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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
Chapter One Introduction
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.
Chapter One Introduction
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
Chapter One Introduction
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
Chapter One Introduction
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
Chapter One Introduction
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
Chapter One Introduction
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
1.4.1 Discovery, structure and expression 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
1.5.1 Discovery, structure and expression 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
Chapter One Introduction
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
Chapter One Introduction
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
among patients with STEMI
64
3.4.3 Correlation between serum leptin and selected demographic and
laboratory variables in STEMI patients
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
Chapter One Introduction
01
among patients with STEMI
3.6.3 Correlation between serum resistin and selected demographic and
laboratory variables in STEMI patients
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
Chapter One Introduction
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
Chapter One Introduction
03
3-8 Admission serum leptin level in STEMI patients
compared to control.
63
3-9 Association of admission leptin level to selected clinical
variables among patients with STEMI.
64
3-10 Correlation between serum leptin level and selected
demographic and laboratory variables in STEMI
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
compared to control.
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
demographic and laboratory variables in STEMI
patients.
74
4-1 Mechanisms postulated for leptin relating to increased
cardiovascular risk
83
Chapter One Introduction
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
Chapter One Introduction
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
variables among patients with STEMI.
57
3-4 Admission serum adiponectin level in STEMI patients
compared to control.
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
compared to control.
63
3-7 Association of admission leptin level to selected
clinical variables among patients with STEMI
65
3-8 Admission serum leptin /adiponectin ratio in STEMI
patients compared to control.
67
3-9 Association of admission leptin level to selected
clinical variables among patients with STEMI
69
3-10 Admission serum resistin level in STEMI patients
compared to control.
71
3-11 Association of admission resistin in level to selected
clinical variables among patients with STEMI
73
Chapter One Introduction
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
Chapter One Introduction
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
Chapter One Introduction
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 .
Chapter One Introduction
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.
Chapter One Introduction
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
Chapter One Introduction
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.
Chapter One Introduction
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].
Chapter One Introduction
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.
Chapter Two Subjects , Materials & Methods
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.
Chapter Two Subjects , Materials & Methods
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.
Chapter Two Subjects , Materials & Methods
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.
Chapter Two Subjects , Materials & Methods
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)
Chapter Two Subjects , Materials & Methods
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:
Chapter Two Subjects , Materials & Methods
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
Chapter Two Subjects , Materials & Methods
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
Chapter Two Subjects , Materials & Methods
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.
Chapter Two Subjects , Materials & Methods
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.
Chapter Two Subjects , Materials & Methods
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.
Chapter Two Subjects , Materials & Methods
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
Chapter Three Results
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 .
Chapter Three Results
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
Chapter Three Results
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).
Chapter Three Results
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
among patients with STEMI
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
Chapter Three Results
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
Chapter Three Results
32
VT: ventricular tachycardia. a: t.test.
*(p value < 0.05 considered significant)
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
Chapter Three Results
33
3.2.4 Correlation between serum cTnI and selected demographic and
laboratory variables in STEMI patients
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
Chapter Three Results
34
BMI: body mass index, S.HDL-c: serum high density lipoprotein cholesterol.
*(p value < 0.05 considered significant)
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**
Values are presented as mean ± SD; n=number.
**Very highly significant difference (p < 0.0001).
Chapter Three Results
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
variables among patients with STEMI
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
in table 3-6 and figure 3-5.
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
Chapter Three Results
36
Table 3-6. Association of admission adiponectin level to selected clinical variables
among patients with STEMI.
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
Chapter Three Results
37
Values are presented as mean ± SD; n=number of patients
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
(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
4.5
5
Me
an A
dip
on
ect
in n
g/m
l
Yes
No
Chapter Three Results
38
3.3.3 Correlation between serum adiponectin and selected demographic
and laboratory variables in STEMI patients
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
Chapter Three Results
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**
Values are presented as mean ± SD; n=number.
** Highly significant difference (p< 0.0001)
Chapter Three Results
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
among patients with STEMI
Studying the association between admission serum leptin 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 3-9 and figure 3-7.
10.03
6.97
0
2
4
6
8
10
12
Contol group Patients group
Me
an L
ep
tin
ng/
ml
patients
control
Chapter Three Results
41
Table 3-9. Association of admission leptin level to selected clinical variables
among patients with STEMI
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
2 Hypertension 9.95 ± 0.96
(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
4 Anterior MI 10.09± 1.12
(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
Values are presented as mean ± SD; n=number of patients
Chapter Three Results
42
Hf : heart failure, AF: atrial fibrillation , VF: ventricular fibrillation
VT: ventricular tachycardia, a: t.test.
*(p value < 0.05 considered significant)
Figure 3.7 Association of admission leptin level to selected clinical variables
(diabetes, hypertension, sex, location of MI, development of HF, development of
9.4
9.6
9.8
10
10.2
10.4
10.6
Me
an L
epti
n n
g/m
l
Yes
N0
Chapter Three Results
43
AF, development of VT and/or VF, and achievement of successful reperfusion)
among patients with STEMI.
3.4.3 Correlation between serum leptin and selected demographic and
laboratory variables in STEMI patients
Studying 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 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
and laboratory variables in STEMI patients
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
4 S. Creatinine 0.137 b 0.341
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
Chapter Three Results
44
9 Serum adiponectin 0.003 b 0.982
10 Serum cTnI -0.185 a 0.199
BMI: body mass index, S. HDL-c: serum high density lipoprotein cholesterol.
*(p value < 0.05 considered significant)
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
compared to control.
Patients
(n=50)
Control
(n=34)
P value
Leptin/adiponectin ratio 2.54 ± 0.71
1.1 ± 0.24
p < 0.0001
Values are presented as mean ± SD; n=number.
** Very highly significant difference (p < 0.0001).
Chapter Three Results
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
clinical variables among patients with STEMI
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
Contol group Patients group
Me
an L
ep
tin
/ A
dip
on
ect
in
rati
o
patients
control
Chapter Three Results
46
Table 3-12. Association of admission leptin/adiponectin ratio to selected clinical
variables among patients with STEMI.
Leptin / adiponectin ratio P value
Yes No
1 Diabetes 2.47± 0.82
(n=15)
2.57± 0.67
(n=35)
0.66 a
2 Hypertension 2.78 ± 0.86
(n=18)
2.41± 0.57
(n=32)
0.07 a
3 Anterior MI 2.53± 0.77
(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
Chapter Three Results
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
Chapter Three Results
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
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 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
4 S. Creatinine 0.072 b 0.621
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
Chapter Three Results
51
BMI: body mass index, S. HDL-c: serum high density lipoprotein cholesterol.
** Very highly significant difference (p < 0.0001).
b: spearman correlation
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**
Values are presented as mean ± SD; n=number.
** Very highly significant difference (p< 0.0001)
Chapter Three Results
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
variables among patients with STEMI
Studying 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) 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
Contol group Patients group
Me
an R
esi
stin
ng/
ml
patients
control
Chapter Three Results
51
Table 3-15. Association of admission resistin level to selected clinical variables
among patients with STEMI.
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
2 Hypertension 13.76 ± 2.71
(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
Chapter Three Results
52
Values are presented as mean ± SD; n=number of patients
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)
0
2
4
6
8
10
12
14
16
18
Me
an R
esi
stin
ng/
ml
Yes
No
Chapter Three Results
53
Figure 3-11. Association of admission resistin 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.
3.6.3 Correlation between serum resistin and selected demographic
and laboratory variables in STEMI patients
Studying the correlation between admission serum resistin 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
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).
Chapter Three Results
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
BMI: body mass index, S. HDL-c: serum high density lipoprotein cholesterol.
** Very highly significant difference (p < 0.0001).
b: spearman correlation
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
Chapter Four Discussion
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
Chapter Four Discussion
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
Chapter Four Discussion
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
Chapter Four Discussion
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].
Chapter Four Discussion
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
Chapter Four Discussion
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].
Chapter Four Discussion
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,
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 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
Chapter Four Discussion
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
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 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
Chapter Four Discussion
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].
Chapter Four Discussion
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.
Chapter Four Discussion
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].
Chapter Four Discussion
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,
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
Chapter Four Discussion
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
Chapter Four Discussion
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
Chapter Four Discussion
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
Chapter Four Discussion
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].
Chapter Four Discussion
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
Chapter Four Discussion
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
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 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
Chapter Four Discussion
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].
Chapter Four Discussion
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.
Chapter Four Discussion
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
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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