Association of Admission Serum Adiponectin, Resistin and … 2014/phd thesis... · Association of Admission Serum Adiponectin, Resistin and Leptin Levels with Acute ST-Segment Elevation

Republic of Iraq

Ministry of Higher Education and Scientific Research

University of Baghdad

College of Pharmacy

Association of Admission Serum Adiponectin,

Resistin and Leptin Levels with Acute ST-

Segment Elevation Myocardial Infarction

A Thesis

Submitted to the Department of Clinical Pharmacy and the

Committee of Graduate Studies of the College of Pharmacy,

University of Baghdad as Partial Fulfillment of the

Requirements of Doctor of Philosophy in Pharmacy (Clinical

Pharmacy)

BY

Dheyaa Jabbar Kadhim

B.Sc. Pharmacy 1997

M.Sc. Pharmacy 2005

Supervised By

Prof. Dr. Kassim J. Al-shamma

Dr. Adeeb J. Hussein

2013 A.D 1434 A.H

76)) يوسف: اآليةسورة

Chapter One Introduction

2

To………

My Parents

My Wife

My sons

My Sisters and Brothers

I Dedicate This Thesis with Love

dheyaa


3

Praise is to our almighty gracious Allah for enabling me to finish and present

this work .

I would like to express my heartfelt gratitude and appreciation to my

supervisors, Prof Dr. Kassim J. Al-shamma and Dr. Adeeb J. Hussein for their

scientific guidance, valuable advice, help and encouragement through the course

of this work wishing them long life and continuous progress.

I would like to express my deepest thanks to Prof. Dr. Alaa A. Abdulrassol

Dean of College of Pharmacy, for his valuable help and support.

My deepest thanks also to to Dr.Mohammed Hassan Assistant Dean for

Postgraduate Studies for his suppor and to Dr.Ibraheam Adhem Chairman of

Clinical Pharmacy Department.

My deepest thanks to pharmacist Ehab Muther for his valuable help.

I am also grateful to the College of Pharmacy, University of Baghdad for

offering the opportunity to continue my graduate study.

My deepest thanks to the staff of Coronary Care Unit at Al-Yarmouk Teaching

Hospital for facilitating the work.


4

My thanks go to the Emergency Department Laboratory staff at Al-Yarmouk

Teaching Hospital for facilitating the work.

Finally, I would like to express my deep gratitude to all kind, helpful and lovely

people who helped me directly or indirectly to complete this work.

Dheyaa


5

Contents Page

Dedication I

Acknowledgment II

Contents III

List of tables VIII

List of figures IX

List of abbreviations X

Abstract XIII

Chapter One: Introduction

1.1 Acute coronary syndrome.

1

1.1.1.Coronary anatomy 1

1.1.2 classification of acute coronary syndrome . 3

1.1.3 Etiology

4

1.1.4 Pathophysiology

4

1.1.4.1 Initial event (coronary occlusion) 4


6

1.1.4.2 Ventricular Remodeling Following an Acute MI

7

1.1. 5 Clinical Presentation

8

1.1.6 Complications

8

1.1.7 Diagnosis 9

1.1.7.1 Electrocardiographic Manifestations

9

1.1.6. 2 Biochemical Markers

9

1.1.8 Treatment of STEMI

11

1.1.8.1 Nonpharmacologic Therapy for STEMI

11

1.1.8.2 Pharmacotherpy for STEMI

12

1.1.8.2.1 Fibrinolytic Therapy

13

1.1.8.2.2 Aspirin 14


7

1.1.8.2.3 Thienopyridines

15

1.1.8.2.4 Glycoprotein IIb/IIIa Receptor Inhibitors 15

1.1.8.2.5 Antithrombins

16

1.1.8.2.5.1Unfractionated heparin (UFH) 16

1.1.8.2.5.2 Low-Molecular-Weight Heparins 17

1.1.8.2.5.3 Direct Thrombin Inhibitors 17

1.1.8.2.6 Nitrates 18

1.1.8.2.7 β-Blockers 18

1.1.8.2.8 Calcium Channel Blockers 19

1.1.8.2.9 Angiotensin Converting Enzyme (ACE) Inhibitors and

Angiotensin Receptor Blockers (ARBs)

19

1.1.8.2. 10 Aldosterone Antagonists 20

1.1.8.2.11 Lipid-Lowering Agents 20

1.2 The Adipose Tissue: Role as an Endocrine Organ 21

1.2.1 Background 21

1.2.2 Endocrine and Secretary Function 22

1.2.3 Obesity and atherosclerosis 25

1.3 Adiponectin 28


8

1.3.1 Discovery, structure and expression 28

1.3.2 Biological functions of adiponectin 28

1.3.3 Involvement of adiponectin in diseases 31

1.3.4 Adiponectin and cardiovascular risk in humans 31

1.4 Resistin 32


1.4.2 Biological Functions of Resistin 32

1.4.3 Involvement of resistin in diseases 33

1.4.4 Resistin and cardiovascular homeostasis 34

1.5 Leptin 35


1.5.2 Biological Functions of Leptin 36

1.5.3 Leptin and cardiovascular homeostasis 39

1.6 Aims of the Study 40

Chapter Two: Subjects ,Materials, and Methods

2.1. Chemicals and instruments 41

2.2. Patients and control subjects 42

2.3 Interpretation of the outcome of thrombolytic therapy

45

2.4 Sample collection and preparation 45


01

2.5. Biochemical assay methods 46

2.5.1. Determination of serum total cholesterol 46

2.5.2. Determination of serum high density lipoprotein-cholesterol

(HDL-c)

46

2.5.3 Determination of serum uric acid 47

2.5.4 Determination of serum creatinine 47

2.5.5 Determination of serum urea 47

2.5.6 Determination of serum cTnI 48

2.5.7 Determination of serum adiponectin 49

2.5.8 Determination of serum resistin 49

2.5.9 Determination of serum leptin 50

2.6. Determination of body mass index (BMI) 50

2.7. Statistical analysis. 51

Chapter Three: Results

3.1 Demographic, clinical characteristics and baseline laboratory variables

of the study groups

542

3.2 Troponin I 53

3.2.1 Determination of cTnI cutoff value for diagnosing STEMI 53

3.2.2 Admission cTnI levels in the patients and control groups 55

3.2.3 Association of admission cTnI level to selected clinical variables

among patients with STEMI

56


00

3.2.4 Correlation between serum cTnI and selected demographic and

laboratory variables in STEMI patients

58

3.3 Adiponectin 59

3.3.1 Adiponectin level in the patients and control groups. 59

3.3.2 Association of admission adiponectin level to selected clinical

variables among patients with STEMI

60

3.3.3 Correlation between serum adiponectin and selected demographic

and laboratory variables in STEMI patients

62

3.4 Leptin 63

3.4.1 Leptin level in the patients and control groups 63

3.4.2 Association of admission leptin level to selected clinical variables


64

3.4.3 Correlation between serum leptin and selected demographic and


66

3.5 Leptin/adiponectin ratio 67

3.5.1 Leptin/adiponectin ratio in the patients and control groups 67

3.5.2 Association of admission leptin /adiponectin ratio with selected

clinical variables among patients with STEMI

68

3.5.3 Correlation between leptin/adiponectin ratio and selected

demographic and laboratory variables in STEMI patients

70

3.6 Resistin 71

3.6.1 Resistin level in the patients and control groups 71

3.6.2 Association of admission resistin level with selected clinical variables 72


01


3.6.3 Correlation between serum resistin and selected demographic and


74

Chapter Four: Discussion and Conclusion

4.1 Admission serum cTnI and STEMI 75

4.2 Admission serum adiponectin and STEMI 77

4.3 Admission serum leptin and STEMI 82

4.4 Admission serum leptin/adiponectin ratio and STEMI 86

4.5 Admission serum resistin and STEMI 87

4.6 Conclusion 92

4.7 Recommendations for Future work 93

References

References 94


02

Table

No.

Title Page

1-1 Sources and functions of key adipokines 24

1-2 Factors that regulate circulating leptin levels 37

2-1 Chemicals and their suppliers 41

2-2 Instruments used in this study and their suppliers 42

3-1 Demographic, clinical characteristics and baseline

laboratory variables of the study groups.

52

3-2 Admission serum cTnI levels in STEMI patients

compared to control group.

55

3-3 Association of admission cTnI level to selected clinical

variables among patients with STEMI.

56

3-4 Correlation between serum cTnI Level and selected

demographic and laboratory variables in STEMI

patients.

58

3-5 Admission serum adiponectin level in STEMI patients

compared to control.

59

3-6 Association of admission adiponectin level to selected

clinical variables among patients with STEMI.

60

3-7 Correlation between serum adiponectin Level and

selected demographic and laboratory variables in

STEMI patients.

62


03

3-8 Admission serum leptin level in STEMI patients


63

3-9 Association of admission leptin level to selected clinical


64

3-10 Correlation between serum leptin level and selected


patients.

66

3-11 Admission serum leptin / adiponectin ratio in STEMI

patients compared to control

67

3-12 Association of admission leptin/adiponectin ratio to

selected clinical variables among patients with STEMI.

68

3-13 Correlation between serum leptin/adiponectin ratio and

selected demographic and laboratory variables in STEMI

patients

70

3-14 Admission serum resistin level in STEMI patients


71

3-15 Association of admission resistin level to selected

clinical variables among patients with STEM.

72

3-16 Correlation between serum resistin level and selected


patients.

74

4-1 Mechanisms postulated for leptin relating to increased

cardiovascular risk

83


04

Figure

No.

Title Page

1-1 Coronary arteries

1-2 Classification of acute coronary syndromes 1

1-3 High-risk plaques of the coronary artery are

characterized by large lipid core and thin fibrous cap.

5

1-4 Myocardial infarction after ischemia 5

1-5 Adipose tissue depots 22

1-6 Biological functions of adipocytes 23

1-7 Increased adiposity (obesity) is associated with

dysregulated adipokine production

28

1-8 Major target tissues and biological actions of

adiponectin.

30

1-9 The anti-inflammatory actions of adiponectin. 31

1-10 Action of leptin on the hypothalamus and peripheral

organs (pancreas, liver, and skeletal muscle)

39

2-1 Flow diagram of the Study 48

3-1 Mean admission serum cTnI levels in those below and 54


05

above the cutoff value.

3-2. Admission serum cTnI levels in STEMI patients

compared to control group.

55

3-3 Association of admission cTnI level to selected clinical


57

3-4 Admission serum adiponectin level in STEMI patients


59

3-5 ssociation of admission adiponectin level to selected

clinical variables among patients with STEMI.

61

3-6 Admission plasma leptin level in STEMI patients


63

3-7 Association of admission leptin level to selected


65

3-8 Admission serum leptin /adiponectin ratio in STEMI

patients compared to control.

67

3-9 Association of admission leptin level to selected


69

3-10 Admission serum resistin level in STEMI patients


71

3-11 Association of admission resistin in level to selected


73


06

ABCA1 ATP-binding cassette transporter-A1

ACC American College Of Cardiology

ACE Angiotensin-converting enzyme

ACC/AHA American College of Cardiology/American Heart

Association

ACS Acute coronary syndrome

ADSF Adipose tissue specific secretory factor

AF Atrial fibrillation

ARBs Angiotensin receptor blockers

BAT Brown adipose tissue

BMI Body mass index

CABG Coronary artery bypass grafting

CBC Complete blood count

CAD Coronary artery disease

cDNA Complementary DNA

CK Creatine kinase

CK-MB Creatine Kinase -myocardial band

CRP C-reactive protein

cTnI Cardiac troponin I

cTnT Cardiac troponin T


07

DVT Deep vein thrombosis

ECG Electrocardiogram

ELISA Enzyme-linked immunosorbent assay

eNOS Endothelial nitric oxide Synthase

EPC Endothelial progenitor cell.

ESC/ACC European Society of Cardiology/American College of

Cardiology

FIZZ Found in Inflammatory Zone

GP Glycoprotein

HDL High-density lipoprotein

HF Heart failure

ICH Intracranial hemorrhage

IL-6 Interleukin-6

LBBB Left bundle branch block

LDL Low-density lipoprotein (HDL)

LMWHs Low-molecular-weight heparins

Lp- PLA2 Lipoprotein-associated phospholipase A2

LV Left ventricular

LVEF Left ventricle ejection fraction

MCP-1 Monocyte chemoattractant protein-1

NCEP National cholesterol education program


08

NEFA Non-esterified fatty acids

NO Nitric oxide

NSTEMI

Non–ST-segment elevation myocardial infarction

PAI-1 Plasminogen activator inhibitor–1

PCI Percutaneous coronary intervention

RBP4 Retinol binding protein-4

RELM Resistin like molecules

STEMI ST-segment elevation myocardial infarction

TF Tissue factor

TNF Tumor necrosis factor

TZD Thiozolidinedione

UA Unstable angina

UFH Unfractionated heparin

VCAM-1 Vascular cell adhesion molecule -1

VF Ventricular fibrillation

VSMC Vascular smooth muscle cells

VT Ventricular tachycardia

WAT White adipose tissue .


11

ABSTRACT

Background:

Complications of atherosclerosis remain the primary cause of death in most

countries despite massive efforts to limit well-documented risk factors. The

relationship between obesity and atherogenesis is multifactorial. Recent advances

in the knowledge of adipose tissue give evidence that it is a secretary organ,

producing a variety of adipokines that may be relevant for development or

progression of atherosclerotic vascular disease. Although most adipokines induce

inflammation, adiponectin inhibits inflammatory reactions and protects against

metabolic and cardiovascular disease (CVD). Resistin is an adipokine, with a

possible association with coronary heart disease. Leptin is an adipokine with both

protective and harmful effects on the cardiovascular system. Although several

studies were investigated the role of adipokines in coronary artery disease (CAD);

but most of them have been conducted on patients with chronic ischemia and the

studies in acute phase of ST-segment elevation myocardial infarction (STEMI)

especially in developing countries are limited and rare.

Objectives:

The present study was designed to evaluate the association between serum

levels of adiponectin, resistin and leptin at time of hospital admission and acute

STEMI in Iraqi patients as well as examining possible associations and correlations

between these three adipokines and selected demographic , clinical and

laboratory variables among patients with STEMI.


10

Subjects and Methods:

The present study was carried out at Al-Yarmouk Teaching Hospital /

Baghdad from December 2011 until June 2012. Serum levels of adiponectin,

resistin and leptin were measured in 50 patients (41 males and 9 females) with

acute STEMI (mean age: 58.16 ± 11.73 years) at the time of hospital admission

and in 34 normal controls (25 males and 9 females)(mean age: 53.98 ± 15.46

years) matched for age, sex and other risk factors. In addition, serum level of

cardiac troponin I (cTnI) was measured in patients and controls groups (mainly for

diagnostic purpose) however, two reading of cTnI were obtained for the patients

(one at admission as well as 6-9 hours later). In addition, patients were clinically

followed up during entire hospitalization period to assess the patients for

response to thrombolytic therapy as well as for the development of any

complications.

Results:

For cTnI levels, there were thirty eight patients (76%) out of fifty patients

presented with cTnI level (at time of hospital admission) above the calculated

cutoff value (2.75 ng/ml) required for diagnosing STEMI and there were twelve

patients (24%) presented with cTnI level below this cutoff value. However, all the

patients had values exceeding the cutoff point 6-9 hours later.

Regarding the association of admission adipokines levels with the

development of STEMI, the study showed that adiponectin level in patients with

acute STEMI (4.19 μg/mL) at time of hospital admission was very highly

significant lower than that of the control group (6.45 μg/mL) (p < 0.0001). The


11

study revealed a significant negative correlation between serum adiponectin level

and serum resistin level among patients with acute STEMI.

Resistin level in patients with acute STEMI (13.08 ng/mL) was very highly

significant higher than that of the control group (5.31 ng/mL) (p < 0.0001). In

addition, serum resistin was significantly higher in female patients than male.

Leptin level in patients with acute STEMI (10.03 ng/mL) was very highly significant

higher than that of the control group (6.97 ng/mL) (p < 0.0001).

Finally no significant associations were found between admission cTnI,

adiponectin, resistin, and leptin levels and some selected clinical variables among

patients with STEMI including diabetes, hypertension, sex, location of myocardial

infarction, development of heart failure, development of atrial fibrillation,

development of ventricular tachycardia and/or ventricular fibrillation, as well as

achievement of successful reperfusion.

Conclusion:

The present study showed that acute STEMI was associated with low serum

adiponectin level at time of hospital admission . In contrast, acute STEMI was

associated with high levels of both serum leptin and serum resistin. In addition,

highly significant inverse correlation between admission serum adiponectin and

serum resistin at time of hospital admission was found. These findings suggest

possible pathologic and diagnostic value for the three adipokines in STEMI.

Finally, no significant associations were found between admission serum cTnI,

adiponectin, resistin, and leptin levels with short-term outcome during

hospitalization period specially the achievement of successful reperfusion by

thrombolytic therapy as well as development of complications.


12

Introduction

1-Hypertension

1-1 Definition

Hypertension is defined by persistent elevation of arterial blood

pressure.

Patients with diastolic blood pressure (DBP) values less than 90 mm Hg

and systolic blood pressure (SBP) values greater than or equal to 140

mm Hg have isolated systolic hypertension.

A hypertensive crisis (blood pressure greater than 180/120 mm Hg)

may be categorized as either a hypertensive emergency (extreme blood

pressure elevation with acute or progressing target organ damage) or a

hypertensive urgency (severe blood pressure elevation without acute

or progressing target organ injury) [1].

1-2 Etiology

Hypertension is an extremely complex interplay of multiple influences

from within and outside of the human body. Hypertension can be

divided into two basic etiologic categories: unknown etiology (primary

or essential hypertension) or a specific known etiology (secondary

hypertension) [references number].


13

1-2-1 Essential Hypertension

than 90% of patients with sustained elevation of arterial BP have

essential hypertension with no identifiable cause. The term essential

hypertension evolved from the mistaken belief that high BP was

essential for adequate tissue perfusion [references number].

بداية جيدة لكن مانكدر نكول كافي من هسة الن يحتاج كثير من التعديالت-1

في نهايىة كل فقرة يكتب رقم المصدر كما هو اعاله-2

وهكذا 1-1يتب تبويب العنواين كما هو اعاله -3

الخط ونوعه وحجمة والمسافة كلها كما هو اعاله-4

كونداري واكتبي عن السكونداري مو خلي باالتيولوجي بس برايماري اي اسينشيال وا ل س-5

بس عنوان

راح ادزلج فواصل توضع بين فصل وفصل -6

سوي هذا التعديالت ودزي اللي باجر-7

اللون االصفر اللي خليته بس للتذكير عود شيليه

Chapter Two Subjects , Materials & Methods

14

CHAPTER TWO

Subjects, Materials and Methods

2.1. Chemicals and instruments

Specific chemicals and kits used in this study are listed in table 2-1 with their

suppliers; while, instruments and their suppliers are listed in table 2-2.

Table 2-1: Chemicals and their suppliers.

Chemicals Suppliers

Adiponectin ELISA Kit Demeditec Diagnostics (Germany)

Creatinine Kit Linear chemical, Spain.

HDL-cholesterol kit Linear chemical, Spain

Leptin ELISA Kit RayBio® ELISA kits (USA)

Resistin ELISA Kit Demeditec Diagnostics (Germany)

Total cholesterol kit Linear chemical, Spain

Troponin I ELISA Kit Oxis International, Inc (USA)

Urea Kit Linear chemical, Spain.

Uric acid Kit Linear chemical, Spain.


15

Table 2-2: Instruments used in this study and their suppliers.

Instruments Suppliers

Biotek/ELx 800 ELISA reader Biotek , USA

Centrifuge-Universal 16A Hettich, Germany

Spectrophotometer-CE 1011 Cecil, England

Water-bath Memert-Laboratory Supply Company

Ollman and Co.KG, Germany

2.2 Patients and control subjects

The present study was carried out at Al-Yarmouk Teaching Hospital /

Baghdad from December 2011 until June 2012. The study protocol was approved

by the postgraduate studies committee in the College of Pharmacy, University of

Baghdad and the Medical Ethics Committee in the Ministry of Health / Republic of

Iraq.

This case-control study was conducted on fifty (50) patients (age range 29-

80, mean 58.16+11.73)(41 males and 9 females) who were treated for acute

STEMI with the following inclusion criteria:

1 .First experience of acute MI.


16

2 .Absence in the electrocardiogram of conditions that might complicate the

interpretation of the ST segment, such as bundle branch block, preexcitation, atrial

fibrillation, atrial flutter, or complete atrioventricular block.

3 .A maximum of 12 hours between the onset of symptoms and initiation of

thrombolytic therapy (alteplase).

The diagnosis of acute MI was made on the basis of a history of chest pain

lasting for more than 30 minutes that is associated with ECG changes suggestive of

ST-segment elevation of 1mm or more in at least 2 contiguous leads and is

unresponsive to nitroglycerin administration[177].

The diagnosis was subsequently be confirmed by elevation of serum cardiac

troponin I activity.

All the patients involved in the study were treated by the standard therapy for

STEMI including:

1- Alteplase (Actilysec®) 15 mg by intravenous injection, followed by

intravenous infusion of 50 mg over 30 minutes, then 35 mg over 60 minutes

(total dose 100 mg over 90 minutes).

2-Aspirin.

3-Clopidogrel.

4-Heparin.

5-β-blocker.

6-ACE inhibitor or ARB.

7-Statin.


17

8-Sublingual nitroglycerin on need.

When necessary, other medications such as antiarrhythmic drugs, digitalis,

analgesics, and dopamine were given to the patient at the discretion of the

physician. In addition to blood samples obtained from the patients for the purpose

of the study, the patients were followed up during the entire hospitalization period

mainly to determine their response to thrombolytic therapy as well as the possible

development of complications, which may include:

1-development of heart failure (HF).

2-development of atrial fibrillation (AF) as evidenced by ECG.

3-development of conduction disturbances as evidenced by ECG.

4-development of ventricular tachycardia (VT) and/or ventricular

fibrillation (VF) as evidenced by ECG.

5- development of cardiogenic shock.

6-stroke.

7-in hospital death.

Finally thirty four (34) subjects were selected as a control group and matched

them with case group for age, sex and other CAD risk factors such as hypertension,

diabetes mellitus, body mass index (BMI), smoking and renal function (figure 2-1).

Patients with a diagnosis of hypertension or those receiving antihypertensive

therapy were accepted as hypertensive. Diabetes was identified with a positive

history for diagnosis of diabetes or with use of an antidiabetic drug.


18

Figure 2-1. Flow diagram of the Study

2.3 Interpretation of the outcome of thrombolytic therapy

The first 2 ECG recordings were taken just before and 90 minutes after the

thrombolytic therapy. Subsequently, at least 1 ECG per day was recorded from

each patient. To analyze the ST-segment elevation resolution, the value of ST-

segment elevation in the first ECG before thrombolytic therapy was calculated and

compared to the ECG taken 90 minutes later. The ECG recordings were interpreted

by the specialist physician . The success of thrombolytic therapy was interpreted

using the following criterion:

Subjects

(84)

STEMI patients

(50)

Control

(34)


21

(The total ST-segment elevation calculated from the ECG recorded 90 minutes

after the initiation of thrombolytic therapy showed 50% or more reduction as

compared to that of the ECG taken just before thrombolytic therapy).

2.4. Sample collection and preparation

Blood samples were collected from all patients by vein puncture (5ml), at

admission before initiation of alteplase and 6-9 hours later to measure the studied

parameters (serum cTnI, serum adiponectin, serum resistin, serum leptin, serum

uric acid, serum creatinine, serum urea, serum total cholesterol, and serum HDL-

c).

The sample was transferred into clean plain tube, left at room temperature

for at least 30 minutes for clotting, centrifuged, then serum separated and stored

to be used for measuring the studied parameters.

2.5. Biochemical assay methods

2.5.1. Determination of serum total cholesterol

Serum total cholesterol was estimated by using enzymatic method of Allain

(1974) [1748], where a ready-made kit is used for this purpose, based on the

oxidation of cholesterol, which resulted in the formation of H2O2 that reacted

with phenol, then a red color of quinonimine was formed and the intensity of

color was measured at 500 nm and compared with standard cholesterol solution

and the results were expressed as mg/dl. The reactions are illustrated in the

following equations:


20

acidfatty freelcholesteroesterase lCholesteroester lCholestero

2234 OHoneencholestoxidase lCholesteroO lCholestero 2

O4HneQuinoneimiperoxidase

yrineaminoantip4phenol O2H 222

2.5.2. Determination of serum high density lipoprotein-cholesterol

(HDL-c)

Serum HDL-c levels were estimated according to the method of Burstein et

al. [179], using a ready-made kit for this purpose. The principle of this method

depends on the precipitation of lipoprotein particles (chylomicrons, VLDL-c, and

LDL-c) contained in the sample by the addition of phosphotungestic acid in the

presence of magnesium ions. The supernatant obtained after centrifugation

contains the HDL-c, which was determined colorimetrically by measurement of

light absorbance at 500 nm.

2.5.3 Determination of serum uric acid

Uric acid is the major product of the catabolism of the purine, nucleosides,

adenosine and guanosine.

Principle Of Assay:

Uricase acts on uric acid to produce allantoin, carbon dioxide and hydrogen

peroxide. Hydrogen peroxide in the presence of peroxidase reacts with a


21

chromogen (amino- antipyrine and dichloro- hydroxybenzen sulfonate) to yeld

quinoneimine, a red coloured complex. The absorbance measured at 520 nm

(490- 530) is proportional to the amount of uric acid in the specimen [180].

2.5.4 Determination of serum creatinine

Serum creatinine level was determined by creatinine reagent set (Kinetic

procedure) [181]. The assay of creatinine has been based on the reaction of

creatinine with alkaline picrate as described by Jaffe. Further modifications have

developed the Jaffe reaction into a kinetic assay that is fast, simple and avoids

interference [182].

Creatinine + Sodium Picrate Alkali Creatinine – Picrate complex

(Yellow-Orange)

Creatinine reacts with picric acid in alkaline condition to form a colored

complex, which absorbs light at 510 nm. The rate of formation of color is

proportional to the creatinine concentration in the sample. The creatinine serum

concentration was expressed in mg/dl.

2.5.5 Determination of serum urea

Serum urea level was determined using urease-modified Barthelot reaction

[183]. In an alkaline medium, the ammonium ion reacts with the salicylat and


22

hydrochlorites to form a green-colored indophenol (2,2-dicarboxyl indophenol),

which can be measured spectrophotometrically at 580 nm and serum urea

concentration was expressed in mg/dl.

2.5.6 Determination of serum cTnI

For troponin, the European Society of Cardiology / American

College of Cardiology task force recommended that the 99th percentile (mean +

2.58 standard deviations) in a presumably normal “control” subjects be used as

the cutoff point, above which any value should be considered abnormal [28].

Accordingly, two blood samples were obtained from the patients, one in the

emergency department and again in 6 to 9 hours after admission, in order to

measure troponin [31]. A single measurement of a biochemical marker is not

adequate to exclude a diagnosis of MI because up to 15% of the values that were

below the level of detection initially (a negative test) are above the level of

detection (a positive test) in the subsequent hours [31].

Serum cTnI level was determined using a ready-made kit for this purpose.

The cTnI ELISA test is based on the principle of a solid phase enzyme-linked

immunosorbent assay. The assay system utilizes four unique monoclonal

antibodies directed against distinct antigenic determinants on the molecule.

Three mouse monoclonal anti-troponin I antibodies are used for solid phase

immobilization (on the microtiter wells). The fourth antibody is in the antibody

enzyme (horseradish peroxidase) conjugate solution.


23

The test sample is allowed to react simultaneously with the four antibodies,

resulting in the troponin I molecules being sandwiched between the solid phase

and enzyme-linked antibodies. After a 90-minute incubation at room

temperature, the wells are washed with water to remove unbound-labeled

antibodies. A solution of tetramethylbenzidine (TMB) Reagent is added and

incubated for 20 minutes, resulting in the development of a blue color. The color

development is stopped with the addition of 1N hydrochloric acid (HCl) changing

the color to yellow. The concentration of troponin I is directly proportional to the

color intensity of the test sample. Absorbance is measured

spectrophotometrically at 450 nm.

2.5.7 Determination of serum adiponectin

Serum adiponectin level was determined using a ready-made kit for this

purpose. The Demeditec® Enzyme-Linked Immunosorbent Assay (ELISA) for

Adiponectin DEE009 is a so-called Sandwich-Assay using two specific and high

affinity antibodies. The Adiponectin in the samples binds to the first antibody

coated on the microtiter plate. In the following step the second specific anti-

Adiponectin-Antibody binds in turn to the immobilized Adiponectin. The second

antibody is biotinylated and will be applied in a mixture with a Streptavidin-

Peroxidase-Enzyme Conjugate. In the closing substrate reaction the turn of the

colour will be catalysed quantitatively depending on the Adiponectin-level of the

samples.


24

2.5.8 Determination of serum resistin

Serum resistin level was determined using a ready-made kit for this purpose.

Demeditec® ELISA for resistin DEE050 is a so-called Sandwich-Assay. It utilizes a

specific high affinity polyclonal rabbit antiserum coated on the wells of a

microtiter plate. The Resistin in the samples binds quantitatively to the

immobilized antiserum. In the following step, the biotinylated antiserum binds in

turn to Resistin. After washing, a Streptavidin-Peroxidase-Enzyme conjugate will

be added, which will bind highly specific to the biotin of the antiserum and will

catalyse in the closing substrate reaction the turn of the colour, quantitatively

depending on the resistin level of the samples.

2.5.9 Determination of serum leptin

Serum leptin level was determined using a ready-made kit for this purpose.

The RayBio® Human Leptin ELISA kit is an in vitro enzyme-linked immunosorbent

assay for the quantitative measurement of human Leptin in serum, plasma, cell

culture supernatants and urine. This assay employs an antibody specific for

human Leptin coated on a 96-well plate. Standards and samples are pipetted into

the wells and Leptin present in a sample is bound to the wells by the immobilized

antibody. The wells are washed and biotinylated antihuman Leptin antibody is

added. After washing away unbound biotinylated antibody, HRP-conjugated

streptavidin is pipetted to the wells. The wells are again washed, a TMB substrate

solution is added to the wells and color develops in proportion to the amount of

Leptin bound. The Stop Solution changes the color from blue to yellow, and the

intensity of the color is measured at 450 nm.


25

2.6. Determination of body mass index (BMI)

The body mass index describes relative weight for height [184]:

)(m Height

(kg) WeightBMI

2

2.7. Statistical Analysis

Statistical analysis was performed by SPSS (version 11; SPSS, Inc., Chicago,

IL).

Nominal variables are compared using chi-square test. Continuous variables

were summarized as mean ± standard deviation (SD). Continuous variables are

tested for normality using shapiro wilk test. Normally distributed variables are

compared using t-test. Non-normally distributed variables are compared using

Mann- Whitney U test.

Pearson's correlation or spearman correlation were performed to evaluate

the relationship between adpiponectin, leptin, leptin/adiponectin ratio, resisitin

and cTnI and the values of other selected clinical variables among patients with

STEMI. In all data present in this study, a probability value P<0.05 was considered

statistically significant.

Chapter Three Results

26

3.1 Demographic, clinical characteristics and baseline laboratory

variables of the study groups.

The demographic and clinical characteristics of the study groups, as well as

laboratory variables are shown in table 3-1. No significant differences were

observed between the patients and the control groups in all of these parameters.

Table 3-1. Demographic, clinical characteristics and baseline laboratory variables

of the study groups.

Patients Control P value *

Number of patients 50 34 0.08 a

Males 41 25 0.74 a

Females 9 9 0.45 a

Age (yr) 58.16 ± 11.73 53.98 ± 15.46 0.16 b

BMI (kg/m2) 28.05 ± 4.27 27.89 ± 3.50 0.96 c

Diabetes 15 4 0.11 a

Hypertension 18 12 0.96 a

Smoking 26 8 0.08 a

S. Uric acid (mg/dl) 4.94± 1.32 5.12± 1.24 0.37 c


27

S. Creatinine (mg/dl) 0.91 ± 0.31 0.85 ± 0.28 0.37 c

S. Urea (mg/dl) 39.12 ± 11.16 37.20± 8.06 0.67 c

S. Total cholesterol (mg/dl) 199.62± 41.09 189.26± 28.35 0.09 c

S. HDL-c (mg/dl) 41.03± 4.79 43.17± 10.56 0.36 c

BMI: body mass index, S. HDL-c: serum high density lipoprotein cholesterol.

a: chi-square test, b: t. test, c: Mann-Whitney U test.

*(p value < 0.05 considered significant)

3.2 Troponin I

3.2.1 Determination of serum cardiac troponin I (cTnI) cutoff value for

diagnosing ST-segment elevation myocardial infarction (STEMI).

A serum cTnI cutoff value of 2.75 ng/ml (0.90+0.72 x 2.58) which equal to

(mean + 2.58 standard deviations) was used to confirm the diagnosis of STEMI

where any value above this cutoff value was considered to be diagnostic for STEMI.

For admission cTnI levels, there were thirty eight patients (76%) out of fifty

patients presented with cTnI level above the cutoff value of 2.75 ng/ml with a mean

value of (3.47 ± 0.58 ng/ml) and there were twelve patients (24%) presented with

cTnI level below the cutoff value of 2.75 ng/ml with a mean value of (2.07 ± 0.68

ng/ml). However, all of them had values exceeding the cutoff point 6-9 hours later .


28

The mean admission serum cTnI levels in those below and above the cutoff

value are shown in figure 3-1.

Figure 3-1. Mean admission serum cTnI levels in those below and above the cutoff

value.

2.07

3.47

0

0.5

1

1.5

2

2.5

3

3.5

4

> cutoff < cutoff

Me

an c

TnI n

g/m

l

below cuoff

above cutoff


31

3.2.2 Admission cTnI levels in the patients and control groups

Results presented in table 3-2 and figure 3-2 showed that admission serum

cTnI level in patients with STEMI was very highly significant higher than in the

control group (3.13 ± 0.84 ng/ml vs. 0.90 ± 0.72 ng/ml, p < 0.0001), respectively.

Table 3-2. Admission serum cTnI levels in STEMI patients compared to control

group.

Patients

(n=50)

Control

(n=34)

P value

Serum cTnI

(ng/ml)

3.13 ± 0.84 0.90 ± 0.72

p < 0.0001**

Values are presented as mean ± SD; n=number.

** Very highly significant difference (p < 0.0001).


30

Figure 3-2. Admission serum cTnI level in STEMI patients compared to control

group.

3.2.3 Association of admission cTnI level to selected clinical variables


Studying the association between admission serum cTnI level and selected

clinical variables among patients with STEMI (diabetes, hypertension, sex, location

of MI, development of HF, development of AF, development of VT and/or VF, and

achievement of successful reperfusion) revealed no significant differences as shown

in table 3-3 and figure 3-3.

3.13

0.9

0

0.5

1

1.5

2

2.5

3

3.5

Contol group Patients group

Me

an c

TnI n

g/m

l

patients

control


31

Table 3-3. Association of admission cTnI level to selected clinical variables among

patients with STEMI.

Clinical

variables

cTnI level (ng/ml) P value*

Yes No

1 Diabetes 3.11 ± 0.99

(n=15) 3.14 ± 0.79

(n=35) 0.91 a

2 Hypertension 3.02 ± 1.01

(n=18) 3.20 ± 0.72

(n=32) 0.44 a

3 Male gender 3.07± 0.80

(n=41 males)

3.44 ± 1.04

(n= 9 females) 0.23 a

4 Anterior MI 3.16 ± 0.85

(n=31)

3.10 ± 0.86

(n= 19)

0.96 a

5 Development

of HF

3.19 ± 0.97

(n=9) 3.12 ± 0.83

(n=41) 0.81 a

6 Development

of AF

2.84 ± 1.05

(n=6) 3.19 ± 0.82

(n=44 ) 0.34 a

7 Development

of VT and/or

VF

3.03 ± 0.521

(n=5 ) 3.16 ± 0.89

(n=45 ) 0.74 a

8 Successful

reperfusion

3.50 ± 0.65

(n=12) 3.02 ± 0.87

(n=38) 0.08 a

Values are presented as mean ± SD; n=number of patients

HF : heart failure, AF: atrial fibrillation , VF: ventricular fibrillation


32

VT: ventricular tachycardia. a: t.test.


Figure 3-3. Association of admission cTnI level to selected clinical variables

(diabetes, hypertension, sex, location of MI, development of HF, development of

AF, development of VT and/or VF, and achievement of successful reperfusion)

among patients with STEMI.

0

0.5

1

1.5

2

2.5

3

3.5

4

Me

an c

TnI n

cg/m

l

Yes

N0


33

3.2.4 Correlation between serum cTnI and selected demographic and


Studying the correlation between admission serum cTnI level and selected

demographic and laboratory variables among patients with STEMI (Age, BMI, S. uric

acid, S. Creatinine, S. urea, S. Total cholesterol, S. HDL-c, serum adiponectin, serum

resistin and serum leptin) revealed no significant correlations between cTnI level

and all these variables as shown in table 3-4.

Table 3-4: Correlation between serum cTnI Level and selected demographic and

laboratory variables in STEMI patients.

Correlation coefficient P value *

1 Age 0.273 0.055

2 BMI -0.201 0.161

3 S. Uric acid 0.145 0.316

4 S. Creatinine 0.086 0.552

5 S. Urea 0.140 0.470

6 S. Total cholesterol 0.140 0.333

7 HDL-c -0.161 0.265

8 Serum resistin 0.180 0.211

9 Serum adiponectin -0.047 0.745

10 Serum leptin -0.185 0.199


34

BMI: body mass index, S.HDL-c: serum high density lipoprotein cholesterol.


3.3 Adiponectin

3.3.1 Adiponectin level in the patients and control groups

Results presented in table 3-5 and figure 3-4 showed that admission serum

adiponectin level in patients with STEMI was very highly significant lower than that

in the control group (4.19 ± 1.03 μg/ml vs. 6.45 ± 1.01 μg/ml, p < 0.0001),

respectively.

Table 3-5. Admission serum adiponectin level in STEMI patients compared to

control.

Patients

(n=50)

Control

(n=34)

P value

Serum adiponectin

(μg/ml)

4.19 ± 1.03 6.45 ± 1.01 p < 0.0001**


**Very highly significant difference (p < 0.0001).


35

Figure 3-4. Admission serum adiponectin level in STEMI patients compared to

control.

3.3.2 Association of admission adiponectin level to selected clinical


Studying the association between admission serum adiponectin level and

selected clinical variables among patients with STEMI (diabetes, hypertension, sex,

location of MI, development of HF, development of AF, development of VT and/or

VF, and achievement of successful reperfusion) revealed a highly significant

difference in serum adiponectin levels between male and female patients (p <

0.001). No significant differences were present for the remaining variables as shown


4.19

6.45

0

1

2

3

4

5

6

7

8

Contolgroup

Patientsgroup

Me

an A

dip

on

ecti

n μ

g/m

l

patients

control


36

Table 3-6. Association of admission adiponectin level to selected clinical variables


Adiponectin level (μg/ml) P value

Yes No

1 Diabetes 4.30± 1.22

(n=15)

4.14± 0.96

(n=35)

0.62 a

2 Hypertension 3.91± 1.17

(n=18)

4.35± 0.90

(n=32)

0.12 a

3 Male gender 4.46 ± 0.92

(n=41 males)

2.95 ± 0.37

(n= 9 females)

< 0.001**a

4 Anterior MI 4.25± 1.03

(n=31)

4.09 ± 1.05

(n= 19)

0.58 a

5 Development of

HF

4.63± 1.19

(n=9)

4.09± 0.98

(n=41)

0.16 a

6 Development of

AF

3.89± 1.21

(n=6)

4.33± 1.02

(n=44 )

0.39 b

7 Development of

VT and/or VF

3.96± 1.06

(n=5 )

4.31±1.05

(n=45 )

0.48 a

8 Successful

reperfusion

3.91± 1.16

(n=12)

4.28± 0.99

(n=38)

0.25 b


37


Hf : heart failure, AF: atrial fibrillation , VF: ventricular fibrillation

VT: ventricular tachycardia. a: t.test, b: Mann-Whitney U test.

** very highly significant difference (P<0.001)

Figure 3-5. Association of admission adiponectin level to selected clinical variables




0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Me

an A

dip

on

ect

in n

g/m

l

Yes

No


38

3.3.3 Correlation between serum adiponectin and selected demographic


Studying the Correlation between admission serum adiponectin level and

selected demographic and laboratory variables among patients with STEMI (Age,

BMI, S. uric acid, S. Creatinine, S. urea, S. Total cholesterol, S. HDL-c, serum leptin,

serum resistin and serum cTnI) revealed a very highly significant negative correlation

between serum adiponectin level and resistin level. No significant correlations were

found between adiponectin level and the remaining variables as shown in table 3-7.

Table 3-7. Correlation between serum adiponectin level and selected

demographic and laboratory variables in STEMI patients.

Correlation coefficient P value

1 Age -0.160 b 0.266

2 BMI -0.211 b 0.140

3 S. Uric acid -0.082 b 0.569

4 S. Creatinine 0.018 b 0.899

5 S. Urea -0.196 b 0.173

6 S. Total

cholesterol

0.064 b 0.661

7 S. HDL-c -0.084 b 0.562

8 Serum leptin 0.004 b 0.978


41

9 Serum resistin -0.861 b <0.0001**

10 Serum cTnI -0.039 b 0.789

BMI: body mass index, S.HDL-c: serum high density lipoprotein cholesterol. ** very

highly significant difference (P<0.0001)

b: spearman correlation

3.4 Leptin

3.4.1 Leptin level in the patients and control groups

Results presented in table 3-8 and figure 3-6 showed that serum leptin level in

patients with STEMI on admission were very highly significant higher than that in the

control group (10.03 ± 1.08 ng/ml vs. 6.97 ± 0.86 ng/ml, p < 0.001), respectively.

Table 3-8. Admission serum leptin level in STEMI patients compared to control

Patients

(n=50)

Control

(n=34)

P value

Serum leptin

(ng/ml)

10.03 ± 1.08

6.97 ± 0.86

p < 0.0001**


** Highly significant difference (p< 0.0001)


40

Figure 3-6. Admission serum leptin level in STEMI patients compared to control.

3.4.2 Association of admission leptin level to selected clinical variables


Studying the association between admission serum leptin level and selected



achievement of successful reperfusion) revealed no significant differences as shown


10.03

6.97

0

2

4

6

8

10

12


Me

an L

ep

tin

ng/

ml

patients

control


41

Table 3-9. Association of admission leptin level to selected clinical variables


Leptin level (ng/ml) P value *

Yes No

1 Diabetes 9.82± 1.05

(n=15)

10.13± 1.09

(n=35)

0.35 a


(n=18)

10.08± 1.14

(n=32)

0.77 a

3 Male gender 10.03 ± 1.13

(n=41 males)

10.07 ± 0.85

(n= 9 females)

0.91a


(n=31)

9.94± 1.02

(n= 19)

0.62 a

5 Development

of HF

9.87± 0.65

(n=9)

10.07± 1.15

(n=41)

0.62 a

6 Development

of AF

10.50± 1.06

(n=6)

10.04± 1.04

(n=44 )

0.31 a

7 Development

of VT and /

or VF

10.28 ± 1.02

(n=5 )

10.07± 1.06

(n=45 )

0.68 a

8 Successful

reperfusion

10.02± 1.10

(n=12)

10.04± 1.08

(n=38)

0.96 a



42


VT: ventricular tachycardia, a: t.test.


Figure 3.7 Association of admission leptin level to selected clinical variables


9.4

9.6

9.8

10

10.2

10.4

10.6

Me

an L

epti

n n

g/m

l

Yes

N0


43



3.4.3 Correlation between serum leptin and selected demographic and


Studying the Correlation between admission serum leptin level and selected


acid, S. Creatinine, S. urea, S. Total cholesterol, S. HDL-c, serum adiponectin, serum

resistin and serum cTnI) revealed no significant correlations between leptin level

and all these variables (Table 3-10).

Table 3-10. Correlation between serum leptin level and selected demographic


Correlation coefficient P value *

1 Age 0.026 a 0.858

2 BMI -0.011 b 0.938

3 S. Uric acid -0.089 b 0.540


5 S. Urea 0.073 b 0.614

6 S. Total cholesterol -0.003 a 0.982

7 S. HDL-c 0.012 b 0.935

8 Serum resistin 0.033 b 0.821


44

9 Serum adiponectin 0.003 b 0.982

10 Serum cTnI -0.185 a 0.199



a: pearson correlation b: spearman correlation

3.5 Leptin/adiponectin ratio

3.5.1 Leptin/adiponectin ratio in the patients and control groups

Results presented in table 3-11 and figure 3-8 showed that admission

serum leptin /adiponectin ratio in patients with STEMI was very highly significant

higher than the control group (2.54 ± 0.71 vs. 1.1 ± 0.24, p < 0.0001), respectively.

Table 3-11. Admission serum leptin / adiponectin ratio in STEMI patients


Patients

(n=50)

Control

(n=34)

P value

Leptin/adiponectin ratio 2.54 ± 0.71

1.1 ± 0.24

p < 0.0001




45

Figure 3-8. Admission serum leptin /adiponectin ratio in STEMI patients compared

to control.

3.5.2 Association of admission leptin /adiponectin ratio with selected


Studying the association between admission serum leptin/adiponectin ratio

and selected clinical variables among patients with STEMI (diabetes, hypertension,

sex, location of MI, development of HF, development of AF, development of VT

and/or VF, and achievement of successful reperfusion) revealed a very highly

significant difference between male and female (p < 0.001). No significant

differences were present for the remaining variables as shown in table 3-12 and

figure 3-9.

2.54

1.1

0

0.5

1

1.5

2

2.5

3


Me

an L

ep

tin

/ A

dip

on

ect

in

rati

o

patients

control


46

Table 3-12. Association of admission leptin/adiponectin ratio to selected clinical


Leptin / adiponectin ratio P value

Yes No

1 Diabetes 2.47± 0.82

(n=15)

2.57± 0.67

(n=35)

0.66 a


(n=18)

2.41± 0.57

(n=32)

0.07 a


(n=31)

2.57± 0.63

(n= 19)

0.85 a

3 Male gender 2.34± 0.56

(n=41 males)

3.46 ± 0.63

(n= 9 females)

< 0.001** a

4 Development

of HF

2.28± 0.68

(n=9)

2.60± 0.72

(n=41)

0.23 a

5 Development

of AF

2.95± 1.04

(n=6)

2.45± 0.66

(n=44 )

0.11 a

6 Development

of VT and/or

VF

2.76± 0.92

(n=5 )

2.48± 0.71

(n=45 )

0.41 a

7 Successful

reperfusion

2.73± 0.70

(n=12)

2.48± 0.72

(n=38)

0.15 a

Values are presented as mean ± SD, n=number of patients


47

Hf: heart failure, AF: atrial fibrillation, VF: ventricular fibrillation

VT: ventricular tachycardia. a: t.test.

** Very highly significant difference (p < 0.001)

Figure 3-9. Association of admission leptin/adiponectin ratio to selected clinical

variables (diabetes, hypertension, sex, location of MI, development of HF,

development of AF, development of VT and/or VF, and achievement of successful

reperfusion) among patients with STEMI.

0

0.5

1

1.5

2

2.5

3

3.5

4

Me

an L

ep

tin

/ad

ipo

ne

ctin

rat

io

Yes

N0


48

3.5.3 Correlation between leptin/adiponectin ratio and selected

demographic and laboratory variables in STEMI patients

Studying the correlation between admission leptin/adiponectin ratio and


BMI, S. uric acid, S. Creatinine, S. urea, S. Total cholesterol, S. HDL-c, serum resistin

and serum cTnI) revealed a highly significant positive correlation between leptin /

adiponectin ratio and resistin level. No significant correlations were found between

leptin / adiponectin ratio and the remaining variables as shown in table 3-13.

Table 3-13. Correlation between serum leptin/adiponectin ratio and selected

demographic and laboratory variables in STEMI patients.

Correlation coefficient P value

1 Age 0.151 b 0.296

2 BMI 0.270 b 0.058

3 S. Uric acid -0.025 b 0.862


5 S. Urea 0.111 b 0.442

6 S. Total cholesterol -0.056 b 0.700

7 S. HDL-c 0.067 b 0.646

8 Serum resistin 0.809 b <0.0001**

9 Serum Troponin I -0.093 b 0.522


51




3.6 Resistin

3.6.1 Resistin level in the patients and control groups

Results presented in table 3-16 and figure 3-10 showed that serum resistin

level in patients with STEMI on admission was very highly significant higher than in

the control group (13.08 ± 2.53 ng/ml vs. 5.31 ± 0.87 ng/ml, p < 0.0001),

respectively.

Table 3-14. Admission serum resistin level in STEMI patients compared to control.

Patients

(n=50)

Control

(n=34)

P value

Serum resistin

(ng/ml)

13.08 ± 2.53 5.31 ± 0.87

p < 0.0001**


** Very highly significant difference (p< 0.0001)


50

Figure 3-10. Admission serum resistin level in STEMI patients compared to control.

3.6.2 Association of admission resistin level with selected clinical


Studying the association between admission serum resistin level and selected



achievement of successful reperfusion) revealed a highly significant difference

between male and female (p < 0.001). No significant differences were present for

the remaining variables as shown in table 3-15 and figure 3-11.

13.08

5.31

0

2

4

6

8

10

12

14

16


Me

an R

esi

stin

ng/

ml

patients

control


51

Table 3-15. Association of admission resistin level to selected clinical variables


Resistin level (ng/ml) P value

Yes No

1 Diabetes 12.70 ± 3.01

(n=15)

13.24 ± 2.33

(n=35)

0.49 a


(n=18)

12.69 ± 2.34

(n=32)

0.14 a

3 Male gender 12.38 ± 2.23

(n=41 males)

16.24± 0.89

(n= 9 females)

< 0.001** b

4 Anterior MI 13.15 ± 2.50

(n=31)

12.95 ± 2.65

(n= 19)

0.77 b

5 Development

of HF

12.4 ± 2.77

(n=9)

13.23 ± 2.49

(n=41)

0.38 b

6 Development

of AF

13.71 ± 3.37

(n=6)

12.86 ± 2.44

(n=44 )

0.38 b

7 Development

of VT and/or

VF

13.64 ± 2.68

(n=5 )

12.89 ± 2.54

(n=45 )

0.49 b

8 Successful

reperfusion

13.90 ± 2.83

(n=12)

12.82 ± 2.42

(n=38)

0.14 b


52



VT: ventricular tachycardia. a: t.test, b: Mann-Whitney U test.

** Very highly significant difference (p< 0.001)

0

2

4

6

8

10

12

14

16

18

Me

an R

esi

stin

ng/

ml

Yes

No


53

Figure 3-11. Association of admission resistin level to selected clinical variables




3.6.3 Correlation between serum resistin and selected demographic


Studying the correlation between admission serum resistin level and selected


acid, S. Creatinine, S. urea, S. Total cholesterol, S. HDL-c, serum leptin, serum

adiponectin and serum cTnI) revealed a very highly significant negative correlation

between serum resistin level and adiponectin level. No significant correlations were

found between resistin level and the remaining variables (Table 3-16).


54

Table 3-16. Correlation between serum resistin level and selected demographic

and laboratory variables in STEMI patients.

Correlation

coefficient

P value

1 Age 0.236 b 0.099

2 BMI 0.080 b 0.580

3 S. Uric acid 0.045 b 0.757

4 S. Creatinine -0.040 b 0.781

5 S. Urea 0.195 b 0.175

6 S. Total cholesterol 0.027 b 0.851

7 S. HDL-c -0.065 b 0.651

8 Serum leptin 0.058 b 0.688

9 Serum adiponectin -0.861 b <0.0001**

10 Serum cTnI 0.232 b 0.105




Chapter Four Discussion

55

CHAPTER FOUR

Discussion

4.1 Admission serum cTnI and STEMI

The current study showed that admission serum cTnI level was significantly

increased in patients with acute STEMI when compared with controls even

though, there were 12 patients (24%) presented with cTnI level below the

diagnostic cutoff (99th percentile) value calculated from the control group.

However, all the patients had values exceeding the cutoff point 6-9 hours later .

This finding is in agreement with the current recommendations about proper

diagnosis of STEMI in which a single measurement of a biochemical marker is not

adequate to exclude the diagnosis of MI because up to 15% of the values that are

below the level of detection initially (a negative test) are above the level of

detection (a positive test) in the subsequent hours [31]. Accordingly, two blood

samples were obtained from the patients, one at time of admission and again in 6

to 9 hours later in order to measure troponin.

In 2000 a Joint Committee of the European Society of Cardiology and the

American College of Cardiology (ESC/ACC) issued new criteria that elevations in

biomarkers were fundamental to the diagnosis of acute myocardial infarction,

[185] because symptoms may be atypical or nonexistent and ECG changes may be

absent or nonspecific [186]. By this time, cardiac troponin had supplanted CK-MB

as the biomarker of choice for the detection of cardiac injury [187]. To avoid


56

false-positive results, the 99th percentile should be used as the cutoff value for

diagnosing acute myocardial infarction.

The measurement of serum cTnI and cTnT is superior in terms of sensitivity

and specificity in the identification of cardiac muscle damage [188]. Raised cardiac

troponin concentrations are now accepted as the standard biochemical marker

for the diagnosis of MI [189].

Cardiac troponins are detected in the serum by the use of monoclonal

antibodies to epitopes of cTnI and cTnT. These antibodies are highly specific for

cardiac troponin and have negligible crossreactivity with skeletal muscle

troponins [190].

The measurement of cardiac troponins as markers of myocardial damage in

the investigation of patients with chest pain has had an important beneficial

effects on clinical practice where more patients with chest pain who would not

have been diagnosed as having myocardial damage with conventional muscle

enzyme assays are being diagnosed with myocardial infarction, even in the

absence of ST segment elevation[191].

Many of these patients are at high risk of full thickness myocardial infarction

or even death in the ensuing six month period, [192] and have been shown to

benefit prognostically from early treatment with low molecular weight heparins,

[193] platelet glycoprotein IIb/IIIa receptor blockers, [194] and coronary

revascularization [195].

The current study revealed no significant association between admission

serum cTnI level and selected clinical outcome variables during hospitalization


57

period (development of heart failure, development of atrial fibrillation,

development of ventricular tachycardia and/or ventricular fibrillation, as well as

achievement of successful reperfusion) (table 3-3). Previous studies showed

controversial results about the predictive strength of troponin assays [196-206].

Many studies used an approach similar to the current study, which was to

assess the value of troponin measurements in predicting short-term adverse

outcomes of ACS. Most findings of these studies [196-199, 201,203,204] were

consistent with finding of the current study and suggested that troponin

measurement was of little value, whereas three [200, 205, 206] suggested that it

was of substantial value.

Prognosis and diagnosis are different, and thus troponin elevations may in

some situations help to make a diagnosis but may not be prognostic. The reason

for this may be that the effect is too small to detect, if it exists at all [28].

4.2 Admission serum adiponectin and STEMI

The current study showed that serum adiponectin level was significantly

decreased in patients with acute STEMI, when compared with controls (table 3-4).

These results are in agreement with similar studies participated on patients with

acute myocardial infarction which similarly reported decreased serum

adiponectin concentrations [207, 208]. One of these studies investigated the

association between adiponectin concentration and acute myocardial infarction

(AMI) in non obese men patients. The results showed that adiponectin levels in


58

patients with AMI (5.2ug/ml) were significantly lower than that of control group

(7.5ug/ml) (P<0.001) [207].

In the other study, plasma adiponectin levels were measured in 43 patients

with AMI at the first 24 hours of admission and 43 normal controls. Adiponectin

levels in patients with AMI (3.36 μg/mL) were significantly lower than that of the

control group (5.03 μg/mL) (p < 0.0001) [208]. It is important to note that all of

these studies are correlative and direct evidence that adiponectin protects against

vascular disease in humans is still lacking. However, these findings do indicate

that use of serum adiponectin levels may be useful biomarkers in the early

diagnosis and prognosis of cardiovascular disease [209].

Despite the growing understanding of the biology of adiponectin, the

relationship between adiponectin and clinical outcomes in patients at risk for and

with established atherosclerosis is less clear. When examined in prospective

studies among individuals without prevalent CVD, higher total adiponectin

concentration has been linked to a lower risk of incident CAD and MI in healthy

men [210-212].

Such clinical data have supported the assertion that adiponectin is

cardioprotective and confers anti-inflammatory and antiatherogenic effects.

Together, these studies, including the current study, provide evidence for the

reported inverse associations between adiponectin and development of CAD.

However, these findings have not remained unopposed. In the Strong Heart

Study (SHS), no significant association with later development of CAD could be

found in American Indians which had been explained by the potential impact of a


61

higher prevalence of diabetes mellitus in this study cohort [213]. The varied

results between studies may be related to the diverse risk profiles of the selected

populations, differing severity of atherosclerosis, small sample size, and other

differences in the design of the studies.

Several independent mechanisms have been proposed to explain the

cardioprotective and anti-atherogenic role of adiponectin. In addition to its

insulin-sensitizing and metabolic activities, studies in both rodents and large

animals have consistently demonstrated the multiple salutary effects of

adiponectin on cardiovascular health, through its direct actions on both the heart

and the vasculature [87].

Endothelial dysfunction, characterized by several abnormalities, including

impaired nitric oxide (NO) production, is a key finding associated with insulin-

resistant states [214]. When endothelial dysfunction is present, the relative lack

of NO production contributes to hypertension and several concomitant

pathologies, including increased expression of adhesion molecules on the

endothelial cell surface and other inflammatory changes that underlie the early

process of atherosclerosis [214].

Data obtained from animal's study demonstrate the protective effects of

adiponectin against endothelial dysfunction primarily through its multiple actions

on the endothelium (Zhu et al., 2008) [215]. Aortic rings isolated from adiponectin

knockout mice exhibit reduced endothelial NO Synthase (eNOS) activation and NO

production compared with those from wild-type controls, and these changes are

reversed by treatment with recombinant adiponectin (Cao et al., 2009) [216].


60

Adiponectin inhibits the production of reactive oxygen species (ROS) induced

by high glucose (Ouedraogo et al., 2006) [217], oxidized LDL (Plant et al., 2008)

[218] and palmitate (Kim et al., 2010) [219] in cultured endothelial cells. In

addition to its effects on eNOS activity and ROS production, adiponectin

suppresses endothelial activation and monocyte attachment, an early step of the

inflammatory reaction leading to atherosclerosis (Zhu et al., 2008) [215]. Indeed,

adiponectin suppresses TNF-α and resistin-induced expression of adhesion

molecules as well as interleukin (IL)-8 (Kobashi et al., 2005) [220].

Another proposed mechanism is related to the promotion of endothelial

repair by adiponectin. Impairment in endothelial repair is a hallmark of vascular

dysfunction and an early step of the atherosclerotic process. Endothelial

progenitor cells (EPCs) are important contributors to endothelial repair following

vascular injury (Szmitko et al., 2003) [221]. Decreased numbers and/or impaired

function of EPCs are causally associated with endothelial dysfunction and CVD

(Fadini et al., 2007) [222]. Both animal and clinical investigations suggest that

adiponectin promotes endothelial repair and angiogenesis by increasing the

number and function of EPCs (Xu et al., 2010) [223]. Adiponectin potently

stimulates survival, proliferation and differentiation of bone marrow-derived EPCs

(Eren et al., 2009) [224], and also promotes the migration activities of EPCs

(Nakamura et al., 2009) [225].

Another proposed mechanism related to the effects of adiponectin on

endothelial inflammation. The anti-inflammatory properties of adiponectin are

mediated partly through activation of AdipoR1 and AdipoR2 in monocytes,

macrophages, and endothelial cells and serve to attenuate inflammatory cell


61

accumulation in sites of vascular injury [219]. Adiponectin inhibits the production

of pro-inflammatory cytokines and chemokines from both immune and

endothelial cells as well as the ability of these cells to become activated in

response to various inflammatory stimuli. Furthermore, it inhibits the growth of

myelomonocytic progenitors [219] as well as down-regulating the expression of

scavenger A receptors and suppressing the transformation of macrophages to

foam cells [226].

In addition to its direct actions on blood vessels, adiponectin acts in an

autocrine manner to inhibit obesity-induced macrophage infiltration and

production of pro-inflammatory cytokines in adipose tissue (Kim et al., 2007;

Ohashi et al., 2010) [218, 227]. This may also contribute to its anti-atherosclerotic

properties by preventing the ‘inflammatory signal’ from adipose tissue to the

vasculature.

Another suggested beneficial role of adiponectin is related to its direct

cardio-protective effects. In addition to its effects on the vasculature, both in vitro

studies and animal experiments demonstrate that adiponectin acts directly on

cardiomyocytes to protect the heart from ischaemic injury, hypertrophy,

cardiomyopathy and systolic dysfunction (Goldstein et al., 2009)[228]. During

ischaemia reperfusion (I/R) injury, the lack of adiponectin exacerbates myocardial

infarct size and myocardial apoptosis and decreases cardiac functions (Tao et al.,

2007)[229]. The cardio-protective effects of adiponectin are attributed to its

ability in suppressing apoptosis, oxidative stress and inflammation in

cardiomyocytes (Tao et al., 2007) [229].


62

Based on the evidence presented above, it is reasonable to assume that as

well as being a key player in vascular homeostasis, adiponectin exerts an

important role in the pathophysiology of ischemic heart disease [230]. However,

most of the mechanistic data currently available are based on observations from

cell culture and animal models, and extrapolations to humans should be made

with caution [230].

Concerning the association between admission serum adiponectin level and

selected clinical variables among patients with STEMI (diabetes, hypertension,


and/or VF, and achievement of successful reperfusion) the current study revealed

no significant differences in all of these parameters except sex difference where

adiponectin level was significantly higher in men than in women patients (table 3-

8) and this is inconsistent with other studies were most of these studies showed

higher adiponectin levels in women in comparison to men [231, 232] although

some other studies showed no statistically significant difference in adiponectin

levels between men and women [208] .

The association between serum adiponectin level short and long-term

outcomes need further investigation since the studies published so far give

contradictory information. According to Inoue et al., in a group of 149 patients

with confirmed CAD, low adiponectin levels were an independent predictor of

cardiovascular events [233]. Pischon et al. drew similar conclusions –in a group of

over 1800 patients during a 6-year follow-up [234]. On the other hand, Cavusoglu

et al., in group of 325 male patients with CAD, showed that high plasma

adiponectin levels independently predict the individual endpoints of all-cause


63

mortality, cardiac mortality, and MI [235]. The same conclusion came from a

study conducted by Laughlin at al., who found that in a group of over 1500

patients, high adiponectin levels were associated with higher risks of

cardiovascular disease death and death from all causes [236].

Regarding the correlation between admission serum adiponectin level and



serum resistin and serum cTnI) the current study revealed a highly significant a

negative correlation between serum adiponectin and serum resistin level with no

significant correlation with all other parameters (table 3-7). In consistent with

current study, no significant correlations were found between adiponectin and

BMI, Total cholesterol, S. Creatinine, and HDL-c [208] . In addition a significant

inverse correlation between adiponectin and resistin levels has also been

reported in the literatures [237, 238] (see section 4-5).

4.3 Admission serum leptin and STEMI

The current study showed that serum leptin level was significantly increased

in patients with acute STEMI, when compared with controls (table 3-8). These

results are in agreement with similar studies done in patients with acute

myocardial infarction [239-241].

In one of these studies, Jose VJ et al tested 94 patients presented with acute

STEMI and 46 control subjects. The serum leptin level in patients with myocardial

infarction was (6.51 ng/ml) versus (2.86 ng/ml) in the control subjects [239]. In

http://www.ncbi.nlm.nih.gov/pubmed?term=Jose%20VJ%5BAuthor%5D&cauthor=true&cauthor_uid=15852893


64

another study serum leptin level was measured in 40 patients with acute STEMI,

and 30 control subjects. Serum leptin concentration was significantly higher in

patients with acute STEMI compared to the control group (8.22 ng/mL) vs (6.37

ng/mL) respectively [240].

Wallander M et al in a case control study demonstrated that compared with

control subjects, patients of both genders had significantly higher leptin levels 2

days after myocardial infarction [241]. These levels were higher than those

obtained at hospital discharge and at 3 months follow-up. They also concluded

that elevated circulating levels of leptin on the first morning after an acute MI

were associated with abnormal glucose tolerance at discharge and with a poorer

long-term prognosis [241].

Several mechanisms had been proposed about leptin role in inducing

cardiovascular disorders (table 4-1) [242].


65

Table 4-1 Mechanisms postulated for leptin relating to increased cardiovascular

risk [242].

• Impaired NO dependent vasorelaxation.

• Increased synthesis and secretion of endothelin-1.

•Enhanced accumulation of cholesterol esters in foam cells at high

glucose concentrations.

• Migration and proliferation of vascular smooth muscle cells.

• Increased expression of matrix metalloproteinase by vascular smooth

muscle cells.

• Generation of reactive oxygen species.

• Promotion of ADP-induced platelet aggregation.

• Increased plasma renin activity and serum angiotensinogen levels.

• Increases sympathetic nervous system activity.

• Down regulation of insulin signaling.


66

One of these mechanisms related to the effects of leptin on endothelial cells.

Functional leptin receptors are present on endothelial cells. Leptin at

pathophysiologically relevant concentrations (but not at low physiological

concentrations) impairs NO dependent vasorelaxation induced by acetylcholine

both in vitro and in vivo [243].

These novel findings suggest hyperleptinemia as a potential mechanism by

which obesity and the metabolic syndrome leads to significant coronary

dysfunction and potentially coronary artery disease. The mechanism of leptin-

induced endothelial dysfunction has not been directly examined but could be

related to inhibition of NO synthase [244], augmented superoxide production

[245] and/or increases in release of endothelin-1 [246].

Other mechanism related to the pro-inflammatory effects of leptin. Leptin

potentiates secretion of tumor necrosis factor and interleukins 2 and 6, [247]

increases generation and accumulation of reactive oxygen species, and enhances

expression of monocyte chemoattractant protein-1 [245]. Physiological

concentrations of leptin stimulate expression of C-reactive protein (CRP) in

primary human hepatocytes [248]. Thus, the ability of leptin to promote

proinflammatory signaling through cytokines and growth factors may contribute

to endothelial dysfunction and atherosclerosis in hyperleptinemic states.

Another proposed mechanism is related to the prothrombotic effects of

leptin. The long form of the leptin receptor is present on platelets and in vitro

exposure to high concentrations of leptin enhances ADP-induced aggregation of

platelet enriched human plasma [249].


67

In men with ischemic heart disease, leptin also positively correlates with the

plasma concentration of plasminogen activator inhibitor-1 [250]. In the Health

Professionals Follow-up Study, leptin significantly correlates with fibrinogen and

von Willebrand factor [251]. In a Swedish population-based study, leptin

positively correlates with plasma fibrinogen and inversely correlates with tissue

plasminogen activator concentration in plasma [252]. An inverse relationship

between leptin and 2 inhibitors of coagulation, protein C and tissue factor

pathway inhibitor, is also noted in patients with end-stage renal disease [253].

Taken together, these data suggest that in some contexts leptin may contribute to

platelet hyperactivity and a pathological shift in the coagulation-fibrinolysis

balance observed in the metabolic syndrome.

Another suggested negative effect of leptin is related to its direct effects on

cardiomyocytes. Within the past several years a number of studies have

addressed the potential for direct effects of leptin on cardiomyocyte function.

Leptin induces hypertrophy of neonatal rat ventricular myocytes [254] and

proliferation of primary pediatric human cardiomyocytes [255]. Leptin inhibits the

contractile function of ventricular myocytes through several intracellular signaling

mechanisms including activation of the endothelin-1 receptor [256]. Taken

together, these findings suggest that hyperleptinemia in obesity may have a direct

negative effect on myocardial function promoting heart failure.

Concerning the association between admission serum leptin level and

selected clinical variables among patients with STEMI (diabetes, hypertension,


and/or VF, and achievement of successful reperfusion) the current study revealed


68

no significant differences in all of these parameters (table 3-9) . In agreement

with the finding of the current study, Basri et al (2006) found no significant

difference in short-term adverse cardiovascular events among STEMI patients

with low and high admission serum leptin level, however, he found that high

admission leptin level was associated with a lesser efficacy of thrombolytic

therapy and an increased need for invasive therapeutic interventions after

thrombolytic therapy [257].

Regarding the correlation between admission serum leptin level and selected

demographic and laboratory variables among patients with STEMI (Age, BMI, S.

uric acid, S. Creatinine, S. urea, S. Total cholesterol, S. HDL-c, serum leptin, serum

resistin and serum cTnI) the current study revealed no significant correlation

between serum leptin with all of these other parameters (table 3-10). This finding

is compatible with taneli et al study that found no significant correlation between

the leptin levels and selected classical coronary risk factors in patients with

chronic stable angina pectoris and ST-elevated myocardial infarction [240].

4.4 Admission serum leptin/adiponectin ratio and STEMI

Since the ratio of leptin ⁄ adiponectin had been suggested to be a better

indicator of insulin resistance than the single adipokines [258] and studies in

lipoatrophic mice demonstrated that only a combination of physiological doses of

leptin and adiponectin was able to fully reverse the insulin resistance, while either

adipokine alone led to only partial reversion [259], the current study also


71

examined the combined effect of leptin and adiponectin by the use of leptin ⁄

adiponectin ratio.

The current study showed that admission serum leptin /adiponectin ratio in

patients with STEMI was significantly higher than the control group (table 3-11).

In addition no significant differences were found in this ratio among different

clinical variables except higher level in men than women patients (table 3-12).

Also no significant correlations were found between leptin / adiponectin ratio and

most of demographic and laboratory variables except the highly significant

positive correlation between leptin / adiponectin ratio and resistin level (table 3-

13).

The results of the current study is compatible with results obtained by

Kappelle et al who found that plasma leptin level and the leptin / adiponectin

ratio were higher in cases than the control group. However inconsistent with the

current study and other study he found that the difference in adiponectin was not

significant [260]. The results of current study is in contrast to a cross-sectional

study in Italian subjects, which suggested that the leptin/adiponectin ratio might

be a better marker than either adiponectin or leptin alone [261].

Overall in this study, the leptin / adiponectin ratio does not yield any

additional information on STEMI risk compared to either adiponectin or leptin

alone.

4.5 Admission serum resistin and STEMI


70

In the investigation of the relationship between the admission serum resistin

level and STEMI, the current study showed that serum resistin level was

significantly elevated in STEMI patients compared to the control group. Previous

studies have similarly reported an increased serum resistin level in STEMI patients

[262-264].

It was reported that resistin levels are substantially higher in human

inflammatory cells when compared with human adipocytes (Yang et al., 2003;

Patel et al., 2003; Kaser et al., 2003)[265-267]. Elevation of resistin in the ACS

might represent the presence of inflammatory process in mononuclear cells—

precede myocardial necrosis. These findings may additionally support the

hypothesis that in the conditions of the ACS, resistin might represent

inflammatory rather than a metabolic processes [268].

Even though, there are still controversies about the association of resistin

with CAD. Diez et al demonstrated no difference in the serum levels of resistin

between end-stage renal disease patients with or without vascular disease [269].

Burnett et al showed that resistin was not independently associated with CAD

[270].

Several mechanisms had been proposed about resistin role in inducing

cardiovascular disorders. Resistin was suggested to affect endothelial function

and the migration of vascular smooth muscle cells (Calabro et al.,2004; Cohen and

Horel, 2009) [142, 271], which are regarded as key pathophysiological

mechanisms of atherosclerosis. Further, resistin has been noted to play a vital

role in increasing the level of very low density lipoprotein (VLDL) and low density

lipoprotein (LDL) in an obese person (Rizkalla et al.) [272] which is directly


71

atherogenic. Resistin induces increases in Monocyte chemo attractant protein-1

(MCP-1) and Vascular cell adhesion molecule -1 (VCAM-1) expression in vascular

endothelial cells which suggest a possible mechanism that contribute to

atherogenesis (Calabro et al., 2004; Cohen and Horel, 2009) [142, 271].

Other reports indicate that resistin promotes proliferation of vascular

smooth muscle cells (VSMC) (Calabro et al., 2004) [142]. Thus resistin is noted to

enhance VSMC migration, which is a known component of athermanous plaque

synthesis (Verma et al., 2003) [141]. Resistin promotes foam cell formation via

dysregulation of scavenger receptors (SR-A) and ATP-binding cassette transporter-

A1 (ABCA1) (Lee et al., 2009) [273] through PPAR gamma. In atherosclerosis,

increased level of resistin causes elevation of soluble TNF-α receptor 2, IL-6 and

lipoprotein-associated phospholipase A2 (Lp- PLA2) (Reilly et al., 2005) [137]. In

addition to that, resistin has been shown to impair endothelium-dependent

dilation of coronary vessels induced by the cardioprotectant bradykinin (Dick et

al., 2006) [274]. Lubos et al. (2007) proposed resistin as a diagnostic marker of MI

and future cardiovascular death [264].

Besides that, several studies have shown that resistin may enhance

thrombus formation during atherosclerotic plaque formation. For example,

treatment of human coronary artery endothelial cells (HCAECs) with resistin has

been shown to cause up-regulation of tissue factor (TF) expression (Calabro et al.,

2011) [275]. The TF plays a pivotal role in the pathophysiology of ACS by triggering

the formation of intracoronary thrombi following endothelial injury (Ragni et al.,

1996) [276].


72

In a recent clinical study, the serum resistin level of 90 patients with the

metabolic syndrome was determined and compared with serum levels of

mediators of thrombosis (Fang et al., 2011) [277]. It was determined that the

average level of resistin in metabolic syndrome patients with or without acute

myocardial or cerebral infarction was significantly higher than that of the control

patients. And, in the patients with metabolic syndrome and infarction, resistin

levels correlated significantly with TF and plasminogen activator inhibitor-1. These

findings suggest that resistin may induce thrombotic complications via mediating

the lipoprotein metabolism and stimulating inflammation in a hypercoagulable

and hyperfibrinolytic environment [278].

Concerning the association between admission serum resistin level

and selected clinical variables among patients with STEMI (diabetes,

hypertension, sex, location of MI, development of HF, development of AF,

development of VT and/or VF, and achievement of successful reperfusion) the

current study revealed no significant differences in all of the parameters except

sex difference where resistin level was significantly higher in women patients than

in men (table 3-17). Regarding the sex difference, the finding of the current study

was in agreement with other studies which had been shown that resistin

concentrations were significantly higher in women compared to men

(Tuttolomondo et al., 2010 ; Yannakoulia et al.,2003) [279, 280]. However, it

remains to be elucidated whether the sexual dimorphism of body fat distribution

or differences in sex steroids are responsible for the observed differences in

resistin levels. Concerning the non-significant prognostic value of admission

serum resistin in predicting the future cardiovascular event, the finding of the

current study was inconsistent with finding of Lubos et al. (2007) who found that


73

systemic resistin level is moderately associated with future cardiovascular death

in patients with documented coronary artery disease. However, the follow up

period of Lubos et al study was significantly longer than the follow up period of

the current study [264].

Regarding the correlation between admission serum resistin level and



serum adiponectin and serum cTnI) the current study revealed a highly significant

negative correlation between serum resistin level and adiponectin level with no

significant correlations with all other parameters (table 3-18). Concerning the

non-significant correlations, similar finding were reported in other studies were

non-significant correlations were found between serum resistin and age, BMI

[262], lipid profile and inflammatory markers [263].

In consistent with current study, a significant inverse correlation between

serum adiponectin and resistin levels has also been reported in the literatures

[237, 238]. It has been reported that those with highest increases of adiponectin

also displayed a trend towards a decline in resistin levels [238]. Both

hypoadiponectinemia and hyperresistinemia were also positively correlated with

hypertension and previous cerebrovascular disease (transient ischemic attack /

ischemic stroke) [279]. Furthermore, both hypoadiponectinemia and

hyperresistinemia were associated with hypertension [281] and may have

prognostic significance for future cardiovascular events in patients with masked

hypertension [282]. Elevated resistin opposed to adiponectin plasma levels was

proposed to be a strong predictive factor for the occurrence of major adverse


74

cardiac events in patients with stable multivessel coronary artery disease over 1-

year follow up [283]. Thus, the balance of the opposite effects of adiponectin and

resistin at the level of the endothelial cell may be an important determinant of

endothelial dysfunction, and in turn the progress of atherosclerosis. Miyamoto et

al. found that resistin may increase the susceptibility of metabolic syndrome by

modulating adiponectin secretion from adipocytes [284].


75

4.6 Conclusion

According to the reported data in the present study, one can conclude that:

1. Lower admission serum adiponectin level is associated with acute STEMI in

Iraqi patients.

2. Iraqi patients with acute STEMI have significantly higher admission serum

resistin and leptin concentrations (similar to the increased serum cardiac

troponin I) compared with controls.

3. Highly significant inverse correlation between admission serum adiponectin and

serum resistin was found.

4. These findings suggest possible pathologic and diagnostic value for the three

adipokines (adiponectin, resistin and leptin) in STEMI.

5. No significant associations were found between admission serum cTnI,

adiponectin, resistin, and leptin levels with short-term outcome during

hospitalization period specially the response to thrombolytic therapy as well as

development of complications.


76

4.7 Recommendations for future work

1. Larger scale and longer duration clinical trial is required to evaluate the

pathologic, diagnostic as well as prognostic value of adiponectin, resistin and

leptin in STEMI.

2. Evaluation of other adipokines such as visfatin, Apelin and adipsin and others

that are secreted from the adipose tissue and their correlations with CAD.

3-Evaluating possible associations between different adipokines and the response

to different anticoagulant drugs in the setting of thrombo-embolic diseases.

77

References

1. Popma JJ. Coronary arteriography and intravascular imaging. In: Braunwald E,

ed. Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed.

Philadelphia: WB Saunders; 2008.

2. Trujillo T, Nolan P. Ischemic heart disease: angina syndrome. In: Marry Anne

koda-kimble(ed) Applied Therapeutics: the clinical use of drugs,9th ed.

Lippincot Williams and W ilkins;2009.

3. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA Guidelines for the

Management of Patients with ST-Elevation Myocardial Infarction: Executive

summary. A report of the American College of Cardiology/American Heart

Association Task Force on Practice Guidelines (Committee to revise the 1999

Guidelines for the Management of Patients with Acute Myocardial Infarction).

Circulation 2004; 110:588–636.

4. Braunwald E, Antman EM, John WB, et al. ACC/AHA 2002 guideline update

for the management of patients with unstable angina and non-ST segment

elevation myocardial infarction: a report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines

(committee on the management of patients with unstable angina). J Am Coll

Cardiol 2002 Oct 2; 40(7):1366-74.

5. Harvey DW, Derek PC. Acute myocardial infarction. Lancet 2008; 372: 570–84

6. Fuster V, Moreno PR, Fayad ZA, et al. Atherothrombosis and high-risk plaque:

Part I: Evolving concepts. J Am Coll Cardiol. 2005;46: 937–954.

7. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: Heart disease

and stroke statistics—2010 update: A report from the American Heart

Association. Circulation 2010;121:948–954

http://www.ncbi.nlm.nih.gov/pubmed/12383588


78

8. Davies MJ, Treasure T, Richardson PD. The pathogenesis of spontaneous

arterial dissection. Heart 1996; 75: 434–435.

9. Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophages, smooth muscle

cells, and tissue factor in unstable angina: implications for cell-mediated

thrombogenicity in acute coronary syndromes. Circulation 1996; 94:3090–

3097.

10. Gibson CM, Pride YB, Frederick PD, et al. Trends in reperfusion strategies,

door-to-needle and door-to-balloon times, and in-hospital mortality among

patients with ST-segment elevation myocardial infarction enrolled in the

National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J

2008; 156:1035–1044.

11. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N

Engl J Med 2005; 352:1685–1695.

12. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation

2005; 111:3481–3488

13. Lee KW, Lip GY, Tayebjee M, et al. Circulating endothelial cells, von

Willebrand factor, interleukin-6, and prognosis in patients with acute coronary

syndromes. Blood 2005; 105:526–532.

14. Stone PH. Triggering myocardial infarction. N Engl J Med 2004; 351:1716–

1718.

15. St John Sutton M, Ferrari VA. Prevention of left ventricular remodeling after

myocardial infarction. Curr Treat Options Cardiovasc Med 2002; 4:97–108.

16. Opie LH, Commerford PJ, Gersh BJ, et al. Controversies in ventricular

remodeling. Lancet 2006; 367:356–67.

81

17. Mann DL. Mechanisms and models in heart failure: A combinatorial

approach. Circulation 1999; 100:999–1008.

18. Corti R, Hutter R, Badimon J, et al. Evolving Concepts in the Triad of

Atherosclerosis, Inflammation and Thrombosis. J Thromb Thrombolysis. 2004

Feb; 17(1):35-44.

19. Andreas S, Rainer S, G. Pathophysiology of Myocardial Infarction : Protection

by Ischemic Pre- and Postconditioning. Herz 2008; 33:88–100.

20. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics-2006

update: a report from the American Heart Association Statistics Committee

and stroke statistics subcommittee. Circulation. 2006; 113:e85-e151.

21. Morrow DA., Antman EM., Charlesworth A, et al. Performance of the

thrombolysis in myocardial infarction risk index for early acute coronary

syndrome in the national registry of myocardial infarction: a simple risk index

predicts mortality in both ST and non-ST elevation myocardial infarction. J Am

Coll Cardiol. 2003; 41SA:365A-366A.

22. Granger CB, Weaver WD. Reducing cardiac events after acute coronary

syndromes. Rev Cardiovasc Med. 2004; 5 Suppl 5:S39-S46.

23. Goodman SG, Huang W, Yan AT, et al. The expanded Global Registry of Acute

Coronary Events: Baseline characteristics, management practices and

outcomes of patients with acute coronary syndromes. Am Heart J 2009;

158:193–205.e5.

24. Fox KAA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in

acute coronary syndromes, 1999–2006. JAMA 2007; 297:1892–1900.

25. Lavie CJ, Gersh BJ. Mechanical and electrical complications of acute

myocardial infarction. Mayo Clin Proc 1990; 65:709–730.

http://www.ncbi.nlm.nih.gov/pubmed?term=Corti%20R%5BAuthor%5D&cauthor=true&cauthor_uid=15277786

http://www.ncbi.nlm.nih.gov/pubmed?term=Hutter%20R%5BAuthor%5D&cauthor=true&cauthor_uid=15277786

http://www.ncbi.nlm.nih.gov/pubmed?term=Badimon%20JJ%5BAuthor%5D&cauthor=true&cauthor_uid=15277786


80

26. Zheng ZJ, Croft JB, Giles WH, et al. Sudden cardiac death in the United States,

1989 to 1998. Circulation 2001; 104:2158–63.

27. Terrence D, Eric H, Yang G, et al. Modern Management of Acute Myocardial

Infarction. Curr Probl Cardiol 2012; 37:237-310.

28. Luciano B, Allan S. Troponin: the biomarker of choice for the detection of

cardiac injury. CMAJ . November 8, 2005. 173(10): 1191-1202.

29. Kent L, Ahchean C, James J. Cardiac Markers for Myocardial Infarction. Am J

Clin Pathol 2002; 118(Suppl 1):S93-S99.

30. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial

infarction. Circulation 2007; 116:2634–2653.

31. Krumholz HM, Anderson JL, Brooks NH, et al. ACC/AHA clinical performance

measures for adults with ST-elevation and non-ST-elevation myocardial

infarction: A report of the American College of Cardiology/American Heart

Association Task Force on Performance Measures (Writing Committee to

Develop Performance Measures on ST-Elevation and Non-ST-Elevation

Myocardial Infarction). J Am Coll Cardiol 2006; 47(1):236–265.

32. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial

infarction. European Heart Journal 2012; 33:2551–2567.

33. Huynh T, Perron S, O'Loughlin J, et al. Comparison of primary percutaneous

coronary intervention and fibrinolytic therapy in ST-segment-elevation

myocardial infarction: Bayesian hierarchical meta-analyses of randomized

controlled trials and observational studies. Circulation 2009; 119:3101–3109.

34. King SB, Smith SC, Hirshfeld JW, et al. 2007 Focused Update of the

ACC/AHA/SCAI 2005 guideline Update for Percutaneous Coronary

Intervention: A report of the American College of Cardiology/American Heart

81

Association Task Force on Practice Guidelines: 2007 Writing Group to Review

New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for

Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing

Committee. Circulation 2008; 117:261–295.

35. Meine TJ, Roe MT, Chen AY, et al. Association of intravenous morphine use

and outcomes in acute coronary syndromes: results from the CRUSADE

Quality Improvement Initiative. Am Heart J. 2005; 149:1043–1049.

36. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA

Guidelines for the Management of Patients with ST-Elevation Myocardial

Infarction (updating the 2004 Guideline and 2007 Focused Update) and

ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating

the 2005 Guideline and 2007 Focused Update): A report of the American

College of Cardiology Foundation/American Heart Association Task Force on

Practice Guidelines. Circulation 2009; 120:2271–2306.

37. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the

ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation

Myocardial Infarction: A report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines.

Circulation. 2008; 117:296–329.

38. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for

fibrinolytic therapy in suspected myocardial infarction: Collaborative overview

of early mortality and major morbidity results from all randomized trials of

more than 1000 patients. Lancet 1994; 343:311–322.

39. Alexander KP, Newby K, Armstrong PW, et al. Acute coronary syndromes in

the elderly, Part II: ST-segment-elevation myocardial infarction. A scientific

82

statement for healthcare professionals from the American Heart Association

Council on Clinical Cardiology. Circulation 2007; 115:2570–2589.

40. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)

Investigators. An international randomized trial comparing four thrombolytic

strategies for acute myocardial infarction. N Engl J Med 1993; 329:673–682.

41. Awtry EH, Loscalzo J. Aspirin. Circulation 2000; 101:1206–1218.

42. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither

among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet

1988; 2:349–360.

43. Campbell CL, Smyth S, Montalescot G, et al. Aspirin dose for the prevention of

cardiovascular disease. JAMA 2007; 297:2018–2024.

44. Antiplatelet Trialists' Collaboration. Collaborative meta-analysis of

randomised trials of antiplatelet therapy for prevention of death, myocardial

infarction, and stroke in high risk patients. Br Med J 2002; 324:71–86.

45. Bertrand ME, Rupprecht HJ, Urban P, et al. Double-blind study of the safety of

clopidogrel with and without a loading dose in combination with aspirin

compared with ticlopidine in combination with aspirin after coronary stenting:

the clopidogrel aspirin stent international cooperative study (CLASSICS).

Circulation 2000; 102:624–629.

46. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy

to reperfusion in acute ST-segment elevation myocardial infarction: A meta-

analysis of randomized trials. JAMA 2005; 293:1759–1765.

47. Antman EM. The search for replacements for unfractionated heparin.

Circulation 2001; 2310-2314.

83

48. Chesebro JH, Fuster V. Antithrombotic therapy for acute myocardial

infarction: Mechanisms and prevention of deep venous left ventricular and

coronary artery thromboembolism. Circulation 1986; 74(Suppl III):1-10.

49. Meltzer RS, Visser CA, Fuster V. Intracardiac thrombi and systemic

embolization. Ann Intem Med 1986; 104:689-698.

50. Trujillo TC, Nolan PE. Unfractionated heparin in acute coronary syndromes:

has its time come and gone? Am J Health Syst Pharm 55:2402–2409, 1998.

51. Wong GC, Giugliano RP, Antman EM. Use of low-molecular-weight heparins in

the management of acute coronary artery syndromes and percutaneous

coronary intervention. JAMA 289:331–342, 2003.

52. Haas S. The present and future of heparin, low molecular weight heparins,

pentasaccharide, and hirudin for venous thromboembolism and acute

coronary syndromes. Semin Vasc Med 3:139–146, 2003.

53. Eikelboom J, White H, Yusuf S. The evolving role of direct thrombin inhibitors

in acute coronary syndromes. J Am Coll Cardiol 41(4 Suppl S):70S–78S, 2003.

54. Gruppo Italioano per Lo Studio della Sopravvivenza Nell'infarcto Myiocardio.

GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and

together on 6-week mortality and ventricular function after acute myocardial

infarction. Lancet 1994; 343:1115–1122.

55. ISIS-4 (Fourth International Study of Infarct Survival Collaborative Group).

ISIS-4: A randomised factorial trial assessing early oral captopril, oral

mononitrate, and intravenous magnesium sulphate in 58,050 patients with

suspected acute myocardial infarction. Lancet 1995; 345:669–685.

56. Gheorghiade M, Goldstein S. Beta-Blockers in the post-myocardial infarction

patient. Circulation 2002; 106:394–398.

84

57. Abernethy DR, Schwartz JB. Calcium-antagonist drugs. N Engl J Med 1999;

341:1447–1457.

58. Boden WE, van Gilst WH, Scheldewaert RG, et al. Diltiazem in acute

myocardial infarction treated with thrombolytic agents: A randomised,

placebo-controlled trial. Incomplete Infarction Trial of European Research

Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT). Lancet

2000; 355:1751–1756.

59. Smith SC, Allen J, Blair SN, et al. AHA/ACC Guidelines for secondary

prevention for patients with coronary and other atherosclerotic vascular

disease: 2006 update. Endorsed by the National Heart Lung and Blood

Institute. J Am Coll Cardiol 2006; 47:2130–2139.

60. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE

inhibitors in the early treatment of acute myocardial infarction: Systematic

overview of individual data from 100,000 patients in randomized trials.

Circulation 1998; 97:2202–2212.

61. Saha, SA, Molnar J, Arora RR. Tissue ACE inhibitors for secondary prevention

of cardiovascular disease in patients with preserved left ventricular function:

A pooled meta-analysis of randomized placebo-controlled trials. J Cardiovasc

Pharmacol 2007; 12:192–204.

62. Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in

myocardial infarction complicated by heart failure, left ventricular

dysfunction, or both. N Engl J Med 2003; 349:1893–1906.

63. Granger CB, McMurray JV, Yusuf S, et al., eds. CHARM Investigators and

Committees. Effects of candesartan in patients with chronic heart failure and

reduced left-ventricular systolic function intolerant to angiotensin-converting-

85

enzyme inhibitors: CHARM Alternative trial. Lancet 2004; 362:772–776.

64. Zillich AJ, Carter BL. Eplerenone: A novel selective aldosterone blocker. Ann

Pharmacother 2002; 36:1567–1576.

65. Executive Summary of the Third Report of the National Cholesterol Education

Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;

285:2486–2497.

66. Grundy SM, Cleeman JI, Bairey Merz, CN, et al., eds. Coordinating Committee

of the National Cholesterol Education Program, Endorsed by the National

Heart, Lung, and Blood Institute, American College of Cardiology Foundation,

and American Heart Association. Implications of Recent Clinical Trials for the

National Cholesterol Education Program Adult Treatment Panel III Guidelines.

Circulation 2004; 110:227–239.

67. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the

management of patients with unstable angina/non ST-elevation myocardial

infarction: A report of the American College of Cardiology/American Heart

Association Task Force on Practice Guidelines (Writing Committee to Revise

the 2002 Guidelines for the Management of Patients With Unstable

Angina/Non ST-Elevation Myocardial Infarction). Developed in collaboration

with the American College of Emergency Physicians, the Society for

Cardiovascular Angiography and Interventions, and the Society of Thoracic

Surgeons. Endorsed by the American Association of Cardiovascular and

Pulmonary Rehabilitation and the Society for Academic Emergency Medicine.

Circulation 2007; 116:803–877.

86

68. Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol

Metab 2000; 11:327–332.

69. Mohamed-Ali V, Pinkney JH, Coppack SW. Adipose tissue as an endocrine and

paracrine organ. Int J Obesity Metab Disorders 1998; 22(12):1145-58.

70. Vazquez-Vela ME, Torres N, Tovar AR. White adipose tissue as endocrine

organ and its role in obesity. Arch Med Res 2008; 39(8):715-728.

71. Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to

its source. Cell 2007; 131:242-256

72. Sandra G, Jon S, Gregory R . Adipose tissue as an endocrine organ. Molecular

and Cellular Endocrinology 2010; 316:129–139.

73. Noriyuki O, Jennifer L. , Jesse J. et al. Adipokines in inflammation and

metabolic disease. Immunology 2011; 11:85-97.

74. Kim S, Moustaid-Moussa N. Secretary, endocrine and autocrine/ paracrine

functions of the adipocyte. J Nutr 2000; 130:3110-3115.

75. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ .J Clin Endocrinol

Metab 2004; 89:2548–2556.

76. Libby P, Okamoto Y, Rocha VZ, et al. Inflammation in atherosclerosis:

transition from theory to practice. Circ J 2010; 74: 213-220.

77. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of obesity and

risk of coronary heart disease in women. N Engl J Med 1990; 322: 882-889

78. McGill HC, McMahan CA, Herderick EE, et al. Obesity accelerates the

progression of coronary atherosclerosis in young men. Circulation 2002; 105:

2712-2718

87

79. Lakka TA, Lakka HM, Salonen R, et al. Abdominal obesity is associated with

accelerated progression of carotid atherosclerosis in men. Atherosclerosis

2001; 154: 497-504

80. Klein S, Burke LE, Bray GA, et al. Clinical implications of obesity with specific

focus on cardiovascular disease: a statement for professionals from the

American Heart Association Council on Nutrition, Physical Activity, and

Metabolism: endorsed by the American College of Cardiology Foundation.

Circulation 2004; 110: 2952-2967

81. Ikeoka D, Mader JK, Pieber TR. Adipose tissue, inflammation and

cardiovascular disease. Rev Assoc Med Bras 2010; 56: 116-121

82. Chatterjee TK, Stoll LL, Denning GM, et al. Proinflammatory phenotype of

perivascular adipocytes: influence of high-fat feeding. Circ Res 2009; 104: 541-

549

83. Wolf AM, Wolf D, Rumpold H, et al. Adiponectin induces the anti-

inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem

Biophys Res Commun 2004; 323: 630-635

84. Hanrui Z, Jian C, Cuihua Z. Emerging role of adipokines as mediators in

atherosclerosis. World J Cardiol 2010 November 26; 2(11): 370-376

85. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to

c1q, produced exclusively in adipocytes. J Biol Chem 1995; 270:26746–9.

86. Nakano Y, Tobe T, Choi-Miura NH, et al. Isolation and characterization of

gbp28, a novel gelatin-binding protein purified from human plasma. J

Biochem (Tokyo) 1996; 120:803–12.

88

87. Pajvani UB, Du X, Combs TP, et al. Structure–function studies of the

adipocyte-secreted hormone acrp30/adiponectin. Implications for metabolic

regulation and bioactivity. J Biol Chem 2003;278:9073–85.

88. Xiaoyan H, Karen S, Paul M, et al. Adiponectin and cardiovascular health: an

update. British Journal of Pharmacology 2012; 165 574–590.

89. Megan M, Mark M. Adiponectin, cardiovascular disease, chronic kidney

disease: emerging data on complex interactions. Pediatr Nephrol (2012)

27:521–527.

90. Magkos F, Sidossis LS. Recent advances in the measurement of adiponectin

isoform distribution. Curr Opin Clin Nutr Metab Care 2007; 10:571–5.

91. Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of AdipoR1 and AdipoR2

causes abrogation of adiponectin binding and metabolic actions. Nat Med

2007, 13:332-339.

92. Hug C, Wang J, Ahmad NS, et al. T-cadherin is a receptor for hexameric and

high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci USA

2004, 101:10308-10313.

93. Giamila F, Theodore M. Adipose tissue and adipokines in health and disease.

2007 Humana Press Inc. p: 50-51.

94. Yoon MJ, Lee GY, Chung J-J, et al. Adiponectin increases fatty acid oxidation in

skeletal muscle cells by sequential activation of AMP-activated protein kinase,

p38 mitogen-activated protein kinase, and peroxisome proliferator-activated

receptor alpha. Diabetes 2006, 55:2562-2570.

95. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose

utilization and fatty-acid oxidation by activating AMP-activated protein kinase.

Nat Med 2002, 8:1288-1295.

011

96. Joshi MB, Philippova M, Ivanov D, et al. T-cadherin protects endothelial cells

from oxidative stress-induced apoptosis. FASEB J 2005, 19:1737-1739

97. Takeuchi T, Adachi Y, Ohtsuki Y, et al. Adiponectin receptors, with special

focus on the role of the third receptor, T-cadherin, in vascular disease. Med

Mol Morphol 2007, 40:115-120.

98. Katherine R, John P, Bala V. Clinical review: Adiponectin biology and its role in

infl ammation and critical illness. Critical Care 2011, 15:221-230.

99. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific

protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999,

257:79-83

100. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene

dysregulated in obesity. J Biol Chem 1996, 271:10697-10703.

101. Han SH, Sakuma I, Shin EK, et al. Antiatherosclerotic and anti-insulin

resistance eff ects of adiponectin: basic and clinical studies. Prog Cardiovasc

Dis, 52:126-140.

102. Hara K, Horikoshi M, Yamauchi T, et al. Measurement of the high-

molecular weight form of adiponectin in plasma is useful for the prediction of

insulin resistance and metabolic syndrome. Diabetes Care 2006, 29:1357-

1362.

103. Hung J, McQuillan BM, Thompson PL, et al. Circulating adiponectin levels

associate with inflammatory markers, insulin resistance and metabolic

syndrome independent of obesity. Int J Obes 2008, 32:772-779.

104. Kaser S, Tatarczyk T, Stadlmayr A, et al. Effect of obesity and insulin

sensitivity on adiponectin isoform distribution. Eur J Clin Invest 2008, 38:827-

834.

010

105. Rovin BH, Song H, Hebert LA, et al. Plasma, urine, and renal expression of

adiponectin in human systemic lupus erythematosus. Kidney Int 2005,

68:1825-1833.

106. Moriconi N, Kraenzlin M, Muller B, et al. Body composition and adiponectin

serum concentrations in adult patients with cystic fi brosis. J Clin Endocrinol

Metab 2006,91:1586-1590.

107. Karmiris K, Koutroubakis IE, Xidakis C, et al. Circulating levels of leptin,

adiponectin, resistin, and ghrelin in inflammatory bowel disease. Inflamm

Bowel Dis 2006, 12:100-105.

108. Otero M, Lago R, Gomez R, et al. Changes in plasma levels of fat-derived

hormones adiponectin, leptin, resistin and visfatin in patients with

rheumatoid arthritis. Ann Rheum Dis 2006, 65:1198-1201.

109. Kazumi T, Kawaguchi A, Sakai K, et al. Young Men With High-Normal Blood

Pressure Have Lower Serum Adiponectin, Smaller LDL Size, and Higher

Elevated Heart Rate Than Those With Optimal Blood Pressure .Diabetes Care

2002;25:971–976.

110. Hotta K, Funahashi T, Bodkin NL, et al. Circulating Concentrations of the

Adipocyte Protein Adiponectin Are Decreased in Parallel With Reduced Insulin

Sensitivity During the Progression to Type 2 Diabetes in Rhesus Monkeys.

Diabetes 2001; 50:1126–1133.

111. Iwashima Y, Katsuya T, Ishikawa K, et al. Hypoadiponectinemia is an

independent risk factor for hypertension. Hypertension 2004; 43:1318–1323.

112. Tan KC, Xu A, Chow,WS, et al. Hypoadiponectinemia is associated with

impaired endothelium-dependent vasodilatation. J Clin Endocrinol Metab

2004;89:765–769.

011

113. Schulze MB, Shai I, Rimm EB, et al. Adiponectin and future coronary heart

disease events among men with type 2 diabetes. Diabetes 2005; 54:534–539.

114. Chen MP, Tsai JC, Chung FM, et al. Hypoadiponectinemia is associated with

ischemic cerebrovascular disease. Arterioscler Thromb Vasc Biol 2005;

25:821–826. Epub 2005 Feb 3.

115. Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin levels

predict progression of coronary artery calcification.Circulation 2005;

111:747–753.

116. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to

diabetes. Nature Jan 18 2001; 409(6818):307–12.

117. Steppan CM, Brown EJ, Wright CM, et al. A family of tissue-specific resistin-

like molecules. Proc Nat cad Sci USA Jan 16 2001; 98(2):502–6.

118. Adeghate E. An update on the biology and physiology of resistin. Cell Mol

Life Sci Oct 2004;61(19–20):2485–96.

119. Aruna B, Ghosh S, Singh AK, et al. Human recombinant resistin protein

displays a tendency to aggregate by forming intermolecular disulfide linkages.

Biochemistry Sep 16 2003; 42(36):10554–9.

120. Patel L, Buckels AC, Kinghorn IJ, et al. Resistin is expressed in human

macrophages and directly regulated by PPAR gamma activators. Biochem

Biophys Res Commun Jan 10 2003; 300(2):472–6.

121. Banerjee R. R. and Lazar M. A. Dimerization of resistin and resistin-like

molecules in determined by a single cysteine. J. Biol. Chem 2001; 276:

25970–25973.

012

122. Rajala M., Obici S., Scherer P., et al . Adipose-derived resistin and gut-

derived resistin-like molecule beta selectively impair insulin action on glucose

production. J.Clin. Invest 2003; 111: 225–230

123. Vernon R. G., Denis R. G. P. and Sorensen A. Signals of obesity. Domestic

Animal Endocrinol. 2001; 21: 197–214

124. Kim K. H., Lee K., Moon Y. S., et al. A cysteinerich adipose tissue-specific

secretory factor inhibits adipocytes differentiation. J. Biol. Chem 2001; 276:

11252–11256

125. Yannakoulia M., Yiannakouris N., Bluher S. et al. Body fat mass and

macronutrient intake in relation to circulating soluble leptin receptor, free

leptin index, adiponectin and resistin concentrations in healthy humans. J.

Clin. Endocrinol. Metab. 2003; 88: 1730–1736

126. Moon B., Kwan J. J., Duddy N., et al. Resistin inhibits glucose uptake in L6

cells independently of changes in insulin signaling and GLUT4 translocation.

Am. J. Physiol. Endocrinol. Metab 2003; 285: E106–115.

127. Sato N, Kobayashi K, Inoguchi T, et al. Adenovirus-mediated high expression

of resistin causes dyslipidemia in mice. Endocrinology Jan 2005; 146(1):273–

9.

128. Satoh H, Nguyen MT, Miles PD, et al. Adenovirus mediated chronic “hyper-

resistinemia” leads to in vivo insulin resistance in normal rats. J Clin Invest Jul

2004; 114(2):224–31.

129. Banerjee RR, Rangwala SM, Shapiro JS, et al. Regulation of fasted blood

glucose by resistin. Science Feb 20 2004; 303(5661):1195–8.

013

130. Rajala MW, Lin Y, Ranalletta M, et al. Cell type specific expression and

coregulation of murine resistin and resistin-like molecule alpha in adipose

tissue. Mol Endocrinol Aug 2002; 16(8):1920–30.

131. Burnett MS, Devaney JM, Adenika RJ, et al. Cross-sectional associations of

resistin, coronary heart disease, and insulin resistance. J Clin Endocrinol

Metab Jan 2006; 91(1):64–8.

132. McTernan PG, Fisher FM, Valsamakis G, et al. Resistin and type 2 diabetes:

regulation of resistin expression by insulin and rosiglitazone and the effects of

recombinant resistin on lipid and glucose metabolism in human

differentiated adipocytes. J Clin Endocrinol Metab Dec 2003; 88(12):6098–

106.

133. Bajaj M, Suraamornkul S, Hardies LJ, et al. Plasma resistin concentration,

hepatic fat content, and hepatic and peripheral insulin resistance in

pioglitazone-treated type II diabetic patients. Int J Obes Relat Metab Disord

Jun 2004; 28(6):783–9.

134. Heilbronn LK, Rood J, Janderova L, et al. Relationship between serum

resistin concentrations and insulin resistance in nonobese, obese, and obese

diabetic subjects. J Clin Endocrinol Metab Apr 2004; 89(4):1844–8.

135. Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels are not

associated with obesity or insulin resistance in humans and are not regulated

by fasting or leptin administration: cross-sectional and interventional studies

in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab

Oct 2003; 88(10):4848–56.

136. Bokarewa M, Nagaev I, Dahlberg L, et al. Resistin, an adipokines with

potent proinflammatory properties. J Immunol May 1 2005; 174(9):5789–95.

014

137. Reilly MP, Lehrke M, Wolfe ML, et al. Resistin is an inflammatory marker of

atherosclerosis in humans. Circulation Feb 22 2005; 111(7): 932–9.

138. Konrad A, Lehrke M, Schachinger V, et al. Resistin is an inflammatory

marker of inflammatory bowel disease in humans. Eur J Gastroenterol

Hepatol Dec 2007; 19(12):1070–4.

139. Sunden-Cullberg J, Nystrom T, Lee ML, et al. Pronounced elevation of

resistin correlates with severity of disease in severe sepsis and septic shock.

Crit Care Med Jun 2007; 35(6):1536–42.

140. Rabe K, Lehrke M, Parhofer KG, et al. Adipokines and insulin resistance. Mol

Med Nov-Dec 2008; 14(11–12):741–51.

141. Verma S, Li SH, Wang CH, et al. Resistin promotes endothelial cell

activation: further evidence of adipokines endothelial interaction. Circulation

2003; 108:736–740

142. Calabro P, Samudio I, Willerson JT, et al. Resistin promotes smooth muscle

cell proliferation through activation of extracellular signal-regulated kinase

1/2 and phosphatidylinositol 3-kinase pathways. Circulation 2004; 110:3335–

3340

143. Kunnari A, Ukkola O, PaivansaloM, et al. High plasma resistin level is

associated with enhanced highly sensitive C-reactive protein and leukocytes. J

Clin Endocrinol Metab 2006; 91:2755–2760

144. Burnett MS, Lee CW, Kinnaird TD, et al. The potential role of resistin in

atherogenesis. Atherosclerosis 2005; 182:241–248

145. Jung HS, Park KH, Cho YM, et al. Resistin is secreted from macrophages in

atheromas and promotes atherosclerosis. Cardiovasc Res 2006; 69:76–85

015

146. Ross R . Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:

115–126.

147. Lehrke M, Reilly MP, Millington SC, et al. An inflammatory cascade leading

to hyperresistinemia in humans. PLoS Med 2004;1:e45.

148. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese

gene and its human homologue. Nature 1994; 372:425–432.

149. Stephens TW, Basinski M, Bristow PK, et al. The role of neuropeptide Y in

the antiobesity action of the obese gene product. Nature 1995; 377: 530–

532.

150. Meister B, Arvidsson U. The hormone leptin reduces body weight. A mutant

gene makes the mouse obese. Lakartidningen 1996; 93:247–251.

151. Misra A, Garg A. Leptin: its receptor and obesity. J Invest Med 1996;

44:540–8.

152. Margetic S, Gazzola C, et al. Leptin: a review of its peripheral actions and

interactions. Int. J. Obes. Relat. Metab. Disord. 2002; 26 (11):1407–1433.

153. Matarese G, Moschos S, et al. Leptin in immunology, J. Immunol. 2005; 174

(6): 3137–3142.

154. Bjørbaek C, Elmquist JK, Michl P, et al. Expression of leptin receptor

isoforms in rat brain microvessels. Endocrinology. 1998; 139:3485-91.

155. Elmquist JK, Bjørbaek C, Ahima RS, et al. Distributions of leptin receptor

mRNA isoforms in the rat brain. J Comp Neurol. 1998; 395:535-47.

156. Chan JL, Moschos SJ, Bullen J, et al. Recombinant methionyl human leptin

administration activates signal transducer and activator of transcription 3

signaling in peripheral blood mononuclear cells in vivo and regulates soluble

016

tumor necrosis factor-alpha receptor levels in humans with relative leptin

deficiency. J Clin Endocrinol Metab. 2005; 90:1625-31.

157. Robertson SA, Leinninger GM, Myers MG Jr. Molecular and neural

mediators of leptin action. Physiol Behav. 2008; 94:637-42.

158. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal

human physiology and clinical implications for hypothalamic amenorrhoea

and anorexia nervosa. Lancet. 2005; 366:74-85.

159. Theodore K, Iosif K, Sharon C, et al. Narrative Review: The Role of Leptin in

Human Physiology: Emerging Clinical Applications. Ann Intern Med. 2010;

152:93-100.

160. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic

spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;

356:237-47.

161. Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the

neuroendocrine response to fasting. Nature. 1996; 382: 250-2.

162. Chan JL, Williams CJ, Raciti P, et al. Leptin does not mediate short-term

fasting-induced changes in growth hormone pulsatility but increases IGF-I in

leptin deficiency states. J Clin Endocrinol Metab. 2008; 93:2819-27.

163. Harris RB, Zhou J, Redmann SM Jr, et al. A leptin dose-response study in

obese (ob/ob) and lean mice. Endocrinology. 1998; 139:8-19.

164. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of leptin on

obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic

dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;

110:1093-103.

017

165. Chan YY, Clifton DK, Steiner RA. Role of NPY neurons in GH- dependent

feedback signaling to the brain. Horm Res 1996; 145:12-14.

166. Pierroz DD, Aebi AC, Huhtaniemi IT, et al. Many LH peaks are needed to

physiologically stimulate testosterone secretion. Am J Physiol 1999; 276:

E603-610.

167. Rohner JF. Aspects of the neuroendocrine regulation of body weight

homeostasis. Am Endocrinol 2002; 63:125-128.

168. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review

of pathobiochemical and clinical chemical aspects of leptin, ghrelin,

adiponectin, and resistin. Clin Chem 2004; 50(9):1511-1525.

169. Flanagan DE, Vaile JC, Petley GW, et al. Gender differences in the

relationship between leptin, insulin resistance and the autonomic nervous

system. Regul Pept 2007; 140:37–42.

170. Cooke JP, Oka RK. Does leptin cause vascular disease? Circulation 2002;

106: 1904–5.

171. Chaldakov GN, Fiore M, Stankulov IS, et al. NGF, BDNF, leptin, and mast

cells in human coronary atherosclerosis and metabolic syndrome. Arch

Physiol Biochem 2001; 109:357–60.

172. Beltowski J, Wojcicka G, Gorny D, et al. Human leptin administered

intraperitoneally stimulates natriuresis and decreases renal medullary Na+,

K+-ATPase activity in the rat – impaired effect in dietary-induced obesity.

Med Sci Monit 2002; 8:BR221–9.

173. Bodary PF, Westrick RJ, Wickenheiser KJ, et al. Effect of leptin on arterial

thrombosis following vascular injury in mice. JAMA 2002; 287: 1706–9.

018

174. Chu NF, Spiegelman D, Rifai N, et al. Glycemic status and soluble tumor

necrosis factor receptor levels in relation to plasma leptin concentrations

among normal weight and overweight US men. Int J Obes Relat Metab

Disord 2000; 24:1085–92.

175. Parhami F, Tintut Y, Ballard A, et al. Leptin enhances the calcification of

vascular cells: artery wall as a target of leptin. Circ Res 2001; 88:954–60.

176. Singhal A, Farooqi IS, Cole TJ, et al. Influence of leptin on arterial

distensibility: a novel link between obesity and cardiovascular disease?

Circulation 2002; 106:1919–24.

177. Angela L, Anne C, Katherine E, et al. Preventative Cardiology and ischemic

heart disease. In: Washington manual of medical therapeutics, 32nd edition.

Lippincot Williams and W ilkins;2007.

178. Allain CC, Poon LS, Chan CS, et al. Enzymatic determination of total serum

cholesterol. Clin Chem 1974; 20(4):470-475.

179. Burstein M, Scholink HR, Morfin R. Measurement of HDL-c in the plasma

with sensitive colorimetric method. J Lipid Res 1970; 19: 583.

180. Fossati, P., Prencipe L., and Berti G. Use of 3.5-dichloro-2-Hydroxybenzene

sulfonic acid / 4 Amino phenazone chromogenic system in direct enzymztic

assays of uric acid in serum and urine. Clin. Chem.1980.26; P:227-231.

181. Vasilades A. Determination of creatinine in blood. J Can Chem 1976;

22:1664.

182. Young DS, Pestaner LC, Gibberman V. Effects of drugs on clinical laboratory

tests. Clin Chem 1975; 21(5):1-432

183. Fawcett JK, Scott JE. Determination of urea in blood or serum. J Clin Path

1960; 13:156-159

001

184. Whitney E, Rolfes SR. Understanding nutrition(10th ed.). Thomson Learning

Inc., Wads Worth, 2005;262-263.

185. Alpert JS, Thygesen K, Antman E, et al. Myocardial infarction redefined — a

consensus document of the Joint European Society of Cardiology/American

College of Cardiology Committee for the redefinition of myocardial infarction.

J Am Coll Cardiol 2000;36:959-69.

186. Lee TH, Rouan GW, Weisberg MC, et al. Sensitivity of routine clinical criteria

for diagnosing myocardial infarction within 24 hours of hospitalization. Ann

Intern Med 1987; 106:181-6.

187. Jaffe AS, Ravkilde J, Roberts R, et al. It’s time for a change to a troponin

standard. Circulation 2000; 102:1216-20.

188. Collinson PO, Boa FG, Gaze DC. Measurement of cardiac troponins. Ann

Clin Biochem 2001; 38:423–9.

189. Bertrand ME, Simoons ML, Fox KA, et al. Management of acute oronary

syndromes: acute coronary syndromes without persistent ST segment

elevation. Recommendations of the task force of the European Society of

Cardiology. Eur Heart J 2000; 21:1406–32.

190. Shave R, Dawson E, Whyte G, et al. The cardiospecificity of third-generation

troponin T assay after exercise-induced muscle damage. Med Sci Sports Exerc

2002; 34:651–4.

191. Jishi F, Hudson PR, Williams CP, et al. Troponin I, laboratory issues, and

clinical outcomes in a district general hospital: crossover study with

000

‘‘traditional’’ markers of myocardial infarction in a total of 1990 patients. J

Clin Pathol 2004; 57:1027–32.

192. Heidenreich PA, Alloggiamento T, Melsop K, et al. The prognostic value of

troponin in patients with non-ST elevation acute coronary syndromes: a

meta-analysis. J Am Coll Cardiol 2001; 38:478–85.

193. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable

coronary disease who benefit from long-term anti-thrombotic protection.

Fragmin in unstable coronary artery disease (FRISC) study. J Am Coll Cardiol

1997; 29:43–8.

194. Hamm CW, Heeschen C, Goldmann BU. Benefit of abciximab in patients

with refractory unstable angina in relation to serum troponin T levels. c7E3

Fab anti-platelet therapy in unstable refractory angina (CAPTURE) study

investigators. N Engl J Med 1999; 340:1623–9.

195. Heidenreich PA, Alloggiamento T, Melsop K, et al. The prognostic value of

troponin in patients with non-ST elevation acute coronary syndromes: a

meta-analysis. J Am Coll Cardiol 2001;38:478–85.

196. Cannon CP, Weintraub WS, Demopoulous LA, et al. Comparison of early

invasive and conservative strategies in patients with unstable coronary

syndromes treated with glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med

2001; 344:1879–87.

197. Morrow DA, Antman EM, Tanasijevic M, et al. Cardiac troponin I for

stratification of early outcomes and the efficacy of enoxaparin in unstable

angina: a TIMI-11B substudy. J Am Coll Cardiol 2000;36:1812-7.

198. DeFilippi CR, Tocchi M, Parmar RJ, et al. Cardiac troponin T in chest pain

unit patients without ischemic electrocardiographic changes: angiographic

001

correlates and long-term clinical outcomes. J Am Coll Cardiol 2000;35:1827-

34.

199. Christenson RH. Evidence based approach to practice guides and decision

thresholds for cardiac markers. Scand J Clin Lab Invest 1999;230:90-102.

200. Möckel M, Störk T, Heller G, H, et al. Troponin T in patients with low grade

or atypical angina. Eur Heart J 1998;19:1802-7.

201. Hamm CW, Goldman BU, Heeschen C, et al. Emergency room triage of

patients with acute chest pain by means of rapid testing for cardiac troponin

T or troponin I. N Engl J Med 1997;337:1648-53.

202. Limkakeng A, Gibler WB, Pollack C, et al. Combination of Goldman risk and

initial cardiac troponin I for emergency department chest pain patient risk

stratification. Acad Emerg Med 2001;8:696-702.

203. Kontos M, Anderson FP, Alimard R, et al. Ability of troponin I to predict

cardiac events in patients admitted from the emergency department. J Am

Coll Cardiol 2000;36:1818-23.

204. Polanczyk CA, Lee TH, Cook EF, et al. Cardiac troponin I as a predictor of

major cardiac events in emergency department patients with acute chest

pain. J Am Coll Cardiol 1998;32:8-14.

205. Hetlund O, Dickstein K. Cardiac markers in the early hours of acute

myocardial infarction: clinical performance of creatine kinase, creatine kinase

MB isoenzyme (activity and mass concentration), creatine kinase MM and MB

subform ratios, myoglobin and cardiac troponin T. Scand J Lab Invest

1996;56:701-13.

002

206. Ebell MH, Flewelling D, Flynn CA. A systematic review of troponin T and

troponin I for diagnosing acute myocardial infarction. J Fam Pract

2000;49:550-6.

207. Mahgoub KA, Abd el MA. Adiponectin in acute myocardial infarction non

obese Egyptian men. J Egypt Soc Parasitol. 2010 Aug; 40(2):489-98.

208. Mohammad S, Abdoreza S, Ghafar S. Is adiponectin associated with

acute myocardial infarction in Iranian non obese patients? Lipids in Health

and Disease 2009, 8:17-23.

209. Gu HF. Biomarkers of adiponectin: plasma protein variation and genomic

DNA polymorphisms. Biomark Insights 2009; 4:123–33.

210. Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and

risk of myocardial infarction in men. JAMA 2004;291: 1730-7.

211. Koenig W, Khuseyinova N, Baumert J, et al. Serum concentrations of

adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in

apparently healthy middle-aged men: results from the 18-year follow-up of a

large cohort from southern Germany. J Am Coll Cardiol 2006;48:1369-77.

212. Sattar N, Wannamethee G, Sarwar N, et al. Adiponectin and coronary heart

disease: a prospective study and meta-analysis. Circulation 2006;114:623-9

213. Lindsay RS, Resnick HE, Zhu J, et al. Adiponectin and coronary heart disease:

the Strong Heart Study. Arterioscler Thromb Vasc Biol 2005;25:e15–e16.

214. Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linking adipocytes and

vascular function. J Clin Endocrinol Metab 2004; 89:2563–8.

215. Zhu W, Cheng KK, Vanhoutte PM, et al. Vascular effects of adiponectin:

molecular mechanisms and potential therapeutic intervention. Clin Sci (Lond)

2008; 114: 361–374.

http://www.ncbi.nlm.nih.gov/pubmed?term=Mahgoub%20KA%5BAuthor%5D&cauthor=true&cauthor_uid=21246956

http://www.ncbi.nlm.nih.gov/pubmed?term=Abd%20el%20MA%5BAuthor%5D&cauthor=true&cauthor_uid=21246956


003

216. Cao Y, Tao L, Yuan Y, et al. Endothelial dysfunction in adiponectin deficiency

and its mechanisms involved. J Mol Cell Cardiol 2009; 46: 413–419

217. Ouedraogo R, Wu X, Xu SQ, et al. Adiponectin suppression of high-glucose-

induced reactive oxygen species in vascular endothelial cells: evidence for

involvement of a cAMP signaling pathway. Diabetes 2006; 55: 1840–1846.

218. Plant S, Shand B, Elder P, et al. Adiponectin attenuates endothelial

dysfunction induced by oxidised low-density lipoproteins. Diab Vasc Dis Res

2008; 5: 102–108.

219. Kim JE, Song SE, Kim YW, et al. Adiponectin inhibits palmitate-induced

apoptosis through suppression of reactive oxygen species in endothelial cells:

involvement of cAMP/protein kinase A and AMP-activated protein kinase. J

Endocrinol 2010; 207: 35–44.

220. Kobashi C, Urakaze M, Kishida M, et al. Adiponectin inhibits endothelial

synthesis of interleukin-8. Circ Res 2005; 97: 1245–1252.

221. Szmitko PE, Fedak PW, Weisel RD, et al. Endothelial progenitor cells: new

hope for a broken heart. Circulation 2003; 107: 3093–3100.

222. Fadini GP, Sartore S, Agostini C, et al. Significance of endothelial progenitor

cells in subjects with diabetes. Diabetes Care 2007; 30: 1305–1313.

223. Xu A, Wang Y, Lam KS, et al. Vascular actions of adipokines molecular

mechanisms and therapeutic implications. Adv Pharmacol 2010; 60: 229–

255.

224. Eren P, Camus S, Matrone G, et al. Adiponectinemia controls pro-

angiogenic cell therapy. Stem Cells 2009; 27: 2712–2721.

004

225. Nakamura N, Naruse K, Matsuki T, et al. Adiponectin promotes migration

activities of endothelial progenitor cells via Cdc42/Rac1. FEBS Lett 2009; 583:

2457–2463.

226. Hopkins TA, Ouchi N, Shibata R, et al. Adiponectin actions in the

cardiovascular system. Cardiovasc Res 2007; 74:11–8.

227. Ohashi K, Parker JL, Ouchi N, et al. Adiponectin promotes macrophage

polarization toward an anti-inflammatory phenotype. J Biol Chem 2010; 285:

6153–6160.

228. Goldstein BJ, Scalia RG, Ma XL. Protective vascular and myocardial effects

of adiponectin. Nat Clin Pract Cardiovasc Med 2009; 6: 27–35.

229. Tao L, Gao E, Jiao X, et al. Adiponectin cardioprotection after myocardial

ischemia/reperfusion involves the reduction of oxidative/nitrative stress.

Circulation 2007; 115:1408–1416.

230. Antoniades C, Antonopoulos AS, Tousoulis D, et al. from obesity to

cardiovascular disease. Obes Rev 2009; 10:269–79.

231. Laughlin GA, Barrett-Connor E, May S, et al. Association of adiponectin with

coronary heart disease and mortality: the Rancho Bernardo study. Am J

Epidemiol. 2007, 165(2):164-174.

232. Y Nakamura, K Shimada, D Fukuda, et al. Implications of plasma

concentrations of adiponectin in patients with coronary artery disease. Heart

2004;90:528–533.

233. Inoue T, Kotooka N, Morooka T, et al: High molecular weight adiponectin as

a predictor of long-term clinical outcome in patients with coronary artery

disease. Am J Cardiol, 2007; 100: 569–74

005

234. Pischon T, Girman CJ, Hotamisligil GS et al: Plasma adiponectin levels and

risk of myocardial infarction in men. JAMA, 2004; 291: 1730–37

235. Cavusoglu E, Ruwende C, Chopra V, et al. Adiponectin is an independent

predictor of all-cause mortality, cardiac mortality, and myocardial infarction

in patients presenting with chest pain. Eur Heart J, 2006; 27: 2300–9

236. Laughlin GA, Barrett-Connor E, May S, et al. Association of adiponectin

with coronary heart disease and mortality: the Rancho Bernardo study. Am J

Epidemiol, 2007; 165: 164–74

237. Wasim H, Al-Daghri NM, Chetty R, et al. Relationship of serum adiponectin

and resistin to glucose intoleranceand fat topography in South-Asians.

Cardiovascular Diabetology 2006, 5:1-5.

238. Lewandowski KC, Szosland K, O’Callaghan C, et al. Adiponectin and resistin

serum levels in women with polycystic ovary syndrome during oral glucose

tolerance test: a significant reciprocal correlation between adiponectin and

resistin independent of insulin resistance indices. Mol Genet Metab 2005,

85:61-69.

239. Jose VJ, Mariappan P, George PV, et al. Serum leptin levels in acute

myocardial infarction. Indian Heart J. 2005 Jan-Feb; 57(1):39-43.

240. Taneli F, Yegane S, Ulman C, et al. Increased serum leptin concentrations in

patients with chronic stable angina pectoris and ST-elevated myocardial

infarction. Angiology. 2006 May-Jun;57(3):267-72

241. Wallander M, Soderberg S, Norhammer A. Leptin—a predictor of abnormal

glucose tolerance and prognosis in patientswithmyocardial infarction and

without previously known Type 2 diabetes. Diabet Med 2008; 25(8):949–55.

http://www.ncbi.nlm.nih.gov/pubmed?term=Jose%20VJ%5BAuthor%5D&cauthor=true&cauthor_uid=15852893

http://www.ncbi.nlm.nih.gov/pubmed?term=Mariappan%20P%5BAuthor%5D&cauthor=true&cauthor_uid=15852893

http://www.ncbi.nlm.nih.gov/pubmed?term=George%20PV%5BAuthor%5D&cauthor=true&cauthor_uid=15852893


http://www.ncbi.nlm.nih.gov/pubmed?term=Taneli%20F%5BAuthor%5D&cauthor=true&cauthor_uid=16703186

http://www.ncbi.nlm.nih.gov/pubmed?term=Yegane%20S%5BAuthor%5D&cauthor=true&cauthor_uid=16703186

http://www.ncbi.nlm.nih.gov/pubmed?term=Ulman%20C%5BAuthor%5D&cauthor=true&cauthor_uid=16703186


006

242. Mukesh S, Updesh SB, Param PS. Leptin and the clinical cardiovascular risk.

International Journal of Cardiology 2010 (140): 266–271.

243. Knudson JD, Dincer UD, Zhang C, et al. Leptin receptors are expressed in

coronary arteries and hyperleptinemia causes significant coronary endothelial

dysfunction. Am J Physiol. 2005; 289:H48–H56.

244. Eiras S, Camina JP, Diaz-Rodriguez E, et al. Leptin inhibits lysophosphatidic

acid-induced intracellular calcium rise by a protein kinase C-dependent

mechanism. J Cell Physiol 2004; 201:214–226.

245. Yamagishi SI, Edelstein D, Du XL, et al. Leptin induces mitochondrial

superoxide production and monocyte chemoattractant protein-1 expression

in aortic endothelial cells by increasing fatty acid oxidation via protein kinase

A. J Biol Chem 2001;276:25096–25100.

246. Quehenberger P, Exner M, Sunder-Plassmann R, et al. Leptin induces

endothelin-1 in endothelial cells in vitro. Circ Res 2002; 90:711–718.

247. Loffreda S, Yang SQ, Lin HZ, et al. Leptin regulates proinflammatory

immune responses. FASEB J. 1998;12: 57–65.

248. Ke Chen, Fanghong Li, Ji Li, et al. Induction of leptin resistance through

direct interaction of C-reactive protein with leptin. Nat Med. 2006; 12:425–

432.

249. Nakata M, Yada T, Soejima N, et al. Leptin promotes aggregation of human

platelets via the long form of its receptor. Diabetes 1999; 48:426–429.

250. Thogersen AM, Soderberg S, Jansson JH, et al. Interactions between

fibrinolysis, lipoproteins and leptin related to a first myocardial infarction. Eur

J Cardiovasc Prev Rehabil. 2004; 11: 33– 40.

007

251. Chu NF, Spiegelman D, Hotamisligil GS, et al. Plasma insulin, leptin, and

soluble TNF receptors levels in relation to obesity related atherogenic and

thrombogenic cardiovascular disease risk factors among men.

Atherosclerosis. 2001; 157:495–503.

252. Soderberg S, Olsson T, Eliasson M, et al. Plasma leptin levels are associated

with abnormal fibrinolysis in men and postmenopausal women. J Intern Med.

1999; 245:533–543.

253. Małyszko J, Wołczyn´ski S, Małyszko J, et al. Leptin correlates with some

hemostatic parameters in CAPD patients. Nephron. 2002; 92: 721–724.

254. Xu FP, Chen MS, Wang YZ, et al. Leptin induces hypertrophy via endothelin-

1 reactive oxygen species pathway in cultured neonatal rat cardiomyocytes.

Circulation 2004; 110:1269–75.

255. Tajmir P, Ceddia RB, Li RK, et al. Leptin increases cardiomyocyte hyperplasia

via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-

dependent signalling pathways. Endocrinology 2004; 145:1550–5.

256. Dong F, Zhang X, Ren J. Leptin regulates cardiomyocyte contractile function

through endothelin-1 receptor-NADPH oxidase pathway. Hypertension 2006;

47:222–9.

257. Basri Ai, Kudret A, Sedat K, et al .Admission Plasma Leptin Level Strongly

Correlates With the Success of Thrombolytic Therapy in Patients With Acute

Myocardial Infarction. Angiology 2006; 57:671–680.

258. Inoue M, Maehata E, Yano M, et al. Correlation between the adiponectin-

leptin ratio and parameters of insulin resistance in patients with type 2

diabetes. Metabolism 2005; 54:281–286.

008

259. Yamauchi T, Kamon J, Waki H et al. The fat-derived hormone adiponectin

reverses insulin resistance associated with both lipoatrophy and obesity. Nat

Med 2001; 7: 941–946.

260. Kappelle PJ, Dullaart RP, van Beek AP, et al. The plasma leptin/adiponectin

ratio predicts first cardiovascular event in men: A prospective nested case-

control study. Eur J Intern Med. 2012 Dec;23(8):755-9.

261. Norata GD, Raselli S, Grigore L, et al. Leptin:adiponectin ratio is an

independent predictor of intima media thickness of the common carotid

artery. Stroke. 2007 Oct;38(10):2844-6.

262. Tarek E , Hesham H , Eman A , et al. Serum resistin in acute myocardial

infarction patients with and without diabetes mellitus. Postgrad Med J.

2011;87:463-467.

263. Songyun C, Wenhui D, Kang L, et al. Plasma resistin associated with

myocardium injury in patients with acute coronary syndrome. Circ J 2008; 72:

1249–1253.

264. Lubos, E., Messow, C. M., Schnabel, R., et al. Resistin, acute coronary

syndrome and prognosis results from the AtheroGene study. Atherosclerosis

2007; 193, 121−128.

265. Yang, R.Z., Huang, Q., Xu, A., et al. Comparative studies of resistin

expression and phylogenomics in human and mouse. Biochem. Biophys. Res.

Commun. 2003;310 (3):927-935.

266. Patel, L., Buckels, A.C., Kinghorn, I.J., et al. Resistin is expressed in human

macrophages and directly regulated by PPAR gamma activators. Biochem.

Biophys. Res. Commun. 2003; 300(2):472-476.

http://www.ncbi.nlm.nih.gov/pubmed?term=Kappelle%20PJ%5BAuthor%5D&cauthor=true&cauthor_uid=22819464

http://www.ncbi.nlm.nih.gov/pubmed?term=Dullaart%20RP%5BAuthor%5D&cauthor=true&cauthor_uid=22819464

http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Beek%20AP%5BAuthor%5D&cauthor=true&cauthor_uid=22819464


http://www.ncbi.nlm.nih.gov/pubmed?term=Norata%20GD%5BAuthor%5D&cauthor=true&cauthor_uid=17823381

http://www.ncbi.nlm.nih.gov/pubmed?term=Raselli%20S%5BAuthor%5D&cauthor=true&cauthor_uid=17823381

http://www.ncbi.nlm.nih.gov/pubmed?term=Grigore%20L%5BAuthor%5D&cauthor=true&cauthor_uid=17823381


011

267. Kaser, S., Kaser, A., Sandhofer, A. Resistin messenger-RNA expression is

increased by proinflammatory cytcokines in vitro. Biochem. Biophys. Res.

Commun. 2003;309(2):286-290.

268. QiaoI X, Yang Y, Xu Z, et al. Relationship between resistin level in serum and

acute coronary syndrome or stable angina pectoris. Zhejiang Univ Sci B 2007

8(12):875-880.

269. Diez JJ, Iglesias P, Fernandez-Reyes MJ, et al. Serum concentrations of

leptin, adiponectin and resistin, and their relationship with cardiovascular

disease in patients with end-stage renal disease. Clin Endocrinol (Oxf) 2005;

62: 242-9.

270. Burnett MS, Devaney JM, Adenika RJ, et al. Cross-sectional associations of

resistin, coronary heart disease, and insulin resistance. J Clin Endocrinol

Metab 2006; 91:64-8.

271. Cohen G, Hörl WH. Resistin as a cardiovascular and atherosclerotic risk

factor and uremic toxin. Semin. Dial. 2009; 22: 373-377.

272. Rizkalla J, Melone M, Zhao A, et al. The Pathophysiological Role of resistin

in Impaired Lipoprotein Metabolism in Obesity. Circulation 2009; 120: S529.

273. Lee TS, Lin CY, Tsai JY, et al. Resistin increases lipid accumulation by

affecting class A scavenger receptor, CD36 and ATP-binding cassette

transporter-A1 in macrophages. Life. Sci. 2009; 16: 97-104.

274. Dick, G. M., Katz, P. S., Farias, M., et al. Resistin impairs endothelium-

dependent dilation to bradykinin, but not acetylcholine, in the coronary

circulation. Am J Physiol Heart Circ Physiol 2006; 291, 997−3002.

010

275. Calabro P, Cirillo P, Limongelli G, et al. Tissue factor is induced by resistin in

human coronary artery endothelial cells by the NF-kB-dependent pathway. J

Vasc Res 2011; 48: 59–66.

276. Ragni M, Cirillo P, Pascucci I, et al. Monoclonal antibody against tissue

factor shortens tissue plasminogen activator lysis time and prevents

reocclusion in a rabbit model of carotid artery thrombosis. Circulation 93:

1913–1918.

277. Fang W, Zhang Q, Peng Y, et al. Resistin level is positively correlated with

thrombotic complications in southern Chinese metabolic syndrome patients.

J Endocrinol Invest 2011; 34: e36–e42.

278. Silha JV, Krsek M, Skrha JV, et al. Plasma resistin, adiponectin and leptin

levels in lean and obese subjects: correlation with insulin resistance. Eur J

Endocrinol 2003; 149:331-5.

279. Tuttolomondo A, Placa SA, Raimondo DD, et al. Adiponectin, resistin and IL-

6 plasma levels in subjects with diabetic foot and possible correlations with

clinical variables and cardiovascular co-morbidity.Cardiovascular Diabetology

2010, 9:50.

280. Yannakoulia M., Yiannakouris N., Bluher S., et al. Body fat mass and

macronutrient intake in relation to circulating soluble leptin receptor, free

leptin index, adiponectin and resistin concentrations in healthy humans. J.

Clin. Endocrinol. Metab. 2003 , 88: 1730–1736.

281. Thomopoulos C, Daskalaki M, Papazachou O, et al. Association of resistin

and adiponectin with different clinical blood pressure phenotypes. J Hum

Hypertens 2011, 25:38-46.

011

282. Papadopoulos DP, Perrea D, Thomopoulos C, et al. Masked hypertension

and atherogenesis: the impact on adiponectin and resistin plasma levels. J Clin

Hypertens 2009, 11:61-65.

283. Krecki R, Krzeminska M, Peruga JZ, et al. Elevated resistin opposed to

adiponectin or angiogenin plasma levels as a strong, independent predictive

factor for the occurrence of major adverse cardiac and cerebrovascular events

in patients with stable multivessel coronary artery disease over 1-year follow-

up. Med Sci Monit 2011, 17: CR26-32.

284. Miyamoto Y, Morisaki H, Kokubo Y, et al. Resistin gene variations are

associated with the metabolic syndrome in Japanese men. Obesity Research

& Clinical Practice 2009, 3:65-74.

012

اىخالصح

:ة خلفي

أمصش ف ىيخ األعاع ذؼقذاخ ذصية اىششا اىغثة ذثق اىشغ ػي اىثيذا اىر اىائيح د اىج

ػاو اىخطسج اىؤدح اى صو نزا اشاض اىؼشفح حاىا تشنو ىيحذ ذثزه ت اىؼالقح جذ. إ

اىذ قذ ت اىغج ؼشفح اىحاى ف ػالقح رؼذدج اىجاة ما ا اىرقذ ذصية اىششا اىغح

ر ىاىر ذغ جرؼح تاالدثماخ ا ادغج فاسص ىنصش اىتأ اىغج اىذ ىظ خاال اا

ذيؼة دسا اا ف حذز ذطس ذصية اىششا.

ػي اىشغ ا ؼظ ز االدثماخ ذق ترحفض االىراتاخ اال ا اىثؼط االخش ا ماالدثنر

ادثم ىقيثح اىػائح. تاالظافح اى رىل اىل صثػ االىراتاخ ستا غاػذ ف اىحاح االشاض ا

اىز ؼرقذ ا ) اىيثر (اىز ؼرقذ تجد ػالقح حريح ى غ اشاض اىقية اىراجح)اىشغغر اخش

. ا اىؼذذ اىذساعاخ قذ اجشد ػي ػالقح (ى ذأششاخ عيثح اجاتح ػي اىجاص اىقيث اىػائ

د ػي حاالخ ضح اا شاخ غ االشاض اىقيثح اىػائح ىن ؼظ ز اىذساعاخ قذ أجاالدثم

دساعرا ف اىحاالخ اىحادج احرشاء ػعيح اىقية فس صى اىغرشف ف ادسج قييح خصصا ف

اح.ىاىثيذا ا

الهدف:

د اىحاىح ا اىذساعح اىشغغر اىيثر غ احرشاء ػعيح دثنراألخ غرااىؼالقح ت ىرق ص

تؼعا غ تاالظافح اى دساعح ػالقح اسذثاغ ز االدثماخ اىصالشح اىؼشاق ىشظاىقية اىحاد ىذ ا

. جاة آخش و اىغششح اىغناح اىخرثشحااىنصش اىؼ تؼط جاة غ

: ةقيالطر

)تغذاد( ىيفرشج اىرؼي اىشك غرشف ف فزخ حاىحاى اىذساعح حر 1100 األه ما حضشا

شعا شظ 41ف صو اىذ ىذ اىشغغر اىيثر دثنرذ قاط غراخ األ .1101

إلظافح إى دخى اىغرشف تاقد عح( ف 00.62 ±47.05احرشاء ػعيح اىقية اىحاد )ؼذه اىؼش

عح( مجػح ظاتطح رافقح غ جػح 04.35 ±42.87شخصا اخش )ؼذه اىؼش 23قاع ىذ

013

تاإلظافح إى رىل فقذ ذ قاط غر إض .أخش خطش ػاواىشظ احح اىؼش اىجظ

) اىرشت (I صسج أعاعح ( حس اىقيث ػذ اىشظ ف اىجػح اىعاتطح ) إلغشاض ذشخصح ت

عاػاخ دخى. 8-5ذ اخز قشائر ىزا اىغشض احذج ػذ دخه اىشط إى اىطاسئ اىصاح تؼذ

ىرق اعرجاتر ىألدح تاألظافح اى رىل فقذ ذ راتؼح اىشظ عششا غيح فرشج اىشقد ف اىغرشف

جح أخش. ح حريحخ شظاىرشق أ ذؼقذاىزثح ىيخصشج جح

النتائج :

%( 65غثر شط ) أ ا 41شعا أصو 27فا خص إض اىرشت اىقيث فقذ ما اىل

ما غر اإلض ىذ عاػح دخى اىغرشف أػي اىحذ األد اىطيب ىرشخص اىشض تا

%( ىن غر 13شعا ) 01اىغرشف اقو اىحذ األد ىذ ما غر اإلض عاػح اىذخه إى

عاػاخ. 8-5اإلض ذجاص اىحذ األد ىذ جغ اىشظ ف اىقشاءج اىصاح اىر ذد تؼذ

ف صو اىذ ىذ شظ احرشاء ػعيح اىقية اىحاد اىثاىغ مشفد اىذساعح إ غر األدثنر (4.19

μg/mL) جذا أغأ ما غرا ف اىجػح اىعاتطح اىثاىغ (6.45 μg/mL) ما اظشخ .

عيث إسذثاغاىذساعح جد .اىشظ غغر ىذاىش غرف صو اىذ غر األدثنر ت ا

ف صو اىذ ىذ شظ احرشاء ػعيح اىقية اىحاد غغرما ا اىذساعح قذ مشفد إ غر اىش

ثاىغ اى (13.08 ng/mL) جذا ػي أ ما غرا ف اىجػح اىعاتطح اىثاىغ (5.31 ng/mL) ما .

ا اىذساعح قذ مشفد إ غر اىيثر ف صو اىذ ىذ شظ احرشاء ػعيح اىقية اىحاد اىثاىغ

(10.03ng/mL) جذا ػي أ ما غرا ف اىجػح اىعاتطح اىثاىغ (6.97 ng/mL) .

أخشا ى ذنشف اىذساعح ػ جد أح ػالقح راخ جذ ت غراخ اىرشت اىقيث االدثنر

اىشغغر اىيثر غ اىؼش اىغنش اسذفاع ظغػ اىذ قغ االحرشاء حذز اىؼجض اىقيث

خ اىخصشج.االسذجاف األر أ اىثط تاإلظافح إى االعرجاتح اىاجحح ىزثا

:اتاالستنتاج

اظشخ اىذساعح اىحاىح اسذثاغ ثغ غر االدثنر غ شض احرشاء ػعيح اىقية اىحاد ىذ

اىشظ اىؼشاق.

ػي اىؼنظ رىل اظشخ اىذساعح اىحاىح اسذثاغ اسذفاع غر اىشغغر اىيثر غ شض احرشاء

اق.ػعيح اىقية اىحاد ىذ اىشظ اىؼش

014

عيث ما أظشخ اىذساعح جد اسذثاغ غغر ىشا غرف صو اىذ غر األدثنر ت ا

.اىشظ ىذ

ز اىرائج ذؤشش ىجد قح حريح ىالدثنر اىشغغر اىيثر ف شظح احرشاء ػعيح اىقية

جح ف ذشخص جح أخش.

ساعح ػ جد ػالقح راخ جذ ت غراخ اىرشت اىقيث االدثنر أخشا ى ذنشف اىذ

اىشغغر اىيثر غ االعرجاتح ىألدح اىزثح ىيخصشج جح غ اىرؼقذاخ اىشظح أشاء فرشج اىشقد

ف اىغرشف جح أخش.

لوتين لريسستين و الوا يديوىييتتيناألبين هستىيات العالقة

حتشاء عضلة القلب الحايد في هصل الدم هع ا

والى الصيدلة السريريةرسالة مقدمة الى فرع

لجنة الدراسات العليا في كلية الصيدلة/ جامعة بغداد كجزء من متطلبات (الصيدلة السريريةالحصول على شهادة الدكتوراه فلسفة في الصيدلة )

من قبل

ضياء جوار كاظن

7991وريوس صيدلة بكال

0225ماجستير صيدلة سريرية

بإشراف

قاسن جليل الشواع الدكتىر االستاذ

ايديب جايدر حسين الدكتىرختصاص الطويب اال

م0274 هـ7141

Documents

Association of Admission Serum Adiponectin, Resistin and … 2014/phd thesis... · Association of Admission Serum Adiponectin, Resistin and Leptin Levels with Acute ST-Segment Elevation