundee, UK. [email protected]</auth-address><titles><title>PTEN: The down side of PI 3-kinase signalling</title><secondary-title>Cell Signal</secondary-title><alt-title>Cellular signalling</alt-title></titles><periodical><full-title>Cell Signal</full-title><abbr-1>Cellular signalling</abbr-1></periodical><alt-periodical><full-title>Cell Signal</full-title><abbr-1>Cellular signalling</abbr-1></alt-periodical><pages>285-95</pages><volume>14</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Inositol Phosphates/chemistry/metabolism</keyword><keyword>Models, Biological</keyword><keyword>PTEN Phosphohydrolase</keyword><keyword>Phosphatidylinositol 3-Kinases/*antagonists &amp; inhibitors</keyword><keyword>Phosphoric Monoester Hydrolases/chemistry/*metabolism</keyword><keyword>Protein Structure, Tertiary</keyword><keyword>Signal Transduction</keyword><keyword>Tumor Suppressor Proteins/chemistry/*metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0898-6568 (Print) 0898-6568 (Linking)</isbn><accession-num>11858936</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11858936</url></related-urls></urls></record></Cite></EndNote>77.

Cardiac hypertrophy due to other causes like pressure overload depends largely on the activation of Akt/mTor signaling pathway as well. In aortic banded mice, there was highly activated Akt/ mTor pathway components, S6K1, S6 phosphorylation had increased and elF4E was up regulated. Rapamycin reduced cardiac hypertrophy and improved the left ventricular function by attenuating S6 and 4E-BP1 phosphorylation therefore reduced the S6K and elF4E activities in both acute and chronic cases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY011bGxlbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY011bGxlbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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ADDIN EN.CITE.DATA 78-80. 4E-BP1 is a translational repressor. In its unphosphorylated state, it binds eIF4E and prevents its interaction with 5′- end of MRNA and prevents translational initiation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA 81.

ROS (oxidative stress) has been reported to play a role in cardiac hypertrophy through activation of Akt pathway, one of the mechanism involved was through activation of Rac 1, a GTPase binding protein PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaW5ndGdlbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaW5ndGdlbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE.DATA 82. A Nox4/Nox1 inhibitor, antioxidant that reduced prevented cardiac hypertrophy and remodeling in the mice models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA 81. In the male wister rats experiment, celecoxib acted as a potent antioxidant by inhibiting gene transcription of multiple antioxidants and by so doing there was also inhibition of Akt/mTor signaling and regression of cardiac hypertrophy in experimental animals. All these support the role of oxidative stress in cardiac hypertrophy when Akt/mTor signaling is activated. Despite the fact that, HCM involves increase in oxidative stress and activation of Akt/mTor signaling pathway in some case, these two facts have been described separately and non of the experiment have ever related the possibility of rising oxidative stress being the cause of Akt/mTor signaling activation in patients with HCM. Further experiments are needed in this area in older to solve the existing puzzle of the cure for HCM.
2.2.2.3. Ca2+/ Calcineurin/ NF-AT signaling pathway;
NF-AT (Nuclear factor of activated T-cell) is a transcription factor that normally exists in the cytoplasm of the cell in its inactive form when the cell is not activated. It is kept inactive by the phosphorylation in its serine and threonine residues, by so doing; they block the NF-AT nuclear localization signal. The calcium binding protein, Calmodulin and calcium dependent phosphatase, calcineurin are responsible for the activation of NF-AT. When the ligand binds the calcium release activated channel, it opens and allows the extracellular calcium to enter the cytoplasm and binds the Calmodulin. Calmodulin undergo conformational change and acts on other cellular proteins one them being Calcineurin. Once bound to calmodulin it becomes active and activates NF-AT by dephosphorylating it. The activated NF-AT enters the nucleus and binds to the promoters of many inducible genes and initiates their transcription PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmFidHJlZTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmFidHJlZTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+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 EN.CITE.DATA 83, 84. Various stimuli have been said to increase intracellular Ca2+ like Angiotensin II, phenylephrine and Endothelin1PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE.DATA 85, and even more interesting some of them are already studied extensively in the pathogenesis of cardiac hypertrophyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bb2tpPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj
TnVtPjI5MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bODYsIDg3XTwvRGlzcGxheVRleHQ+PHJlY29y
ZD48cmVjLW51bWJlcj4yOTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i
IGRiLWlkPSJhdDBkMmUyMjRyZHpmMWU5ZnBicHQ1OWY5dHhzcHJ4OXd0MDIiPjI5Mjwva2V5Pjwv
Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw
ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QW9raSwgSC48L2F1dGhvcj48YXV0aG9y
PlNhZG9zaGltYSwgSi48L2F1dGhvcj48YXV0aG9yPkl6dW1vLCBTLjwvYXV0aG9yPjwvYXV0aG9y
cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNhcmRpb3Zhc2N1bGFyIERpdmlzaW9uLCBC
ZXRoIElzcmFlbCBEZWFjb25lc3MgTWVkaWNhbCBDZW50ZXIgYW5kIERlcGFydG1lbnQgb2YgTWVk
aWNpbmUsIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJvc3RvbiwgTWFzc2FjaHVzZXR0cyAwMjIx
NSwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPk15b3NpbiBsaWdodCBjaGFpbiBr
aW5hc2UgbWVkaWF0ZXMgc2FyY29tZXJlIG9yZ2FuaXphdGlvbiBkdXJpbmcgY2FyZGlhYyBoeXBl
cnRyb3BoeSBpbiB2aXRybzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQgTWVkPC9zZWNvbmRh
cnktdGl0bGU+PGFsdC10aXRsZT5OYXR1cmUgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48
cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQgTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+TmF0dXJl
IG1lZGljaW5lPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRs
ZT5OYXQgTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+TmF0dXJlIG1lZGljaW5lPC9hYmJyLTE+PC9h
bHQtcGVyaW9kaWNhbD48cGFnZXM+MTgzLTg8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1i
ZXI+MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5Bbmdpb3RlbnNpbiBJSS9waGFybWFjb2xv
Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DYXJkaW9tZWdh
bHkvKmVuenltb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3Jk
PjxrZXl3b3JkPk15b3Npbi1MaWdodC1DaGFpbiBLaW5hc2UvKm1ldGFib2xpc208L2tleXdvcmQ+
PGtleXdvcmQ+UGhlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPlBoZW55bGVwaHJpbmUvcGhhcm1h
Y29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29y
ZD5SYXRzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHMsIFdpc3Rhcjwva2V5d29yZD48a2V5d29yZD5T
YXJjb21lcmVzL2RydWcgZWZmZWN0cy8qdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jk
cz48ZGF0ZXM+PHllYXI+MjAwMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkZlYjwvZGF0ZT48L3B1
Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwNzgtODk1NiAoUHJpbnQpJiN4RDsxMDc4LTg5NTYgKExp
bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEwNjU1MTA3PC9hY2Nlc3Npb24tbnVtPjx1cmxz
PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEw
NjU1MTA3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51
bT4xMC4xMDM4LzcyMjg3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+
PENpdGU+PEF1dGhvcj5GYXJlaDwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJlY051bT4yOTM8
L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI5MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz
PjxrZXkgYXBwPSJFTiIgZGItaWQ9ImF0MGQyZTIyNHJkemYxZTlmcGJwdDU5Zjl0eHNwcng5d3Qw
MiI+MjkzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs
ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5GYXJlaCwgSi48
L2F1dGhvcj48YXV0aG9yPlRvdXl6LCBSLiBNLjwvYXV0aG9yPjxhdXRob3I+U2NoaWZmcmluLCBF
LiBMLjwvYXV0aG9yPjxhdXRob3I+VGhpYmF1bHQsIEcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u
dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TVJDIE11bHRpZGlzY2lwbGluYXJ5IFJlc2VhcmNoIEdy
b3VwIG9uIEh5cGVydGVuc2lvbiwgQ2xpbmljYWwgUmVzZWFyY2ggSW5zdGl0dXRlIG9mIE1vbnRy
ZWFsLCBVbml2ZXJzaXR5IG9mIE1vbnRyZWFsLCBDYW5hZGEuPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+RW5kb3RoZWxpbi0xIGFuZCBhbmdpb3RlbnNpbiBJSSByZWNlcHRvcnMgaW4gY2Vs
bHMgZnJvbSByYXQgaHlwZXJ0cm9waGllZCBoZWFydC4gUmVjZXB0b3IgcmVndWxhdGlvbiBhbmQg
aW50cmFjZWxsdWxhciBDYTIrIG1vZHVsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2ly
YyBSZXM8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkNpcmN1bGF0aW9uIHJlc2VhcmNoPC9h
bHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2lyYyBSZXM8L2Z1bGwt
dGl0bGU+PGFiYnItMT5DaXJjdWxhdGlvbiByZXNlYXJjaDwvYWJici0xPjwvcGVyaW9kaWNhbD48
YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2lyYyBSZXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5D
aXJjdWxhdGlvbiByZXNlYXJjaDwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjMwMi0x
MTwvcGFnZXM+PHZvbHVtZT43ODwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxrZXl3b3Jkcz48
a2V5d29yZD5Bbmdpb3RlbnNpbiBJSS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1h
bHM8L2tleXdvcmQ+PGtleXdvcmQ+QXRyaWFsIE5hdHJpdXJldGljIEZhY3Rvci8qYW5hbHlzaXM8
L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5D
YXJkaW9tZWdhbHkvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlbGxz
LCBDdWx0dXJlZDwva2V5d29yZD48a2V5d29yZD5FbmRvdGhlbGlucy9tZXRhYm9saXNtPC9rZXl3
b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+UmFkaW9saWdhbmQgQXNzYXk8L2tl
eXdvcmQ+PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBTcHJhZ3VlLURhd2xl
eTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvciwgRW5kb3RoZWxpbiBBPC9rZXl3b3JkPjxrZXl3
b3JkPlJlY2VwdG9ycywgQW5naW90ZW5zaW4vKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+
UmVjZXB0b3JzLCBFbmRvdGhlbGluLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh
dGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0
ZXM+PC9kYXRlcz48aXNibj4wMDA5LTczMzAgKFByaW50KSYjeEQ7MDAwOS03MzMwIChMaW5raW5n
KTwvaXNibj48YWNjZXNzaW9uLW51bT44NTc1MDc0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh
dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzg1NzUwNzQ8
L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bb2tpPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj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=
ADDIN EN.CITE.DATA 86, 87.

Figure SEQ Figure * ARABIC 6; calcineurin/ NF-AT signaling pathway
Schematic diagram shows calcinerin activation by increased intracellular calcium which then cause NFAT dephosphorylation and nuclear. Some calcinerin inhibitors are shown in the cytoplasm which antagonizes its nuclear translocationor even facilitating its egress. While green lines denote activation events, the red lines denote its inhibitory events PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxraW5zPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxraW5zPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
UmVjTnVtPjE5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4OF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+
PHJlYy1udW1iZXI+MTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi
LWlkPSIwejllZmE1ZXgyd2Q5cmU5czl0eDk5Mm05OXpmdGVhc3p4YXoiIHRpbWVzdGFtcD0iMTUx
NzMxNTUxNiI+MTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB
cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldpbGtp
bnMsIEIuIEouPC9hdXRob3I+PGF1dGhvcj5Nb2xrZW50aW4sIEouIEQuPC9hdXRob3I+PC9hdXRo
b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgTW9sZWN1bGFyIENh
cmRpb3Zhc2N1bGFyIEJpb2xvZ3ksIENpbmNpbm5hdGkgQ2hpbGRyZW4mYXBvcztzIEhvc3BpdGFs
IE1lZGljYWwgQ2VudGVyLCBDaW5jaW5uYXRpLCBPSCA0NTIyOS0zMDM5LCBVU0EuPC9hdXRoLWFk
ZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2FsY2l1bS1jYWxjaW5ldXJpbiBzaWduYWxpbmcgaW4gdGhl
IHJlZ3VsYXRpb24gb2YgY2FyZGlhYyBoeXBlcnRyb3BoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRs
ZT5CaW9jaGVtIEJpb3BoeXMgUmVzIENvbW11bjwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+
QmlvY2hlbWljYWwgYW5kIGJpb3BoeXNpY2FsIHJlc2VhcmNoIGNvbW11bmljYXRpb25zPC9hbHQt
dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QmlvY2hlbSBCaW9waHlzIFJl
cyBDb21tdW48L2Z1bGwtdGl0bGU+PGFiYnItMT5CaW9jaGVtaWNhbCBhbmQgYmlvcGh5c2ljYWwg
cmVzZWFyY2ggY29tbXVuaWNhdGlvbnM8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2Rp
Y2FsPjxmdWxsLXRpdGxlPkJpb2NoZW0gQmlvcGh5cyBSZXMgQ29tbXVuPC9mdWxsLXRpdGxlPjxh
YmJyLTE+QmlvY2hlbWljYWwgYW5kIGJpb3BoeXNpY2FsIHJlc2VhcmNoIGNvbW11bmljYXRpb25z
PC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MTE3OC05MTwvcGFnZXM+PHZvbHVtZT4z
MjI8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwv
a2V5d29yZD48a2V5d29yZD5DYWxjaW5ldXJpbi9jaGVtaXN0cnkvKm1ldGFib2xpc20vcGh5c2lv
bG9neTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv
cmQ+KkNhbGNpdW0gU2lnbmFsaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkNhcmRpb21lZ2FseS8qZXRp
b2xvZ3kvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkROQS1CaW5kaW5nIFByb3RlaW5zL21l
dGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5ORkFUQyBU
cmFuc2NyaXB0aW9uIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+TnVjbGVhciBQcm90ZWlucy9t
ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNj
cmlwdGlvbiBGYWN0b3JzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNjcmlwdGlv
biwgR2VuZXRpYzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA0PC95ZWFyPjxw
dWItZGF0ZXM+PGRhdGU+T2N0IDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDA2
LTI5MVggKFByaW50KSYjeEQ7MDAwNi0yOTFYIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51
bT4xNTMzNjk2NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDov
L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTMzNjk2NjwvdXJsPjwvcmVsYXRlZC11cmxz
PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9qLmJicmMuMjAwNC4wNy4x
MjE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA 88.
Calcineurin/ NF-AT signaling have been discovered to participate in the development of HCM. This was proved so in the transgenic mutant mice with dominant negative mutant for P38 gene that developed HCM; this was due to the fact that, P38 regulates NF-AT signaling by inhibiting its dephosphorylation. In these mice models with negative P38, NF-AT was hyperactivated and developed HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF6PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF6PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA 89. In patients with hypertrophic obstructive cardiomyopathy, calcineurin activities were highly increased due to proteolysis of the calcineurin autoinhibitory domain; this led to increased NF-AT activities in these patients and suggests its involvement in the pathogenesis of the disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaXR0ZXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaXR0ZXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 90.
NF-AT signaling have also been reported in other cardiac hypertrophies which are not HCM, experiments on laboratory animals with cardiac hypertrophy from various causes like aortic banding, hypertension, carnitine deficiency demonstrated increased activity above range of this pathway PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy
PjxSZWNOdW0+NDQ8L1JlY051bT48RGlzcGxheVRleHQ+Wzg1LCA5MS05M108L0Rpc3BsYXlUZXh0
PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw
cD0iRU4iIGRiLWlkPSJkZXJmZXQwems5d3hzcmV0cDA5cHp3eHJ4NTBkZnZ4YXI1OTIiIHRpbWVz
dGFtcD0iMTUxNTQxMzExOSI+NDQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i
Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0
aG9yPk1vbGtlbnRpbiwgSi4gRC48L2F1dGhvcj48YXV0aG9yPkx1LCBKLiBSLjwvYXV0aG9yPjxh
dXRob3I+QW50b3MsIEMuIEwuPC9hdXRob3I+PGF1dGhvcj5NYXJraGFtLCBCLjwvYXV0aG9yPjxh
dXRob3I+UmljaGFyZHNvbiwgSi48L2F1dGhvcj48YXV0aG9yPlJvYmJpbnMsIEouPC9hdXRob3I+
PGF1dGhvcj5HcmFudCwgUy4gUi48L2F1dGhvcj48YXV0aG9yPk9sc29uLCBFLiBOLjwvYXV0aG9y
PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTW9s
ZWN1bGFyIEJpb2xvZ3kgYW5kIE9uY29sb2d5LCBUaGUgVW5pdmVyc2l0eSBvZiBUZXhhcyBTb3V0
aHdlc3Rlcm4gTWVkaWNhbCBDZW50ZXIgYXQgRGFsbGFzLCA3NTIyNS05MTQ4LCBVU0EuPC9hdXRo
LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QSBjYWxjaW5ldXJpbi1kZXBlbmRlbnQgdHJhbnNjcmlw
dGlvbmFsIHBhdGh3YXkgZm9yIGNhcmRpYWMgaHlwZXJ0cm9waHk8L3RpdGxlPjxzZWNvbmRhcnkt
dGl0bGU+Q2VsbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q2VsbDwvYWx0LXRpdGxlPjwv
dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNlbGw8L2Z1bGwtdGl0bGU+PGFiYnItMT5D
ZWxsPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZWxs
PC9mdWxsLXRpdGxlPjxhYmJyLTE+Q2VsbDwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2Vz
PjIxNS0yODwvcGFnZXM+PHZvbHVtZT45Mzwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxrZXl3
b3Jkcz48a2V5d29yZD5Bbmdpb3RlbnNpbiBJSS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdv
cmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbmltYWxzLCBOZXdib3JuPC9rZXl3b3JkPjxr
ZXl3b3JkPkF0cmlhbCBOYXRyaXVyZXRpYyBGYWN0b3IvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdv
cmQ+Q2FsY2luZXVyaW4vZ2VuZXRpY3MvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2Fy
ZGlvbWVnYWx5L2Vuenltb2xvZ3kvKmdlbmV0aWNzL3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwv
a2V5d29yZD48a2V5d29yZD5DZWxsIE51Y2xldXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y
ZD5ETkEtQmluZGluZyBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdBVEE0
IFRyYW5zY3JpcHRpb24gRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1cHByZXNzaXZl
IEFnZW50cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5
d29yZD5NaWNlLCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk15b2NhcmRpdW0vbWV0YWJv
bGlzbS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5GQVRDIFRyYW5zY3JpcHRpb24gRmFj
dG9yczwva2V5d29yZD48a2V5d29yZD5OYXRyaXVyZXRpYyBQZXB0aWRlLCBCcmFpbjwva2V5d29y
ZD48a2V5d29yZD4qTnVjbGVhciBQcm90ZWluczwva2V5d29yZD48a2V5d29yZD5QaGVueWxlcGhy
aW5lL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5Qcm9tb3RlciBSZWdpb25zLCBHZW5l
dGljL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlJhdHM8L2tleXdvcmQ+PGtleXdvcmQ+UmVj
b21iaW5hbnQgRnVzaW9uIFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1
Y3Rpb24vKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNjcmlwdGlvbiBGYWN0b3Jz
L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNjcmlwdGlvbiwgR2VuZXRpYzwva2V5
d29yZD48a2V5d29yZD5UcmFuc2NyaXB0aW9uYWwgQWN0aXZhdGlvbi8qcGh5c2lvbG9neTwva2V5
d29yZD48a2V5d29yZD5aaW5jIEZpbmdlcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll
YXI+MTk5ODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwciAxNzwvZGF0ZT48L3B1Yi1kYXRlcz48
L2RhdGVzPjxpc2JuPjAwOTItODY3NCAoUHJpbnQpJiN4RDswMDkyLTg2NzQgKExpbmtpbmcpPC9p
c2JuPjxhY2Nlc3Npb24tbnVtPjk1Njg3MTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt
dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvOTU2ODcxNDwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj40NDU5NjQ2PC9jdXN0b20yPjwvcmVjb3Jk
PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxpbTwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+PFJlY051
bT40NTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDU8L3JlYy1udW1iZXI+PGZvcmVpZ24t
a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJkZXJmZXQwems5d3hzcmV0cDA5cHp3eHJ4NTBkZnZ4
YXI1OTIiIHRpbWVzdGFtcD0iMTUxNTQxMzQxOCI+NDU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVm
LXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48
YXV0aG9ycz48YXV0aG9yPkxpbSwgSC4gVy48L2F1dGhvcj48YXV0aG9yPkRlIFdpbmR0LCBMLiBK
LjwvYXV0aG9yPjxhdXRob3I+U3RlaW5iZXJnLCBMLjwvYXV0aG9yPjxhdXRob3I+VGFpZ2VuLCBU
LjwvYXV0aG9yPjxhdXRob3I+V2l0dCwgUy4gQS48L2F1dGhvcj48YXV0aG9yPktpbWJhbGwsIFQu
IFIuPC9hdXRob3I+PGF1dGhvcj5Nb2xrZW50aW4sIEouIEQuPC9hdXRob3I+PC9hdXRob3JzPjwv
Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQZWRpYXRyaWNzLCBDaGls
ZHJlbiZhcG9zO3MgSG9zcGl0YWwgTWVkaWNhbCBDZW50ZXIsIFVuaXZlcnNpdHkgb2YgQ2luY2lu
bmF0aSwgT2hpbywgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNhbGNpbmV1cmlu
IGV4cHJlc3Npb24sIGFjdGl2YXRpb24sIGFuZCBmdW5jdGlvbiBpbiBjYXJkaWFjIHByZXNzdXJl
LW92ZXJsb2FkIGh5cGVydHJvcGh5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNpcmN1bGF0aW9u
PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5DaXJjdWxhdGlvbjwvYWx0LXRpdGxlPjwvdGl0
bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNpcmN1bGF0aW9uPC9mdWxsLXRpdGxlPjwvcGVy
aW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2lyY3VsYXRpb248L2Z1bGwtdGl0
bGU+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MjQzMS03PC9wYWdlcz48dm9sdW1lPjEwMTwvdm9s
dW1lPjxudW1iZXI+MjA8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y
ZD48a2V5d29yZD5DYWxjaW5ldXJpbi9tZXRhYm9saXNtLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxr
ZXl3b3JkPkNhbGNpbmV1cmluIEluaGliaXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FyZGlvbWVn
YWx5LypldGlvbG9neS9tZXRhYm9saXNtLypwaHlzaW9wYXRob2xvZ3kvcHJldmVudGlvbiAmYW1w
OyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkN5Y2xvc3BvcmluZS9waGFybWFjb2xvZ3k8L2tl
eXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5GZW1h
bGU8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5zaW9uLypjb21wbGljYXRpb25zPC9rZXl3b3Jk
PjxrZXl3b3JkPkltbXVub3N1cHByZXNzaXZlIEFnZW50cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+
PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBTcHJhZ3VlLURhd2xleTwva2V5
d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+
TWF5IDIzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyNC00NTM5IChFbGVjdHJv
bmljKSYjeEQ7MDAwOS03MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMDgyMTgy
MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp
Lm5sbS5uaWguZ292L3B1Ym1lZC8xMDgyMTgyMjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48
L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5TaGltb3lhbWE8L0F1dGhvcj48WWVhcj4xOTk5
PC9ZZWFyPjxSZWNOdW0+NDY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2PC9yZWMtbnVt
YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZGVyZmV0MHprOXd4c3JldHAw
OXB6d3hyeDUwZGZ2eGFyNTkyIiB0aW1lc3RhbXA9IjE1MTU0MTM1MTEiPjQ2PC9rZXk+PC9mb3Jl
aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj
b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TaGltb3lhbWEsIE0uPC9hdXRob3I+PGF1dGhv
cj5IYXlhc2hpLCBELjwvYXV0aG9yPjxhdXRob3I+VGFraW1vdG8sIEUuPC9hdXRob3I+PGF1dGhv
cj5ab3UsIFkuPC9hdXRob3I+PGF1dGhvcj5Pa2EsIFQuPC9hdXRob3I+PGF1dGhvcj5Vb3p1bWks
IEguPC9hdXRob3I+PGF1dGhvcj5LdWRvaCwgUy48L2F1dGhvcj48YXV0aG9yPlNoaWJhc2FraSwg
Ri48L2F1dGhvcj48YXV0aG9yPllhemFraSwgWS48L2F1dGhvcj48YXV0aG9yPk5hZ2FpLCBSLjwv
YXV0aG9yPjxhdXRob3I+S29tdXJvLCBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y
cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2FyZGlvdmFzY3VsYXIgTWVkaWNpbmUsIFVu
aXZlcnNpdHkgb2YgVG9reW8sIEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2luZSwgYW5kIHRoZSBU
b2t5byBNZXRyb3BvbGl0YW4gSW5zdGl0dXRlIG9mIE1lZGljYWwgU2NpZW5jZSwgVG9reW8sIEph
cGFuLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNhbGNpbmV1cmluIHBsYXlzIGEgY3Jp
dGljYWwgcm9sZSBpbiBwcmVzc3VyZSBvdmVybG9hZC1pbmR1Y2VkIGNhcmRpYWMgaHlwZXJ0cm9w
aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2lyY3VsYXRpb248L3NlY29uZGFyeS10aXRsZT48
YWx0LXRpdGxlPkNpcmN1bGF0aW9uPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1
bGwtdGl0bGU+Q2lyY3VsYXRpb248L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9k
aWNhbD48ZnVsbC10aXRsZT5DaXJjdWxhdGlvbjwvZnVsbC10aXRsZT48L2FsdC1wZXJpb2RpY2Fs
PjxwYWdlcz4yNDQ5LTU0PC9wYWdlcz48dm9sdW1lPjEwMDwvdm9sdW1lPjxudW1iZXI+MjQ8L251
bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5Bb3J0YSwg
QWJkb21pbmFsL3BoeXNpb3BhdGhvbG9neS9zdXJnZXJ5PC9rZXl3b3JkPjxrZXl3b3JkPkF0cmlh
bCBOYXRyaXVyZXRpYyBGYWN0b3IvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+KkJsb29kIFZv
bHVtZTwva2V5d29yZD48a2V5d29yZD5Cb2R5IFdlaWdodDwva2V5d29yZD48a2V5d29yZD5DYWxj
aW5ldXJpbi9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DYWxjaW5ldXJp
biBJbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkNhcmRpb21lZ2FseS9kaWFnbm9zdGljIGlt
YWdpbmcvKm1ldGFib2xpc20vKnByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5
d29yZD5Db25zdHJpY3Rpb24sIFBhdGhvbG9naWM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBN
b2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5FY2hvY2FyZGlvZ3JhcGh5PC9rZXl3b3Jk
PjxrZXl3b3JkPkZpYnJvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbi9waHlz
aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmVzLCBJbW1lZGlhdGUtRWFybHkvcGh5c2lvbG9n
eTwva2V5d29yZD48a2V5d29yZD5IZWFydCBSYXRlL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5
d29yZD5JbW11bm9zdXBwcmVzc2l2ZSBBZ2VudHMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3
b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TXlvY2FyZGl1bS9wYXRob2xvZ3k8L2tleXdvcmQ+
PGtleXdvcmQ+UHJvdG8tT25jb2dlbmUgUHJvdGVpbnMgYy1mb3MvZ2VuZXRpY3M8L2tleXdvcmQ+
PGtleXdvcmQ+UHJvdG8tT25jb2dlbmUgUHJvdGVpbnMgYy1qdW4vZ2VuZXRpY3M8L2tleXdvcmQ+
PGtleXdvcmQ+UmF0czwva2V5d29yZD48a2V5d29yZD5SYXRzLCBXaXN0YXI8L2tleXdvcmQ+PGtl
eXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlvbi9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRh
Y3JvbGltdXMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5
OTk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5EZWMgMTQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl
cz48aXNibj4xNTI0LTQ1MzkgKEVsZWN0cm9uaWMpJiN4RDswMDA5LTczMjIgKExpbmtpbmcpPC9p
c2JuPjxhY2Nlc3Npb24tbnVtPjEwNTk1OTU5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk
LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEwNTk1OTU5PC91
cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlpv
dTwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJlY051bT40OTwvUmVjTnVtPjxyZWNvcmQ+PHJl
Yy1udW1iZXI+NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk
PSJkZXJmZXQwems5d3hzcmV0cDA5cHp3eHJ4NTBkZnZ4YXI1OTIiIHRpbWVzdGFtcD0iMTUxNTQx
Mzg2MSI+NDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp
Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlpvdSwgWS48
L2F1dGhvcj48YXV0aG9yPkhpcm9pLCBZLjwvYXV0aG9yPjxhdXRob3I+VW96dW1pLCBILjwvYXV0
aG9yPjxhdXRob3I+VGFraW1vdG8sIEUuPC9hdXRob3I+PGF1dGhvcj5Ub2tvLCBILjwvYXV0aG9y
PjxhdXRob3I+Wmh1LCBXLjwvYXV0aG9yPjxhdXRob3I+S3Vkb2gsIFMuPC9hdXRob3I+PGF1dGhv
cj5NaXp1a2FtaSwgTS48L2F1dGhvcj48YXV0aG9yPlNoaW1veWFtYSwgTS48L2F1dGhvcj48YXV0
aG9yPlNoaWJhc2FraSwgRi48L2F1dGhvcj48YXV0aG9yPk5hZ2FpLCBSLjwvYXV0aG9yPjxhdXRo
b3I+WWF6YWtpLCBZLjwvYXV0aG9yPjxhdXRob3I+S29tdXJvLCBJLjwvYXV0aG9yPjwvYXV0aG9y
cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2FyZGlvdmFzY3Vs
YXIgU2NpZW5jZSBhbmQgTWVkaWNpbmUsIENoaWJhIFVuaXZlcnNpdHkgR3JhZHVhdGUgU2Nob29s
IG9mIE1lZGljaW5lLCBDaGliYS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DYWxjaW5l
dXJpbiBwbGF5cyBhIGNyaXRpY2FsIHJvbGUgaW4gdGhlIGRldmVsb3BtZW50IG9mIHByZXNzdXJl
IG92ZXJsb2FkLWluZHVjZWQgY2FyZGlhYyBoeXBlcnRyb3BoeTwvdGl0bGU+PHNlY29uZGFyeS10
aXRsZT5DaXJjdWxhdGlvbjwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q2lyY3VsYXRpb248
L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaXJjdWxhdGlvbjwv
ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNpcmN1
bGF0aW9uPC9mdWxsLXRpdGxlPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjk3LTEwMTwvcGFnZXM+
PHZvbHVtZT4xMDQ8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+
QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5Bb3J0YSwgQWJkb21pbmFsL3BhdGhvbG9neTwva2V5
d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZTwva2V5d29yZD48a2V5d29yZD5Cb2R5IFdlaWdo
dDwva2V5d29yZD48a2V5d29yZD5DYWxjaW5ldXJpbi9nZW5ldGljcy8qbWV0YWJvbGlzbTwva2V5
d29yZD48a2V5d29yZD5DYXJkaW9tZWdhbHkvKmV0aW9sb2d5L3BhdGhvbG9neS8qcGh5c2lvcGF0
aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhdGFseXNpczwva2V5d29yZD48a2V5d29yZD5Db25z
dHJpY3Rpb24sIFBhdGhvbG9naWM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFu
aW1hbDwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3
b3JkPkVjaG9jYXJkaW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+RW56eW1lIEFjdGl2YXRpb24v
Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Rmlicm9zaXMvcGF0aG9sb2d5PC9rZXl3b3JkPjxr
ZXl3b3JkPkdlbmUgRXhwcmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5HZW5lcywgRG9taW5hbnQ8
L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXMsIEltbWVkaWF0ZS1FYXJseTwva2V5d29yZD48a2V5d29y
ZD5IeXBlcnRlbnNpb24vKmNvbXBsaWNhdGlvbnMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48
a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIFRyYW5zZ2VuaWM8L2tleXdvcmQ+
PGtleXdvcmQ+TWl0b2dlbi1BY3RpdmF0ZWQgUHJvdGVpbiBLaW5hc2VzL21ldGFib2xpc208L2tl
eXdvcmQ+PGtleXdvcmQ+TXV0YWdlbmVzaXMsIFNpdGUtRGlyZWN0ZWQ8L2tleXdvcmQ+PGtleXdv
cmQ+T3JnYW4gU2l6ZTwva2V5d29yZD48a2V5d29yZD5PcmdhbiBTcGVjaWZpY2l0eS9nZW5ldGlj
czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAxPC95ZWFyPjxwdWItZGF0ZXM+
PGRhdGU+SnVsIDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI0LTQ1MzkgKEVs
ZWN0cm9uaWMpJiN4RDswMDA5LTczMjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEx
NDM1MzQ1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3
Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzExNDM1MzQ1PC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE.DATA 85, 91-93. Even physiologic cardiac hypertrophy do activate calcineurin pathway ADDIN EN.CITE <EndNote><Cite><Author>Eto</Author><Year>2000</Year><RecNum>47</RecNum><DisplayText>94</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1515413670″>47</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Eto, Y.</author><author>Yonekura, K.</author><author>Sonoda, M.</author><author>Arai, N.</author><author>Sata, M.</author><author>Sugiura, S.</author><author>Takenaka, K.</author><author>Gualberto, A.</author><author>Hixon, M. L.</author><author>Wagner, M. W.</author><author>Aoyagi, T.</author></authors></contributors><auth-address>Department of Cardiovascular Medicine, University of Tokyo, Japan.</auth-address><titles><title>Calcineurin is activated in rat hearts with physiological left ventricular hypertrophy induced by voluntary exercise training</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title></periodical><alt-periodical><full-title>Circulation</full-title></alt-periodical><pages>2134-7</pages><volume>101</volume><number>18</number><keywords><keyword>Animals</keyword><keyword>Calcineurin/*physiology</keyword><keyword>Hypertrophy, Left Ventricular/*metabolism/physiopathology</keyword><keyword>Physical Conditioning, Animal/*physiology</keyword><keyword>Rats</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2000</year><pub-dates><date>May 9</date></pub-dates></dates><isbn>1524-4539 (Electronic) 0009-7322 (Linking)</isbn><accession-num>10801751</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/10801751</url></related-urls></urls></record></Cite></EndNote>94. Calcineurin inhibitors like cyclosporine A and FK506, which prevent calcineurin’s ability to activate NF-AT transcription factors have proved success in treating cardiac hypertrophy in most experimental animal models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE.DATA 84, 85, even inhibition by Adenovirus expressing calcineurin inhibitory domain of AKAP79 demonstrated the same results PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWlnZW48L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWlnZW48L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 95. MAPK pathway have been reported to associate with NF-AT pathway in causing cardiac hypertrophy in a mechanism not well understoodPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy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ADDIN EN.CITE.DATA 84, the mechanism could be in part due to the ability of MAPKs to increase intracellular Ca2+PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xrZW50aW48L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE.DATA 85.
The relationship of oxidative stress to this pathway is largely due to its interaction with MAPK/ ERK signaling pathway which is largely affected by oxidative stress as explained above. PICOT (PKC- Interacting cousin of thioredoxin) which is a protein kinase C inhibitor has amino terminal thioredoxin homology. While theoredoxin cause regression of cardiac hypertrophy by reducing oxidative stressPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZW9uZzwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZW9uZzwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl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ADDIN EN.CITE.DATA 96, PICOT does so by inhibiting the activity of NF-AT signaling pathwayPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGE8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGE8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO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=
ADDIN EN.CITE.DATA 97, 98.

2.2.2.4. NF- kB signaling;
NF-kB (Nuclear factor kappa- light- chain- enhancer of activated B cell) is the protein complex that controls transcription. The pathway is involved in B-cell maturation and lymphoid organogenesis hence plays a great role in immune system and response. It is reported to be activated by cytokines, reactive oxygen species, bacterial cell wall products, viral infections, vasopressors and DNA damage ADDIN EN.CITE <EndNote><Cite><Author>Brasier</Author><Year>2006</Year><RecNum>56</RecNum><DisplayText>99</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1515589293″>56</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Brasier, A. R.</author></authors></contributors><auth-address>Department of Internal Medicine and Sealy Center for Molecular Sciences, University of Texas Medical Branch, Galveston, TX 77555-1060, USA. [email protected]</auth-address><titles><title>The NF-kappaB regulatory network</title><secondary-title>Cardiovasc Toxicol</secondary-title><alt-title>Cardiovascular toxicology</alt-title></titles><periodical><full-title>Cardiovasc Toxicol</full-title><abbr-1>Cardiovascular toxicology</abbr-1></periodical><alt-periodical><full-title>Cardiovasc Toxicol</full-title><abbr-1>Cardiovascular toxicology</abbr-1></alt-periodical><pages>111-30</pages><volume>6</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Biotransformation/physiology</keyword><keyword>Cell Nucleus/physiology</keyword><keyword>Humans</keyword><keyword>I-kappa B Kinase/physiology</keyword><keyword>NF-kappa B/genetics/*physiology</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2006</year></dates><isbn>1530-7905 (Print) 1530-7905 (Linking)</isbn><accession-num>17303919</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17303919</url></related-urls></urls></record></Cite></EndNote>99. Under normal conditions, the pathway is inactive where NIK (NF-kB inducing kinase) is bound to a protein complex of TRAF3 (TNF receptor associated factor 3), TRAF2 (TNF receptor associated factor 2) and CiAP1/2 (cellular inhibitor of apoptosis 1 and 2). The latter protein, ubiquinate NIK leading into proteasome degradation hence NIK is maintained in low levels. When the ligand binds the receptor, NIK is released from the complex and it phosphorylates IKK?. Activated IKK?, interacts with inactive protein dimer of P100/RelB which leads into a formation of a new protein dimer P52/RelB. The P52/RelB enter the nucleus and initiate the transcription of genes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW5pZXJpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW5pZXJpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
UmVjTnVtPjczPC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMDAsIDEwMV08L0Rpc3BsYXlUZXh0Pjxy
ZWNvcmQ+PHJlYy1udW1iZXI+NzM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i
RU4iIGRiLWlkPSJkZXJmZXQwems5d3hzcmV0cDA5cHp3eHJ4NTBkZnZ4YXI1OTIiIHRpbWVzdGFt
cD0iMTUxNTc1NjI0MSI+NzM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91
cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y
PlBhbmllcmksIEUuPC9hdXRob3I+PGF1dGhvcj5TYW50b3JvLCBNLiBNLjwvYXV0aG9yPjwvYXV0
aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTW9sZWN1bGFy
IEJpb3RlY2hub2xvZ3kgYW5kIEhlYWx0aCBTY2llbmNlcywgTW9sZWN1bGFyIEJpb3RlY2hub2xv
Z3kgQ2VudGVyLCBVbml2ZXJzaXR5IG9mIFRvcmlubywgVHVyaW4sIEl0YWx5LjwvYXV0aC1hZGRy
ZXNzPjx0aXRsZXM+PHRpdGxlPlJPUyBzaWduYWxpbmcgYW5kIHJlZG94IGJpb2xvZ3kgaW4gZW5k
b3RoZWxpYWwgY2VsbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2VsbCBNb2wgTGlmZSBTY2k8
L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkNlbGx1bGFyIGFuZCBtb2xlY3VsYXIgbGlmZSBz
Y2llbmNlcyA6IENNTFM8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs
ZT5DZWxsIE1vbCBMaWZlIFNjaTwvZnVsbC10aXRsZT48YWJici0xPkNlbGx1bGFyIGFuZCBtb2xl
Y3VsYXIgbGlmZSBzY2llbmNlcyA6IENNTFM8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJp
b2RpY2FsPjxmdWxsLXRpdGxlPkNlbGwgTW9sIExpZmUgU2NpPC9mdWxsLXRpdGxlPjxhYmJyLTE+
Q2VsbHVsYXIgYW5kIG1vbGVjdWxhciBsaWZlIHNjaWVuY2VzIDogQ01MUzwvYWJici0xPjwvYWx0
LXBlcmlvZGljYWw+PHBhZ2VzPjMyODEtMzAzPC9wYWdlcz48dm9sdW1lPjcyPC92b2x1bWU+PG51
bWJlcj4xNzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3
b3JkPkVuZG90aGVsaWFsIENlbGxzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFu
czwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWEvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl
eXdvcmQ+TkFEUEggT3hpZGFzZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TmVvdmFz
Y3VsYXJpemF0aW9uLCBQaHlzaW9sb2dpYy8qcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD4q
T3hpZGF0aW9uLVJlZHVjdGlvbjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIFR5cm9zaW5lIFBo
b3NwaGF0YXNlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJlYWN0aXZlIE94eWdlbiBT
cGVjaWVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1Y3Rpb24v
KnBoeXNpb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48
cHViLWRhdGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0MjAt
OTA3MSAoRWxlY3Ryb25pYykmI3hEOzE0MjAtNjgyWCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv
bi1udW0+MjU5NzIyNzg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0
dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU5NzIyNzg8L3VybD48L3JlbGF0ZWQt
dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczAwMDE4LTAxNS0x
OTI4LTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0
aG9yPlZlcm1hPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVjTnVtPjgxPC9SZWNOdW0+PHJl
Y29yZD48cmVjLW51bWJlcj44MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF
TiIgZGItaWQ9ImRlcmZldDB6azl3eHNyZXRwMDlwend4cng1MGRmdnhhcjU5MiIgdGltZXN0YW1w
PSIxNTE1OTA5OTQxIj44MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy
bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+
VmVybWEsIEkuIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl
c3M+VGhlIFNhbGsgSW5zdGl0dXRlLCBMYWJvcmF0b3J5IG9mIEdlbmV0aWNzLCAxMDAxMCBOb3J0
aCBUb3JyZXkgUGluZXMgUm9hZCwgTGEgSm9sbGEsIENBIDkyMDM3LCBVU0EuIHZlcm1hQHNhbGsu
ZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TnVjbGVhciBmYWN0b3IgKE5GKS1rYXBw
YUIgcHJvdGVpbnM6IHRoZXJhcGV1dGljIHRhcmdldHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+
QW5uIFJoZXVtIERpczwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QW5uYWxzIG9mIHRoZSBy
aGV1bWF0aWMgZGlzZWFzZXM8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10
aXRsZT5Bbm4gUmhldW0gRGlzPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW5uYWxzIG9mIHRoZSByaGV1
bWF0aWMgZGlzZWFzZXM8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxs
LXRpdGxlPkFubiBSaGV1bSBEaXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5Bbm5hbHMgb2YgdGhlIHJo
ZXVtYXRpYyBkaXNlYXNlczwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPmlpNTctaWk2
MTwvcGFnZXM+PHZvbHVtZT42MyBTdXBwbCAyPC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkRy
dWcgUmVzaXN0YW5jZS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y
ZD48a2V5d29yZD5JLWthcHBhIEIgUHJvdGVpbnMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29y
ZD5JbmZsYW1tYXRpb24vZHJ1ZyB0aGVyYXB5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5
d29yZD5ORi1rYXBwYSBCLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzLypwaHlzaW9sb2d5
PC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1Y3Rpb24vcGh5c2lvbG9neTwva2V5d29y
ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Tm92
PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwMy00OTY3IChQcmludCkmI3hEOzAw
MDMtNDk2NyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTU0Nzk4NzM8L2FjY2Vzc2lv
bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv
di9wdWJtZWQvMTU0Nzk4NzM8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+MTc2
Njc3NzwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEzNi9hcmQuMjAwNC4w
MjgyNjY8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
AG==
ADDIN EN.CITE.DATA 100, 101 and promote its functions like inflammation, oncogenesis, cell growth and differentiation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 102. It also plays a great role in cardiovascular growth and gene network expression in inflammation ADDIN EN.CITE <EndNote><Cite><Author>Brasier</Author><Year>2006</Year><RecNum>56</RecNum><DisplayText>99</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1515589293″>56</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Brasier, A. R.</author></authors></contributors><auth-address>Department of Internal Medicine and Sealy Center for Molecular Sciences, University of Texas Medical Branch, Galveston, TX 77555-1060, USA. [email protected]</auth-address><titles><title>The NF-kappaB regulatory network</title><secondary-title>Cardiovasc Toxicol</secondary-title><alt-title>Cardiovascular toxicology</alt-title></titles><periodical><full-title>Cardiovasc Toxicol</full-title><abbr-1>Cardiovascular toxicology</abbr-1></periodical><alt-periodical><full-title>Cardiovasc Toxicol</full-title><abbr-1>Cardiovascular toxicology</abbr-1></alt-periodical><pages>111-30</pages><volume>6</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Biotransformation/physiology</keyword><keyword>Cell Nucleus/physiology</keyword><keyword>Humans</keyword><keyword>I-kappa B Kinase/physiology</keyword><keyword>NF-kappa B/genetics/*physiology</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2006</year></dates><isbn>1530-7905 (Print) 1530-7905 (Linking)</isbn><accession-num>17303919</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17303919</url></related-urls></urls></record></Cite></EndNote>99.

Figure SEQ Figure * ARABIC 7; NF-KB signaling pathway activation.Upon activation by Cardiac hypertrophic agonists, Gq-coupled receptors activate PKC, which can lead to activation of NF-?B through degradation of I?B?. Activated NF-?B-p50 and NF-?B-p65 proteins in cytoplasm move into nucleus where they bind to the promoter of GRK5. This activated protein complex may interact with other transcription factors and coactivators in the promoter region, thereby enhancing the transcription of GRK5. As ROS have shown to be important in the process of activation, NF-KB inhibitors like antioxidants can block the whole event of activation.

Very few studies have been done in the involvement of NF-kB pathway in the pathogenesis of HCM. NF-kB regulates inflammatory genes and circulating inflammatory cytokines are raised in patients with HCM. Johanna et al found low-grade myocardial inflammation in endomyocardial samples and in the circulation of patients with HCM. These cytokines correlated with the histopathological myocardial fibrosis. In this study the NF-kB activity was high suggesting it to be a cause of myocardial fibrosis in HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdXVzaXN0bzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdXVzaXN0bzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+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ADDIN EN.CITE.DATA 103. In myocarditis and other inflammatory cardiomyopathies, NF-kB activation was found to be the most important pathway PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWllcjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWllcjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl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ADDIN EN.CITE.DATA 104. There are existing evidences on NF-kB pathway activation in some cases of cardiac hypertrophy with causes other than HCM. The clear pathway on how it is involved is still yet to be discovered but the interleukin (IL) family of cytokines like IL-6, have been studied to cause cardiac myocyte hypertrophy through NF-kB activation ADDIN EN.CITE <EndNote><Cite><Author>Gordon</Author><Year>2011</Year><RecNum>96</RecNum><DisplayText>105</DisplayText><record><rec-number>96</rec-number><foreign-keys><key app=”EN” db-id=”derfet0zk9wxsretp09pzwxrx50dfvxar592″ timestamp=”1519901619″>96</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Gordon, J. W.</author><author>Shaw, J. A.</author><author>Kirshenbaum, L. A.</author></authors></contributors><auth-address>Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.</auth-address><titles><title>Multiple facets of NF-kappaB in the heart: to be or not to NF-kappaB</title><secondary-title>Circ Res</secondary-title><alt-title>Circulation research</alt-title></titles><periodical><full-title>Circ Res</full-title><abbr-1>Circulation research</abbr-1></periodical><alt-periodical><full-title>Circ Res</full-title><abbr-1>Circulation research</abbr-1></alt-periodical><pages>1122-32</pages><volume>108</volume><number>9</number><keywords><keyword>Animals</keyword><keyword>Apoptosis/*physiology</keyword><keyword>Autophagy/physiology</keyword><keyword>Cytokines/physiology</keyword><keyword>*Heart Failure/metabolism/pathology/physiopathology</keyword><keyword>Humans</keyword><keyword>Myocytes, Cardiac/*pathology/physiology</keyword><keyword>NF-kappa B/*physiology</keyword><keyword>Necrosis</keyword></keywords><dates><year>2011</year><pub-dates><date>Apr 29</date></pub-dates></dates><isbn>1524-4571 (Electronic) 0009-7330 (Linking)</isbn><accession-num>21527742</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21527742</url></related-urls></urls><electronic-resource-num>10.1161/CIRCRESAHA.110.226928</electronic-resource-num></record></Cite></EndNote>105. In a transgenic mouse model of TGT400N with cardiac hypertrophy, NF-kB was among the pathways activated and Akt/mTor being the other PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW5lcmplZTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+
PFJlY051bT41ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTA2XTwvRGlzcGxheVRleHQ+PHJlY29y
ZD48cmVjLW51bWJlcj41ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg
ZGItaWQ9ImRlcmZldDB6azl3eHNyZXRwMDlwend4cng1MGRmdnhhcjU5MiIgdGltZXN0YW1wPSIx
NTE1NjY5NDA1Ij41ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFs
IEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFu
ZXJqZWUsIFMuIEsuPC9hdXRob3I+PGF1dGhvcj5NY0dhZmZpbiwgSy4gUi48L2F1dGhvcj48YXV0
aG9yPkh1YW5nLCBYLiBOLjwvYXV0aG9yPjxhdXRob3I+QWhtYWQsIEYuPC9hdXRob3I+PC9hdXRo
b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2FyZGlvdmFzY3VsYXIgSW5zdGl0dXRl
LCBEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIFBpdHRzYnVyZ2gsIFBpdHRz
YnVyZ2gsIFBBIDE1MjEzLTI1ODIsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5B
Y3RpdmF0aW9uIG9mIGNhcmRpYWMgaHlwZXJ0cm9waGljIHNpZ25hbGluZyBwYXRod2F5cyBpbiBh
IHRyYW5zZ2VuaWMgbW91c2Ugd2l0aCB0aGUgaHVtYW4gUFJLQUcyIFRocjQwMEFzbiBtdXRhdGlv
bjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvc2Vjb25kYXJ5
LXRpdGxlPjxhbHQtdGl0bGU+QmlvY2hpbWljYSBldCBiaW9waHlzaWNhIGFjdGE8L2FsdC10aXRs
ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwv
ZnVsbC10aXRsZT48YWJici0xPkJpb2NoaW1pY2EgZXQgYmlvcGh5c2ljYSBhY3RhPC9hYmJyLTE+
PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CaW9jaGltIEJpb3BoeXMg
QWN0YTwvZnVsbC10aXRsZT48YWJici0xPkJpb2NoaW1pY2EgZXQgYmlvcGh5c2ljYSBhY3RhPC9h
YmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+Mjg0LTkxPC9wYWdlcz48dm9sdW1lPjE4MDI8
L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QU1QLUFjdGl2YXRl
ZCBQcm90ZWluIEtpbmFzZXMvY2hlbWlzdHJ5LypnZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3Jk
PjxrZXl3b3JkPipBbWlubyBBY2lkIFN1YnN0aXR1dGlvbjwva2V5d29yZD48a2V5d29yZD5Bbmlt
YWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFzcGFyYWdpbmU8L2tleXdvcmQ+PGtleXdvcmQ+Q2FyZGlv
bWVnYWx5L2Vuenltb2xvZ3kvKmdlbmV0aWNzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+RE5BIFByaW1lcnM8L2tleXdvcmQ+PGtleXdvcmQ+R2x5Y29nZW4gU3RvcmFnZSBEaXNl
YXNlIFR5cGUgSUliL2Vuenltb2xvZ3kvZ2VuZXRpY3MvKnBoeXNpb3BhdGhvbG9neTwva2V5d29y
ZD48a2V5d29yZD5IZWFydC9waHlzaW9sb2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5
d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNl
LCBUcmFuc2dlbmljPC9rZXl3b3JkPjxrZXl3b3JkPk5GLWthcHBhIEIvbWV0YWJvbGlzbTwva2V5
d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UG9seW1lcmFz
ZSBDaGFpbiBSZWFjdGlvbi9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPlJOQS9nZW5ldGljcy9p
c29sYXRpb24gJmFtcDsgcHVyaWZpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRocmVvbmluZTwv
a2V5d29yZD48a2V5d29yZD5VcC1SZWd1bGF0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz
Pjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWI8L2RhdGU+PC9wdWItZGF0ZXM+
PC9kYXRlcz48aXNibj4wMDA2LTMwMDIgKFByaW50KSYjeEQ7MDAwNi0zMDAyIChMaW5raW5nKTwv
aXNibj48YWNjZXNzaW9uLW51bT4yMDAwNTI5MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRl
ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDAwNTI5Mjwv
dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAx
Ni9qLmJiYWRpcy4yMDA5LjEyLjAwMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+
PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW5lcmplZTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE.DATA 106. NF-kB have been reported to be an important factor in the initiation and cardiac hypertrophy and progression of it to heart failure, this was supported by the increase in activity of this pathway during these two phases and its inhibition with PDTC appeared to improve the cardiac function in these animal modelsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXB0YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXB0YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl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ADDIN EN.CITE.DATA 107. NF-kB signaling as a cause of cardiac hypertrophy in HCM have not been studied which warrants further research.

ROS have been involved in activating NF-kB in a number of activities. During cardiac hypertrophy, the normal pattern of cardiac gene expression is altered which provide different outcome. A number of transcription factors are involved in this alteration including NF-kB where ROS have been reported to activate them during the process ADDIN EN.CITE <EndNote><Cite><Author>Sag</Author><Year>2014</Year><RecNum>282</RecNum><DisplayText>108</DisplayText><record><rec-number>282</rec-number><foreign-keys><key app=”EN” db-id=”at0d2e224rdzf1e9fpbpt59f9txsprx9wt02″>282</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Sag, C. M.</author><author>Santos, C. X. C.</author><author>Shah, A. M.</author></authors></contributors><auth-address>British Heart Fdn Ctr Excellence, Kings Coll London, Div Cardiovasc, London, England</auth-address><titles><title>Redox regulation of cardiac hypertrophy</title><secondary-title>Journal of Molecular and Cellular Cardiology</secondary-title><alt-title>J Mol Cell Cardiol</alt-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></periodical><alt-periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></alt-periodical><pages>103-111</pages><volume>73</volume><keywords><keyword>hypertrophy</keyword><keyword>cardiac</keyword><keyword>redox</keyword><keyword>signaling</keyword><keyword>nadph oxidase</keyword><keyword>nitric-oxide synthase</keyword><keyword>induced cardiomyocyte hypertrophy</keyword><keyword>nox2-containing nadph oxidase</keyword><keyword>disulfide bond formation</keyword><keyword>heart-failure</keyword><keyword>myocardial-infarction</keyword><keyword>angiotensin-ii</keyword><keyword>sarcoplasmic-reticulum</keyword><keyword>pressure-overload</keyword><keyword>oxidative stress</keyword></keywords><dates><year>2014</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0022-2828</isbn><accession-num>WOS:000337551000013</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000337551000013</url></related-urls></urls><electronic-resource-num>10.1016/j.yjmcc.2014.02.002</electronic-resource-num><language>English</language></record></Cite></EndNote>108. Studies in mouse models showed NOX2 dependent activation of NF-kB and matrix metalloproteinase in causing cardiac interstitial fibrosis ADDIN EN.CITE <EndNote><Cite><Author>Sag</Author><Year>2014</Year><RecNum>282</RecNum><DisplayText>108</DisplayText><record><rec-number>282</rec-number><foreign-keys><key app=”EN” db-id=”at0d2e224rdzf1e9fpbpt59f9txsprx9wt02″>282</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Sag, C. M.</author><author>Santos, C. X. C.</author><author>Shah, A. M.</author></authors></contributors><auth-address>British Heart Fdn Ctr Excellence, Kings Coll London, Div Cardiovasc, London, England</auth-address><titles><title>Redox regulation of cardiac hypertrophy</title><secondary-title>Journal of Molecular and Cellular Cardiology</secondary-title><alt-title>J Mol Cell Cardiol</alt-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></periodical><alt-periodical><full-title>J Mol Cell Cardiol</full-title><abbr-1>Journal of molecular and cellular cardiology</abbr-1></alt-periodical><pages>103-111</pages><volume>73</volume><keywords><keyword>hypertrophy</keyword><keyword>cardiac</keyword><keyword>redox</keyword><keyword>signaling</keyword><keyword>nadph oxidase</keyword><keyword>nitric-oxide synthase</keyword><keyword>induced cardiomyocyte hypertrophy</keyword><keyword>nox2-containing nadph oxidase</keyword><keyword>disulfide bond formation</keyword><keyword>heart-failure</keyword><keyword>myocardial-infarction</keyword><keyword>angiotensin-ii</keyword><keyword>sarcoplasmic-reticulum</keyword><keyword>pressure-overload</keyword><keyword>oxidative stress</keyword></keywords><dates><year>2014</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0022-2828</isbn><accession-num>WOS:000337551000013</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000337551000013</url></related-urls></urls><electronic-resource-num>10.1016/j.yjmcc.2014.02.002</electronic-resource-num><language>English</language></record></Cite></EndNote>108. Mice with genetically increased NOX4 had higher levels of oxidative stress and developed cardiac hypertrophy via activated Akt/mTor and NF-kB pathway, using antioxidant the activated pathways were reduced so did the cardiac hypertrophy ADDIN EN.CITE <EndNote><Cite><Author>Xu</Author><Year>2016</Year><RecNum>285</RecNum><DisplayText>109</DisplayText><record><rec-number>285</rec-number><foreign-keys><key app=”EN” db-id=”at0d2e224rdzf1e9fpbpt59f9txsprx9wt02″>285</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Xu, L. F.</author><author>Brink, M.</author></authors></contributors><auth-address>Univ Basel, Dept Biomed, Hebelstr 20, CH-4031 Basel, Switzerland Univ Basel Hosp, Hebelstr 20, CH-4031 Basel, Switzerland</auth-address><titles><title>mTOR, cardiomyocytes and inflammation in cardiac hypertrophy</title><secondary-title>Biochimica Et Biophysica Acta-Molecular Cell Research</secondary-title><alt-title>Bba-Mol Cell Res</alt-title></titles><periodical><full-title>Biochimica Et Biophysica Acta-Molecular Cell Research</full-title><abbr-1>Bba-Mol Cell Res</abbr-1></periodical><alt-periodical><full-title>Biochimica Et Biophysica Acta-Molecular Cell Research</full-title><abbr-1>Bba-Mol Cell Res</abbr-1></alt-periodical><pages>1894-1903</pages><volume>1863</volume><number>7</number><keywords><keyword>protein synthesis</keyword><keyword>protein degradation</keyword><keyword>mtor</keyword><keyword>nf-kappab</keyword><keyword>inflammation</keyword><keyword>cardiomyocyte</keyword><keyword>nf-kappa-b</keyword><keyword>ubiquitin-proteasome system</keyword><keyword>protein-kinase-c</keyword><keyword>focal adhesion kinase</keyword><keyword>p70 s6 kinase</keyword><keyword>mammalian target</keyword><keyword>heart-failure</keyword><keyword>molecular-mechanisms</keyword><keyword>pressure-overload</keyword><keyword>signaling pathways</keyword></keywords><dates><year>2016</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0167-4889</isbn><accession-num>WOS:000378360400023</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000378360400023</url></related-urls></urls><electronic-resource-num>10.1016/j.bbamcr.2016.01.003</electronic-resource-num><language>English</language></record></Cite></EndNote>109
The role of ROS activating NF-kB pathway plays in the development cardiac hypertrophy was proved further by the studies on mice where treatment with pyrrolidine dithiocarbamate (PDTC) an antioxidant that inhibit NF-kB through direct oxidation of thiols on NF-kBPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYXBwYW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpYXBwYW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy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ADDIN EN.CITE.DATA 110, prevented the development of cardiac hypertrophyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA 81, 110, 111
CHAPTER 3: METHODOLOGY.3.1. STUDY DESIGN3.1.1. Type and site of the studyThe study was a prospective experimental design conducted at Wuhan Union hospital, Wuhan city, Hubei province in Peoples’ Republic of China.

3.1.2. Study populationThe study sample was taken from the heart sample after heart transplant from the patients who were diagnosed to have congenital Hypertrophic cardiomyopathy.

Inclusion criteria.Samples from children below 14 years, which is the age group considered as pediatric patient.

Samples that had already been proven by the pathologist to have pathological features of hypertrophic cardiomyopathy.

Exclusion criteria.Age above 14 years, adult patients.

Cardiac hypertrophy due to other causes other that genetic hypertrophic cardiomyopathy such as hypertension.
Samples with no pathological features of genetic hypertrophic cardiomyopathy.

3.2. PATIENT’S HISTORY;From the above inclusion and Exclusion criteria and the timeline of our study we were able to obtain three heart samples that had Hypertrophic cardiomyopathy and one control sample. In the diseased heart sample, the first heart and the second heart were from patients with diastolic dysfunction, while the third heart was from a patient having systolic dysfunction heart failure judged from the ejection fraction and the appearance of the heart.
3.2.1. Patient 1;Patient ZY
Age; 8 years and 3 months old
Sex; Female
Patient treated with recurrent episode of pneumonia from local hospital. She currently presented to the hospital with difficulty in breathing, chest tightness and lower limb edema. Upon investigation, she was diagnosed to have restrictive cardiomyopathy and was referred to our hospital for further management.
o/e conscious, well oriented to time, place and person, lethargic, nasal flaring and lower limb edema. Pulse rate 80 beats/min, Respiratory rate 30 cycles/min, BP 90/60 mmHg and Temperature of 36.8C.

Respiratory system
Supraclavicular, intercostals and sub costal retractions
Bronchial breath sounds and wet rales in the lower left lung field
Basal crepitationsCardiovascular system
Blood pressure of 93/61 mmHg
Apex beat on the 6th intercostals space 1cm lateral to the mid clavicular line
Echocardiography;
Thickening of the ventricular walls more on the left ventricle
Features of interstitial fibrosis
Ejection fraction of 54%
Diagnosis; Heart failure secondary to restrictive cardiomyopathy and severe pneumonia.Management;
Antibiotics due pneumonia
Medications for heart failure
Heart transplant done after two weeks
Pathology of the heart tissue reveled, interstitial fibrosis, myocyte hypertrophy and myocyte disarray which confirmed the diagnosis of Hypertrophic cardiomyopathy.

3.2.2. Patient 2; Patient JC,
Age: 11 years and 2 months old
Sex: Male child
He was a known case of Restrictive cardiomyopathy, which was diagnosed from Shanghai Children’s Hospital since 2 years ago.
Chief complains: Fever, cough and Difficulty in breathing. The cough was productive with expectoration of yellow sputum and had severe chest pain.

Past history: Two years ago, he presented to the local hospital with repeated episodes of fever and productive cough and after investigations they noted a heart disease, was then referred to Shanghai Children’s hospital where was diagnosed to have Restrictive cardiomyopathy. The child was given antibiotics and symptomatic cardiac medications like captopril, Furosemide, Spironolactone and Aspirin. The symptoms were controlled for sometime but after one year, he presented with severe respiratory distress, severe body weakness, lower limb edema and shortness of breath after minor activity. He was then diagnosed to have severe pneumonia and heart failure. Intravenous antibiotics were administered together with cardiotonic drugs were added to the cardiac medications. Symptoms improved but from this time he started having recurrent admissions due to severe pneumonia and heart failure, which ended up with the referral for possible heart transplant. No history of Hepatitis or Tuberculosis was reported. No history of surgery or blood transfusion before.
Review of other systems: Other systems like the gastrointestinal system, central nervous system, genital urinary system, Musculoskeletal and endocrine systems were essentially normal.

Family history: No history of similar illness was reported in the family.
Physical examination: conscious, alert, oriented to time place and person, normal skin color, no rashes and had lower limb edema. Vitals; temperature 36.5C, pulse rate 90 Beats/min, BP 79/59 mmHg, respiratory rate 20 Cycles/min. He had a weight of 24kg and the height of 137 cm. In here we noticed the patient having poor growth and hypotensive.
Systemic examination:
Respiratory system; coarse breath sounds and basal crepitationCardiovascular system; Heart rate of 88 Beats/min, no obvious murmur was reported.

Gastrointestinal system; Hepatomegaly, 3 Cm below the right costal margin
Central nervous system, Genital-urinary system, musculoskeletal systems were essentially normal
Echocardiography from Shanghai children’s hospital; Bilateral atrial enlargement, left ventricular hypertrophy, mild to moderate mitral regurgitation, left ventricular systolic function was in the lower limit of normal, diastolic dysfunction.

The echocardiography in our hospital showed the right and left atrium to be increased significantly and there was left ventricular inhomogeneous thickening. The left heart function decreased; the left ventricular basal segment and interventricular septal myocardial interstitial band low signal perfusion defect, delayed enhancement scan suspected myocardial fibrosis; mild mitral insufficiency; interstitial pulmonary edema and hepatic congestion;the ejection fraction was 51%.

Gene sequencing from Shanghai Children’s hospital; missense mutation in the TNN13 gene
Diagnoses:
Heart failure NYHA stage IV secondary to Hypertrophic cardiomyopathyDdx- Restrictive cardiomyopathySevere pneumonia
Management;
Antibiotics
Cardiac medications like Metoprolol, Furosemide, captopril, sodium nitroprusideAfter 1week Heart transplant was done due to rapid deterioration of the condition.

Pathological report; Myocyte hypertrophy, interstitial fibrosis and myocyte disarray.3.2.3. Patient 3;Patient RH
Age; 11 years and six months
Sex; female
History of the present illiness;
One year before the admission patient presented in the local hospital with sudden onset of shortness of breath, chest tightness, nausea, and vomiting and abdominal discomfort. Upon different examination, color Doppler ultrasonography showed severe mitral valve regurgitation where mitral valvuloplasty was opted and was done successfully. The patient was then discharged with medication like digoxin, Betaloc, Furosemide, Spironolactone, captopril to improve and enhance cardiac function.
Two months later, symptoms of chest tightness and shortness of breathe reappeared and currently she developed Oliguria and edema of the lower extremities. Echocardiography showed severe mitral and tricuspid valves regurgitation, severe double ventricular functional impairment with Left ventricular ejection fraction of 20% and the right ventricular ejection fraction of 30%. Had also mild aortic regurgitation, pulmonary hypertension and mild pulmonary valve regurgitation. She was then referred to our hospital with the possible diagnosis of heart failure secondary to dilated cardiomyopathy for possible heart transplantation.

During Admission;
On Examination; the patient was conscious, well oriented to time, place and person, had dyspnea with supraclavicular, intercostal and subcostal retractions and had lower limb edema. The vitals; temperature of 36.3C, pulse rate 120 Beats/min, Respiratory rate 20 cycles/min, BP 87/59 mmHg, weight of 34 kg.
Echocardiography;
Left ventricular basal segment, middle segment, inferior wall and lateral wall endocardial non-compact myocardium with delayed enhancement and suggestive of myocardial fibrosis.

Myocardial thickening
Enlarged left ventricle and left cardiac function significantly reduced with ejection fraction (EF) of 17%
Mitral valve changes associated with severe mitral insufficiency.

Widened pulmonary artery and inferior vena cava.
Chest X-ray; Increased pulmonary blood flow suggesting pulmonary hypertension.
Diagnoses;
Heart failure NYHA stage IV secondary to dialated cardiomyopathySevere mitral regurgitation after mitral valvuloplasty.
Management; heart transplant was done
Pathology; cardiomyocyte hypertrophy, interstitial fibrosis. Features suggestive of hypertrophic cardiomyopathy.3.3. RESEARCH CONCEPTThe aim of the experiment was to prove and support the existence of increased oxidative stress in the hearts with hypertrophic cardiomyopathy (HCM) since oxidative stress was long being implicated as the important progressive factor for the expression of the disease.

Reactive oxygen species (ROS) are very reactive molecules which makes it difficult to measure them directly, measuring their end product have long being used as a possible mechanism to measure them, one of the methods is through fluorescence microscopy of Dihydroethidium (DHE), which was the method employed in our experiment. DHE is a reduced form of DNA dyes Ethidium bromide; it has high reactivity and can diffuse passively into cells, hence used to detect cytosolic superoxide PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb21lczwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
Y051bT4yMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTEyLCAxMTNdPC9EaXNwbGF5VGV4dD48cmVj
b3JkPjxyZWMtbnVtYmVyPjIwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0iMHo5ZWZhNWV4MndkOXJlOXM5dHg5OTJtOTl6ZnRlYXN6eGF6IiB0aW1lc3RhbXA9
IjE1MTc3MjY0OTciPjIwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5H
b21lcywgQS48L2F1dGhvcj48YXV0aG9yPkZlcm5hbmRlcywgRS48L2F1dGhvcj48YXV0aG9yPkxp
bWEsIEouIEwuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+
UkVRVUlNVEUsIERlcGFydGFtZW50byBkZSBRdWltaWNhLUZpc2ljYSwgRmFjdWxkYWRlIGRlIEZh
cm1hY2lhLCBVbml2ZXJzaWRhZGUgZG8gUG9ydG8sIFJ1YSBBbmliYWwgQ3VuaGEsIDE2NCwgNDA5
OS0wMzAgUG9ydG8sIFBvcnR1Z2FsLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkZsdW9y
ZXNjZW5jZSBwcm9iZXMgdXNlZCBmb3IgZGV0ZWN0aW9uIG9mIHJlYWN0aXZlIG94eWdlbiBzcGVj
aWVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQmlvY2hlbSBCaW9waHlzIE1ldGhvZHM8L3Nl
Y29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkpvdXJuYWwgb2YgYmlvY2hlbWljYWwgYW5kIGJpb3Bo
eXNpY2FsIG1ldGhvZHM8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs
ZT5KIEJpb2NoZW0gQmlvcGh5cyBNZXRob2RzPC9mdWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBv
ZiBiaW9jaGVtaWNhbCBhbmQgYmlvcGh5c2ljYWwgbWV0aG9kczwvYWJici0xPjwvcGVyaW9kaWNh
bD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBCaW9jaGVtIEJpb3BoeXMgTWV0aG9kczwv
ZnVsbC10aXRsZT48YWJici0xPkpvdXJuYWwgb2YgYmlvY2hlbWljYWwgYW5kIGJpb3BoeXNpY2Fs
IG1ldGhvZHM8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz40NS04MDwvcGFnZXM+PHZv
bHVtZT42NTwvdm9sdW1lPjxudW1iZXI+Mi0zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFu
aW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+KkZsdW9yZXNjZW50IER5ZXMvY2hlbWlzdHJ5PC9rZXl3
b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeWRyb2dlbiBQZXJveGlkZS9h
bmFseXNpczwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5bCBSYWRpY2FsL2FuYWx5c2lzPC9rZXl3
b3JkPjxrZXl3b3JkPlBlcm94aWRlcy9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5SZWFjdGl2
ZSBPeHlnZW4gU3BlY2llcy8qYW5hbHlzaXMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5T
aW5nbGV0IE94eWdlbi9hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5TcGVjdHJvbWV0cnksIEZs
dW9yZXNjZW5jZTwva2V5d29yZD48a2V5d29yZD5TdXBlcm94aWRlcy9hbmFseXNpczwva2V5d29y
ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVj
IDMxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDE2NS0wMjJYIChQcmludCkmI3hE
OzAxNjUtMDIyWCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTYyOTc5ODA8L2FjY2Vz
c2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmlo
Lmdvdi9wdWJtZWQvMTYyOTc5ODA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9u
aWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5qYmJtLjIwMDUuMTAuMDAzPC9lbGVjdHJvbmljLXJl
c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5XYXJkbWFuPC9BdXRob3I+
PFllYXI+MjAwNzwvWWVhcj48UmVjTnVtPjIxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4y
MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjB6OWVmYTVl
eDJ3ZDlyZTlzOXR4OTkybTk5emZ0ZWFzenhheiIgdGltZXN0YW1wPSIxNTE3NzI2NTk3Ij4yMTwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2FyZG1hbiwgUC48L2F1dGhv
cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IG9mIE94
Zm9yZCwgR3JheSBDYW5jZXIgSW5zdGl0dXRlLCBNb3VudCBWZXJub24gSG9zcGl0YWwsIE5vcnRo
d29vZCwgTWlkZGxlc2V4IEhBNiAySlIsIFVLLiB3YXJkbWFuQGdjaS5hYy51azwvYXV0aC1hZGRy
ZXNzPjx0aXRsZXM+PHRpdGxlPkZsdW9yZXNjZW50IGFuZCBsdW1pbmVzY2VudCBwcm9iZXMgZm9y
IG1lYXN1cmVtZW50IG9mIG94aWRhdGl2ZSBhbmQgbml0cm9zYXRpdmUgc3BlY2llcyBpbiBjZWxs
cyBhbmQgdGlzc3VlczogcHJvZ3Jlc3MsIHBpdGZhbGxzLCBhbmQgcHJvc3BlY3RzPC90aXRsZT48
c2Vjb25kYXJ5LXRpdGxlPkZyZWUgUmFkaWMgQmlvbCBNZWQ8L3NlY29uZGFyeS10aXRsZT48YWx0
LXRpdGxlPkZyZWUgcmFkaWNhbCBiaW9sb2d5ICZhbXA7IG1lZGljaW5lPC9hbHQtdGl0bGU+PC90
aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+RnJlZSBSYWRpYyBCaW9sIE1lZDwvZnVsbC10
aXRsZT48YWJici0xPkZyZWUgcmFkaWNhbCBiaW9sb2d5ICZhbXA7IG1lZGljaW5lPC9hYmJyLTE+
PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5GcmVlIFJhZGljIEJpb2wg
TWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+RnJlZSByYWRpY2FsIGJpb2xvZ3kgJmFtcDsgbWVkaWNp
bmU8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz45OTUtMTAyMjwvcGFnZXM+PHZvbHVt
ZT40Mzwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5GbHVvcmVz
Y2VudCBEeWVzLypjaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr
ZXl3b3JkPipMdW1pbmVzY2VudCBNZWFzdXJlbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+Tml0cmlj
IE94aWRlL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aW9uLVJlZHVjdGlvbjwv
a2V5d29yZD48a2V5d29yZD5PeHlnZW4vbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5SZWFj
dGl2ZSBOaXRyb2dlbiBTcGVjaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlJlYWN0aXZlIE94eWdlbiBT
cGVjaWVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8
L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3QgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp
c2JuPjA4OTEtNTg0OSAoUHJpbnQpJiN4RDswODkxLTU4NDkgKExpbmtpbmcpPC9pc2JuPjxhY2Nl
c3Npb24tbnVtPjE3NzYxMjk3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy
bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE3NzYxMjk3PC91cmw+PC9yZWxh
dGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouZnJlZXJh
ZGJpb21lZC4yMDA3LjA2LjAyNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D
aXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb21lczwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl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ADDIN EN.CITE.DATA 112, 113. Upon reaction with superoxide anions, DHE forms a red fluorescent product 2-hydroxyethidiumPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA 114, which intercalates with DNA and exhibit red fluorescent ADDIN EN.CITE <EndNote><Cite><Author>Bucana</Author><Year>1986</Year><RecNum>23</RecNum><DisplayText>115</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1517726921″>23</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bucana, C.</author><author>Saiki, I.</author><author>Nayar, R.</author></authors></contributors><titles><title>Uptake and accumulation of the vital dye hydroethidine in neoplastic cells</title><secondary-title>J Histochem Cytochem</secondary-title><alt-title>The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society</alt-title></titles><periodical><full-title>J Histochem Cytochem</full-title><abbr-1>The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society</abbr-1></periodical><alt-periodical><full-title>J Histochem Cytochem</full-title><abbr-1>The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society</abbr-1></alt-periodical><pages>1109-15</pages><volume>34</volume><number>9</number><keywords><keyword>Animals</keyword><keyword>Cell Line</keyword><keyword>Cytophotometry</keyword><keyword>Ethidium/*analogs &amp; derivatives/metabolism</keyword><keyword>Fibrosarcoma/*metabolism</keyword><keyword>Flow Cytometry</keyword><keyword>*Fluorescent Dyes</keyword><keyword>Humans</keyword><keyword>Melanoma/*metabolism</keyword><keyword>Mice</keyword><keyword>Microscopy, Fluorescence</keyword><keyword>Spectrometry, Fluorescence</keyword><keyword>*Staining and Labeling</keyword></keywords><dates><year>1986</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0022-1554 (Print) 0022-1554 (Linking)</isbn><accession-num>2426339</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/2426339</url></related-urls></urls><electronic-resource-num>10.1177/34.9.2426339</electronic-resource-num></record></Cite></EndNote>115. DHE cannot only be used to detect superoxide but also ONOO and OH PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb21lczwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb21lczwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl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ADDIN EN.CITE.DATA 112, 116.
3.4. MATERIALSMaterials used in this study were;
Na2HPO4.12H2O
NaH2PO4.2H2O
Distilled water
Sucrose
Dihydroethidium powder (DHE)
HBSS solution (Hank’s Balanced Salt Solution)
DMSO solution (Anhydrous dimethyl sulfoxide)
Pipette
Filter paper
OCT compound (Optimal Cutting Temperature Compound)
Dark box
Centrifuge
Stop watch
Microtome
Glass slides
Refrigerator
Sterile glass box
Fluorescent microscopy
3.5. METHODS3.5.1. Making PB solution0.2 Mol/L of PB solution was made by mixing 14.505g of Na2HPO4.12H2O, 1.4815g of NaH2PO4.2H2O and 250mls of distilled water.

3.5.2. Making 30% sucrose solution15.0g of sucrose were mixed with 25.0 mls of PB solution and 25.0 mls of distilled water.

3.5.3. Making 20% sucrose solution10g of sucrose was mixed with 25.0mls of PB solution and 25.0 mls of distilled water.

3.5.4. Making the store solutionDHE is in powder form, to make a solution, 5mg of DHE was dissolved in 3.17 mls of DMSO solution, and the mixture was then centrifuged to mix properly. The solution produced was 5mMol of DHE that is a store solution stored in -20C refrigerator.

3.5.5. Making a working solutionFrom the store solution, a working solution of 50nMol DHE was made by mixing 5mMol of DHE with HBSS solution in a ratio of 1 to 98. The solution is then centrifuged to ensue complete mixing.

3.5.6. Fixing and slicing the heart samplesDifferent chambers of the heart pieces were first put in 20% sucrose solution for 12 hours and then in 30% sucrose solution for another 12 hours. This process made the heart tough and tenacious for slicing
From 30% sucrose solution, the heart pieces were put in the OCT compound ready to be sliced.

The heart pieces were then sliced with a microtome into 5?m thin pieces and put into the glass slides ready for staining.
3.5.7. Staining of the heart samples and ROS visualization.Three drops of the DHE working solution were dropped on every heart sample on the slide and were left for 60 minutes to allow staining. Because DHE is affected by light, this process was done in the dark box to prevent light interference.
After 60 minutes, the slides were washed with HBSS solution for 5 minutes three times. And this was also done in the dark box.

ROS was then visualized under fluorescent microscope under the blue light.

3.5.8. AnalysisThe fluorescent images were analyzed using the IMAGE J program so as to get the numerical data for statistical analysis. Then SPSS version 24 was used for statistical analysis. First ANOVA test as used to compare the mean differences in oxidative stress between the four heart chambers in each heart and the normal and then Post- hoc test for Anova was used to compare specific group differences. The tests compared
3.6. ETHICAL CONSIDERATIONThis study was made possible after being approved by my academic supervisor, the head of pediatric department of Wuhan Union Hospital of China, Tongji Medical College of Huazhong University of Science and Technology (HUBEI, CHINA).

The research was conducted in considering good clinical practice guidelines and we respected all the applicable regulatory rules under the guiding principles of the Declaration of Helsinki.

CHAPTER 4: RESULTS4.1. Microscopy images and Image J analysisAfter fluorescent microscopy of the fixed sections, images were taken. The red dots in the images represented the oxidative stress present in the sections. Below are some of the images that were obtained from different sections of different chambers of the hearts.

left179705a b
c d
e f
g h
Figure SEQ Figure * ARABIC 8; fluorescent microscopy images showing ROS in different heart chambers with HCM. The red bright dots in the slides are the ROS that were stained after DHE staining and visualized in green fluorescent light. a. Left ventricle of the third patient’s heart; b. Inter-ventricular septum of the third patient’s heart; c. Right ventricle in the third patient’s heart; d. Right atrium in the third patient’s heart; e. Left ventricle of the seconds patient’s heart; f. Right atrium of the second patient’s heart; g. Right Atrium of normal heart; h. Right Atrium normal heart. ROS were mostly noticed in the Left ventricle slides than others.

The images were then analyzed using Image J program to obtain pixel values of ROS in the fluorescent images.
a b
c d
e f
g h
Figure 9; Image j analysis of the above fluorescent images from figure 8. The black dotes denotes ROS for easy visualization
4.2. SPSS statistical analysis.Four hearts were analyzed differently and the comparison was made between the oxidative stress of the diseased heart and the normal heart.

4.2.1. Analysis of the First heart.Table SEQ Table * ARABIC 1: Description statistics of the first heart.
Heart Chambers N Mean Std. Deviation 95% Confidence Interval for Mean Minimum Maximum
Lower Bound Upper Bound Intden-LV 100 17766.42 10238.074 15734.96 19797.88 7430 99420
Intden-RV 100 7496.84 3266.349 6848.73 8144.95 1969 16777
Intden-IV 100 9768.28 2962.194 9180.52 10356.04 1908 17993
Intden-RA 100 5331.65 3003.573 4735.68 5927.62 1156 23435
Intden-Normal 100 2126.51 1091.42 1909.95 2343.07 147 4976
Total 500 8497.94 7386.698 7848.91 9146.97 147 99420

Figure SEQ Figure * ARABIC 10; bar chart showing the mean amount of reactive oxygen species in the heart chambers of the first patient’s heart.
The left ventricle had the highest amount of reactive oxygen species followed by the interventricular septim, the right ventricle, the right atrium and lastly the normal heart.

In the first heart, the left ventricle had the highest oxidative stress with highest amount of reactive oxygen species measured. The mean reactive oxygen species were 17766.42 units with the standard deviation of 10238.074 units. The 95% confidence interval was 15734.96 – 19797.88. The Inter-ventricular septum followed with the mean reactive oxygen species of 9768.28 units with a standard deviation of 2962.194 and a 95% confidence interval of 9180.52 – 10356.04. The Right ventricle followed the list with mean of 7496.84 unit of reactive oxygen species with the standard deviation of 3266.349 and a 95% confidence interval of 6848.73 – 8144.95. The Right atrium had the least amount of reactive oxygen species compared to the rest of the heart chambers with the mean of 5331.65 and a standard deviation of 3003.573 with a 95% confidence interval of 4735.68 – 5927.62. The normal heart chamber had the mean reactive oxygen species of 2126.51 units and a standard deviation of 1091.42 from the mean with a 95% confidence interval of 1909.95 – 2343.07. Seeing the difference in oxidative stress between the heart chambers, the significance of the difference were found using ANOVA test since we compared more than three means.
Table SEQ Table * ARABIC 2: ANOVA of ROS in the first heartSum of Squares dfMean Square F Sig.

Between Groups 13914119905 4 3478529976 129.338 <0.0001
Within Groups 13312970782 495 26894890.47 Total 27227090686 499 From the ANOVA tests we found a significant difference in the oxidative stress between heart chambers which was described as F= 129.338, df= 4 and a p value of <0.0001. Since there was significance, we went further to conduct a post – Hoc ANOVA test to find which chambers had a significant difference among them. The Turkeys Post- Hoc test was used, as there was equal N value in all the chambers.
Table SEQ Table * ARABIC 3: Multiple comparison of ROS in the first heartDependent Variable: level of oxidative stress Tukey HSD Section groups Section groups Mean Difference Sig. 95% Confidence Interval
Lower Bound Upper Bound
Intden-LV Intden-RV 10269.580* <0.0001 8261.59 12277.57
Intden-IV 7998.140* <0.0001 5990.15 10006.13
Intden-RA 12434.770* <0.0001 10426.78 14442.76
Intden-Normal 15639.910* <0.0001 13631.92 17647.9
Intden-RV Intden-IV -2271.440* 0.018 -4279.43 -263.45
Intden-RA 2165.190* 0.027 157.2 4173.18
Intden-Normal 5370.330* <0.0001 3362.34 7378.32
Intden-IV Intden-RA 4436.630* <0.0001 2428.64 6444.62
Intden-Normal 7641.770* <0.0001 5633.78 9649.76
Intden-RA Intden-Normal 3205.140* <0.0001 1197.15 5213.13
* The mean difference is significant at the 0.05 levels. From the post Hoc test, all the chambers had significant difference in mean reactive oxygen species from one another where between the Left Ventricle and Inter-ventricular septum, the left Ventricle and Right Ventricle, the Left Ventricle and Right Atrium, the Left Ventricle and Normal heart, the Right ventricle and the normal heart, the Inter-Ventricular septum and the right Atrium, The Inter-ventricular area and the Normal heart and the Right Atrium and the Normal heart, all had a significance in mean difference with a p value of <0.0001. For the Right Ventricle and the Inter-Ventricular site, there was a significant mean difference with the p value of 0.018 and the Right Ventricle and Right Atrium had a significant mean difference with the p value of 0.027.
4.2.2. Analysis of the second heart.Table SEQ Table * ARABIC 4: Descriptive statistic of ROS in the second heart
Heart
Chambers N Mean Std. Deviation 95% Confidence Interval for Mean Maximum
Lower Bound Upper Bound Minimum Intden-LV 65 14387.25 4692.534 13224.49 15550 6028 30326
Intden-IV 65 16888.02 5880.873 15430.81 18345.22 6807 33924
Intden-RV 65 6111.18 3797.71 5170.16 7052.21 513 16054
Intden-RA 65 4568.09 2782.912 3878.52 5257.66 568 12254
Intden-Normal 100 2126.51 1091.42 1909.95 2343.07 147 4976
Total 360 8165.82 6958.546 7444.58 8887.07 147 33924

Figure SEQ Figure * ARABIC 11; bar chart showing the mean value of ROS in different chambers of the second heart.
The mean ROS in the inter-ventricular septum was the highest followed by the left ventricle then the right ventricle, the right Atrium and lastly the normal heart.

In the second heart sample, the inter-ventricular area had high amount of reactive oxygen species than any other parts of the heart. The mean amount of reactive oxygen species was 16888.02 units with the standard deviation of 5880.873. The 95% confidence interval was 15430.81 – 18345.22. The left ventricle with mean reactive oxygen species of 14387.25 units followed the range with the standard deviation of 4692.534 and a 95% confidence interval of 13224.49 – 15550. Next in the list was the Right ventricle with mean reactive oxygen species of 6111.18 units with the standard deviation of 3797.71. Its 95% confidence interval is 5170.16 – 7052.21. The least amount of reactive oxygen species were found in the Right Atrium which had a mean of 4568.09 units of reactive oxygen species and a standard deviation of 2782.912. Its 95% confidence interval was 3878.52 – 5257.66 units. The same normal heart was compared as the first heart. Following the different values of Reactive oxygen species in the different heart chambers and the normal heart in general, the significance of the mean were found using Analysis Of Variance (ANOVA). This was used as we compared more than three means.
Table SEQ Table * ARABIC 5: ANOVA of ROS in the second heartSum of Squares dfMean Square F Sig.

Between Groups 12223946971 4 3055986743 210.275 <0.0001
Within Groups 5159319909 355 14533295.52 Total 17383266881 359 From the ANOVA test, there was a significant difference in the means of reactive oxygen species between the heart chambers which was described by F= 210.275, df = 4 and a p value of <0.0001. To know which chambers had a significant difference in the level of reactive oxygen species, a Post Hoc ANOVA test was done and Scheffe post Hoc ANOVA test was used since the N value was different between sample groups.
Table SEQ Table * ARABIC 6: Multiple comparison in the mean ROS in the second heartDependent Variable: level of oxidative stress Scheffe Section groups Section groups Mean Difference Sig. 95% Confidence Interval
Lower Bound Upper Bound
Intden-LV Intden-IV -2500.769* 0.008 -4571.45 -430.09
Intden-RV 8276.062* <0.0001 6205.38 10346.74
Intden-RA 9819.154* <0.0001 7748.47 11889.83
Intden-Normal 12260.736* <0.0001 10379.95 14141.52
Intden-IV Intden-RV 10776.831* <0.0001 8706.15 12847.51
Intden-RA 12319.923* <0.0001 10249.24 14390.6
Intden-Normal 14761.505* <0.0001 12880.72 16642.29
Intden-RV Intden-RA 1543.092 0.258 -527.59 3613.77
Intden-Normal 3984.675* <0.0001 2103.89 5865.46
Intden-RA Intden-Normal 2441.582* 0.003 560.79 4322.37
* The mean difference is significant at the 0.05 level. From the Post Hoc ANOVA test above, there was NO significant difference in the mean reactive oxygen species between the Right ventricle and Right Atrium. The was a significance difference in the mean reactive oxygen species between the Left Ventricle and Right Ventricle, Left ventricle and right Atrium, Left ventricle and Normal heart, Inter-ventricular septum and Right ventricle, Inter-Ventricular septum and Right Atrium, Inter-Ventricular Septum and Normal heart and Right Ventricle and the Normal ventricle with the p value <0.0001. how ever there was also significant difference in the mean Reactive oxygen species between the Left Ventricle and Inter-Ventricular septum with the P value of 0.008 and between Right Atrium and Normal heart with a P value of 0.003.

4.2.3. Analysis of the Third heart Sample.Table SEQ Table * ARABIC 7: Descriptive statistic of ROS in the third heartHeart chambers N Mean Std. Deviation 95% Confidence Interval for Mean Minimum Maximum
Lower Bound Upper Bound Intden-IV 100 9324.56 2639.536 8800.82 9848.31 4144 15508
Intden-RV 100 8930.59 4720.279 7993.98 9867.2 1728 30508
Intden-RA 100 3537.48 1782.385 3183.82 3891.14 861 10705
Intden-LV 100 14972.38 5070.743 13966.23 15978.53 8059 36159
Intden-Normal 100 2126.51 1091.42 1909.95 2343.07 147 4976
Total 500 7778.3 5735.244 7274.38 8282.23 147 36159

Figure SEQ Figure * ARABIC 12; bar chart showing mean value of ROS in different chambers of the third heart.
The left ventricle had the highest mean ROS followed by the inter-ventricular region then the right ventricle, the right atrium and lastly the normal heart chamber.

In the third heart, the left ventricle had high amount of Reactive Oxygen Species than any other heart chamber. Its mean amount of Oxidative stress was 14972.38 units with the standard deviation of 5070.743 from the mean. The 95% confidence interval was 13966.23 – 15978.53. This was followed by Inter-ventricular area with mean amount of oxidative stress 9324.56 units and a standard deviation of 2639.536 from the mean. The 95% confidence interval was 8800.82 – 9848.31. The Right Ventricle followed by close range to the Inter–Ventricular area, its mean amount of Reactive oxygen species was 8930.59 with a standard deviation of 4720.279 from the mean and a 95% confidence interval of 7993.98 – 9867.2. The lowest amount of reactive oxygen species was found in the Right Atrium, which had the mean of 3537.48 and the standard deviation of 1782.385 and the 95% confidence interval of 3183.82 – 3891.14. Again in this heart, the normal heart chamber seemed to have the lowest amount of reactive oxygen species compared to any chamber in the diseased heart. To find if the difference in the amount of Reactive Oxygen species was significant, the Analysis of Variance (ANOVA) test was conducted. Again this was used due to the fact that, more than three means were compared. The results are shown in the table below
Table SEQ Table * ARABIC 8; ANOVA of ROS in the third heart
Sum of Squares dfMean Square F Sig.

Between Groups 10540077541 4 2.64E+09 222.069 <0.0001
Within Groups 5873542769 495 11865742.97 Total 16413620310 499
The ANOVA Test showed a significant difference in the mean reactive oxygen species between the heart chambers describes by the F= 222.069, df= 4 and p value <0.0001. To find which chambers exactly have significant difference in the mean oxidative stress, the Post –Hoc ANOVA test was conducted to precise the Turkey post Hoc ANOVA test because the sample size (N value) was the same in all the heart chambers. The results are well described below.

Table SEQ Table * ARABIC 9: Multiple comparison of mean ROS from the third heartDependent Variable: Level of oxidative stress Turkey HSD
Section groups Section groups Mean Difference Sig. 95% confidence interval
Lower Bound Upper Bound
Intden-IV Intden-RV 393.974 0.928 -939.77 1727.72
Intden-RA 5787.084* <0.0001 4453.34 7120.83
Intden-LV -5647.816* <0.0001 -6981.56 -4314.07
Intden-Normal 7198.054* <0.0001 5864.31 8531.8
Intden-RV Intden-RA 5393.110* <0.0001 4059.36 6726.86
Intden-LV -6041.790* <0.0001 -7375.54 -4708.04
Intden-Normal 6804.080* <0.0001 5470.33 8137.83
Intden-RA Intden-LV -11434.900* <0.0001 -12768.65 -10101.15
Intden-Normal 1410.970* 0.032 77.22 2744.72
Intden-LV Intden-Normal 12845.870* <0.0001 11512.12 14179.62
* The mean difference is significant at the 0.05 level The Post Hoc ANOVA test shows there is no significant difference in the mean reactive Oxygen species between the Inter-Ventricular area and the Right ventricle with the P value of 0.928. The significant difference in the mean Reactive Oxygen species existed between the Inter-Ventricular septum and the Right Atrium, inter-ventricular septum and the Left Ventricle, Inter-Ventricular septum and the normal heart chamber, Right ventricle and the Right Atrium, Right Ventricle and Left Ventricle, Right Ventricle and the normal heart chamber, Right Atrium and the Left Ventricle and the Normal heart chamber. In all these the p value was <0.0001. Moreover, there was also a significant difference in the mean Reactive Oxygen species between the right Atrium and the Normal heart chamber with the p value of 0.032.
Though ROS was increased in all the three hearts, no heart had totally completely high ROS in all the chambers compared to the others. This means no single heart had completely increased oxidative stress compared to the other two hearts.

Figure SEQ Figure * ARABIC 13; chamber wise comparison of mean ROS in the three hearts. The graphs show no one heart had the highest amount of ROS in all the chambers. While one heart had the highest mean ROS in one chamber, the other had the highest in another chamber.

CHAPTER 5: DISCUSSIONHCM is the disease of sarcomere proteins and it affects heart muscles. Several evidences exist on the involvement of oxidative stress in the pathogenesis of the illness. Oxidative stress does affect cardiac myocytes in various ways like apoptosis, necrosis and even causing cardiac hypertrophy, which makes antioxidants as a potential therapeutic target for reversing cardiac hypertrophy phenotype in patients with HCM.
Our research has proved the significant increase in oxidative stress in the patients with HCM as compared to the normal. This has been supported by a number of experiments done. To start with, many experiments measured the serum levels of indicators of oxidative stress like 8-Isoprostaglandin F2?, not a human heart tissue sample since it is difficult to get human samples to do the experiment. Powel et al measured the serum of 57 patients with HCM and found significant increase in 8-Isoprostaglandin F2 ? as compared to the normal controls 35.4 ± 10.2 versus 29.9 ± 9.9 Pg/ml with the p value of <0.001. Though all patients had significant increase in oxidative stress than controls, the oxidative stress in those with left ventricular outflow obstruction were even higher than the non obstructive type ADDIN EN.CITE <EndNote><Cite><Author>Dimitrow</Author><Year>2009</Year><RecNum>38</RecNum><DisplayText>117</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app=”EN” db-id=”0z9efa5ex2wd9re9s9tx992m99zfteaszxaz” timestamp=”1519294046″>38</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Dimitrow, P. P.</author><author>Undas, A.</author><author>Wolkow, P.</author><author>Tracz, W.</author><author>Dubiel, J. S.</author></authors></contributors><auth-address>2nd Department of Cardiology, Collegium Medicum, Jagiellonian University, Kopernika 17, PL 31-501 Krakow, Poland. [email protected]</auth-address><titles><title>Enhanced oxidative stress in hypertrophic cardiomyopathy</title><secondary-title>Pharmacol Rep</secondary-title><alt-title>Pharmacological reports : PR</alt-title></titles><periodical><full-title>Pharmacol Rep</full-title><abbr-1>Pharmacological reports : PR</abbr-1></periodical><alt-periodical><full-title>Pharmacol Rep</full-title><abbr-1>Pharmacological reports : PR</abbr-1></alt-periodical><pages>491-5</pages><volume>61</volume><number>3</number><keywords><keyword>Cardiomyopathy, Hypertrophic/*blood/complications/diagnostic imaging/pathology</keyword><keyword>Cohort Studies</keyword><keyword>Dinoprost/*analogs &amp; derivatives/blood</keyword><keyword>Echocardiography</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Oxidative Stress</keyword><keyword>Ventricular Outflow Obstruction/*blood/complications/diagnostic imaging/pathology</keyword></keywords><dates><year>2009</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>1734-1140 (Print) 1734-1140 (Linking)</isbn><accession-num>19605948</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19605948</url></related-urls></urls></record></Cite></EndNote>117. Our three patients had non-obstructive type of HCM and they had also significant increase in oxidative stress.
A close related study was the one that was done by Nakamura et al, where they used Endomyocardial biopsy samples obtained through internal jugular venous approach where the samples were taken on the right ventricular side of the septum. In this study they measured the amount of Oxidative stress in patients with HCM by measuring the amount of 4-hydroxy-2-nonenol (HNE) from the biopsy samples. HNE is an aldehyde obtained as a final product in the lipid peroxidation of lipid cell membranes done by ROS. 31 patients were involved in the study and these patients had left ventricular systolic dysfunction. Significantly high levels of HNE expression was found in patients with HCM compared to the control group (16,753 ± 10,723 in those with HCM versus 3548 ± 2574 ?m2 in the control group with the P value of 0.0005). The levels were even higher in patients with systolic dysfunction compared to both obstructive and non-obstructive group PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWthbXVyYTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWthbXVyYTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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ADDIN EN.CITE.DATA 118.
Left ventricular systolic dysfunction HCM is the rare group of patients comprising 10-15% of patients with HCM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWthbXVyYTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWthbXVyYTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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ADDIN EN.CITE.DATA 118, in our study patient 3 had left ventricular systolic dysfunction with the ejection fraction of 17%. The study by Nakamura et al was meant to find the possible enhancement of oxidative stress in patients with HCM and systolic dysfunction compared to the one with diastolic dysfunction HCM and the relationship between systolic dysfunction and the level of oxidative stress. In their study, different results were obtained since all the hearts had increased oxidative stress compared to the normal and no heart had superior results compared to the other two. According to the study done by Nakamura et al, the hearts of patients with systolic dysfunction had higher oxidative stress compared to the one without it, which made them to conclude oxidative stress to be a cause for systolic heart failure. According to our study, all the hearts had proportional increase in ROS as the heart with systolic heart failure had higher ROS in some chambers compared to other hearts but again less ROS in other chambers compared to the others. So no one heart was superior to the other in terms of amount of ROS. This should not totally negate the concept concluded by Nakamura et al because the effect might have been caused by the very small number of sample size we were working on. Further research with large sample size could be useful.
Myocardial hypertrophy, interstitial fibrosis and myofibrillar disarray in HCM are normally seen in the lower chambers more than the upper ones. The left ventricle is normally affected more than the right one specifically in its inter-ventricular septum. Since ROS is implicated in causing the cardiac phenotypes present in HCM, then it is expected to be seen more in the lower chambers specifically the left ventricle in its inter-ventricular septum followed by the right ventricle and the upper chambers being the last. Our study supports this as the lower chambers had significantly higher ROS compared to the upper ones. In the first heart sample and the third heart sample, the left ventricle had significantly higher oxidative stress followed by the inter-ventricular septum and then the right ventricle and lastly the upper chambers. For the second heart, the inter-ventricular septum had significantly higher oxidative stress than the left ventricle, which was followed by the right ventricle and ended up with the upper chambers. The inter-ventricular septum had higher oxidative stress probably because it was the inter-ventricular side of the left ventricle while in the first heart and the third heart; the inter-ventricular septum had right ventricular side of origin.

From the analysis of this study, there is significantly higher reactive oxygen species in the hearts with HCM compared to the normal hearts. The ROS is higher in the lower chambers than the upper chambers where the left ventricle is affected more than the right one especially in its inter-ventricular septum. The hearts with Systolic dysfunction HCM have higher oxidative stress compared to the ones with diastolic dysfunction though all have increase in the amount of ROS.

5.1. LIMITATION AND STREGHTH OF THE STUDYThe major limitation of this study was limited number of samples. Getting a sample of human heart have been very difficult and takes a long time.

Not only that but also we were able to work on only three chambers of the heart, this is because the left atrium was never provided so the oxidative stress status of the left atrium remain to be unknown.

There was only one normal heart sample which was compared with the rest of the diseased heart samples and the normal heart sample was the right atrium a chamber which is not affected much by oxidative stress as we have discussed above. A control of the left ventricle would have been the best control as it is the chamber which is affected most in HCM.

CHAPTER 6: CONCLUSIONHypertrophic cardiomyopathy is one of the devastating diseases due to its risk of sudden cardiac death and the risk of heart failure. As from our study and many other, oxidative stress have shown a significant role of its involvement in the phenotypic expression of the disease as it cause destruction of the heart muscles and weaken them in various ways mostly important its ability to activate various signaling pathways to cause the phenotypes present in the HCM.
Antioxidants would play a great role reversing the phenotype present in the disease and even preventing the occurrence of the phenotype for the genetically affected individuals as not all the genetic carriers do express the disease which gives even more hope. Since much of the antioxidants reversed the phenotype in experimental animal models but none have shown good results in human subjects, targeting the cell signaling pathways which are activated by ROS together with antioxidant will be a brilliant move.
Further studies need to be done on the signaling pathways that are activated by ROS. Individualizing the treatment, that is finding which pathway is activated by ROS in which patient and blocking it would provide possible means of finding cure for this disease.
CHAPTER 7: REFERENCES. ADDIN EN.REFLIST 1.Michels, M., et al., Life-long tailoring of management for patients with hypertrophic cardiomyopathy : Awareness and decision-making in changing scenarios. Neth Heart J, 2017. 25(3): p. 186-199.

2.Maron, B.J., et al., Patterns of inheritance in hypertrophic cardiomyopathy: assessment by M-mode and two-dimensional echocardiography. Am J Cardiol, 1984. 53(8): p. 1087-94.

3.Marian, A.J. and R. Roberts, The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol, 2001. 33(4): p. 655-70.

4.Fernlund, E., et al., Serum Biomarkers of Myocardial Remodeling and Coronary Dysfunction in Early Stages of Hypertrophic Cardiomyopathy in the Young. Pediatr Cardiol, 2017. 38(4): p. 853-863.

5.Maron, B.J. and A. Pelliccia, The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death. Circulation, 2006. 114(15): p. 1633-44.

6.Vakrou, S. and M.R. Abraham, Hypertrophic cardiomyopathy: a heart in need of an energy bar? Front Physiol, 2014. 5: p. 309.

7.Maron, B.J., et al., Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation, 1995. 92(4): p. 785-9.

8.Maron, B.J., et al., The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol, 2004. 44(10): p. 2044-53.

9.Ommen, S.R., et al., Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol, 2005. 46(3): p. 470-6.

10.Rastegar, H., et al., Results of surgical septal myectomy for obstructive hypertrophic cardiomyopathy: the Tufts experience. Ann Cardiothorac Surg, 2017. 6(4): p. 353-363.

11.Mitsui, T., et al., A Pregnancy with Severe Hypertrophic Obstructive Cardiomyopathy after Surgery for an Implantable Cardioverter Defibrillator: A Case Report and Literature Review. Case Rep Obstet Gynecol, 2016. 2016: p. 4690790.

12.Spoladore, R., et al., Pharmacological treatment options for hypertrophic cardiomyopathy: high time for evidence. Eur Heart J, 2012. 33(14): p. 1724-33.

13.Collis, R., et al., Early and medium-term outcomes of Alfieri mitral valve repair in the management of systolic anterior motion during septal myectomy. J Card Surg, 2017.

14.Marian, A.J., Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet, 2000. 355(9197): p. 58-60.

15.Lombardi, R., et al., Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation, 2009. 119(10): p. 1398-407.

16.Senthil, V., et al., Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ Res, 2005. 97(3): p. 285-92.

17.Marian, A.J., et al., Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation. J Am Coll Cardiol, 2006. 47(4): p. 827-34.

18.Tirouvanziam, R., et al., High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci U S A, 2006. 103(12): p. 4628-33.

19.Takimoto, E. and D.A. Kass, Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension, 2007. 49(2): p. 241-8.

20.R, L., et al., Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms. Circulation, 2009.

21.Giam, B., et al., N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure. Physiol Rep, 2016. 4(7).

22.Oi, S., et al., Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells. Eur J Pharmacol, 1999. 376(1-2): p. 139-48.

23.Moriyama, T., et al., Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction. Kidney Int, 2001. 59(6): p. 2095-103.

24.Delbosc, S., et al., Simvastatin prevents angiotensin II-induced cardiac alteration and oxidative stress. Hypertension, 2002. 40(2): p. 142-7.

25.Chen, M.S., et al., Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis. J Mol Cell Cardiol, 2004. 37(4): p. 889-96.

26.Patel, R., et al., Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation, 2001. 104(3): p. 317-24.

27.Houston, B.A. and G.R. Stevens, Hypertrophic cardiomyopathy: a review. Clin Med Insights Cardiol, 2014. 8(Suppl 1): p. 53-65.

28.Lopes, L.R., et al., Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet, 2013. 50(4): p. 228-39.

29.Viswanathan, S.K., et al., Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PLoS One, 2017. 12(11): p. e0187948.

30.Liu, W., et al., Mutation spectrum in a large cohort of unrelated Chinese patients with hypertrophic cardiomyopathy. Am J Cardiol, 2013. 112(4): p. 585-9.

31.Fourey, D., et al., Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy: Revisiting the Gene-Dose Effect. Circ Cardiovasc Genet, 2017. 10(2).

32.Mirowski, M., et al., Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med, 1980. 303(6): p. 322-4.

33.Wang, N., et al., Implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: an updated systematic review and meta-analysis of outcomes and complications. Ann Cardiothorac Surg, 2017. 6(4): p. 298-306.

34.Nishimura, R.A., J.D. Symanski, and D.G. Hurrell, Images in cardiovascular medicine. Dual-chamber pacing in a patient with hypertrophic cardiomyopathy. Circulation, 1997. 96(5): p. 1701.

35.Nishimura, R.A., et al., Dual-chamber pacing for hypertrophic cardiomyopathy: a randomized, double-blind, crossover trial. J Am Coll Cardiol, 1997. 29(2): p. 435-41.

36.Pezzulich, B., L. Montagna, and P.G. Lucchina, Successful treatment of end-stage hypertrophic cardiomyopathy with biventricular cardiac pacing. Europace, 2005. 7(4): p. 388-91.

37.El Masry, H. and J.A. Breall, Alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Curr Cardiol Rev, 2008. 4(3): p. 193-7.

38.Maron, B.J., et al., American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol, 2003. 42(9): p. 1687-713.

39.Maron, B.J., Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation, 2007. 116(2): p. 196-206; discussion 206.

40.Burton, G.J. and E. Jauniaux, Oxidative stress. Best Pract Res Clin Obstet Gynaecol, 2011. 25(3): p. 287-99.

41.Hool, L.C. and B. Corry, Redox control of calcium channels: from mechanisms to therapeutic opportunities. Antioxid Redox Signal, 2007. 9(4): p. 409-35.

42.Uttara, B., et al., Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol, 2009. 7(1): p. 65-74.

43.Akhileshwar, V., S.P. Patel, and S.S. Katyare, Diabetic cardiomyopathy and reactive oxygen species (ROS) related parameters in male and female rats: A comparative study. Indian J Clin Biochem, 2007. 22(1): p. 84-90.

44.Song, Y., et al., Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility. Rev Diabet Stud, 2007. 4(3): p. 159-68.

45.Liu, X., et al., Ablation of ALCAT1 mitigates hypertrophic cardiomyopathy through effects on oxidative stress and mitophagy. Mol Cell Biol, 2012. 32(21): p. 4493-504.

46.Zhang, C., et al., Celecoxib prevents pressure overload-induced cardiac hypertrophy and dysfunction by inhibiting inflammation, apoptosis and oxidative stress. J Cell Mol Med, 2016. 20(1): p. 116-27.

47.Fosslien, E., Review: Mitochondrial medicine–cardiomyopathy caused by defective oxidative phosphorylation. Ann Clin Lab Sci, 2003. 33(4): p. 371-95.

48.Christiansen, L.B., et al., Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol, 2015. 308(10): p. H1237-47.

49.Holmgren, D., et al., Cardiomyopathy in children with mitochondrial disease; clinical course and cardiological findings. Eur Heart J, 2003. 24(3): p. 280-8.

50.Angelini, C., et al., Hypertrophic cardiomyopathy with mitochondrial myopathy. A new phenotype of complex II defect. Jpn Heart J, 1993. 34(1): p. 63-77.

51.Lin, C.S., et al., Alteration of endogenous antioxidant enzymes in naturally occurring hypertrophic cardiomyopathy. Biochem Mol Biol Int, 1997. 43(6): p. 1253-63.

52.McCain, J., The MAPK (ERK) Pathway: Investigational Combinations for the Treatment Of BRAF-Mutated Metastatic Melanoma. P T, 2013. 38(2): p. 96-108.

53.Orton, R.J., et al., Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. Biochem J, 2005. 392(Pt 2): p. 249-61.

54.Force, T., et al., Stress-activated protein kinases in cardiovascular disease. Circ Res, 1996. 78(6): p. 947-53.

55.Kyriakis, J.M. and J. Avruch, Protein kinase cascades activated by stress and inflammatory cytokines. Bioessays, 1996. 18(7): p. 567-77.

56.Robinson, M.J. and M.H. Cobb, Mitogen-activated protein kinase pathways. Curr Opin Cell Biol, 1997. 9(2): p. 180-6.

57.Kyriakis, J.M. and J. Avruch, Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev, 2001. 81(2): p. 807-69.

58.Gelb, B.D. and M. Tartaglia, RAS signaling pathway mutations and hypertrophic cardiomyopathy: getting into and out of the thick of it. J Clin Invest, 2011. 121(3): p. 844-7.

59.Hahn, A., et al., Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog. Am J Med Genet A, 2015. 167A(4): p. 744-51.

60.Yue, T.L., et al., Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J Biol Chem, 2000. 275(48): p. 37895-901.

61.Mallis, R.J., J.E. Buss, and J.A. Thomas, Oxidative modification of H-ras: S-thiolation and S-nitrosylation of reactive cysteines. Biochem J, 2001. 355(Pt 1): p. 145-53.

62.Gabriela M. Kuster, M., et al., Alpha-Adrenergic Receptor–Stimulated Hypertrophy in Adult Rat Ventricular Myocytes Is Mediated via Thioredoxin-1–Sensitive Oxidative Modification of Thiols on Ras. Circulation, 2005.

63.Guyton, K.Z., et al., Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem, 1996. 271(8): p. 4138-42.

64.Stevenson, M.A., et al., X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates. Cancer Res, 1994. 54(1): p. 12-5.

65.Sundaresan, M., et al., Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem J, 1996. 318 ( Pt 2): p. 379-82.

66.Irani, K., et al., Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science, 1997. 275(5306): p. 1649-52.

67.Li, J.M., et al., Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension, 2002. 40(4): p. 477-84.

68.Hemmings, B.A. and D.F. Restuccia, The PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol, 2015. 7(4).

69.Hemmings, B.A. and D.F. Restuccia, PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol, 2012. 4(9): p. a011189.

70.Pal, S.K. and K.L. Reckamp, Mammalian target of rapamycin, Akt, and phosphatidylinositol 3-kinase signaling. J Thorac Oncol, 2010. 5(12 Suppl 6): p. S487-9.

71.Harvey, P.A. and L.A. Leinwand, The cell biology of disease: cellular mechanisms of cardiomyopathy. J Cell Biol, 2011. 194(3): p. 355-65.

72.Sciarretta, S., M. Volpe, and J. Sadoshima, Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ Res, 2014. 114(3): p. 549-64.

73.Marin, T.M., et al., Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest, 2011. 121(3): p. 1026-43.

74.Ballou, L.M. and R.Z. Lin, Rapamycin and mTOR kinase inhibitors. J Chem Biol, 2008. 1(1-4): p. 27-36.

75.Schramm, C., et al., The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling. Am J Physiol Heart Circ Physiol, 2012. 302(1): p. H231-43.

76.Li, T. and G. Wang, Computer-aided targeting of the PI3K/Akt/mTOR pathway: toxicity reduction and therapeutic opportunities. Int J Mol Sci, 2014. 15(10): p. 18856-91.

77.Leslie, N.R. and C.P. Downes, PTEN: The down side of PI 3-kinase signalling. Cell Signal, 2002. 14(4): p. 285-95.

78.McMullen, J.R., et al., Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation, 2004. 109(24): p. 3050-5.

79.Shioi, T., et al., Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation, 2003. 107(12): p. 1664-70.

80.Gao, X.M., et al., Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens, 2006. 24(8): p. 1663-70.

81.Xu, L. and M. Brink, mTOR, cardiomyocytes and inflammation in cardiac hypertrophy. Biochim Biophys Acta, 2016. 1863(7 Pt B): p. 1894-903.

82.Hingtgen, S.D., et al., Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy. Physiol Genomics, 2006. 26(3): p. 180-91.

83.Crabtree, G.R., Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT. Cell, 1999. 96(5): p. 611-4.

84.Molkentin, J.D., Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res, 2004. 63(3): p. 467-75.

85.Molkentin, J.D., et al., A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell, 1998. 93(2): p. 215-28.

86.Aoki, H., J. Sadoshima, and S. Izumo, Myosin light chain kinase mediates sarcomere organization during cardiac hypertrophy in vitro. Nat Med, 2000. 6(2): p. 183-8.

87.Fareh, J., et al., Endothelin-1 and angiotensin II receptors in cells from rat hypertrophied heart. Receptor regulation and intracellular Ca2+ modulation. Circ Res, 1996. 78(2): p. 302-11.

88.Wilkins, B.J. and J.D. Molkentin, Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. Biochem Biophys Res Commun, 2004. 322(4): p. 1178-91.

89.Braz, J.C., et al., Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest, 2003. 111(10): p. 1475-86.

90.Ritter, O., et al., Calcineurin in human heart hypertrophy. Circulation, 2002. 105(19): p. 2265-9.

91.Lim, H.W., et al., Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy. Circulation, 2000. 101(20): p. 2431-7.

92.Shimoyama, M., et al., Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. Circulation, 1999. 100(24): p. 2449-54.

93.Zou, Y., et al., Calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy. Circulation, 2001. 104(1): p. 97-101.

94.Eto, Y., et al., Calcineurin is activated in rat hearts with physiological left ventricular hypertrophy induced by voluntary exercise training. Circulation, 2000. 101(18): p. 2134-7.

95.Taigen, T., et al., Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A, 2000. 97(3): p. 1196-201.

96.Jeong, D., et al., PICOT inhibits cardiac hypertrophy and enhances ventricular function and cardiomyocyte contractility. Circ Res, 2006. 99(3): p. 307-14.

97.Cha, H., et al., PICOT is a critical regulator of cardiac hypertrophy and cardiomyocyte contractility. J Mol Cell Cardiol, 2008. 45(6): p. 796-803.

98.Jeong, D., et al., PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling. Circ Res, 2008. 102(6): p. 711-9.

99.Brasier, A.R., The NF-kappaB regulatory network. Cardiovasc Toxicol, 2006. 6(2): p. 111-30.

100.Panieri, E. and M.M. Santoro, ROS signaling and redox biology in endothelial cells. Cell Mol Life Sci, 2015. 72(17): p. 3281-303.

101.Verma, I.M., Nuclear factor (NF)-kappaB proteins: therapeutic targets. Ann Rheum Dis, 2004. 63 Suppl 2: p. ii57-ii61.

102.Lin, R.J., C.L. Liao, and Y.L. Lin, Replication-incompetent virions of Japanese encephalitis virus trigger neuronal cell death by oxidative stress in a culture system. J Gen Virol, 2004. 85(Pt 2): p. 521-33.

103.Kuusisto, J., et al., Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy. Heart, 2012. 98(13): p. 1007-13.

104.Maier, H.J., et al., Cardiomyocyte-specific IkappaB kinase (IKK)/NF-kappaB activation induces reversible inflammatory cardiomyopathy and heart failure. Proc Natl Acad Sci U S A, 2012. 109(29): p. 11794-9.

105.Gordon, J.W., J.A. Shaw, and L.A. Kirshenbaum, Multiple facets of NF-kappaB in the heart: to be or not to NF-kappaB. Circ Res, 2011. 108(9): p. 1122-32.

106.Banerjee, S.K., et al., Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation. Biochim Biophys Acta, 2010. 1802(2): p. 284-91.

107.Gupta, S., et al., Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB. J Mol Biol, 2008. 375(3): p. 637-49.

108.Sag, C.M., C.X.C. Santos, and A.M. Shah, Redox regulation of cardiac hypertrophy. Journal of Molecular and Cellular Cardiology, 2014. 73: p. 103-111.

109.Xu, L.F. and M. Brink, mTOR, cardiomyocytes and inflammation in cardiac hypertrophy. Biochimica Et Biophysica Acta-Molecular Cell Research, 2016. 1863(7): p. 1894-1903.

110.Mariappan, N., et al., NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res, 2010. 85(3): p. 473-83.

111.Li, Y., et al., NF-kappaB activation is required for the development of cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol, 2004. 287(4): p. H1712-20.

112.Gomes, A., E. Fernandes, and J.L. Lima, Fluorescence probes used for detection of reactive oxygen species. J Biochem Biophys Methods, 2005. 65(2-3): p. 45-80.

113.Wardman, P., Fluorescent and luminescent probes for measurement of oxidative and nitrosative species in cells and tissues: progress, pitfalls, and prospects. Free Radic Biol Med, 2007. 43(7): p. 995-1022.

114.Zhao, H., et al., Detection and characterization of the product of hydroethidine and intracellular superoxide by HPLC and limitations of fluorescence. Proc Natl Acad Sci U S A, 2005. 102(16): p. 5727-32.

115.Bucana, C., I. Saiki, and R. Nayar, Uptake and accumulation of the vital dye hydroethidine in neoplastic cells. J Histochem Cytochem, 1986. 34(9): p. 1109-15.

116.Kalyanaraman, B., et al., Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic Biol Med, 2012. 52(1): p. 1-6.

117.Dimitrow, P.P., et al., Enhanced oxidative stress in hypertrophic cardiomyopathy. Pharmacol Rep, 2009. 61(3): p. 491-5.

118.Nakamura, K., et al., Relationship between oxidative stress and systolic dysfunction in patients with hypertrophic cardiomyopathy. J Card Fail, 2005. 11(2): p. 117-23.