Tabriz University of Medical Sciences Faculty of Pharmacy

Tabriz University of Medical Sciences

Faculty of Pharmacy A Dissertation submitted for Pharm D degree

Entitle:

A Randomized controlled trial of effect of Co-Enzyme Q10 on Plasma Level

of Cardiac Troponin-I and Creatinine Kinase- MB in patients with

myocardial infarctions who undergo Angiplasty.

By:

Fatemeh Houshmand

Supervisors:

Dr. Taher Entezari Maleki

Dr. Naser Aslanabadi

Advisors:

Dr. Alireza Garjani

Dr. Samad Ghaffari

May 2015 Number of thesis: 3772

Clarification and Copyright Declaration

I hereby declare that I am the sole author of this thesis. I take full responsibility of

this work and declare that the results of this study are original and based on my

personal work. All scientific materials used in this thesis are fully referenced.

All rights are transferred to Faculty of pharmacy, Tabriz University of Medical

sciences. The Faculty of pharmacy is authorized to lend or reproduce this thesis,

in total or in part.

Professor name : Dr. Taher Entezari Maleki

Signature:

Name: Fatemeh Houshmand Student No:

8813120463

Date: 2015.5.6

Signature:

Dedication:

I would like to dedicate this Doctoral dissertation to my parents whose words of

encouragement and push for tenacity ring in my ears. Thank you for your

unconditional support with my studies. I am honored to have you as my parents.

Thank you to give me a chance to prove and improve myself through all my walks

of life. Please do not ever change. I love you.

To my sisters, Azam and Akram and my brother, Mohammad who never left my

side and whose good examples have taught me to work hard for the things that I

aspire to achieve. Thank you for believing in me. Please do not ever doubt my

dedication and love for you.

I also dedicate this dissertation to my friends, Narges, Dena, Zahra, Arezoo,

Sanaz, Masoome, Mahdis, Mahtab and Fereshteh who assisted, advised, and

supported my research and writing efforts over the years. Your friendship makes

my life a wonderful experience. Thank you all for being my friends during these

years.

I would like to sincerely thank my supervisors, Dr. Entezari and Dr. Aslanabadi

and also my advisors Dr. Garjani and Dr. Gaffari for their guidance and support

throughout this study, and especially for their confidence in me.

My especial gratitude and appreciation to Dr. Taher Entezari Maleki, for the deft

ways in which lovingly challenged and supported me throughout the whole of this

work; knowing when to push and when to let up. I hope you find some kind of

satisfaction in this modest thesis. Thank you so much!

I

List of Abbreviations

ACC American College of Cardiology

ACCF American College of Cardiology Foundation

ACS Acute Coronary Syndrome

AHA American Heart Association

AMI Acute Myocardial Infarction

ATP Adenosine Tri Phosphate

CABG Coronary Artery Bypass Graft

CAD Coronary Artery Disease

CHF Congestive Heart Failure

CK-MB Creatinine Kinase-MB

CMP Cardiomyopathy

COPD Chronic Obstructive Pulmonary Disease

CoQ10 Coenzyme Q10

DM Diabetes Mellitus

ESC European Society of Cardiology

HMG-COA Hydroxymethylglutaryl-Coenzyme A

hs-CRP High Sensitivity C- reactive protein

HTN Hypertension

ICTRP International Clinical Trials Registry Platform

IHD Ischemic Heart Disease

II

LAD Left Anterior Descending

LCX Left Circumflex

LDL Low Density Lipoprotein

MACE Major Adverse Cardiac Effect

OM Obtuse Marginal artery

PCI Percutaneous Coronary Intervention

PDA Posterior Descending Artery

PMI Periprocedural Myocardial Injury

rANOVA repeated measures Analysis of Variance

RCA Right Coronary Artery

RCT RCT Randomized Controlled Trials

SBO Side Branch Occlusion

SD Standard Deviation

SVG Saphenous Venous Graft

ULN Upper Limit of Normal

WHF World Heart Federation

III

List of Contents

Abstract .................................................................................................................... 1

Chapter 1: Introduction ............................................................................................ 3

1.1 Objectives & Hypothesis ................................................................................... 4

1.1.1 General objective ............................................................................................ 4

1.1.2 Specific Objectives ......................................................................................... 4

1.1.3 Applicational Objectives ...................................................................................... 4

1.2 Hypothesis or Questions .................................................................................... 4

Chapter 2: Literature Reviews ................................................................................. 5

2.1 Biochemistry and Physiology of Ubiquinone .................................................... 5

2.2 Sources .............................................................................................................. 7

2.3 Absorption and excretion of Coenzyme Q10 .................................................... 7

2.4 Deficiency of Coenzyme Q10 ........................................................................... 8

2.5 Cardiomyopathy ................................................................................................ 8

2.6 Myocardial Preservation and Intervention ........................................................ 9

2.7 Plasma lipoproteins ........................................................................................... 9

2.8 Statin Toxicity ................................................................................................. 10

2.9 Periprocedural Myocardial Infarction ............................................................. 11

2.9.1 Definition of Periprocedural Myocardial Infarction ..................................... 11

2.9.2 Incidence ....................................................................................................... 12

2.10 Mechanisms of Periprocedural myocardial infarction and Risk Factors ....... 12

2.10.1 Mechanisms of the Relationship between PMI and long term Mortality ..... 13

IV

2.10.2 Prognostic Value of PMI .............................................................................. 13

2.11 Prevention of Periprocedural Myocardial Infarction ....................................... 14

Chapter 3: Methods ............................................................................................... 16

3.1 Study design and setting .................................................................................. 16

3.2 Study population .............................................................................................. 17

3.3 Blood sampling ................................................................................................ 18

3.4 End points ........................................................................................................ 18

3.5 Statistical analysis ........................................................................................... 18

3.6 Power calculation ............................................................................................ 19

Chapter 4: Results .................................................................................................. 20

4.1 Demographic data ............................................................................................ 20

4.2 Risk Factors ..................................................................................................... 27

4.3 Drug History .................................................................................................... 28

4.4 Stented Target .................................................................................................. 29

4.5 CK-MB Results ............................................................................................... 30

4.6 Troponin I Results ........................................................................................... 32

4.7 hs-CRP Results ................................................................................................ 34

Chapter 5: Discussion and Conclusion .................................................................. 36

5.1 Discussion ........................................................................................................ 36

5.2 Conclusion ....................................................................................................... 40

5.3 Limitations ....................................................................................................... 41

References ............................................................................................................. 42

V

List of Figures

Figure 2.1 Mevalonate pathway and terminal steps in the synthesis of CoQ.

............................................................................... Error! Bookmark not defined.

Figure 4.1 Consort flow diagram of the study ...................................................... 21

Figure 4.2 Patients gender in both groups ............................................................ 23

Figure 4.3 Incidence of risk factors in both groups. ............................................. 24

Figure 4.4 Drug history of patients in both groups ............................................... 25

Figure 4.5 Target vessels of patients in both groups. ........................................... 26

Figure 4.6 Plasma levels of CK-MB in both groups ............................................ 31

Figure 4.7 Plasma levels of Troponin I in both groups ........................................ 33

Figure 4.8 Plasma levels of hs-CRP in both groups ............................................. 35

VI

List of Tables

Table 4.1 Demographic and Clinical data of the study patients ........................... 22

Table 4.2 The incidence of risk factors in the study groups ................................. 27

Table 4.3 Drug history of patients in both groups ................................................ 28

Table 4.4 Stented target vessels in the study groups ............................................ 29

Table 4.5 Mean CK-MB level at baseline, 8, and 24 h after PCI in the study

groups .................................................................................................................... 30

Table 4.6 Mean Troponin I level at baseline, 8, and 24 h after PCI in the study

groups .................................................................................................................... 32

Table 4.7 Mean hs-CRP level at baseline and 24 h after PCI in the study groups

............................................................................................................................... 34

Table 4.8 Incidence of MACE .............................................................................. 36

Abstract | P a g e 1

Abstract

Introduction: Despite the novel technical and medical improvement in performing

of percutaneous coronary intervention (PCI), some myocardial complications

occur during this procedure. Thus, periprocedural myocardial injury (PMI)

following PCI has received serious attention due to its notable relation to

mortality and morbidity. Therefore, cardioprotection during PCI is still a

worldwide need.

Aim: Concerning the potential clinical benefits of CoQ10, this trial was

performed to investigate the CoQ10 pretreatment benefits in reduction of PMI in

patients undergoing elective PCI.

Methods: A randomized controlled trial of 100 patients undergoing elective PCI

was designed. The intervention group (n=50) received 300 mg CoQ10 in a single

dose and the standard treatment 12 hours before PCI. But the control group (n=50)

had the standard treatment only. To evaluate the myocardial injury during PCI, the

levels of CK-MB and troponine-I were measured at baseline, 8 h, and 24 h after

PCI, and hs-CRP levels were measured at baseline and 24 h after PCI. Afterwards,

all patients were assessed for the major adverse cardiac effects in a 1-month

following up period.

Results: No significant changes in the CK-MB levels at 8 h (p=0.079) and 24 h

(p=0.242) following PCI were found in intervention group when compared with

the control group. In the same way, no significant changes in troponine-I at 8 h

(p=0.062) and 24 h (p=0.826) after PCI were observed. The results of hs-CRP

levels indicated significant changes at 24 h (p=0.031) after PCI.

Conclusions: Although the biomarker’s changes were not significant in

intervention group, there was a trend toward the potential benefits of CoQ10. On

the other hand, the changes of hs-CRP were statistically significant, that can

relatively support the potential cardioprotective effects of CoQ10 in the

prevention of PMI following PCI.

Abstract | P a g e 2

Keywords: Coenzyme Q10, Periprocedural myocardial injury, PCI, Cardiac

biomarkers, Creatine kinase-MB, Troponin-I, hs-CRP

Introduction

Introduction | P a g e 3

Ever since the resumption of percutaneous coronary Intervention (PCI), the

number of this procedure has increased all over the world due to its important role

in organizing ischemic heart Diseases (IHD) [1-3]. Despite the unprecedented

technical and medical progress in the PCI performance, it has been obvious that

some myocardial injury was related to this procedure [4]. Thus, periprocedural

myocardial injury (PMI) is the mortality-related complication of PCI by affecting

the early and late results of patients who undergo PCI [5]. In 2007, the “joint

ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial

Infarction” described a new definition of PMI during PCI(type 4a MI) as an

increase of cardiac biomarkers more than three times the 99th percentile upper

limit normal (ULN). As a result, the elevation between 1 and 3 times ULN was

supposed as PMI [6,7]. The probable occurrence of PMI was estimated to be one

third of all elective PCIs [8]. Given this fact, ACC/AHA guidelines have

considered this important issue and for assessing the outcomes, recommended

(class 2A) the check of cardiac biomarkers 8-12 h after PCI [7].

Different mechanisms are supposed to be involved in PMI development, such as

ischemic conditions, thrombosis formation, platelet activation, inflammation and

oxidative stress which must be planned to reduce these conditions in PCI [7].

Coenzyme Q10(ubiquinone), a natural content of human’s diet, which is also

synthesized in body cells from the amino acid tyrosine, has clinical benefits due to

its ability to improve ATP production, antioxidant activity and membrane

stabilizing properties [9-12].

Concerning the diversity of functions of coenzyme Q10 and the mechanisms of

PMI development, this study was designed to evaluate whether the pretreatment

with coenzyme Q10 could reduce the PMI in patients who are undergoing elective

PCI.

Introduction | P a g e 4

1.1 Objectives & Hypothesis

1.1.1 General Objective:

A Randomized controlled trial of CoEnzyme Q10 on Plasma Level of Cardiac

Troponin-I and Creatinine Kinase- MB in patients with myocardial infarctions

who undergo Angioplasty.

1.1.2 Specific Objectives:

1. Level of Cardiac Troponin-I, Creatinine Kinase- MB and High sensitivity C-

reactive protein before PCI.

2. Level of Cardiac Troponin-I, Creatinine Kinase- MB and High sensitivity C-

reactive protein after PCI.

3. Comparison of the mentioned groups.

1.1.3 Applicated Objectives:

Evaluation of CoQ10 effect on myocardial damage in patients undergoing

angiography.

1.2 Hypothesis or Questions:

Level of Cardiac Troponin-I, Creatinine Kinase- MB and hs-CRP in CoQ10 group

is less than control group.

Literature

Review

Literature Reviews | P a g e 5

Coenzyme Q10 (ubiquinone) is a natural content in human’s diet and is also

synthesized in all kinds of body cells especially the muscles. The synthesis of

ubiquinone in body cells from the amino acid tyrosine is a process with different

stages requiring at least eight vitamins and several phytochemicals [9-12]. The

deficiency of any of these micronutrients may result into ubiquinone deficit.

CoQ10 deficiency of the neurons, cardiomyocytes and arterial cells can interact in

predisposing circadian rhythm of cardiovascular events by causing disorder in the

suprachiasmatic nucleus, pituitary function and melatonin release from the pineal

gland of the brain [9-18].

2.1 Biochemistry and Physiology of Ubiquinone

The biosynthesis of ubiquinone are based on three main steps; the first step is the

synthesis of the ring structure from the essential amino acids tyrosine and

phenylalanine, the second step is the formation of the side chain called isoprenoid

from acetyl-CoA residues within the mevalonate pathway, and the third step is a

condensation of structures formed in previous steps by means of enzyme

polyprenyl-transferase, in the Golgi apparatus. It is also probable that one

essential step in regulating the synthesis seems to be the hydroxymethylglutaryl

(HMG)-coenzyme A reductase reaction, common with a step in cholesterol

synthesis, but other steps may also be regulated. (figure 2.1)

Ubiquinone has a strong influence on at least three mitochondrial enzymes

(complexes I, II and III) which are involved in the oxidative phosphorylation

pathway and are essential for the synthesis of ATP which is required for cell

function [10,11]. It may prevent cellular damage during myocardial ischemia and

reperfusion and the oxidation of LDL cholesterol and also inhibits atherosclerosis

and disruption of plaque.


The ability to improve ATP production, anti-oxidant activity and membrane

stabilizing properties are some clinical benefits of CoQ10 in prevention and

treatment of heart diseases [9-12]. The anti-oxidant activity of Ubiquinone in

cooperation with vitamin E can be applied in the prevention of membrane and

plasma lipid damages [13]. Protection against Atherosclerosis can be offered by

activating smooth muscle cells in rich content of CoQ10, and by preventing the

formation of lipid peroxidation and low density lipoprotein cholesterol oxidation

[6,8].

Figure 2.1 The mevalonate pathway and the terminal steps in the synthesis of CoQ


Ubiquinone might have the ability to preserve the integrity of myocardial calcium,

sodium and potassium channel during ischemic attacks. It might therefore

improve cellular integrity during ischemia by activating potassium channels the

same as Nicorandil and decreases cellular calcium due to channel modulation [17-

19].

2.2 Sources

CoQ exists in the plant and animal cells. Q9 is found in rats and mice. Q6, Q7,

and Q8 are plentiful in the yeast and bacteria. Ubiquinone is found in all tissues,

but it is rich in the heart and skeletal muscles, liver and kidneys. The lowest levels

of CoQ10 are found in the lungs. The reduced form of ubiquinone is the most

important form in all tissue cells except in the brain and lung tissues. The

ubiquinone level in the human plasma ranges between 0.75 to 1.0 ng/ml of which

75% is in the reduced form. The total content of ubiquinone in the body which is

found in the muscle has been estimated at 1.0-1.5 g. The reduction in ubiquinone

levels may lead to aging. The amount of ubiquinone may be elevated by

biosynthesis, from food and supplementation. The biosynthesis of ubiquinone

may be intensified by exercise. Some rich sources of ubiquinone are pork heart,

vegetables, fish, soya bean, particularly cauliflower and sweet potato. The dietary

intake of ubiquinone was estimated to be 3-5 mg/day and 2-3 mg/day in Denmark

and India, respectively. The dietary intake of 10-30mg/day may be enough for

healthy individuals. The plasma levels of ubiquinone are lower in South Asians in

comparison with Caucasians and Chinese [13].

2.3 Absorption and excretion of Coenzyme Q10

Ubiquinone absorption is slow from the gastrointestinal tract due to its lipid-

soluble nature. The mean plasma level following a single dose of 100 mg orally is

1.004 ± 0.37 ug/ml [9,10]. It is estimated that the mean steady state level after

three daily administrations of 100 mg is 5.4 ug/ml. The ubiquinone’s half-life in

plasma is 33.9 ± 5.32 hours due to its low clearance rate from the plasma. A large

portion of the exogenous administration of ubiquinone is deposited in the liver


and stored as very low density lipoprotein. It is excreted via the biliary tract and

about 62.5% of the drug may be recovered in the stools. The drug is concentrated

in adrenal, spleen, lung, kidney, liver, brain and myocardial tissue during chronic

administration.

2.4 Deficiency of Coenzyme Q10

Insufficient dietary intake, impairment in CoQ10 biosynthesis and excessive

utilization by the body; or a combination of any three may lead to ubiquinone

deficiency [9-14]. A various diseases such as coronary artery disease, particularly

with angina pectoris, congestive heart failure, mitral valve prolapse, etc. may

increase the consumption of CoQ10 by body tissues. The poor body stores or low

dietary intake may predispose several diseases and ubiquinone supplementation

may have beneficial effects. The oxidative stress in the tissues may be increased

by some environmental oxidants like pollutants, pesticides, heavy metals,

industrial fumes, radiation and increased consumption of linoleic acid and

therefore enhance the ubiquinone requirement. The two-fold higher amount of

ubiquinone in vegetarians in comparison with the omnivores indicates that a high

intake of these foods may provide high CoQ10 levels (0.86 vs. 0.44 ug/ml) [9-12].

2.5 Cardiopymopathy

The cause or effect of ubiquinone deficiency in cardiomyopathy (CMP) has not

yet been verified [20,21]. In one study, the tissue levels of ubiquinone in NYHA

class IV subjects of CMP were significantly lower in comparison with class 1 and

2 subjects [12]. It was indicated that the best response to ubiquinone treatment

was due to the greater deficiency of it. In a randomized double blind study with

administration of CoQ10, notable improvement was observed in patients with

dilated CMP with class III and IV heart failure [22,23].

CoQ10 and hs-CRP are important markers to assess the oxidative stress and

inflammatory status of patients with CMP.


2.6 Myocardial Preservation and Intervention

It was indicated that prior ubiquinone therapy contributes to protection against

ischemia-reperfusion [9-12]. In a rabbit heart model of ischemia and reperfusion,

the role of CoQ10 in protecting ischemic myocardium against both structural and

functional changes was observed. The CoQ10-pretreated animals were able to

retain oxidative phosphorylation and cellular ATP generating capacity, and

pretreatment with ubiquinone can prevent cellular and mitochondrial calcium

overload. The clinical and metabolic beneficial effects were considerably similar

to those observed with propranolol and verapamil [9]. It was demonstrated that

CoQ10 can protect both Calcium and Na-K dependent ATPase activity. In a

randomized study on humans the efficacy of ubiquinone in preventing low cardiac

output following cardiac surgery was examined. Judy et al. [24] studied

myocardial protection by CoQ10-pretreatment for 15 days before heart surgery

and compared with 30 days treatment after the surgery. The CoQ10 group

demonstrated optimal blood and tissue CoQ10 and tissue ATP levels, elevation in

cardiac pumping and ejection fraction and short recovery period compared to

placebo group.

2.7 Plasma lipoproteins

In one in vitro experiment, it has been shown that after exposure to free radical

source (Azo compounds), low density lipoproteins (LDL) deployed their

antioxidant reserve which were applied when inhibiting the oxidative attack.

When LDL, depleted of ascorbic acid, was exposed to free radical source,

peroxidation remained under control as long as some ubiquinol was present. The

findings suggested that the antioxidant activity of ubiquinone may be more

efficient than tocopherol and carotenoids in preventing the oxidation of LDL [14].

A double blind controlled-trialed study [14], in patients with hypercholesterolemia

indicated that the plasma level of CoQ10 in patients treated with HMG-COA

reductase inhibitor (lovastatin) was significantly lower than placebo group [25].

The same biosynthetic pathway of CoQ10 and cholesterol appears to be the cause

of CoQ10 reduction. These findings were confirmed in a crossover trial with


CoQ10 and HMG-COA reductase inhibitors [26]. Singh et al. [27] showed that

lovastatin has a average antioxidant activity similar to fluvastatin. Despite a

decrease in CoQ10, induced by statins, oxidation of LDL is inhibited by the

statins without serious adverse effect of CoQ10 deficiency. However, co-

treatment of hypercholesterolemia with HMG-COA reductase inhibitors and

CoQ10 may make better results in the recovery of coronary atherosclerosis and

prevention of cardiac complications. In a study, it was demonstrated that CoQ10

treatment may significantly reduce lipoprotein level and plasma insulin levels in

patients with acute coronary syndrome [28,29].

2.8 Statin Toxicity

Statin induced myopathy has become an important complication in the western

world and also in developing countries [30,31]. The main predisposing reasons for

statin toxicity are high dose statin monotherapy, combination with other

medications such as cyclosporine, fibrates, macrolide antibiotics, certain

antifungal drugs and niacin. One of the most important factors for predicting risk

of myopathy is also the way of metabolization of statins. Most of them are

metabolized by cytochrome P 450 family with the exception of pravastatin [31].

CoQ10 is ubiquitous substance serving also like coenzyme in mitochondrial

phosphorylation. It also is synthesized by endogenous way from

mevalonateisoprene as well as the result of HMG-CoA reductase activity.

Therefore, the resduction of CoQ10 levels is reasonable during statin therapy due

to reduction and inhibition of LDL cholesterol synthesis. Hence, the significant

decrease of CoQ10 during statin therapy was observed (up to 40%) and myopathy

may occur due to subsequent disorder of mitochondrial energetic metabolism

[31,32].

Based on the recommendation of International College of Cardiology, possible

risks of widely prescribed statin therapy should be reduced by lower doses

administration, co-treatment with CoQ10 and avoidance of risky combinations of

drugs interfering with the metabolism via cytochrome P 450.The role of lipid

lowering diet plus exercise is incontestable and may support lower doses or even


consumption of lipid lowering drugs. In a randomized, controlled, trial, the

adverse effects of statins in patients with acute myocardial infarction (AMI) in

two groups with CoQ10 (CoQ10, 120mg/day) +lovastatin (10-20mg/day) or

lovastatin alone were compared for one year [33]. Of 144patients, 49.3% of

CoQ10 group and 43.6% of control group were receiving lovastatin (10-

20mg/day). The results of adverse effects showed that fatigue (40.8 vs 6.8%,

P<0.01) was significantly more common in the control group compared to CoQ10

group indicating that CoQ10 may have beneficial effects in preventing lovastatin

adverse effects. In another study performed by Caso, after a 30-day intervention

by CoQ10 in the patients with statin induced myopathy, the pain severity and pain

interference with daily activities were significantly lower in patients received

CoQ10 Compared to those who were treated with vitamin E. In addition,

coenzyme Q10 supplementation may decrease muscle pain associated with statin

treatment and may offer an alternative to stopping treatment with these vital drugs

[34].

2.9 Periprocedural Myocardial Infarction

In the current era of antiplatelet therapy and routine stenting, acute ischemic

complications occurring following percutaneous coronary interventions (PCI)

have been reduced. However, the periprocedural increase in cardiac biomarkers

continues to occur in a substantial proportion of patients [35].

2.9.1 Definition of Periprocedural Myocardial Infarction

The initially definition published in 2000 was any rise and fall in cardiac

biomarkers (creatine kinaseMB fraction [CK-MB] or troponin) above the upper

limit of normal (ULN) [36]. Later in 2007, the American College of Cardiology

(ACC) defined PCI-related myocardial infarction as an elevation of biomarkers

(CK-MB or troponin) greater than 3 times ULN, and the elevations of cardiac

biomarkers between 1 and 3 times ULN was concerned as indicative of

periprocedural myocardial necrosis [6]. An isolated elevation in troponin above 3

times ULN was considered enough to define PMI. An isolated elevation in cardiac


biomarkers as opposed to the general definition of MI that includes the additional

presence of symptoms or electrocardiographic or imaging abnormalities

suggestive of ischemia is enough to define PMI. This definition applies for

patients with normal baseline biomarkers. Above documents cannot support the

diagnosis of PMI if the biomarkers value are abnormal or increase before PCI. If

the biomarkers’ values are stable or falling, recurrent infarction is diagnosed in

case of≥20% increase of a previously downward trending troponin or CK-MB

value [6].

2.9.2 Incidence

The incidence (3.6%–48.8%) and importance of myocardial injury after PCI

depends on the patient’s presentation (acute coronary syndrome [ACS] vs stable

coronary artery disease [CAD]), the angiographic and procedural characteristics,

the adjunctive pharmacotherapy, and the biomarker and thresholds applied to

detect its presence [37,38]. On average, 23% of patients have a rise in CK-MB

above ULN following PCI, and 27% of patients have an elevation in troponin I

[37]. The elevation of CK-MB to greater than 3 times ULN occurs after 6% to

18% of PCIs [8-10]. According to the ACC guidelines published in 2005, the

levels of CK-MB and troponin must be measured routinely, 8 to 12 hours after

PCI in all patients regardless of symptoms, for prognostic evaluation [41].

2.10 Mechanisms of Periprocedural MI and Risk Factors

Q-wave MI and large non–Q-wave MI are associated with angiographically

documented complications during PCI including flow-limiting dissection, abrupt

vessel closure that is not quickly treated, branch vessel occlusion, or macroscopic

embolization [37]. Most PMI are, however, diagnosed after apparently

uncomplicated PCIs. In these cases without clear evidence of angiographic

complications, intravascular ultrasound studies have demonstrated a close

relationship between the amount of atherosclerotic plaque burden and PMI,

indicating the significance of atheroembolization in the pathophysiology of PMI

[42]. In addition, microvascular thrombosis, platelet activation, microcirculatory

inflammation and oxidative stress, and no-reflow phenomenon occur due to


release of prothrombotic bio factors into the coronary circulation following plaque

disruption [4]. Patients with multivessel disease, multiple or long lesions, or

diffusely diseased arteries have a larger atherosclerotic burden and are more

susceptible to PMI. Also, complex lesions requiring complex PCI predispose to

PMI [37]. Saphenous venous graft (SVG) lesions are at high risk of PMI as high

as 15%, associated with the raised incidence of micro- and macro-embolization,

particularly in grafts older than 3 years [44,45] This incidence is decreased by

∼50% with the consumption of embolic protection devices [44].

2.10.1 Mechanisms of the Relation Between PMI and Long-term

Mortality

The elevation of biomarkers following PCI shows some degree of myocardial

injury that has been confirmed by MRI findings [46]. These studies have

demonstrated that despite the use of preloaded clopidogrel and abciximab,

irreversible myocardial injury occurred in almost 30% of patients following

complex or multivessel PCI. There was a salient relation between the troponin I

raise following PCI and the magnitude of MRI-defined irreversible injury, which

suggests that troponin elevation in the setting of PCI, represents true myocardial

cell death, rather than troponin leak without cellular necrosis. This injury might

affect the function of left ventricular and cause arrhythmias. In fact, the risk of

PMI increases in patients with baseline LV systolic dysfunction or incomplete

revascularization [47]. In addition, the biomarkers elevation predicts extensive

and unstable atherosclerotic burden that predisposes to future ischemic events.

[49].

2.10.2 Prognostic Value of PMI

Prognostic Value of CK-MB Elevation:

In Stone et al. [40] study of 7147 patients, CK-MB raised greater than 3 times

ULN in 18% of patients, and Q-wave MI developed in 0.6% of patients. Another

study indicated that CK-MB elevation to greater than 10 times ULN is related to


the increased risk of 3-year mortality [48]. Two meta-analysis proved that smaller

elevation of CK-MB was associated with an increased risk of death [49,8].

Prognostic Value of Troponin Elevation:

Several studies have addressed the prognostic value of periprocedural troponin

increase. One recent analysis from Cornell Angioplasty Registry indicated that

troponin I levels greater than 5 times ULN were independently related to a 1.8-

fold increase of long-term mortality [50]. Otherwise, several older studies do not

support the relation between troponin elevation after PCI and long-term mortality

[51,52]. Despite the guidelines for PMI definition, the prognostic value of

troponin elevation is less clear [6].

Prognostic Value of C-reactive protein:

Several studies indicated the association of elevated CRP levels with cardiac

events and also short-term and longterm morality risk not only for patients with

acute and chronic ischemic heart disease but also for those at risk for

atherosclerosis [54]. The Centers for Disease Control/AHA guidelines

demonstrate that low risk (< 1.0 mg/l), average risk (1–3 mg/l), and high risk (>

3.0 mg/l) is assigned to those patients with an intermediate 10-year CHD risk

[55].

2.11 Prevention of Periprocedural Myocardial Infarction:

Antiplatelet Therapies:

In several trials including CREDO, PCI-CURE and ARMYDA-2, the effect of

Clopidogrel on reduction of cardiovascular events was confirmed [56,58].

Another studies like EPISTENT and ESPRIT trials indicated that glycoprotein

IIb/IIIa antagonists reduced the 30-day risk of MI by 50%, partly through a

reduction in PMI [39,59]. The combination of glycoprotein IIb/IIIa antagonists


and clopidogrel further reduced the risk of MI, particularly PMI, in ISAR-REACT

2 trial [60].

Statin Therapy:

Several studies indicated the effect of atorvastatin on reduction of PMI [61-63]. It

seems that a single high dose of statin reduces PMI by different mechanisms,

including modification of inflammatory responses, plaque stability, and inhibiting

thrombus formation.

Mechanical Approaches:

In SVG interventions, distal embolic protection devices decrease PMI and 30-day

MI rate by ∼50%, with a trend toward lower 30-day mortality (1.0% vs 2.3% in

one trial, P=0.17) [44]. However, these devices were not useful in acute MI

related to native coronary disease [64]; thus, their only coronary application is

currently in SVG interventions. Proximal embolic protection might further reduce

the incidence of MI in SVG interventions [65].

Ischemic Preconditioning:

Ischemic preconditioning can make local protection and might have a salutary

effect on ischemia-reperfusion injury of remote tissues [66]. In fact, ischemic

preconditioning reduces troponin release following PCI and in major adverse

cardiac events at 6 months [67]. Although additional studies are needed to

evaluate the value of ischemic and remote ischemic preconditioning, the available

data suggest a beneficial effect of these strategies.

Methods

Methods | P a g e 16

3.1 Study design and setting

This was a pilot, prospective, single-blinded, randomized, controlled trial, which

was conducted in Shahid Madani Heart Center (the largest referral hospital for

cardiovascular disorders at the northwest of Iran), affiliated to the Tabriz

University of Medical Sciences(TBZMED) from August 2014 to October 2014. It

was approved in the ethical committee of the university and then was registered in

the International Clinical Trials Registry Platform (ICTRP) with identifier

IRCT201311278307N3.


3.2 Study population

In this study all consented patients suffering ischemic heart disease with the age

between 18 and 80 years old who were undergoing elective PCI (angioplasty and

stent insertion) were entered. Exclusion criteria of the study were: elevation of

CK-MB and troponin-I before PCI, history of previous and acute MI, history of

coronary artery bypass graft (CABG) during the last 3 months, unsuccessful PCI,

patients with renal dysfunction (serum creatinine above 2.5 mg/dl), patients who

are undergoing dialysis, patients with cardiogenic shock, pregnant women,

unconsented patients, patients with inability in filling and understanding the

consent form and those patients who wanted to discontinue the study at any time.

The demographic data of patients, including sex, age, weight, height, drug history

(DH), and clinical data including past medical history (PMH), laboratory data and

positive family history of CVD were recorded in a data collecting form.

All patients undergoing elective PCI were randomized by the permuted block

randomization procedure into CoQ10-treated group (n=50) or the control group

(n=50). All patients were admitted a day before elective PCI. CoQ10 (100 mg

tablet, generic dosage form) was given as 300 mg orally in a single dose 12 hours

before PCI. Both groups received the standard pretreatment protocol of PCI,

including aspirin 325 mg, clopidogrel 300 mg, weight-adjusted intravenous

heparin with a target activated clotting time of 250–350 s and also received drug-

eluted stent. The same interventional cardiologists conducted all PCIs with the

standard method. All patients were assessed in a 1-month follow up for the major

adverse cardiac effect (MACE) including death, Q wave MI, target vessel

revascularization and ischemic stroke.


3.3 Blood sampling

The CK-MB and troponin-I levels were measured at the baseline as well as 8 and

24 h after PCI in two groups. hs-CRP was also measured at the baseline and after

PCI. Detection limits for blood levels of CK-MB, troponin-I were 1 ng/ml and 0.1

ng/ml, respectively.

3.4 End point outcomes

The primary outcome of this study included the comparison of CK-MB and

troponin-I levels at baseline, 8, and 24 h after PCI and also the comparison of hs-

CRP before and after PCI in two groups. The secondary outcome was regarded as

an incidence of MACE (death, Q wave MI, target vessel revascularization,

ischemic stroke) during 1 month following PCI.

3.5 Statistical analysis

Data analysis was performed by SPSS 16.0 software (Chicago, SPSS Inc., 2007).

Kolmogorov–Smirnov test was done to identify if the data had a normal

distribution. For assessing between- and within-subject interactions, the repeated

measures analysis of variance (rANOVA) was performed. Bonferroni adjustment

was conducted for pair wise comparisons. Paired t-test (for normal data),

Wilcoxon, Mann–Whitney and independent sample t-tests were applied to

compare the means within the groups. Chi-square and Fisher’s exact tests were

applied to perform the frequency analysis. Continuous data were shown as

means± standard deviation (SD). The p values less than 0.05 were reputed as the

statistically significant.


3.6 Study power calculation

The observed power for CK-MB and troponin-I were 0.805 and 0.986,

respectively based on repeated measures ANOVA analysis SPSS. The power

calculation with the sample size of 100, tw0 equal groups, three times of

measurements, and α = 0.05 using G*power 3.1.9.2 were as follows: for CK-MB

with partial eta-square = 0.055 and calculated effect size (F) = 0.241, the power

(1- βerror) was calculated 0.999. Accordingly, the power for troponin-I regarding

the partial eta-square = 0.117 and calculated effect size (F) = 0.364 was calculated

1.0.

Results

Results | P a g e 20

4.1 Demographic data

A total number of 118 patients took part in this study. Among these, 18 patients

were excluded due to elevation of CK-MB/ Troponin I (n=10) 48 hours before

PCI; history of CABG during last three months (n=6) and renal dysfunction (n=2).

At last, 100 patients (control=50 and intervention=50) were included in the study

and their data entered in to the final analysis (Figure 4.1).


Figure 4.1 consort flow diagram of the study

Assessed for eligibility (n=118)

Excluded (n=18)

Randomized

(n=100)

Allocation

Allocated to non-

intervention (n=50)

Received standard

treatment + angioplasty

Allocated to

intervention (n=50)

Received 300 mg

C0Q10 + standard

treatment + angioplasty

Follow-up

and analysis

Followed up and

analysis (n=50)

Received drug-eluted

stent (n=50)

Followed up and

analysis (n=50)

Received drug-eluted

stent (n=50)


More than half of the patients were men (60 % in control and 56 % in intervention

group). The mean±SD for age were 59.4 ±11.3 and 59.8±10.12 in the control and

intervention group, respectively. Demographic and clinical data of the study

groups are shown in Table 4.11.

Table 4.1 Demographic and clinical data of the study patients

Demographic/Clinical data

of patients

Intervention

(n=50)

Control

(n=50)

P value

Age (years), mean±SD 59.8±10.12 59.4±11.3 0.860

Male sex,n(%) 28(56) 30(60) 0.685

Weight (kg), mean±SD 75.9±13.4 78.7±11.3 0.263

Height (cm), mean±SD 164.8±10.5 166.2±22.8 0.711

), mean±SD2(kg/mBody Mass Index 28±5 27.4±3.5 0.470

Serum creatinine (mg/dl), mean±SD 1.1±0.2 1.2±0.22 0.005

Blood urea nitrogen (mg/dl), mean±SD 15.3±4.4 18.4±5.5 0.003

Fasting blood sugar (mg/dl), mean±SD 103.4±22.6 103.3±39.5 0.991

Hemoglobin (g/dl), mean±SD 13.3±1.5 13.3±1.1 0.947

Triglyceride (mg/dl), mean±SD 211.6±107.2 187.3±78.7 0.207

Cholesterol (mg/dl), mean±SD 186.6±46.6 177±38.5 0.264

Low Density Lipoprotein (mg/dl),

mean±SD

110.2±29.7 117.8±28.3 0.217

High Density Lipoprotein (mg/dl),

mean±SD

40±7.3 38.1±5.5 0.140


Figure 4.2 Patients gender in both groups


4.2 Risk Factors

The most important risk factors in patients of both groups were Hypertension and

positive family history for cardiovascular diseases.

Risk factors in patients Intervention

(n=50)

Control

(n=50)

P value

Ejection fraction (%), mean±SD 49.7±7.2 49.9±8.7 0.932

Smoking, n(%) 20(40) 27(54) 0.161

Opium, n(%) 1(2) 1(2) 1

Alcohol, n(%) 0(0) 2(4) 0.495

Diabetes mellitus, n(%) 14(28) 15(30) 1

Hypertension, n(%) 36(72) 37(74) 1

Hyperlipidemia, n(%) 16(32) 8(16) 0.061

Congestive heart failure, n(%) 3(6) 1(2) 0.618

Chronic obstructive pulmonary

disease, n(%)

1(2) 0(0) 1

Other past medical history, n(%) 8(16) 8(16) 1

Positive family history for

cardiovascular diseases, n(%)

31(62) 28(56) 0.542

Previous bypass surgery, n(%) 1(2) 0(0) 1

Previous coronary intervention, n(%) 2(4) 0(0) 0.495

Table 4.2 The incidence of risk factors of the study groups


4.3 Drug History

The most drugs used by patients belonged to cardiovascular agents.

Drug history of patients Intervention

(n=50)

Control

(n=50)

P value

Cardiovascular drug history, n(%) 35(70) 30(60) 0.295

Anti-diabetic drug history, n(%) 13(26) 12(24) 0.817

Anti-lipid drug history, n(%) 18(36) 10(20) 0.075

Psychiatric drug history, n(%) 1(2) 2(4) 1

Other drug history, n(%) 5(10) 2(4) 0.436

Table4.3 Drug history of patients of both groups


4.4 Stented Target

All participants were deployed with drug-eluted stents. The stented target vessels

of the patients were shown in Table 4.4.

The most stented vessels are LAD and RCA.

Table 4.4 Stented target vessels in the study groups

Target vessel Intervention

(N=50)

Control

(N=50)

P value

LAD, n(%) 17(34) 19(38) 0.677

LCX, n(%) 7(14) 3(6) 0.182

OM, n(%) 4(8) 4(8) 1

RCA, n(%) 8(16) 12(24) 0.317

PDA, n(%) 1(2) 1(2) 1

LAD+LCX, n(%) 1(2) 0(0) 1

LAD+OM, n(%) 4(8) 1(2) 0.362

LAD+RCA, n(%) 2(4) 4(8) 0.678

LCX+OM, n(%) 1(2) 1(2) 1

OM+RCA, n(%) 1(2) 1(2) 1

RCA+PDA, n(%) 2(4) 0(0) 0.495

RCA+LAD+LCX, n(%) 1(2) 0(0) 1

LAD+RCA+PDA, n(%) 0(0) 1(2) 1

other, n(%) 1(2) 3(6) 0.617


4.5 CK-MB Results

The baseline level of CK-MB (p=0.184) was not different in both control and

intervention groups. No significant differences in CK-MB levels 8 h (p=0.079)

and 24 h (p=0.242) after PCI were observed in CoQ10 group in comparison at the

control group. The delta mean for changes of CK-MB between baseline and 8 h

after PCI (p=0.760), baseline and 24 h after PCI (p=0.803) and 8 h and 24 h after

PCI (p=0.456) was not significantly different between the two groups (Table 4.5).

Table 4.5 Mean CK-MB level at baseline, 8, and 24 h after PCI in the study groups.

CK-MB levels Intervention

(n=50)

Control

(n=50)

P value

Baseline 20.5±4.1 23±8.6 0.184

At 8 h 23.6±10.9 27.6±18.9 0.079

At 24 h 24.9±13.3 26.7±13.4 0.242

Baseline—8h -3.1±10 -4±20.2 0.760

Baseline—24 h -4.4±13.5 -3.7±13.2 0.803

8–24 h -1.3±9.8 0.35±12 0.456


Figure 4.6 The plasma levels of CK-MB in both groups.


4.6 Troponin I Results

The baseline level of troponine-I in both control and intervention groups was not

statistically different (p=1.44). There was no significant differences in troponine-I

level at 8 h (p=0.062) and 24 h (p=0.826) after PCI in control group when

compared with the CoQ10 treated group. In addition, the delta means of

troponine-I changes between baseline and 8 h after PCI (p=0.881), baseline and

24 h after PCI (p=0.461), 8 h and 24 h after PCI (p=1) were not significantly

different between the two groups (Table 4.6).

Table 4.6 Mean troponin I level at baseline, 8, and 24 h after PCI in the study groups.

Troponin I levels Intervention

(n=50)

Control

(n=50)

P value

Baseline 0.12±0.06 0.2±0.46 1.44

At 8 h 0.2±0.38 0.29±0.47 0.062

At 24 h 0.38±0.6 0.38±0.6 0.826

Baseline—8h -0.08±0.38 -0.09±0.41 0.881

Baseline—24 h -0.25±0.6 -0.17±0.46 0.461

8–24 h -0.17±0.38 -0.17±0.46 1


Figure 4.7 The plasma levels of Troponin I in both groups.


4.7 hs-CRP Results

The baseline hs-CRP level in both groups was statistically different (p=0.004).

Significant difference was also observed in hs-CRP levels at 24 h after PCI in

both groups (p=0.031). In addition, the delta means for changes of hs-CRP

between baseline and 24 h after PCI (p=0.0001) were statistically different

between the two proups (Table 4.7).

Table 4.7 Mean hs-CRP level at baseline and 24 h after PCI in the study groups.

hs-CRP levels Intervention

(n=50)

Control

(n=50)

P value

Baseline 7.6±6.9 5.4±5.6 0.004

At 24 h 6.4±5.6 9.4±7.8 0.031

Baseline—24 h 1.2±3.3 -3.75±4.3 0.0001


Figure 4.8 The plasma levels of hs-CRP in both groups.


4.8 MACE reports

The incidence of MACE was recorded during four-month period. Chest pain was

reported in two patient of control group and two in intervention group. Pacemaker

implantation was reported in one patient of intervention group after 2 month.

Angiography procedure was done in one patient of intervention group two months

after PCI. One of the patients of control group died after 4 month (Table 4.8).

Table 4.8 The incidence of MACE.

Event Intervention

(n=50)

Control

(n=50)

P Value

Chest Pain, (n%) 2(4%) 2(4%) 1

Pace-Maker implantation, (n%) 1(2%) 0(0%) 1

Angiography, (n%) 1(2%) 0(0%) 1

Death, (n%) 0(0%) 1(2%) 1

Discussion

And

Conclusion

Discussion | P a g e 37

5.1 Discussion

What is new in the present study is that this randomized controlled trial was the

first investigation that evaluated the effect of CoQ10 in the prevention of PMI in

patients who undergo elective PCI. This study could not confirm the potential

benefits of CoQ10 in the prevention of PMI in the setting of elective PCI based on

the cardiac biomarkers (CK-MB and troponine-I) changes. However, the results of

hs-CRP evaluation as a marker of inflammation can support the hypothesis of

preventing the PMI in the setting of elective PCI.

According to the new definition proffered on 2007, the incidence of PCI related

MI was 14.5% [8]. The cardiac biomarkers elevation following PCI was reported

31% and 28-32.9% for CK-MB and troponines, respectively [8, 68,69]. Several

meta-analysis studies have elucidated the prognostic significance of cardiac

biomarkers elevation following PCI [8, 68-71]. For instance, in the meta-analysis

including 11 randomized controlled trials with 23,230 patients, the elevation of 1-

3, 3-5 and >5 fold of CK-MB level after PCI, predicted the increased risk of

mortality by 1.5, 1.8 and 3.1 fold, respectively [8]. Also, in some meta-analysis, it

has been clarified that there is an important relationship between the elevation of

CK-MB after PCI and 6-month mortality [70,71]. In another meta-analysis study

of 20 RCTs, including 15,581 patients, the elevation of cardiac troponins after

PCI was clearly related to the increased mortality rate (4.4 vs. 3.3%, p=0.001; OR

1.35) [69].

More than 15 prospectively conducted clinical trials have demonstrated that CRP

is related to the early and late outcomes of patient with acute and chronic ischemic

heart disease and also for those patients at risk for atherosclerosis [54].

PMI is classified into two types (proximal and distal) based on its mechanisms.

The first type or proximal happens due to side branch occlusion (SBO) during

stent replacement or balloon inflation. The second type or distal which has several

mechanisms, is responsible for 50-75% of all PMIs. The thrombotic components

during angioplasty and distal embolization of thrombotic plaque, activation of


coagulation factors which lead to platelet activation and thrombosis formation,

activation of neurohormonal system and coronary vasospasm, the oxidative stress

as a result of the increased amount of some biomarkers like isoprostane-PGF2α

and ischemic-modified albumin, and at last, inflammation which is identified by

elevation of some biomarkers like IL-6 and CRP during angioplasty, are

mechanisms involved in the development of second type [7].

According to the mechanistic basis of PMI, several investigators have studied the

advantages of some medications as a cardio-protective agent in the prevention of

PMI [72-79]. The effect of atorvastatin in the prevention of PMI in patients who

undergo elective PCI have been studied in ARMYDA and NAPLES trials [72,73].

Correspondingly, the beneficial effect of statins on reduction of PMI in the setting

of urgent PCI has been proved in ARMYDA-RECTATURE (reloading of

atorvastatin before PCI), ARMYDA-ACS (loading of atorvastatin) and Yun et al.

(loading of rosuvastatin) trials [62,63,74]. Also, in Merla et al’s meta-analysis on

9 trials, including 4751 patients, the effect of pretreatment with statin in the

prevention of PMI has been elucidated. The incidence of PMI in statin-treated

group and non-statin group was reported 9% and 17.5%, respectively [75].

Furthermore, a large number of studies illustrated the potential role of

propranolol, adenosine, omega-3 and cyclosporine in the prevention of PMI [76-

79].

According to the Piot et al. (pretreatment cyclosporine) [79], Froughinia et al.

(pretreatment omega-3) [78], and Yun et al. (loading of rosuvastatin) [74] studies,

the changes of troponins were not statistically significant which is in agreement

with our study’s results. On the other hand, in these studies CK-MB levels

increased significantly in control groups in comparison with the intervention

groups. Although in the present study, pretreatment with CoQ10 could not

meaningfully decrease CK-MB and troponin-I levels 8h and 24 h after PCI there

was a trend toward the potential benefit of CoQ10. However, in Wang et al’s

study, cosupplementation with vitamin E plus CoQ10 had anti-inflammatory


effects against vascular diseases as judged by CRP concentration (p=0.019) that is

in agreement with our study results[80].

It has been shown that ubiquinone (CoQ10) has a strong influence on at least three

mitochondrial enzymes, which are involved in the oxidative phosphorylation

pathway, and hence, is useful for ATP synthesis required for cell function [10,11].

The ability to improve ATP production, antioxidant activity and membrane

stabilizing properties are some clinical benefits of CoQ10 in prevention and

treatment of heart diseases [9-12]. The antioxidant activity of ubiquinone in

cooperation with vitamin E can be utilized in the prevention of membrane and

plasma lipid damages [13]. The antioxidant, membrane stabilizing characteristics

and free radical scavenging properties of ubiquinone provides protection to

ischemic myocardium by restraining LDL oxidation [9-11]. Protection against

atherosclerosis can be offered by activating smooth muscle cells in rich content of

CoQ10, and by preventing the formation of lipid peroxidation and LDL oxidation

[14-16]. Ubiquinone might have the ability to preserve the integrity of myocardial

calcium, sodium and potassium channels during ischemic attacks. It might

therefore improve cellular integrity during ischemia by activating potassium

channels, in the same way as nicorandil, and decreases cellular calcium due to

channel [17-19].

According to the experimental and clinical benefits of CoQ10 in the treatment of

cardiovascular diseases, with regard to the cost and safety issues, this study was

designed to investigate the CoQ10 benefits in prevention of PMI following PCI.

The result of this study can be justified by some explanations. First, regarding to

the lack of the same studies, the exact timing and dosing of CoQ10 pretreatment

in the prevention of PMI following PCI was not distinguished. Hence, it is

suggested to conduct the same investigations to identify the exact timing and

dosing of CoQ10 in the prevention of PMI following PCI. The longer period and

larger loading doses of CoQ10 pretreatment may lead to the better results.

Secondly, it was a pilot study with small sample size, which could indicate the


non-significant results of the study. Besides, it is obvious that the potential

benefits of CoQ10 would be more evident in large-scale trials. And the third

reason that could affect the result of the study was the probable disparity between

the detection limits of kits. In addition, according to cardiac biomarker’s changes

(CK-MB and troponine), this study failed to support the potential benefits of

CoQ10 in PMI prevention. But the results of hs-CRP evaluation as a marker of

inflammation confirmed the study hypothesis.


5.2 Conclusion

Concerning the diversity of CoQ10’s functions and the mechanisms involved in

the development of PMI following PCI, the study was designed to evaluate the

potential cardioprotective benefits of CoQ10 in the reduction of PMI following

elective PCI. Although the biomarkers changes were not significant in

intervention group which could not confirm our hypothesis, the trend was toward

the potential benefits of CoQ10. On the other hand, the changes of hs-CRP were

statistically significant that can relatively support the potential cardioprotective

effects of CoQ10 in the prevention of PMI following PCI. Thus, the large scale

and long-term trials are required to clarify the potential benefits of CoQ10 in the

prevention of PMI following elective PCI.


5.3 Limitations

There are some limitations to this randomized controlled trial. First, this study was

a single-blind trial. Second, our research had a relatively small sample size and

also we had time and cost restrictions. Thus, the large long-term randomized trials

are required to be conducted to confirm the study’s hypothesis.

Acknowledgments

We would like to thank the Cardiovascular Research Center and Shahid Madani

Heart Center of Tabriz University of Medical Sciences for support of the study.

Conflict of interest

The authors declare that they have no any conflict of interest about this work.

Founding

None.

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References |P a g e 43

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دانشگاه علوم پزشکی تبریز

دانشکده داروسازی

نامه جهت دریافت دکتری عمومی داروسازی پایان

عنوان:

در MB -و آنزیم کراتین کیناز I -بر روی سطح تروپونین قلبی 01ارزیابی اثر کوآنزیم کیو

بیماران تحت انجام آنژیوپلاستی : کارآزمایی بالینی کنترل شده تصادفی

نگارش:

فاطمه هوشمند

اساتید راهنما:

دکتر طاهر انتظاری ملکی

تر ناصر اصلان آبادیدک

اساتید مشاور:

دکتر علیرضا گرجانی

دکتر صمد غفاری

9773شماره پایان نامه: 0931اردیبهشت

خلاصه

میر بیماران وبا مرگ PCI پیروکرهای قلبی افزایش بیومارگذشته، مطالعات طبق : مقدمه

یکی از اهداف مهم در نظر گرفته PCIدارد. بنابراین حفاظت قلبی در حین مستقیم ارتباط

های ایسکمیک قلبی این مطالعه در بیماری 01کوآنزیم کیو با توجه به اثرات بالقوه می شود.

PCIدر برابر آسیب میو کاردی حین 01کوآنزیم کیو برای بررسی اثرات محافظت قلبی

طراحی شد.

MB-و آنزیم کراتین کیناز I-بر روی سطح تروپونین قلبی 01کوآنزیم کیو : ارزیابی اثر هدف

.در بیماران تحت انجام آنژیوپلاستی

صورت تصادفی به دو نفر بود که به 011عداد کل بیماران در این مطالعه : تکار و مواد روش

( تقسیم شدند گروه کنترل فقط درمان استاندارد و گروه 01( و گروه مداخله )01گروه کنترل )

دریافت کردند. برای PCIقبل 01کوآنزیم کیو mg 911مداخله علاوه بر درمان استاندارد ،

بعد از ساعت 31و 8، در وضعیت پایه cTnIو CK-MBارزیابی آسیب میوکارد سطح خونی

PCI و نیز سطح پلاسماییhs-CRP ساعت بعد 31در حالت پایه وPCI .اندازه گیری شد

بیماران تا یک ماه بعد نیز از نظر عوارض قلبی وسیع تحت پیگیری قرار گرفتند.

( =173/1Pساعت ) CK-MB ،8: تفاوت معنی داری بین دو گروه از نظر ها یافته

ساعت 31( و =163/1P) I ،8تروپونین و نیز از نظر PCI( بعد از =313/1Pساعت ) 31و

(836/1P= بعد از )PCI ه مداخله و گروه کنترل پیدا نشد. ولی دو گروه از نظر بین گروhs-

CRP ،31 ( 190/1ساعتP= ) بعد ازPCI .تفاوت قابل توجهی داشتند

های قلبی را نتوانست بیومارکر 01کوآنزیم کیو : در این مطالعهپیش درمانی باگیرینتیجه

شد. بنابراین برای تصمیم گیری hs-CRP دارکاهش دهد. از طرف دیگر باعث کاهش معنی

قطعی نیاز به اجرای مطالعات مشابه با تعداد نمونه بیشتر است.

، بیو مارکر های قلبی ، کراتین آسیب میوکارد حین جراحی ،01کوآنزیم کیو : واژگان کلیدی

.I ،hs-CRP، تروپونین MB-کیناز

أ

مقدمه:

درصد 10آسیب ایسکمیک قلبی موجب مشکلات اقتصادی و سلامتی فراوانی میشود.بیش از

مرگ و میردرکشورهای اروپای شمالی در دهه ی گذشته گزارش شده که ناشی از بیماریهای

درصد 08ایسکمی قلبی و عروقی بوده است. شرایط مشابهی در کانادا وجود دارد و بیش از

ی مربوط به ایسکمی قلبی است. قبل از اینکه بتوانیم آسیب مرگ و میرهای قلبی و عروق

IL-1و TNF-αایسیکمیک قلبی را درمان کنیم ،فاکتورهایی را باید مد نظر قرار دهیم. تجمع

دربافت ایسکمیک علاوه بر اینکه منجربه آسیب مستقیم بافتی میشود،با آزادسازی رادیکالهای

اند. آزاد اکسیژن به اندوتلیوم آسیب میرس

مروری بر متون:

Yamumura و گروهش اولین کسانی بودند که ازCoEnzyme Q10

(Ubiquinoneبرای درمان بیماری های قلبی )- 0373ستفاده کردند. در سال .0عروقی ا

Littarru از ایتالیا و گروهش کمبودCoQ10 در بیماری قلبی در بیماران با عمل

bypass .اثبات کردند

Stocker کارانش برای اولین بار نشان دادند که و همCoQ10 میتواند باعث مهار آترو

اسکلروزیس شود.

را روی عملکرد اندوتلیوم در افراد با Q10و همکارانش اثر مثبت کو آنزیم Littaruاخیراً

مشکلات شریان کرونر نشان دادند.

ب

CoQ10 خصوص سلول یک ترکیب طبیعی در رژیم غذایی است که توسط همه سلول ها به

های عضلانی سنتز میشود. این ترکیب از اسید آمینه تیروزین سنتز میشود که یک فرآیند چند

ویتامین و چندین فوتوکمیکال است. 8مرحله ای نیازمند حداقل

در سلول CoQ10می شود. کمبود CoQ10فقدان هر کدام از موارد مذکور سبب فقدان

عروقی می تواند در ریتم شبانه روزی این سلول ها اختلال ایجاد کند .-های عصبی وقلبی

Hiasa آزمایشی جهت کنترل وضعیت بیماران آنژینی انجام داد. در این آزمایش در بیمارانی

مصرف میکردند در مقایسه با پلاسبو زمان ورزش افزایش یافت. CoQ10که

بدون اینکه بر ریت قلبی تأثیر داشته باشد، می تواند CoQ10د که در نهایت نتیجه این ش

پنج آزمایش برای اثبات مطالب مذکور 0330تا 0381شود. از سال STباعث افزایش موج

.انجام شده است

از طریق برقراری فسفریلاسیون اکسیداتیو و تولید CoQ10شواهد بر این است که درمان با

ATPمقابل ایسکمی میشود. باعث محافظت قلب در

می تواند باعث مهار ترومبوز از طریق مهار بیان CoQ10مطالعات حاکی از آن است که

( داشته باشد.AMIرسپتور ویترونکتین شود و اثر مثبتی بر درمان انفارکتوس میوکارد حاد )

در ونیز اختلال CoQ10مطالعات فراوانی نشان داده است که استاتین ها سبب کاهش سطح

زنجیره انتقال انرژی در میتئکندری شده و در نهایت منجر به میوپاتی می گردد.

در نهایت برای جلوگیری از این سمیت استاتین ها می توان میزان دوز این داروها را کاهش داد

را به رژیم دارویی افزود. CoQ10و

ج

برابر حد 9(به بیشتر ازCK-MBو -Iافزایش بیومارکرهای قلبی)تروپونین ACCبر اساس تعریف

برابر آنزیم ها نکروز درنظر 0-9نرمال انفارکتوس در نظر گرفته می شود،در حالی که افزایش

گرفته می شود. مطالعات اولیه ذکر می کردند که این افزایش سطح بیومارکرهای قلبی فقط

نشان می دهد یک نشت ساده آنزیمی بدون درگیری طولانی مدت می باشد ولی مطالعات اخیر

در کوتاه مدت،میان مدت وبلند مدت با PCIکه افزایش آنزیم ها بعد از انجام آنژیوگرافی و

پیامدهای جانبی و به خصوص مرگ ومیر ارتباط معنی داری دارد.

توصیه می کند در تمامی بیماران بدون در نظر گرفتن علایم،اندازه ACC/AHAگاید لاینهای

به طور روتین برای ارزیابی افزایش آنها انجام PCIساعت بعد از 8-03گیری بیومارکرهای قلبی

شود.

با افزایش PCIدر بیماران تحت CK-MBچندین مطالعه نشان داده است که افزایش اندک

به CK-MBبرابری 0-3مرگ ومیر در آنها در ارتباط است، نشان داده شده است افزایش

بیشتر از سطح نرمال یک ریسک فاکتور غیر مستقیم برای مرگ و میر است،در حالی که

9به کمتر از CK-MBبرابری آن ریسک فاکتور مستقیم مرگ و میر است.افزایش 9افزایش

می تواند با افزایش مرگ و میر در بیماران دارای سایر ریسک فاکتورهای برابر سطح نرمال

بیماری های قلبی در ارتباط باشد.

مشخص شد که بار ultrasoundبا تصاویر داخل عروقی PCIبیمار تحت 3306در مطالعه

ز بعد ا CK-MBپلاک)میزان پلاک( می تواند به عنوان نشانه ای برای برای پیش بینی افزایش

PCI عمل کند. همچنین ارتباط خطی قوی بین افزایش بیومارکرهای قلبی وسایز آسیب غیر

د

post proceduralقابل برگشت قلبی وجود دارد ونیز رابطه خطی بین مرگ و میر و افزایش

CK-MB . وجود داردFeldman برابر سطح تروپونین 0و همکارانش نشان دادند که افزایش

I ن مرگ و میر در طولانی مدت در ارتباط است. مطالعه تصاویر با افزایش میزاmagnetic

resonance ارتباط مستقیم بین افزایش تروپونین-I قابل برگشت قلبی را نشان و آسیب غیر

. در کل افزایش بیومارکرهای قلبی منجر به گسترش وناپایداری بار آترواسکلروتیک می می دهد

.های آینده مستعد می کند ایسکمی شود که بیمار رابرای

و وقوع حوادث قلبی عروقی CRPبین افزایش سطح داریدر مطالعات فراوانی ارتباط معنی

چنین افزایش این فاکتور ارتباط مستقیمی با افزایش مرگ و میر به نشان داده شده است. هم

حاد ومزمن و نیز صورت کوتاه مدت و بلند مدت در بیمارانی که در خطر ابتلا به ایسکمی قلبی

بیمارانی که دچار آترواسکلروز هستند وجود دارد.

بر روی سطح CoEnzyme Q10اثر بر اساس مطالعات فوق هدف از این مطالعه بررسی

در بیماران ایسکمیک قلبی تحت انجام MB -و آنزیم کراتنین کیناز I -تروپونین قلبی

می باشد. آنژیوگرافی

ه

نمونه:

سال که فرم رضایت نامه 08نفرازبیماران بالای 011این مطالعه به صورت پایلوت بر روی

به مرکز تحقیقاتی و درمانی شهید مدنی تبریز، ایران PCIاخلاقی را تکمیل نموده و برای

مراجعه کرده اند ، به صورت تصادفی و با روش تصادفی سازی سیستماتیک و اعداد حاصله از

و گروه کنترل تقسیم CoEnzyme Q10نفری گروه تحت درمان با 01و گروه کامپیوتر به د

انفارکتوس حاد ،mg/dl 3کراتینین سرم بالای فاکتورهای خروج از مطالعه شامل میشوند .

سابقه نارسایی کلیوی مرحله آخریا دیالیز ، شوک کاردیوژنیک، سندرم کرونری ناپایدار ،میوکارد

عروق اصلی branchانجام آنژوپلاستی وتعبیه استنت بیمارانی که در حین و شدن

compromise .میشود

روش کار:

اطلاعات دموگرافیک، بالینی، آزمایشگاهی و درمانی اولیه بیماران از طریق بررسی پرونده

ن اطلاعات پزشکی بیماران و مصاحبه حضوری با آن ها در فرم مخصوص ثبت می گردد. ای

سابقه بیماری/ بیماریها، سابقه مصرف دارویی، داروهای مصرفی سن، جنس، وزن، قد، شامل

باشد.می کنونی )نام، شکل دارویی، دوز، مسیر و فواصل تجویز، تاریخ شروع و پایان مصرف(

همه ی بیماران همان پروتکل معمول آماده سازی برای آنژیو پلاستی را که شامل هیدراسیون

⧵ccکنند .هیدراسیون با نرمال سالینقبل و بعد جراحی میباشد دریافت می 𝑘𝑔0.0- 0 6 از

CoEnzyme Q10ساعت بعد عمل انجام میشود.در گروه تحت درمان 6ساعت قبل عمل تا

تجویز می شود ارزیابی های پاراکلینیکال در آزمایشگاه PCIقبل از mg911 با دوز

و

بیماران و پروتکل مطالعه ناآگاه بیمارستانی انجام می شود و کارکنان آزمایشگاه نسبت به

هستند.آنژیوپلاستی کرونری با استفاده ازماده کنتراست ایزو اسمولار غیر

Iopramide یا( vesipaque320- GE.healthcare.corl20Irelandیونی)

(ultravist300.scheringAG.Gerinang) نوع ماده کنتراست بوسیله کاردیولوژیست

Interventional که جراحی را انجام می دهد انتخاب شده است در همه ی بیماران سطح

-hsونیز سطح PCI از ساعت بعد 31و 8ساعت قبل و CK-MB 03وIسرمی تروپونین قلبی

CRP ساعت بعد 31در حالت پایه وPCI اندازه گیری می برای بررسی میزان آسیب قلبی

شود.

نتایج:

نفر به دلیل سطح بالای 08بیمار در مطالعه شرکت کردند که از بین آنها 011در کل

نارسایی و PCIماه قبل از 9پس قلبی ی بایسابقه، PCIساعت قبل 18بیومارکرهای قلبی

شدند و اطلاعات آنها آنالیز شد. بیمار وارد مطالعه 011کلیوی از مطاله خارج شدند. نهایتا

در گروه مداخله( که نشان دهنده شیوع %06در گروه کنترل و %61) مرد بودند اکثر بیماران

بیشتر بیماریهای قلبی و عروقی در مردان است.

های قلبی عروقی و فشارخون ریسک فاکتورهای عمده در هر دو گروه سابقه خانوادگی بیماری

ه داروهای قلبی عروقی بود. بالا بودند. بیشترین داروهای مصرفی در هر دو گروه متعلق به دست

در تمامی بیماران نوع استنت بکار رفته، دارویی بود.

ز

RCAو LADعروقی که بیشترین استنت گذاری روی آنها انجام شده در هر دو گروه به ترتیب

بودند.

CK-MB (081/1پایه در هر دو گروه ازمشابه بود=P در. )CK-MB 8 ساعت بعد از 31وPCI

ساعت بعد 8و مداخله تفاوت معنی داری نداشتند. میانگین تفاوت مقادیر پایه ودو گروه کنترل

PCI (761/1P=مقادیر پایه و ،)ساعت بعد 31PCI (819/1P= و مقادیر )ساعت بعد 31و 8

PCI (106/1P= )بین گروه کنترل و مداخله معنی دار نبود.

(. میانگین تفاوت =11/0Pدر هر دو گروه در حالت پایه بی معنی بود ) Iتغییرات تروپونین

و PCI (160/1P=)ساعت بعد 31، پایه و PCI (880/1P=)ساعت بعد 8مقادیر مقادیر پایه و

( معنی دار نبود.=0P) PCIساعت بعد 31و 8مقادیر

(. میانگین =111/1Pداری داشت )در حالت پایه برای هر دو گروه تفاوت معنی hs-CRPسطح

(.=1110/1Pمعنی دار بود ) PCIساعت بعد 31تفاوت مقادیر پایه و

: گیرینتیجه بحث و

مکانیسم های متعددی در گسترش آسیب میوکارد حین جراحی دخیل هستندکه عبارتند از:

مثل انسداد شاخه جانبی ناشی از باد کردن بالون یا جایگذاری استنت، آمبولی دیستال پلاکهای

هورمونی و استرس -آترومی، فعال سازی پلاکت و تشکیل ترومبوز، فعال سازی عصبی

استفاده PCI به همین دلیل بعضی از داروها بعنوان محافظ قلب قبل از اکسیداتیو و التهاب.

.می شوند

ح

ساعت I 8وتروپونین CK-MB نتوانست سطح 01کوآنزیم کیودر این مطالعه پیش درمانی با

به طور معنی داری کاهش دهد، elective PCIرا در بیماران تحت PCIساعت بعد از 31و

بود ولی از 01کوآنزیم کیوبه نفع اثرات سودمند PCIمارکر ها بعد از هر چند روند تغییرات بیو

توانست به 01عنی دار نرسید. از طرف دیگر پیش درمانی با کوآنزیم کیونظر آماری به سطح م

تواند تا حدودی فرضیه را در گروه مداخله کاهش دهد که می hs-CRPداری سطح طور معنی

در این مطالعه می توان به حجم نمونه کوچک و ها احتمالی یافتهمطالعه را تایید کند. از علل

01کوآنزیم کیوتوانایی تشخیصی محدود کیت ها اشاره کرد. از طرفی زمان و دوز پیش درمانی

به طور دقیق در مطالعات مشخص نشده است و شاید انجام مطالعات در مقیاس وسیع تر بتواند

ن کند و بتوان قطعی تر تصمیم گرفت.برامحدودیت های مطالعه حال حاضر را ج

Tabriz University of Medical Sciences Faculty of Pharmacy

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