EFFECT OF HIGH CORONARY CALCIUM SCORE ON THE ASSESSMENT OF CORONARY ARTERY DISEASE USING CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY: AN INVESTIGATION OF

Transcription

1 EFFECT OF HIGH CORONARY CALCIUM SCORE ON THE ASSESSMENT OF CORONARY ARTERY DISEASE USING CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY: AN INVESTIGATION OF THE CLINICAL VALUE OF 3D VIRTUAL INTRAVASCULAR ENDOSCOPY DR WOO SZE YANG MASTER OF RADIOLOGY UNIVERSITY OF MALAYA

2 EFFECT OF HIGH CORONARY CALCIUM SCORE ON THE ASSESSMENT OF CORONARY ARTERY DISEASE USING CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY: AN INVESTIGATION OF THE CLINICAL VALUE OF 3D VIRTUAL INTRAVASCULAR ENDOSCOPY By DR WOO SZE YANG M.B.B.S. INTERNATIONAL MEDICAL UNIVERSITY (IMU) 2008 Submitted to the Department of Biomedical Imaging Faculty of Medicine, University of Malaya in partial fulfilment of the requirement for the Degree of MASTER OF RADIOLOGY Year 2017

3 TABLE OF CONTENTS PAGES DISCLAIMER... I ACKNOWLEDGEMENT... II ABSTRACT... III LIST OF TABLES... V LIST OF FIGURES... VII ABBREVIATIONS AND ACRONYMS...IX CHAPTER ONE INTRODUCTION... 1 CHAPTER TWO OBJECTIVES GENERAL OBJECTIVE SPECIFIC OBJECTIVES... 4 CHAPTER THREE LITERATURE REVIEW ANATOMY AND PHYSIOLOGY OF THE HEART CORONARY ARTERY DISEASE IMAGING MODALITIES CHAPTER FOUR METHODOLOGY STUDY DESIGN PATIENT SELECTION AND FOLLOW UP CCTA IMAGING TECHNIQUE CCTA DATA EVALUATION VIRTUAL INTRAVASCULAR ENDOSCOPY (VIE) DATA EVALUATION... 44

4 4.6 INTRAVASCULAR CORONARY ANGIOGRAPHY (ICA) EVALUATION STATISTICAL ANALYSIS CHAPTER FIVE RESULTS PATIENT DEMOGRAPHICS PREVALENCE OF CORONARY ARTERY DISEASE RISK FACTORS COMPARISON OF CALCIUM SCORES FOR DIFFERENT CAD RISK FACTORS PREVALENCE OF CORONARY ARTERY STENOSIS ACCORDING TO SEVERITY AND NUMBER OF VESSELS INVOLVED PREVALENCE OF CLINICAL AND TREATMENT OUTCOME COMPARISON OF DEGREE OF STENOSIS BETWEEN CCTA AND ICA COMPARISON OF CORONARY STENOSIS BETWEEN VIE AND ICA RESULTS FROM GENERATION OF VIE IMAGES FROM CCTA CHAPTER SIX DISCUSSION CHAPTER SEVEN LIMITATIONS OF STUDY AND FUTURE DEVELOPMENTS LIMITATIONS OF STUDY FUTURE DEVELOPMENTS CHAPTER EIGHT CONCLUSION REFERENCES APPENDICES APPENDIX A APPENDIX B APPENDIX C APPENDIX D

5 DISCLAIMER I declare that this dissertation records the result of the study performed by me and that it is of my own composition. DR. WOO SZE YANG Date: 28 th February I

6 ACKNOWLEDGEMENT I would like to express my thanks and appreciation to my thesis supervisor Professor Dr Yang Faridah Abdul Aziz and Professor Dr Ng Kwan Hoong for the continuous support throughout my Master of Radiology study as well as providing their extensive knowledge and guidance in successfully completing my thesis. Without their enthusiasm, encouragement, support and optimism this thesis would not have been completed. My sincere gratitude to Professor Sun Zhong Hua (Professor of Medical Imaging, Curtin University, Australia) and Dr Nor Ashikin Md Sari (Cardiologist, Department of Medicine, University of Malaya, Malaysia). Their guidance in their respective field have helped me immensely in providing insight and steered me to the right direction whenever I needed it. I also want to express my warmest gratitude to Dr Yeong Chai Hong who has made available her support especially during the crucial times. With her committed participation and input, my thesis and data analysis have been successfully conducted. Special appreciation is also directed to the UMRIC members for their assistance in completing my thesis. Finally, I am thankful to my family especially to my beloved wife, Dr Rachel Wong Su Gwen for her continuous guidance, help and love throughout my course of my Master of Radiology study and in completing my thesis. I am forever indebted to my parents for giving me the opportunities and experiences that have shaped me who I am today. This journey would not have been possible if not for them. II

7 ABSTRACT Objectives: The objective of the study is to investigate the relationship between a high calcium score of > 400 and the diagnostic capability of coronary computed tomography angiography (CCTA) in comparison with the conventional invasive coronary angiogram. Secondary objectives are to investigate the diagnostic value of 3D virtual intravascular endoscopy (VIE) in patients with high calcium score with regards to the coronary wall changes from coronary plaques and assessment of coronary lumen stenosis. Method: Over a period of 3 years and 6 months, 103 patients underwent coronary calcium score and CCTA. A questionnaire regarding associated cardiac risk factors and clinical outcome was provided to each patient and demographic data was collected. A total of 35 patients subsequently underwent invasive coronary angiography (ICA) for further evaluation and management. Out of these patients whom underwent ICA, coronary 3D VIE reconstruction and evaluation was done for 14 patients. Three main coronary artery branches were assessed for coronary artery stenosis. Degree of coronary artery stenosis was measured and comparison was made between CCTA with ICA as the gold standard. Subsequently, comparison was also made between VIE and ICA for the assessment of coronary artery stenosis. Reconstruction and analysis of VIE images were done in Australia by an experienced professor in medical imaging. Subsequently statistical analysis comparing the coronary artery stenosis for CCTA, VIE and ICA were done. III

8 Results: There was reduced sensitivity of CCTA compared to ICA in determining distal left circumflex artery stenosis at 50.0%; however the accuracy is significantly high at 84.0%. The overall sensitivity, specificity and accuracy in the rest of the coronary vessels were not significantly reduced in this group of patients with high calcium score ranging from 62.5% %, 54.2% % and 61.8% % respectively. Specificity of VIE in determining LAD artery stenosis was significantly low at 20%, however the sensitivity and accuracy were high at 100% and 92.3% respectively (p = 0.125). The sensitivity, specificity and accuracy for the left circumflex artery (p = 1.000) and right coronary artery (p = 1.000) were not significantly reduced. Additional information of the coronary wall changes can be obtained via VIE based on the composition of coronary plaques. A smooth intraluminal appearance on VIE is usually observed for a simple calcified or non-calcified plaque. However, irregular intraluminal appearance is seen in heavily calcified or mixed calcified and non-calcified plaques. Conclusion: A high calcium score of > 400 does not significantly reduced the accuracy, sensitivity and specificity of CCTA; however, it decreases the sensitivity of detecting significant stenosis at the distal left circumflex artery. VIE images clearly demonstrate the coronary wall changes with significant accuracy and sensitivity in determining significant coronary artery stenosis. Therefore, VIE could be used as a complementary tool to CCTA for coronary artery analysis. Keywords: 3D Virtual intravascular endoscopy, coronary artery stenosis, coronary CT angiogram, coronary wall changes, high calcium score, invasive coronary angiography. IV

9 LIST OF TABLES PAGES Table 1: Calcium score guidelines and recommendations. 32 Table 2: Coronary artery stenosis detection of between CCTA/VIE and ICA. 49 Table 3: Prevalence of severity of coronary artery stenosis in CAD. 62 Table 4: Prevalence of main coronary arteries with significant stenosis in CAD. 64 Table 5: Prevalence of patients with/without chest pain post CCTA. 65 Table 6: Prevalence of patients underwent cardiac intervention post CCTA. 66 Table 7: Degree of stenosis of proximal LAD artery between CCTA and ICA. 68 Table 8: Degree of stenosis of mid LAD artery between CCTA and ICA. 69 Table 9: Degree of stenosis of distal LAD artery between CCTA and ICA. 69 Table 10: Degree of stenosis of proximal LCX artery between CCTA and ICA. 70 Table 11: Degree of stenosis of mid LCX artery between CCTA and ICA. 70 Table 12: Degree of stenosis of distal LCX artery between CCTA and ICA. 71 Table 13: Degree of stenosis of proximal RCA between CCTA and ICA. 71 Table 14: Degree of stenosis of mid RCA between CCTA and ICA. 72 Table 15: Degree of stenosis of distal RCA between CCTA and ICA. 72 Table 16: ROC results of the degree of stenosis between CCTA and ICA. 73 Table 17: p-value for significant stenosis detection between CCTA and ICA. 74 Table 18: Degree of stenosis of LAD artery between 3D-VIE and ICA. 75 Table 19: Degree of stenosis of LCX artery between 3D-VIE and ICA. 75 Table 20: Degree of stenosis of RCA between 3D-VIE and ICA. 76 V

10 LIST OF TABLES PAGES Table 21: ROC results of the degree of stenosis between VIE and ICA. 76 Table 22: p-value for significant stenosis detection between VIE and ICA. 77 VI

11 LIST OF FIGURES PAGES Figure 1: Anatomy and location of the heart. 7 Figure 2: Anatomy of the heart. 9 Figure 3: Chambers and circulation of the heart. 10 Figure 4: Coronary vessels from the anterior and posterior heart views. 15 Figure 5: The cardiac conduction system. 18 Figure 6: Cardiac enzymes. 25 Figure 7: Flow chart of data collection and analysis. 40 Figure 8: Recommended quantitative grading of coronary artery stenosis by CCTA. 44 Figure 9: Coronary VIE views of the left main stem, LAD and LCX arteries. 45 Figure 10: Coronary VIE view of the RCA. 46 Figure 11: Recommended quantitative grading of coronary artery stenosis by ICA. 48 Figure 12: Age distribution of patients in the study. 52 Figure 13: Ethnicity distribution of patients in the study. 52 Figure 14: Sex distribution of patients in the study. 53 Figure 15: Prevalence of CAD risk factors. 54 Figure 16: Prevalence of CAD risk factors according to sex. 55 Figure 17: Box plot showing comparison of calcium score with history of smoking. 56 Figure 18: Box plot showing comparison of calcium score with diabetes mellitus. 57 Figure 19: Box plot showing comparison of calcium score with dyslipidaemia. 58 Figure 20: Box plot showing comparison of calcium score with hypertension. 59 VII

12 LIST OF FIGURES PAGES Figure 21: Box plot showing comparison of calcium score with history of stroke. 60 Figure 22: Box plot showing comparison of calcium score with family history of CAD. 61 Figure 23: Prevalence of severity of coronary artery stenosis in CAD. 63 Figure 24: Prevalence of main coronary arteries with significant stenosis in CAD. 64 Figure 25: Prevalence of patients with/without chest pain with CAD. 67 Figure 26: Prevalence of patients with/without chest pain underwent cardiac intervention. 67 Figure 27: Coronary VIE views of LAD artery plaque with smooth luminal appearance. 79 Figure 28: Coronary VIE views of LCX artery plaque with smooth luminal appearance. 79 Figure 29: Coronary VIE views of RCA plaque with smooth luminal appearance. 80 Figure 30: Coronary VIE views of LAD artery plaque with irregular luminal appearance. 80 Figure 31: Coronary VIE views of LCX artery plaque with irregular luminal appearance. 81 Figure 32: Coronary VIE views of RCA plaque with irregular luminal appearance. 81 Figure 33: CCTA and VIE views of a calcified plaque at the LAD artery. 87 Figure 34: CCTA and VIE views of extensively calcified plaques at the LAD artery. 88 Figure 35: CCTA and VIE views of mixed plaques at the LAD artery. 88 VIII

13 ABBREVIATIONS AND ACRONYMS 2D 2 Dimensions 3D 3 Dimensions 3D VIE 3 Dimension Virtual Intravascular Endoscopy ACS Acute coronary syndrome AV node Atrioventricular node CABG Coronary artery bypasses graft CAC Coronary artery calcium CAD Coronary artery disease CCTA Coronary computed tomography angiography CK Creatinine kinase CT Computed tomography DICOM Digital imaging and communications in medicine EBCT Electron-beam computed tomography ECG Electrocardiography FRS Framingham Risk Score GRACE Global Registry of Acute Coronary Events GTN Glyceryl trinitrate HDL High-density lipoprotein ICA Invasive coronary angiography IX

14 LAD artery Left anterior descending artery LBBB Left bundle branch block LCX artery Left circumflex coronary artery LDL Low-density lipoprotein MDCT Multidetector computed tomography mgy miligray MI Myocardial infarction MIP Maximum intensity projection MPR Multiplanar reconstruction MRI Magnetic resonance imaging NSTEMI Non-ST elevation myocardial infarction PET Positron emission tomography RCA Right coronary artery ROC Receiver operating characteristic SA node Sinoatrial node SPECT Single-photon emission computed tomography SPSS Statistical Package for Social Sciences STEMI ST elevation myocardial infarction UA Unstable angina WHO World Health Organization X

15 CHAPTER ONE 1.0 INTRODUCTION Coronary artery disease (CAD) is a known cause of mortality and morbidity with the disease reaching endemic proportions (1). It is the most important cause of death in Malaysia with the mortality rate of 20-25% in public hospitals (2). The gold standard investigative diagnosis for CAD is invasive coronary angiography (ICA) as it provides an assessment of the coronary anatomy as well as the degree of luminal stenosis. However, the limitation of coronary angiography is that it is an invasive procedure with a potential for complications such as periprocedural myocardial infarction (0.1%) and stroke ( %) (3). Furthermore, it only offers a two dimensional visualization of the coronary lumen and is unable to demonstrate the atherosclerotic changes within the vessel wall which is important when correlating with the clinical outcome (4). Due to technological advances in computed tomography (CT) scanner over the recent years, coronary computed tomographic angiography (CCTA) has emerged as a less invasive imaging modality for coronary artery assessment with high sensitivity and negative predictive value in determining the site and degree of coronary artery luminal stenosis (5-7). In addition, CCTA enables visualization and quantitative assessment of atherosclerotic plaques thus assisting in characterization of the different types of plaque (7). As CCTA rapidly expands, this technique will be utilized in predicting patients with high risk of cardiac events and in assisting in the management of patients based on the morphological features of plaques and coronary luminal stenosis (6). 1

16 Despite the very high negative predictive value of CCTA, the diagnostic accuracy of CCTA is limited by extensive coronary artery calcification when present (taken as coronary calcium score >400), resulting in blooming artefacts. These blooming artefacts will cause the calcified lesions to appear larger in size and leading to a perceived narrower coronary lumen (7). However, it still remains a controversy that a high calcium score should be regarded as a limiting factor on whether a patient warrants a CCTA scan. The main impact of a high calcium score on the diagnostic capability of CCTA is due to overestimation of coronary luminal stenosis which results in a high false positive finding. Multiple studies have concluded that there is a significant reduction in specificity in patients with a high calcium score >400 as compared to other patients with calcium score <400 (8). Alternatively, Chen et al. (9) found that the overall diagnostic accuracy for a coronary artery assessment in a patient with a high calcium score was not drastically impaired with no significant difference in sensitivity. The main objective of this study is to determine the diagnostic capability of CCTA and to correlate the clinical outcomes of these patients with high calcium scores. The CCTA offers 2D axial and multiplanar reformatted images for the assessment of the coronary plaques. However, it still lacks the direct visualization of the coronary artery lumen of plaques (if present) that is afforded by ICA. This limitation can be overcome by using a reconstruction tool known as 3D virtual intravascular endoscopy (3D VIE) which is purported to be able to provide a more extensive diagnostic evaluation of the coronary tree (6). With this imaging tool, a more accurate assessment can be done with regards to the plaque location in relation to the coronary ostium, plaque composition and coronary wall stenosis due to the presence of plaque within the coronary artery. Identification of intraluminal appearances of calcified plaques is considered to allow more accurate assessment of coronary stenosis by detecting superficial and deep calcified plaques (7). This study will also investigate the feasibility of using 3D VIE as a supplementary tool to CCTA and determine the accuracy of assessing coronary lumen stenosis in patients with high calcium score. 2

17 Since CCTA is continuously evolving, hopefully in the near future this technique will become a mainstay in CT scanning and be used as risk stratification for patients developing cardiac events, based on the plaque morphology and associated coronary lumen changes (6). 3

18 CHAPTER TWO 2.0 OBJECTIVES 2.1 GENERAL OBJECTIVE To evaluate the diagnostic values of CCTA for the assessment of coronary artery disease in patients with high calcium score in comparison with the conventional invasive coronary angiogram. 2.2 SPECIFIC OBJECTIVES a) To investigate the diagnostic value of 3D VIE in the visualisation of coronary wall changes due to the effect of coronary plaques in high CAC scores b) To correlate 3D VIE findings with conventional 2D and 3D visualisations in terms of the degree of coronary lumen stenosis or occlusion caused by high CAC scores c) To explore the potential role of 3D VIE as a supplementary tool to conventional coronary CT angiography in improving diagnostic evaluation of patients with high CAC scores d) To investigate the relationship between the CCTA and the clinical outcome of these patients with high CAC scores 4

19 CHAPTER THREE 3.0 LITERATURE REVIEW 3.1 ANATOMY AND PHYSIOLOGY OF THE HEART Anatomy of the heart The heart is one of the most important organs in the human body. Heart is shaped almost similar to a pyramid, wide superiorly and tapering towards the apex. Size of a heart is approximately that of a closed fist. The weight of an average heart is between 7 and 15 ounces (200 to 425 grams), depending on the size of the human host. The normal rate of contraction of the heart ranges from beats per minute. Given the average rate of contraction of 75 beats per minute, a human heart expand and contract about 108,000 times in one day, more than 39 million times in one year and nearly 3 billion times during an average 75 year lifespan. This equates to approximately 70 ml of blood per contraction in a resting adult in each of the heart chamber. That in turn would be equal to 5.25 litres of blood per minute and approximately 14,000 litres per day and 10,000,000 litres over a year. The main function of the heart is that of the body s circulatory pump. The heart consists of the right and left atrium and right and left ventricle. In summary, the right atrium accepts deoxygenated blood via the veins, flows to the right ventricle and delivers to the lungs for oxygenation. The oxygenated blood is then returned to the left atrium which subsequently 5

20 flows to the left ventricle before pumping it into the various arteries to deliver the oxygen and nutrition to the entire body Location of the heart The heart is located in the middle of the thoracic cavity known as the middle mediastinum. It lies obliquely in between the right and left lungs. The oblique nature of the heart causes the ventricles to locate antero-inferiorly to the atria. As the heart is rotated clockwise about its axis, the right atrium and ventricle is higher than the left atrium and ventricle. The base or posterior aspect of the heart is formed by the left atrium while the anterior aspect is formed by the right ventricle. Right border of the heart is formed by the right atrium while the left border and apex is formed by the left ventricle. Inferior aspect of the heart is formed by both ventricles anteriorly and right atrium posteriorly. The posterior aspect of the heart is in close approximation to the thoracic vertebral bodies while the anterior aspect of the heart is located just behind the sternum and costal cartilages. Figure 1 shows the anatomy and location of the heart within the thoracic cavity. 6

21 Coronal view Figure 1: Anatomy and location of the heart (Adapted from Anatomy and Physiology, OpenStax CNX) (10). 7

22 3.1.3 Heart chambers The heart is divided into the left and right heart which contains two main chambers in each side. There are one atrial and one ventricular chamber in each side. The upper chambers which consists of the right and left atrium serves as a receiving chamber for blood and contracts to divert the blood to the lower chambers which are the right and left ventricles. The ventricles function as the main pumping mechanism to supply blood to the lungs via the right ventricle and rest of via the left ventricle. The right atrium receives blood that returns from the systemic circulation via two major systemic veins, the superior and inferior vena cava as well as the coronary sinus. The superior vena cava empties into the superior and posterior surface of the right atrium while the inferior vena cava also empties into the posterior surface of the atrium, but inferior to the opening of the superior vena cava. The opening of the coronary sinus is located superior and medial to the opening of the inferior vena cava on the posterior surface of the atrium. Function of the coronary sinus is to return systemic blood from the heart. The atrium receives continuous venous flow and pump blood into the right ventricle prior to ventricular contraction. The blood flow between the right atrium and ventricle is controlled by the tricuspid valve. The right ventricle receives blood during contraction of the right atrium through the tricuspid valve. When the right ventricle is filled with blood and begins to contracts, there is increased in intraventricular pressure. To prevent backflow of blood into the right atrium, the papillary muscles also contract causing tension to the chordae tendineae which holds the closed valve in place. Therefore, blood flows towards the pulmonary trunk through the patent pulmonary semilunar valve at the base of the pulmonary trunk into the pulmonary circulation. Figure 2 shows papillary muscles and chordae tendineae attached to the tricuspid valve. 8

23 The left atrium receives highly oxygenated blood via one of the right or left pulmonary veins which are further divided into the superior and inferior pulmonary veins. There is continuous blood flow from the pulmonary veins into the atrium and subsequently into the left ventricle during the relaxation phase. Near the end of the ventricular relaxation phase, the left atrium will contract to send blood into the left ventricle. The blood flow between the left atrium and ventricle is controlled by the mitral valve. The left ventricle has a thicker muscular layer than the right ventricle. Similar to the tricuspid valve, the mitral valve is connected to the papillary muscle via the chordae tendineae. The main function of this ventricle is to pump blood to the thoracic aorta through the aortic semilunar valve to the systemic circulation. Figure 2: Anatomy of the heart. The atrioventricular septum has been removed to show the bicuspid and tricuspid valves (Adapted from Anatomy and Physiology, OpenStax CNX) (10). 9

24 3.1.4 Pulmonary and systemic circulations The human blood circulation is divided into the pulmonary and systemic circulations which are inadvertently linked to each other. The circulation carries blood and its contents to be delivered to their respective organs. One of the main functions for these circulations are the exchange of oxygen and carbon dioxide gasses. The pulmonary circulation starts with the right ventricle transporting deoxygenated blood with carbon dioxide to the lungs via the pulmonary trunk which bifurcates into the left and right pulmonary arteries and further divides before reaching the pulmonary capillaries. Here, deoxygenated blood is exchanged for oxygenated blood which is then returned back to the heart via the pulmonary capillaries to merge to become the pulmonary veins. The pulmonary veins transport the oxygenated blood to the left atrium which then contracts to send the blood to the left ventricle. The left ventricle contracts to send oxygenated blood to the aorta which branches into many smaller arteries to supply the systemic circulation of the head, neck and rest of the body. As these systemic arteries branches further, these vessels will finally lead to the systemic capillaries of each individual organ. Oxygen and nutrients will be used by these organs for their metabolite process and carbon dioxide and waste products are returned to the systemic circulation. The systemic capillaries then combine to form larger systemic veins, finally arriving into two large veins which are the superior and inferior vena cava that returns the blood back to the right atrium. The right atrium then contracts to send the blood to the right ventricle to begin the pulmonary circulation process. Figure 3 shows the heart chambers and circulation. 10

25 Figure 3: Chambers and circulation of the heart (Adapted from Anatomy and Physiology, OpenStax CNX) (10) Coronary anatomy and circulation The heart is essentially a pumping machine made out of cardiac muscle cells or cardiomyocytes that requires to be constantly active throughout its lifetime. The heart delivers oxygenated blood and nutrients to many cells in the human body including to its cardiomyocytes. Due to the continuous activity of the heart, the supply of oxygenated blood 11

26 is more crucial compared to other typical cells in the body. Therefore it has its own complex and extensive circulation called the coronary circulation to do this job. The coronary circulation is a cycle whereby it reaches a peak when the heart muscles are relaxed and nearly halts when the muscles are fully contracted. Coronary arteries functions to supply oxygenated blood and nutrients primarily to the myocardium. The immediate division of the aorta after it arises from the left ventricle forms the coronary arteries. The coronary arteries arise from the sinuses of Valsalva which are actually dilatation above the semilunar cusps of the aortic valve. This comprises of three cusps which are the anterior, left posterior and right posterior aortic sinuses. The left coronary and right coronary arteries originate from the left posterior and anterior aortic sinus respectively. The right posterior aortic sinus does not usually forms a vessel. Epicardial arteries are coronary vessel that runs on the surface of the heart. Figure 4 shows the coronary vessels on the surface of the heart. The left coronary artery supplies mainly the left side of the heart; left atrium and ventricle as well as the interventricular septum. It consists as the left main stem and courses posteriorly and to the left of the pulmonary trunk to arrive at the left atrioventricular groove. Two major branches of the left coronary artery which consists of the left circumflex and left anterior descending artery. The left circumflex artery follows the atrioventricular groove laterally, branch further distally and finally joins with the branches of the right coronary artery. The larger left anterior descending artery follows the interventricular groove. There are several branches from the left anterior descending artery which fuses with the branches of the posterior interventricular artery forming anastomoses. 12

27 Branches of the left circumflex artery are as follows: Obtuse marginal branch supply the lateral wall of the left ventricle Atrial branches Branches of the left anterior descending artery are as follows: Septal branches Diagonal branches supply the anterolateral wall of the left ventricle A branch to the right ventricle The right coronary artery follows the coronary sulcus to the right and supplies blood to the right atrium, part of the right and left ventricles as well as the heart conduction system. There are usually more than one marginal artery from the right coronary artery just inferior to the right atrium which supply blood to the superficial areas of the right ventricle. At the posterior aspect of the heart, the right coronary artery give rise to the posterior interventricular artery also called the posterior descending artery. This particular artery courses along the posterior aspect of the interventricular sulcus towards the apex of the heart supplying the interventricular septum and parts of both ventricles. Branches of the right coronary artery are as follows: Conus artery to the pulmonary outflow tract Atrial and ventricular branches Branch to sinoatrial node Acute marginal branches - supplies the right ventricle Branch to atrioventricular node Posterior interventricular artery - supplies the inferior surface of the left ventricle and the posterior two-thirds of the interventricular septum. 13

28 Coronary dominance is defined by the vessel which the posterior descending artery arises from. This particular artery supplies the posterior and lateral walls of the left ventricle. Majority of the population (80-85%) has a right dominance, in which the RCA gives rise to the posterior descending artery and continues around in the atrioventricular groove, giving branches to the posterolateral wall of the left ventricle. In left-dominant situations, the right coronary artery is short. The posterior descending artery arises from the left circumflex artery or less commonly from the left anterior descending artery. A co-dominant situation occurs when a single or duplicated posterior descending artery is supplied by both the right coronary artery and the left circumflex or left anterior descending artery. Coronary veins are located along the main coronary arteries and functions to drain the deoxygenated blood and waste back to the heart. The great cardiac vein is located along the interventricular sulcus and subsequently follows the coronary sulcus to drain into the coronary sinus at the posterior surface of the right heart. The particular vein courses with the anterior interventricular artery and drains the area supplied by this vessel. There are several branches draining into the great cardiac vein which includes the middle cardiac vein, small cardiac vein and posterior cardiac vein. The coronary sinus is a large vein located on the posterior surface of the heart, between the atrioventricular sulcus and emptying directly into the right atrium. The middle cardiac vein courses with the posterior interventricular artery and drains the respective area supplied by this artery. The small cardiac vein courses with the right coronary artery and drains the posterior surfaces of the right atrium and ventricle. Finally the posterior cardiac vein courses with the marginal artery branch of the circumflex artery and drains the respective area supplied by this artery. There is an exception for the anterior cardiac vein whereby it doesn t merge with the coronary sinus and drains directly into the 14

29 right atrium. The anterior cardiac vein courses with the small cardiac arteries and drain the anterior surface of the right ventricle. Figure 4: Coronary vessels from the anterior and posterior heart views (Adapted from Anatomy and Physiology, OpenStax CNX) (10) Conduction System of the Heart The contraction of the heart is controlled by the heart s electrical system or better known as the cardiac conduction system. This system comprises of the cardiomyocytes and their respective conducting fibres that are specialized in initiating electrical impulses and 15

30 conducting these impulses rapidly and efficiently throughout the heart. This process coordinates the heart contraction and thus initiates the normal cardiac cycle. The cardiac conduction system is broadly classified into: sinoatrial (SA) node atrioventricular (AV) node bundle of His left and right bundle branches Purkinje fibres Heart contractions is initiated when electrical stimulus are sent from the SA node which is located 1mm from the epicardial surface in the right atrial sulcus terminalis at the junction of the anteromedial aspect of the atrio-caval junction. The SA node is known as the pacemaker of the heart as it initiates the cardiac cycle. With each stimulus, the SA node produces an electrical impulse which passes to the cardiomyocytes of both atria causing a coordinated wave of contraction. This causes the fully filled atria to contract and diverts the blood through the patent valves into their respective ventricles. The electrical stimulus from the SA node then passes to the AV node which is located just inferior to the right atrium endocardium, anterior to the opening of the coronary sinus and superior to the septal leaflet insertion of the tricuspid valve. There is a slight delay when the stimulus travels from the SA node to the AV node to allow for the atria to contract adequately in order to pump all the blood into the ventricles. As soon as the blood is completely emptied from the atria, their respective valves close and the atria begins the refilling process again. At the same time, the electrical stimulus passes through the AV node into the Bundle of His, 16

31 right and left bundle branches and to the Purkinje fibres within the ventricular walls. Figure 5 shows the cardiac conduction system. Stimulation of these fibres causes both ventricles to contract almost simultaneously. However, the left ventricle contracts slightly earlier than the right ventricle. Contraction of the ventricles is called systole. During systole, the right ventricle pumps blood to the pulmonary circulation while the left ventricle pumps blood to the systemic and coronary circulation. Soon after ventricular contraction, the ventricles relax while waiting for the next impulse. Relaxation of the ventricles is known as diastole. During diastole, both ventricles are void of blood, both atria are filled with blood and the valves between them are closed. Subsequently the SA node releases another electrical impulse and the cardiac conduction system reinitiates. During each cycle, the SA and AV node only contain one stimulus. Therefore, the SA and AV node recharges during the refilling of the atria and ventricles respectively before continuing with the next cycle. This whole process of recharging takes less than one third of a second. The term discharge or release of an electrical stimulus is known as depolarization and the term for recharging is known as repolarization. In summary, the stages of a single heart beat comprises of an initial atrial depolarization, followed by ventricular depolarization and finally atrial and ventricular repolarization. 17

32 Figure 5: The cardiac conduction system (Adapted from StudyBlue, Biology Chapter 19 lecture. Chemeketa Community College, Oregon) (11). 18

33 3.2 CORONARY ARTERY DISEASE Coronary artery disease (CAD) is one of the most common causes of mortality and morbidity throughout the world with the disease increasing every year. Compilation of health statistics from more than 190 countries revealed that heart disease is still the top cause of death with 17.3 million attributed deaths each year, according to Heart Disease and Stroke Statistics 2015 Update: A Report From the American Heart Association. The report concluded that by year 2030, the number is predicted to increase to more than 23.6 million (12). According to the latest statistics obtained from World Health Organization (WHO) published in May 2014, deaths from CAD has amounted to which is approximately 23.10% of total deaths. Malaysia is ranked number 33 in the world with an age adjusted death rate of per population. The trend of this disease in Malaysia is largely reflected by most developing countries worldwide (1). Patients with CAD in Malaysia presents at a mean age of 59±12 years, which is 6 years younger than those in the Global Registry of Acute Coronary Events (GRACE). Therefore, the population of Malaysia has a high risk factor of developing CAD (13) Terminology Patients with CAD may be classified into stable angina or as acute coronary syndrome (ACS). Stable angina is a medical term used to define symptoms of chest discomfort that radiates to the jaw, shoulder, back or arms and usually occurs during physical or emotional stress and relieved by rest of sublingual glyceryl trinitrate (GTN). Less commonly the discomfort may arise from the epigastric region. Stable angina is usually used to explain the symptoms which are caused by myocardial ischaemia (14). 19

34 ACS is a broad spectrum of disease depending on severity of myocardial ischaemia and degree of coronary artery stenosis. It occurs when the plaque buildup is unstable and causes partial or total coronary artery occlusion. It is further classified into: unstable angina (UA) non-st elevation myocardial infarction (NSTEMI) ST elevation myocardial infarction (STEMI) A patient diagnosed with unstable angina may deteriorate and presents as NSTEMI or STEMI depending on the severity of luminal stenosis and myocardial injury (15). Unstable angina may present as: new onset severe exertional angina with no significant pain at rest non exertional angina within the past month but not within the last 48 hours (subacute angina at rest) angina at rest within 48 hours (acute angina at rest) (15). Unstable angina occurs when there is significant myocardial ischemia with absent myocardial injury. The cardiac biochemical markers are usually normal as there is no myocardial damage. In myocardial infarction (MI) which encompasses NSTEMI and STEMI, cardiac biomarkers are raised due to significant myocardial damage. ECG changes are also evident in MI, while in UA they are usually absent or only last for a brief moment if present (2). 20

35 3.2.2 Pathogenesis ACS usually occurs when there is rupture or ulceration of the atherosclerotic plaque with associated coronary vascular thrombosis and vasospasm. Therefore patient can present as UA, NSTEMI or STEMI depending on the acuteness of the disease, degree of coronary luminal stenosis and the presence of collaterals to supply the affected myocardial segment. Possible causes atherosclerotic plaque rupture or ulceration has not been determined, however it is hypothesized that underlying inflammation, infection, uncontrolled hypertension and chronic smoking may lead to this phenomenon (15). Further subdivisions of ACS are: Primary unrelated to a non-cardiac condition and occurring de novo Secondary directly related to a non-cardiac condition Post-infarct occurs within two weeks of an acute MI Secondary ACS may occur due to a precipitating condition such as in thyrotoxicosis with tachycardia, high fever with increased myocardial oxygen demand, hypotension leading to reduced myocardial blood flow and anemia or hypoxemia causing reduced myocardial oxygen delivery (15) Diagnosis According to the WHO, a diagnosis of ACS is made when a patient satisfies at least two criteria which indicate high probability or three criteria which indicate a definite diagnosis of: 21

36 A typical clinical history of ischemic chest pain lasting more than 20 minutes Significant changes in serial ECG monitoring Significant rise and fall of serum cardiac biomarkers Clinical history Symptoms of UA and NSTEMI are very similar and may be difficult to tell apart from STEMI. The chief complaint of patients with ACS is chest pain or discomfort. The location of the pain felt is usually left sided, central or retrosternal and often radiates to the shoulder, jaw or upper limb. It can present as a crushing, pressing or even burning pain with a variable severity (15). There are instances whereby patients, predominantly those with diabetes and the elderly presents with atypical symptoms of shortness of breath without any prior chest pain. Other atypical symptoms include profuse sweating, nausea, vomiting, syncope, and lethargy. High risk patients of developing a cardiac event includes patients with a previous history of CAD or stroke, family history of premature CAD, dyslipidemia, diabetes mellitus, hypertension and long standing history of smoking (15) Physical examination A thorough physical examination is important for patients with ACS in order to identify: possible causes cardiac or extra-cardiac causes precipitating causes consequences or complications related to ACS 22

37 Patients with uncontrolled hypertension, long standing anemia, severe thyrotoxicosis, severe aortic stenosis, hypertrophic cardiomyopathy and chronic lung disease should be elicited. Complications from ACS such as left ventricular failure and arrhythmias needs to be identified as these signs indicate a poor prognosis. Other signs such as carotid bruits and peripheral vascular disease are highly suggestive of an extensive atherosclerotic disease with a possibility of concomitant CAD (15) Electrocardiography (ECG) ECG is an essential part of the investigation for the workup ACS. It supports the diagnosis of ACS and to some extent, provides information regarding the outcome of the disease. The best time for an ECG recording is during an episode of chest pain. ECG recording should also be undertaken within 10 minutes of the patient s admission at the Accident and Emergency Department. Occasionally in the initial stages, the ECG findings may be non-diagnostic or equivocal. Therefore, ECG should be repeated at least every 15 minutes to identify any dynamic ST/T changes. Comparison with previous ECG recordings may be helpful in obtaining a diagnosis (15). Features suggestive of an ACS episode are: dynamic ST/T changes ST depression/ elevation > 0.5 mm in 2 or more contiguous leads T-wave inversion deep symmetrical T-wave inversion Other ECG findings include new onset left bundle branch block (LBBB) and cardiac arrhythmias. Previous or recent myocardial infarctions can present as Q waves (15). 23

38 Cardiac biomarkers For assessment of myocardial damage, the recommended cardiac biomarkers are troponin T or I. These markers show high sensitivity and specificity in diagnosing myocardial injury. Besides that, they also provides important prognosis for the patient as there is evidence of correlation between the level of troponin with the extent of myocardial injury and related cardiac complications. However, if the troponin markers are taken early in the initial few hours of symptoms (< 6 hours), the troponin level may not be significant. Therefore, a repeat troponin level needs to be done within 6-12 hours of admission to safely exclude an acute coronary syndrome. This investigation can be done in the laboratory which will display accurate levels or can be tested with a hand held semi-quantitative assay for immediate results. Troponin levels are elevated in the blood for at least 5 to14 days post myocardial injury. Other causes besides cardiac causes of high troponin enzymes include acute myocarditis, acute pulmonary embolism, a dissecting aortic aneurysm, heart failure, septic shock and severe renal dysfunction. As with ACS, significantly high levels of troponin enzymes are indicative of an increase in mortality in the affected patients. Another cardiac enzyme that is routinely used is creatinine kinase (CK) and its MB fraction (CKMB). The disadvantage of this biomarker compared to troponin is that they are less sensitive and specific. The benefit of CK and CKMB is that they have a shorter half-life and therefore helpful in diagnosing myocardial reinfarction. Almost all patients with NSTEMI will have elevated troponins but the CKMB may be not elevated in about 10-20% of these patients. No prognostic information can be obtained if there is a raised CKMB without an associated elevated troponin level. 24

39 Myoglobin is elevated from as early as 2 hours from the symptoms of chest pain. However, myoglobin is not cardiac specific and is not frequently used as a biomarker for myocardial infarction. The only benefit is that if this biomarker tested negative, it can help in excluding myocardial infarction (15). Figure 6 shows the different cardiac enzymes and its respective maximum concentration. Figure 6: Cardiac enzymes (Adapted from French, J.K. and H.D. White, Clinical implications of the new definition of myocardial infarction. Heart, (1): p ) (16). 25

40 3.3 IMAGING MODALITIES In patients presenting with symptoms of chest pain, initial clinical assessment is important to confirm whether it is due to an underlying ACS. Once a preliminary diagnosis of ACS is made, further assessment with imaging is made in order to: confirm the diagnosis of CAD assessment of the degree and functional significance of a coronary stenosis assessment of the viability of the affected myocardium assessment of global and regional ventricular function CAD is not solely diagnosed based on the degree of coronary artery narrowing but includes an assessment on the plaque volume and its characteristics. A significant stenosis usually means that the coronary artery is narrowed to lead to ischemia of the cardiomyocytes. Definition of viability is functioning live myocardium. Therefore, viability study is crucial in assessing the chances for functional recovery after undergoing angioplasty. The left ventricular function is important in determining the prognosis following an episode of ischaemic heart disease (17). The different types of cardiac imaging available for the investigation of a provisional diagnosis of CAD can be classified as follows (17): Invasive techniques o o Invasive coronary angiography Intravascular endoscopic ultrasound Non-invasive techniques o Direct visualization of the coronary arteries coronary calcium score 26

41 coronary CT angiography MRI of the coronary arteries o Assessment of the degree of coronary stenosis SPECT/PET myocardial perfusion scintigraphy stress echocardiography MRI cardiac including stress and delayed enhancement sequences Invasive coronary angiography The current practice for achieving the best images of coronary arteries in patients with coronary artery disease is by venous catheterization, injection of contrast media and the using a fluoroscopic machine (18). This technique is known as invasive coronary angiography (ICA) and is considered the gold standard in the current practice. ICA is useful in providing a thorough picture of the entire coronary vasculature as well as identifying the presence and extent of atherosclerotic coronary artery disease. If a coronary angioplasty is needed for treatment of coronary luminal stenosis, a prior ICA must be undertaken to guide the cardiologist. However, ICA has its own limitations namely that is an invasive procedure and is associated with multiple complications which range from minor problems with minimal sequelae to life threatening irreversible problems if the issue goes undetected. Complications can be grouped into cardiac and non-cardiac complications. Examples of cardiac complications are acute pulmonary oedema, myocardial infarction, conduction disturbances while non-cardiac complications are embolic stroke, local vascular injury, nephropathy to name a few. Allergy reaction can also arise from the use contrast media and local/general anaesthesia while performing the procedure (19). 27

42 Moreover, ICA is can only offer a two-dimensional view of the coronary tree and cannot reliably reveal the nature of the atherosclerotic plaques which are important in determining the best method of treatment and the clinical outcome of the patient (4). Therefore, a complementary CT or MRI cardiac may need to be employed to assist in overcoming the shortcomings of the ICA (18) Magnetic resonance imaging (MRI) cardiac MRI cardiac is a non-invasive, non-ionizing, imaging technique that utilizes a powerful magnetic field, radio frequency pulses and a computer to produce images of the heart. When compared to cardiac nuclear scintigraphy, MRI has a better spatial and temporal resolution with better tissue characterization. Furthermore, MRI does not require any ionizing radiation when compared to CT scan or cardiac scintigraphy (20). There are many functions of this imaging mainly consist of: evaluating the anatomy and function of the heart chambers, valves and blood flow through major vessels and surrounding structures i.e. pericardium diagnosing cardiovascular related disorders such as tumors, infections and inflammatory conditions evaluating the effects of a cardiac event such as expansion and late wall thinning of infarcted segments, left ventricular volume and shape as well as hypertrophy of the non-infarcted myocardium (20). With the recent advances in MRI imaging, this method of imaging has been used extensively in the diagnosis of coronary artery disease. Although there is significant overlap of function 28

43 with other cardiac imaging modalities, MRI cardiac is most often used as a complementary tool to confirm or resolve diagnostic dilemmas. In the near foreseeable future, MRI cardiac will play an important role in the diagnosis of cardiac diseases and assist in cardiac interventions (20) Coronary computed tomography angiography and CAC Score (Calcium Score) CCTA technology has been advancing rapidly in the last few decades. In 1998, the first four slice CT machines was used, followed by sixteen slice in 2001 and sixty four slice in 2004 (3). Currently, CCTA is already confirmed as a highly accurate, effective and less invasive imaging modality in the diagnosis of coronary artery disease (CAD). This is mainly due to the rapid technological advances which improves the spatial and temporal resolution of multislice CT scanners (6, 7). Considerable accuracy have been shown in the diagnostic capabilities in detecting significant coronary artery luminal stenosis of CCTA compared to ICA in the recent years (21, 22). According to Mollet, N.R. et al., significant coronary artery stenosis were detected by sixty four slice CT scanners with a high sensitivity and specificity of 99% and 95% respectively when compared to ICA (23). Further comparison made with sixty four slice CCTA with MRI angiography and stress nuclear imaging has showed that CCTA has a higher accuracy in detecting coronary artery stenosis (24). Early comparative studies between CCTA and ICA have also suggested that CCTA has an advantage over ICA in certain groups of patients (25). Framingham Risk Score (FRS) (26) is an established method and widely used by doctors in predicting cardiovascular risk in asymptomatic patients with no underlying CAD (27). 29

44 According to Wilson et al. (28), the accuracy for FRS to predict a cardiovascular event is stated to be approximately 75%. In order to improve the accuracy of FRS, other imaging studies have been proposed. One such technique that is widely used is the detection of coronary artery calcium score using a non-contrasted multidetector computed tomography (MDCT) or electron-beam computed tomography (EBCT) (27). This particular investigation has been recommended as a screening tool prior to ICA as it can assist in stratification of patients with intermediate or high risk of developing coronary artery disease (9). Our hospital at University Malaya Medical Centre uses non-contrasted MDCT to assess coronary artery calcium (CAC) score. CAC score has a high negative predictive value of 95-99%. This implies that if the CAC score is 0 in an asymptomatic low risk patient, the presence of atherosclerotic plaque or significant coronary artery stenosis is unlikely and this is associated with a very low risk of acute coronary syndrome within 2-5 years (27, 29, 30). However, a positive CAC score means there are calcium deposits within the coronary arteries identified on CT scan and confirm the presence of atherosclerosis. The CAC score is directly proportional to the CAD risk indicating that patients with higher CAC score, has higher risk of developing CAD (27). This is particularly helpful for the cardiologists to avoid performing unnecessary ICA (9). However, there are a few shortfalls when using CAC score as a screening tool. Firstly, there are different types of atherosclerotic plaques namely calcified, non-calcified and mixed plaques. Therefore, a plain CT scan cannot identify non-calcified or mixed plaques accurately which may cause significant coronary artery disease. Secondly, CAC screening is not recommended for very high risk, very low risk or even in patients with underlying CAD. Next, CAC score does not give any reliable information regarding the degree of coronary artery stenosis and patients may warrant further investigation such as contrasted coronary CT 30

45 angiography or ICA. Finally, there are no established guidelines for repeat calcium scoring for re-evaluation of coronary artery disease risk (31-33). The pathogenesis of coronary artery calcification is thought to be due to the formation of fatty streaks within the vessel walls which progresses to fatty build up over the years forming a non-calcified plaque. This particular plaque is known as an unstable plaque as only a thin layer of arterial wall covering the fatty plaque. If the arterial wall is injured or ruptured, the fatty material will be secreted into the vascular system causing aggregation of platelets to plug the site of injury. As the platelets accumulates and forms a clot, it may obstruct the lumen and impede the blood flow within the coronary artery leading to an acute coronary syndrome. However, if the fatty plaque does not rupture, it will mature and develop into a fibrous hard plaque and finally a calcified plaque. When the plaque calcifies, it is pushed towards the outer vessel wall and can lead to significant stenosis if the plaque is large enough (34). Agatston score is the standard method in calculating the CAC score. This method was first introduced by Arthur Agatston and his colleagues in A dedicated software is used to identify any structures with calcified densities along the coronary artery measuring equal to or more than 130 Hounsfield units (HU) and within an area of 1 mm2 or more. These calcified densities are then recorded as calcified focus and these foci overlying the coronary arteries are considered to represent calcified plaques. For every identified segmented calcified plaque, the maximum density in HU was determined and a density scoring of 1 to 4 was assigned. The assigned density scores of 1, 2, 3 and 4 represented the highest densities HU, HU, HU and 400 HU respectively. The weighted density score is calculated by multiplying the density score with the total area of each calcified plaque. Finally the total 31

46 Agatston score or CAC score (also known as Calcium Score) is calculated by adding the weighted density scores of each calcified plaque throughout the coronary arteries (35, 36). Table 1 shows the significance of calcium score in relation to plaque burden, probability of significant CAD, implications of cardiovascular risks and treatment recommendations. Table 1: Calcium score guidelines and recommendations (37). Calcium score Plaque burden 0 No identifiable plaque Minimal identifiable plaque burden. Probability of significant CAD Very low, generally <5%. Very unlikely, <10%. Implications for cardiovascular risk Very low. Low. Recommendations Reassure patient. Discuss general public health guidelines for primary prevention of cardiovascular disease. Discuss general public health guidelines for primary prevention of cardiovascular disease Definite, at least mild atherosclerotic plaque burden Definite, at least moderate atherosclerotic plaque burden. > 400 Extensive atherosclerotic plaque burden. CAD: Coronary artery disease Mild or minimal coronary stenosis likely. Non obstructive CAD highly likely although obstructive disease possible. High likelihood, >50% of at least one significant coronary stenosis. Moderate. Moderately high. High. Counsel about risk factor modification, strict adherence with primary prevention goals. Daily aspirin. Institute risk factor modification and secondary prevention goals. Consider exercise testing for further risk stratification. Daily aspirin. Institute very aggressive risk factor modification. Consider exercise for nonpharmacologic nuclear stress testing to evaluate for inducible ischemia. Daily aspirin. 32

47 While measuring the calcium burden of the coronary arteries has been shown to give an indicator of the degree of the atherosclerotic disease present in the arteries; presence of a high calcium burden in the coronary arteries had been used as a limiting factor to a subsequent contrasted CCTA. This is due to the fact that the presence of abundant calcium causes blooming artefacts that obscure the underlying vessels and hence objective analysis of luminal patency would be hindered. Studies had shown that patients with calcium score of more than 400 affects the diagnostic performance of CCTA and therefore has been suggested that these patients should not proceed with CCTA (38). The cut off at 400 was chosen because multiple studies have concluded that there is a significant reduction in specificity in patients with a high calcium score >400 as compared to patients with calcium score <400 (8). Alternatively, a more current literature suggests that a calcium score of 400 and above is not a deterrent to a subsequent CCTA (9). Decisions on whether or not to pursue with a subsequent CCTA should be based on composition, clustering and position of the calcium burden rather than on the absolute calcium score value. Apart from the assessment of the coronary luminal stenosis, CCTA is able to visualize the atherosclerotic plaque therefore identifying its location and distribution in the coronary arteries. Further advantage of CCTA lies in its ability to characterize the different types of plaques as well as assess the composition of plaques (7). This is particularly helpful in identifying the non-stenotic plaques that can go undetected by ICA (39). There are many studies that have shown the capability of CT scanners in differentiating between calcified, non-calcified and mixed plaques based on the CT attenuation value measured in Hounsfield units (7). Classification of coronary plaque composition via CCTA is important in patients with CAD. By identifying the high risk plaques, management can be target towards these plaques (40). There are significant association of plaque composition with myocardial injury which can assist in the prediction of future cardiac events and the prognosis of the patient (4). 33

48 Although significant technological advances have been made in MRI and CT scanners, invasive coronary angiography still remains the gold standard in obtaining the diagnosis of coronary artery stenosis (18). With continued improvement in the speed and resolution of imaging, CCTA will still play an important role in the early detection and characterization of coronary plaques thus preventing major adverse cardiac events through immediate treatment strategy (40) Coronary 3D virtual intravascular endoscopy Coronary virtual intravascular endoscopy (VIE) is a specific intraluminal visualization technique using 3-dimensional volume rendering technique with the help of computer software. This technique is useful in the assessment of the normal coronary artery anatomy and in patient with coronary artery disease. The advantage of coronary VIE compared to conventional angioscopy is it is a less invasive procedure with very low complication rate (41). Coronary VIE images are generated using a CT number thresholding technique. The three main coronary arteries which are the left anterior descending (LAD) artery, left circumflex (LCX) artery and right coronary artery (RCA) are identified. The CT attenuation of these arteries are measured and the CT number threshold when the contrast enhanced blood within these vessels are not visualized is ascertained. Subsequently, the CT number threshold which was obtained is applied into the computer software in order to generate the intraluminal images of the coronary ostium, lumen surface and coronary wall. The method for post processing coronary VIE images requires the accurate selection of CT number threshold as a small difference in the value may lead to artefacts. These artefacts when present will affect the VIE image quality leading to poor visualization and interpretation of the coronary artery 34

49 lumen, degree of arterial stenosis and plaque morphology if present. Besides acquiring the appropriate CT number threshold, the quality of the original source CT is also important in order to produce acceptable coronary VIE images (41, 42). Once the coronary VIE images are generated, interpretation of these data should be done together with the multiplanar reformatted images of the original CT coronary scan. This is useful in determining the exact anatomy of the coronary artery. Besides generating static VIE images, endoscopic views can be reconstructed via the fly through technique in a dynamic format. This technique is achieved by placing virtual cameras along the fly path of the respective coronary artery and the computer will automatically generate an endoscopic view at regular intervals. The dynamic fly through visualization is achieved when the data obtained is viewed in cine imaging format. An average of less than 20 minutes is required by an experienced operator with the aid of fast speed workstation to complete the VIE image post processing. Therefore, it is a practical complementary visualization tool with a relatively short post processing time (41, 42). Coronary VIE provides important information regarding coronary plaques in relation to the location, plaque morphology as well as coronary wall changes and stenosis due to the presence of plaques within the coronary artery. The coronary wall changes and plaque morphology on VIE are related to the amount and types of plaques. There are three types of coronary plaques which can be classified into calcified, non-calcified and mixed plaques (41, 42). In patients with high coronary artery calcium score, the intraluminal plaques were clearly identified on VIE and is more accurate than the CCTA as it is not affected by the blooming artefacts from the extensive coronary artery calcifications. These extensive calcifications 35

50 decrease luminal visualization causing overestimation of the coronary artery stenosis and thereby reducing the diagnostic accuracy on CCTA. VIE concentrates on the intraluminal appearance as compared to the extra luminal appearance on CCTA which makes it more accurate in determining the degree of coronary artery stenosis (42) Functional cardiac imaging Cardiac stress imaging is used as a complementary imaging to demonstrate areas of the myocardium that receives inadequate blood supply for the demands of the cardiac tissue. There are many ways to induce stress to the heart which can be classified into nonpharmacological method through physical activity and pharmacological methods. Pharmacological agents are infused into the venous system which either increases the strength of the heart contractions such as dobutamine or dilates the vessel and reduces the delivery of blood to affected vessels such as adenosine and dipyridamole (18). Imaging of the heart is commenced as soon as the heart is subjected to the stressor. 36

51 CHAPTER FOUR 4.0 METHODOLOGY 4.1 STUDY DESIGN This study is based on a retrospective and prospective study on 103 patients whom had proceeded with CCTA with an initial CAC score of > 400. The period of study was from January 2011 to June Patients were referred by the Department of Cardiology, University Malaya Medical Centre, Kuala Lumpur to the Department of Biomedical Imaging, University Malaya Medical Centre, Kuala Lumpur for suspected CAD. All examinations were done at the CT scan suite (C1), Department of Biomedical Imaging, University Malaya Medical Centre, Kuala Lumpur. 4.2 PATIENT SELECTION AND FOLLOW UP The inclusion criteria were patients with suspected CAD having calcified plaques detected on CCTA with CAC score > 400. ICA was performed as the gold standard technique to confirm the diagnosis. The exclusion criteria were calcified, non-calcified plaques or mixed plaques on CCTA with calcium score <400, contraindications for iodinated contrast media with history of allergy and not covered with prednisolone, renal dysfunction/renal insufficiency, heart rate faster than 100 beats per minute, atrial fibrillation or arrhythmia and hemodynamic instability. 37

52 A structured interview and clinical history were acquired via telephone interviews and the following coronary artery disease risk factors were assessed via a questionnaire (Appendix A): The CAD risk factors which were identified in this study were: prior or current history of smoking and its duration diabetes mellitus (defined as a fasting glucose level of 7 mmol/l or the need for subcutaneous insulin or oral hypoglycemic agents) (43) dyslipidemia (defined as a total cholesterol level 5 mmol/l or treatment with lipidlowering drugs) (44, 45) hypertension (defined as blood pressure 140/90 mm Hg or the use of antihypertensive medication) (46) stroke (defined as clinical symptoms/signs of focal and/or global loss of cerebral function, with symptom persists more than 24 hours or leading to mortality) (47) positive family history of CAD (defined as the presence of CAD in first degree relatives younger than 55 [male] or 65 [female] years of age) (48) Follow-up information was obtained by either hospital chart review and/or telephone interviews. These patients were followed up for at least 1 year and up to 4 years later for the health status in relation to their cardiac complaints and are classified as: no cardiac event or asymptomatic unstable angina or NSTEMI STEMI revascularization (percutaneous coronary intervention or CABG) cardiac death (defined as death caused by acute myocardial infarction) 38

53 A total of 64 questionnaires were obtained from the patients. The questionnaire for the remaining patients were unsuccessful due to various reasons i.e. wrong or no contact details, patient whom are not free to undergo an interview and patient whom are not keen to divulge personal information. Laboratory tests for serum levels of total cholesterol, low-density lipoprotein (LDL), highdensity lipoprotein (HDL) and patient s initial blood pressure prior to CCTA were obtained from the hospital chart and via online laboratory investigations. This study was approved by the local research ethics committee in University of Malaya (ethics committee approval number: ). Prior to the CCTA, information regarding the study was explained to the patients as per the patient information sheet (Appendix B). An informed written consent (Appendix C) was obtained from all patients or patient s relative before proceeding with the CCTA. Figure 7 illustrates the process of sample collection. 39

54 Patients with suspected CAD with calcium score > 400 and not in the exclusion criteria (n=103) Informed consent and/or questionnaire not available due to: - unavailable contact details (n=34) - patient not free for interview (n=3) - patient not keen to participate (n=2) Patients with suspected CAD with calcium score > 400 and proceed with CCTA (n=103) Patients who subsequently underwent ICA (n=35) Informed consent and/or questionnaire obtained (n=64) Coronary VIE reconstruction not available due to: - data unavailable (n=20) - technical error (n=1) Coronary VIE reconstruction from CCTA images available (n=14) VIE analysis based on: - location and degree of stenosis - intraluminal plaque characteristics ICA analysis based on: - location and degree of stenosis Comparison Figure 7: Flow chart of data collection and analysis. 40

55 4.3 CCTA IMAGING TECHNIQUE Patient preparation All patients undergoing contrasted CCTA were required to fast for a minimum of 6 hours prior to the imaging. Patient who had a history of allergy and/or asthma was prescribed with oral prednisolone 50mg (to be taken 13 hours, 7 hours and 1 hour before imaging). Oral Metoprolol 100mg -150mg and oral Lorazepam 1 mg were given to all patients with heart rate > 60 beats/minute. Sublingual GTN 0.5 mg was given to all patients prior to commencement of CCTA CCTA protocol All patients were scanned using a dual source 64-slice CT scanner (Sensation 64 Cardiac, Siemens Medical Systems, Forchheim, Germany). An initial non enhanced ECG-gated scan was performed for calcium scoring. An initial bolus-timing single-slice scan using 10 mls of contrast (intravenous Ultravist with iodine content 370 mg/ml) followed by a 50 mls saline chaser was done. Subsequently, a contrast scan was performed using 50-60mls of contrast injected through an 18G branula (minimum size requirement) preferably located antecubital vein at 6 mls/s followed by 50 mls saline chaser. The scan parameters were: 64 x 0.6 mm collimation with dual focal spots per detector row; rotation time 330 ms; table feed 3.8 mm/ rotation; tube voltage 120 kv; effective ma 750 to 850; volumetric CT dose index mgy and; with tube current modulation. Temporal resolution ranges between milliseconds depending on each patient s heart rate. 41

56 Electrocardiographically gated datasets were reconstructed automatically at 65% of the R-R cycle length and 35% of the R-R cycle length to approximate end-systole and end-diastole respectively. Additional reconstruction windows were constructed after examination of datasets if any motion artifacts were present. 4.4 CCTA DATA EVALUATION Data analysis was conducted in the CT scan suite (C1), Department of Biomedical Imaging, University Malaya Medical Centre, Kuala Lumpur. Data sets were transferred to an image processing workstation (Leonardo; Siemens Medical Solutions) prior to evaluation. All images were analyzed and interpreted immediately after scanning by an experience radiologist with more than 10 years of experience in cardiac imaging blinded to patient s identity. Images were initially displayed at the predefined image display setting (window 700 Hounsfield units, level 200 Hounsfield units) and adjustment of the window and level settings were performed at the discretion of the observer if deemed necessary Coronary artery calcium score The coronary artery calcium scores of all patients were calculated with a dedicated software tool and quantified as Agatston score. The Agatston score is based on the extent of coronary artery calcification detected by an unenhanced CT scan. It is a commonly used scoring method that calculates the highest calcified speck density of a specific coronary artery that is measured in Hounsfield unit which is subsequently converted to a density score. The density score obtained is then multiplied by the area covered in square millimeters to give the scoring for the particular calcified speck giving the weighted density score. The total coronary artery calcium score is calculated by adding up the weighted density score obtained for every 42

57 calcified speck for all tomographic slices (35, 36). The extent of CAD is graded according to the amount of calcium score expressed in Agatston score: No evidence of CAD with a score of 0 Minimal evidence of CAD with a score of 1-10 Mild evidence of CAD with a score of Moderate evidence of CAD with a score of Extensive evidence of CAD with a score of > Coronary artery stenosis estimation and grading Quantitative estimation of the severity of coronary artery stenosis was made using digital tools which measure luminal area stenosis based on maximal luminal diameter stenosis. Coronary vessels in axial and longitudinal (MIP and MPR) views were used for stenosis estimation (49). Quantitative grading of coronary artery stenosis as recommended by the Society of Cardiovascular Computed Tomography are as stated below and Figure 8. Grade 0 Absence of plaque and no luminal stenosis Grade 1 Minimal Plaque with < 25% stenosis Grade 2 Mild Plaque with 25% - 49% stenosis Grade 3 Moderate Plaque with 50% - 69% stenosis Grade 4 Severe Plaque with 70% - 99% stenosis Grade 5 Total occlusion with 100% stenosis 43

58 a b c d e Figure 8: Recommended quantitative grading of coronary artery stenosis by CCTA. (a) No luminal stenosis. (b) Mild luminal stenosis or less than 25% stenosis. (c) Minimal luminal stenosis or 25% to 49% stenosis. (d) Moderate luminal stenosis or 50% to 69% stenosis. (3) Severe luminal stenosis or 70%-99% stenosis. Arrows pointing to the area of coronary stenosis (50). 4.5 VIRTUAL INRATVASCULAR ENDOSCOPY (VIE) DATA EVALUATION CCTA data obtained from Department of Biomedical Imaging, University Malaya Medical Centre, Kuala Lumpur were sent to Department of Medical Radiation Sciences, Curtin University of Technology, Perth, Australia for interpretation. The data in the original DICOM (digital imaging and communications in medicine) images were transferred to a another workstation equipped with Analyze V 11.0 (AnalyzeDirect, Inc, Lexana, KS) for image postprocessing and generation of 3D VIE images. VIE images were generated by an observer with >15 years of working experience in 3D VIE imaging of cardiovascular disease. VIE images of 44

59 the LAD artery, LCX artery and RCA are depicted in Figure 9 and 10. Non-significant coronary artery disease was determined with <50% luminal narrowing while significant coronary artery disease was determined with 50% lumen stenosis as assessed on CCTA/VIE measurements (7). Figure 9: Coronary VIE views of the left main stem, LAD and LCX arteries. (a) Coronary VIE view of the left main stem ostium. (b) Coronary VIE view of left main stem bifurcation showing the LAD and LCX ostia. (c) Coronary VIE view of the LAD ostium. (d) Coronary VIE view of the LCX ostium (41). 45

60 Figure 10: Coronary VIE of right coronary artery ostium from the proximal, middle and distal views with normal intraluminal appearance (41). 46

61 4.6 INTRAVASCULAR CORONARY ANGIOGRAPHY (ICA) EVALUATION ICA was performed by an experienced cardiologist via a radial or femoral vascular access. Angiography data sets were analyzed by a consultant cardiologist > 10 years of experience in random order, blinded to patient identities and previous imaging findings Coronary artery stenosis estimation and grading Quantitative estimation of stenosis severity was made using digital tools which measured in projections showing the most severe narrowing of three main coronary arteries which are the LAD artery, LCX artery and RCA. Quantitative coronary arterial stenosis grading similar to the CCTA stenosis grading as recommended by the American Journal of Cardiology are as stated below (51, 52) and Figure 11. Grade 0 Absence of plaque and no luminal stenosis Grade 1 Plaque with 1-24% stenosis Grade 2 Mild Plaque with 25% - 49% stenosis Grade 3 Moderate Plaque with 50% - 69% stenosis Grade 4 Severe Plaque with 70% - 99% stenosis Grade 5 Total occlusion with 100% stenosis 47

62 a b c d e f Figure 11: Recommended quantitative grading of coronary artery stenosis by ICA. (a) No luminal stenosis. (b) Mild luminal stenosis or less than 25% stenosis. (c) Minimal luminal stenosis or 25% to 49% stenosis. (d) Moderate luminal stenosis or 50% to 69% stenosis. (e) Severe luminal stenosis or 70%-99% stenosis. (f) Complete total occlusion or 100% stenosis. However for analysis purposes, comparison of the degree of coronary lumen stenosis between CCTA and ICA is classified into: no stenosis mild stenosis (<50%) moderate stenosis (50% 69%) severe stenosis ( 70%) Non-significant coronary artery disease was determined with <50% luminal narrowing (no to mild stenosis) while significant coronary artery disease was determined with 50% lumen narrowing (moderate to severe stenosis) as assessed on ICA measurements. 48

63 4.7 STATISTICAL ANALYSIS All data were analyzed using SPSS 21.0 (SPSS Inc, Chicago, IL). Firstly, the normality of data was tested using Shapiro Wilk test. Since most of the data were not normally distributed and the sample sizes were small, non-parametric statistical tests were used in the subsequent analysis. Mann Whitney U test was used to compare the calcium scores for different risk factor groups which were history of smoking, diabetes mellitus, dyslipidemia, hypertension, stroke and family history of CAD. Using ICA as the gold standard, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for the detection of significant coronary artery stenosis ( 50%) on CCTA were calculated for each individual segments (proximal, mid, distal) of each major coronary arteries (LAD, LCX, RCA). The formula to calculate these values are presented in Table 2. Table 2: Coronary artery stenosis detection of between CCTA/VIE and ICA. CCTA/VIE Coronary artery No stenosis ICA Coronary artery Significant stenosis Total No stenosis True negative (TN) False negative (FN) TN + FN Significant stenosis False positive (FP) True positive (TP) FP + TP Total TN + FP TP + FN TN + FN + FP + TP CCTA: Coronary computed tomography angiography; VIE: Virtual intravascular endoscopy; ICA: Invasive coronary angiography Sensitivity = Specificity = TP x 100% TP + FN TN x 100% TN + FP 49

64 Posiive predictive value = Negative predictive value = Accuracy = TP x 100% TP + FP TN x 100% TN + FN TP + TN x 100% TP + TN + FP + FN Similarly, sensitivity, specificity, accuracy, PPV and NPV for the detection of significant coronary artery stenosis on VIE were calculated for each of the major coronary arteries. Non parametric, marginal homogeneity test and McNemar test were used to assess the diagnostic accuracy of CCTA and VIE in the detection of coronary stenosis comparing to ICA. A p value of <0.05 was considered statistically significant. 50

65 CHAPTER FIVE 5.0 RESULTS 5.1 PATIENT DEMOGRAPHICS There were 131 patients with a high calcium score of > 400 identified for this study. Out of this, 103 patients proceeded with CCTA and not in the exclusion criteria were recruited. The age range of the 103 recruited patients was between 26 to 86 years old with mean age of 66.7 ± 10.7 years. Figure 12 shows the age distribution of patients. Distribution of ethnicity revealed 38 patients were Chinese (36.9%), 33 patients were Indian (32.0%), 22 patients were Malay (21.4%) and 10 patients were from other races (9.7%) Figure 13 shows the ethnicity distribution of patients. Number of male patients recruited for the study was 57 (55.3%) and female patients were 46 (44.7%) Figure 14 shows the gender distribution of patients. 51

66 Figure 12: Age distribution of patients included in the study. Ethnicity of study patients 9.7% 21.4% 32% Malay Chinese Indian Others 36.9% Figure 13: Ethnicity distribution of patients included in the study. 52

67 Sex of study patients 44.7% 55.3% Male Female Figure 14: Sex distribution of patients included in the study. 5.2 PREVALENCE OF CORONARY ARTERY DISEASE RISK FACTORS Total number of patients with each of the associated risk factors having a high calcium score of > 400 on CCTA are as follows; history of smoking 11 patients (10 male, 1 female), diabetes mellitus 33 patients (12 male, 21 female), dyslipidaemia 54 patients (31 male, 23 female), hypertension 29 patients (14 male, 15 female), history of stroke 6 patients (3 male, 3 female) and family history of CAD 18 patients (11 male, 7 female). Prevalence of the six listed CAD risk factors having a high calcium score of > 400 on CCTA are as follows; history of smoking 16.4% (90.9% male, 9.1% female), diabetes mellitus 49.3% (36.4% male, 63.6% female), dyslipidaemia 77.1% (57.4% male, 42.6% female), hypertension 69.0% (48.3% male, 51.7% female), history of stroke 9.0% (50.0% male, 50.0% female) and family history of CAD 27.3% (61.1% male, 38.9% female). Figure 15 shows the 53

68 Percentage prevalence of the respective CAD risk factors and Figure 16 shows the prevalence of CAD risk factors according to sex Prevalence of CAD risk factors CAD risk factors Figure 15: Prevalence of CAD risk factors. 54

69 Percentage 100% 90% 80% 70% 60% Sex distribution of CAD risk factors % 40% % 20% 10% Female Male 0% CAD risk factors Figure 16: Prevalence of CAD risk factors according to sex. 55

70 5.3 COMPARISON OF CALCIUM SCORES FOR DIFFERENT CAD RISK FACTORS Comparison of calcium score for different risk factors are shown in Figure 17 (history of smoking), Figure 18 (diabetes mellitus), Figure 19 (dyslipidaemia), Figure 20 (hypertension), Figure 21 (history of stroke) and Figure 22 (family history of CAD). p = Figure 17: Box plot showing comparison of calcium score with history of smoking. 56

71 p = Figure 18: Box plot showing comparison of calcium score with diabetes mellitus. 57

72 p = Figure 19: Box plot showing comparison of calcium score with dyslipidaemia. 58

73 p = Figure 20: Box plot showing comparison of calcium score with hypertension. 59

74 p = Figure 21: Box plot showing comparison of calcium score with history of stroke. 60

75 p = Figure 22: Box plot showing comparison of calcium score with family history of CAD. In conclusion, there was no significant correlation between high calcium score > 400 with the risk factors associated with CAD which were history of smoking, diabetes mellitus, dyslipidaemia, hypertension, history of stroke and family history of CAD (p > 0.05). 61

76 5.4 PREVALENCE OF CORONARY ARTERY STENOSIS ACCORDING TO SEVERITY AND NUMBER OF VESSELS INVOLVED The severity of the LAD artery, LCX artery and RCA are classified into no stenosis, mild stenosis, moderate stenosis and severe stenosis. The prevalence of the LAD artery, LCX artery and RCA in relation to the severity of arterial stenosis are summarized in Table 3 and depicted in Figure 23. Significant coronary artery stenosis is taken as luminal stenosis of 50%. The three main coronary arteries were assessed for significant coronary artery stenosis throughout its length and the prevalence are summarized in Table 4 and depicted in Figure 24. Table 3: Prevalence of severity of coronary artery stenosis in CAD. Number Percentage LAD artery No % Mild % Moderate % Severe % Total % LCX artery No % Mild % Moderate % Severe % Total % RCA No % Mild % Moderate % Severe % Total % LAD: Left anterior descending; LCX: Left circumflex; RCA: Right coronary artery 62

77 Percentage Prevalence of degree of coronary artery stenosis 100% 90% % 70% 60% % 40% 30% 20% Severe Moderate Mild No 10% % Left anterior descending artery Left circumflex artery Right coronary artery Coronary arteries Figure 23: Prevalence of severity of coronary artery stenosis in CAD. 63

78 Percentage Table 4: Prevalence of number of main coronary arteries with significant stenosis in CAD. Number Percentage No vessel involvement % 1 vessel involvement % 2 vessels involvement % 3 vessels involvement % Total % 4000% Prevalence of CAD 3500% 3000% 2500% 2000% 1500% % % 0% No vessel disease 1 vessel disease 2 vessels disease 3 vessels disease Number of significant vessel stenosis Figure 24: Prevalence of number of main coronary arteries with significant stenosis in CAD.. 64

79 5.5 PREVALENCE OF CLINICAL AND TREATMENT OUTCOME Patients in this study were followed up via a questionnaire to determine any significant cardiac chest pain post CCTA. There were 17.2% of a total of 64 patients complained of cardiac related chest pain while the majority of the patients had no chest pain with a prevalence of 82.8%. Table 5 shows the prevalence of patients with/without chest pain post CCTA. Patients were also followed up to ascertain whether any cardiac intervention was done and the type of cardiac intervention undertaken. A total of 21 patients (32.8%) had undergone cardiac intervention. Out of these 21 patients, 16 patients (61.6%) had percutaneous intervention, 5 patients (19.2%) had thrombolytic therapy and the remaining 5 patient (19.2%) underwent coronary artery bypass graft. Table 6 shows the prevalence of patients who underwent cardiac intervention post CCTA. Table 5: Prevalence of patients with/without chest pain post CCTA. Number Percentage Chest pain Yes % No % Total % CCTA: Coronary computed tomography angiography 65

80 Table 6: Prevalence of patients underwent cardiac intervention post CCTA. Cardiac intervention Types of cardiac intervention CCTA: Coronary computed tomography angiography Number Percentage Yes % No % Total % Thrombolytic % therapy Percutaneous % intervention Coronary artery % bypass graft Total % The prevalence of patients with chest pain having at least 1 significant coronary artery stenosis was 81.8% and prevalence of patients with no symptoms of chest pain having at least 1 significant coronary artery stenosis was 79.2%. Figure 25 shows the prevalence of patients with/without chest pain with significant coronary artery stenosis. Another correlation was made with patient complaining of chest pain at least 1 year post CCTA and patients with no symptoms of chest pain undergoing at least 1 cardiac intervention. The prevalence of patients with chest pain undergoing at least 1 cardiac intervention is slightly higher than the patients without symptoms of chest pain at 45.5% and 30.2% respectively. Figure 26 shows the prevalence of patients with/without chest pain undergoing cardiac intervention. 66

81 Percentage Percentage Prevalence of patients with/without chest pain with significant coronary artery stenois 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Yes Chest pain No No significant stenosis At least 1 significant stenosis Figure 25: Prevalence of patients with/without chest pain with significant coronary artery stenosis. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Prevalence of patients with/without chest pain undergoing cardiac intervention Yes Chest pain No No cardiac intervention Underwent cardiac intervention Figure 26: Prevalence of patients with/without chest pain underwent cardiac intervention. 67

82 5.6 COMPARISON OF DEGREE OF STENOSIS BETWEEN CCTA AND ICA A comparison was made between CCTA and ICA of the three major coronary arteries which were the LAD artery, LCX artery and right coronary artery with regards to the severity of stenosis. Each of these three vessels was further divided into proximal, mid and distal segments with the degree of each coronary artery segment stenosis summarized in Table 7 to Table 15. Table 7: Degree of stenosis detection of proximal LAD artery between CCTA and ICA. CCTA ICA Proximal LAD artery Proximal LAD No Mild Moderate Severe Total artery stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value * LAD: Left anterior descending; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography *p < 0.05 is considered statistically significant different. 68

83 Table 8: Degree of stenosis detection of mid LAD artery between CCTA and ICA. CCTA Mid ICA Mid LAD artery LAD artery No Mild Moderate Severe Total stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value LAD: Left anterior descending; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography Table 9: Degree of stenosis detection of distal LAD artery between CCTA and ICA. CCTA Distal ICA Distal LAD artery LAD artery No Mild Moderate Severe Total stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value LAD: Left anterior descending; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography 69

84 Table 10: Degree of stenosis detection of proximal LCX artery between CCTA and ICA. CCTA ICA Proximal LCX artery Proximal LCX No Mild Moderate Severe Total artery stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value * LCX: Left circumflex; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography *p < 0.05 is considered statistically significant different. Table 11: Degree of stenosis detection of mid LCX artery between CCTA and ICA. CCTA Mid ICA Mid LCX artery LCX artery No Mild Moderate Severe Total stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value LCX: Left circumflex; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography 70

85 Table 12: Degree of stenosis detection of distal LCX artery between CCTA and ICA. CCTA Distal ICA Distal LCX artery LCX artery No Mild Moderate Severe Total stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value LCX: Left circumflex; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography Table 13: Degree of stenosis detection of proximal RCA between CCTA and ICA. CCTA ICA Proximal RCA Proximal RCA No Mild Moderate Severe Total stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value RCA: Right coronary artery; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography 71

86 Table 14: Degree of stenosis detection of mid RCA between CCTA and ICA. CCTA Mid RCA No Mild ICA Mid RCA Moderate Severe Total stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value RCA: Right coronary artery; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography Table 15: Degree of stenosis detection of distal RCA between CCTA and ICA. CCTA Distal ICA Distal RCA RCA No Mild Moderate Severe Total stenosis stenosis stenosis stenosis No stenosis Mild stenosis Moderate stenosis Severe stenosis Total p- value RCA: Right coronary artery; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography 72

87 The sensitivity, specificity, PPV, NPV and accuracy were calculated for each of the proximal, mid and distal segments of the left anterior descending artery, left circumflex artery and right coronary artery. Table 16 shows the results of significant coronary artery stenosis detection between CCTA and ICA. Table 16: Receiver operating characteristic (ROC) results of the degree of stenosis by CCTA in comparison to the gold standard, ICA. LAD artery LCX artery RCA artery Prox Mid Dist Prox Mid Dist Prox Mid Dist Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) LAD: Left anterior descending; LCX: Left circumflex; RCA: Right coronary artery; Prox: proximal; Dist: distal; PPV: positive predictive value; NPV: negative predictive value. 73

88 Table 17 shows the summary of p-values obtained from the marginal homogeneity test for significant arterial stenosis detection between CCTA and ICA for the respective coronary arteries. Table 17: p-value for significant arterial stenosis detection between CCTA and ICA. Coronary artery Segments p-value LAD artery Proximal 0.028* Mid Distal LCX artery Proximal 0.002* Mid Distal RCA Proximal Mid Distal LAD: Left anterior descending; LCX: Left circumflex; RCA: Right coronary artery *p < 0.05 is considered statistically significant different. The results indicated that there was significant difference of the proximal left anterior descending artery and proximal left circumflex artery stenosis between CCTA and ICA modalities with p-value of and respectively. However, no significant difference is noted in the rest of the coronary arteries (p > 0.05). 74

89 5.7 COMPARISON OF CORONARY STENOSIS BETWEEN VIE AND ICA A comparison was made between 3D VIE reconstruction and ICA with three major coronary arteries which were left anterior descending artery, left circumflex artery and right coronary artery with regards to the significance of stenosis. The significant stenosis of each coronary artery is summarized in Table 18 to Table 20. Table 18: Degree of stenosis detection of LAD artery between 3D VIE and ICA. 3D-VIE LAD ICA LAD artery artery No stenosis Significant Total stenosis No stenosis Significant stenosis Total p-value LAD: Left anterior descending; 3D-VIE: 3 dimensional virtual intravascular endoscopy; ICA: Invasive coronary angiography Table 19: Degree of stenosis detection of LCX artery between 3D VIE and ICA. 3D-VIE LCX ICA LCX artery artery No stenosis Significant Total stenosis No stenosis Significant stenosis Total p-value LCX: Left circumflex; 3D-VIE: 3 dimensional virtual intravascular endoscopy; ICA: Invasive coronary angiography 75

90 Table 20: Degree of stenosis detection of RCA between 3D VIE and ICA. 3D-VIE RCA ICA RCA No stenosis Significant stenosis Total p-value No stenosis Significant stenosis Total RCA: Right coronary artery; 3D-VIE: 3 dimensional virtual intravascular endoscopy; ICA: Invasive coronary angiography The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated for each of the left anterior descending artery, left circumflex artery and right coronary artery. Table 21 shows the results of significant coronary artery stenosis detection between VIE and ICA. Table 21: Receiver operating characteristic (ROC) results of the degree of stenosis by VIE in comparison to the gold standard, ICA. LAD artery LCX artery RCA Sensitivity 100.0% 66.7% 66.7% Specificity 20.0% 90.0% 90.9% PPV 66.7% 66.7% 66.7% NPV 100.0% 90.0% 90.9% Accuracy 92.3% 84.6% 85.7% LAD: Left anterior descending; LCX: Left circumflex; RCA: Right coronary artery; PPV: positive predictive value; NPV: negative predictive value. 76

91 A non parametric test, Two-Related-Samples test, McNemar test was done to calculate the p- values for the left anterior descending, left circumflex and right coronary arteries. Table 22 shows the p-value results for the respective coronary arteries. Table 22: p-value for significant stenosis detection between VIE and ICA. Coronary Artery p-value LAD LCX RCA LAD: Left anterior descending; LCX: Left circumflex; RCA: Right coronary artery; In conclusion, there is no significant difference of the left anterior descending artery, left circumflex artery and right coronary artery stenosis between 3D VIE and ICA modalities (p > 0.05). 77

92 5.8 RESULTS FROM GENERATION OF VIE IMAGES FROM CCTA VIE images were generated from the CCTA data obtained from Department of Biomedical Imaging, University Malaya Medical Centre, Kuala Lumpur. Images showing smooth intraluminal plaque appearance of LAD artery, LCX artery and RCA are depicted in Figure 27, 28 and 29 respectively. Images showing irregular intraluminal plaque appearance of LAD artery, LCX artery and RCA are depicted in Figure 30, 31 and 32 respectively. 78

93 Figure 27: Coronary VIE views of plaque at LAD artery with smooth luminal appearance (a) Coronary VIE demonstrates eccentric plaque with no significant stenosis. (b) Coronary VIE demonstrates eccentric plaque in the coronary wall causing significant stenosis. Figure 28: Coronary VIE views of plaque at LCX artery with smooth luminal appearance (a) Coronary VIE demonstrates eccentric plaque with no significant stenosis. (b) Coronary VIE demonstrates eccentric plaque in the coronary wall causing significant stenosis. 79

94 Figure 29: Coronary VIE views of plaque at RCA with smooth luminal appearance (a) Coronary VIE demonstrates eccentric plaque with no significant stenosis. (b) Coronary VIE demonstrates eccentric plaque in the coronary wall causing significant stenosis. Figure 30: Coronary VIE views of plaques at LAD artery with irregular luminal appearance (a) Coronary VIE demonstrates eccentric plaques (arrows) with no significant stenosis. (b) Coronary VIE demonstrates eccentric plaques (arrows) in the coronary wall causing significant stenosis. 80

95 Figure 31: Coronary VIE views of plaques at LCX artery with irregular luminal appearance (a) Coronary VIE demonstrates eccentric plaques (arrows) with no significant stenosis. (b) Coronary VIE demonstrates eccentric plaques (arrows) in the coronary wall causing significant stenosis. Figure 32: Coronary VIE views of plaques at RCA with irregular luminal appearance (a) Coronary VIE demonstrates eccentric plaques (arrows) with no significant stenosis. (b) Coronary VIE demonstrates eccentric plaques (arrows) in the coronary wall causing significant stenosis. 81

96 CHAPTER SIX 6.0 DISCUSSION Calcium score is an important part of the CCTA examination prior to contrast injection to determine the atherosclerotic calcified plaque burden of the coronary arteries. It has been used as a screening tool for patients with risk factors of developing CAD to predict future cardiac events (9). Performing a calcium score scan is an efficient and useful method as the scanning time is short with a low radiation dose to patients (53). Coronary artery calcification have been linked to the presence of atherosclerotic CAD and to an extent related to the severity of the disease as a whole (8). However, there is no direct correlation between the presence of coronary calcification with the degree and location of coronary artery stenosis (9). According to the European Society of Cardiology, CCTA should be done in all patients with mild to moderate risk of developing CAD and those patients with suspicious yet inconclusive stress test (54). A zero calcium score does not mean that the particular patient is safe from CAD as noncalcified lipid rich plaque may result in coronary luminal stenosis (9). Therefore, a patient presenting with typical chest symptoms and/or multiple risk factor for CAD with a low calcium score should undergo ICA/CCTA to appropriately characterise the degree of stenosis and plaque morphology. There are six risk factors of CAD identified in this study which were history of smoking, diabetes mellitus, dyslipidaemia, hypertension, history of stroke and family history of CAD. Significant number of patients in this study has dyslipidaemia, hypertension and diabetes mellitus with a prevalence of 77.1%, 69.0% and 49.3% respectively. The rest of the risk factors of CAD showed a prevalence of < 30.0%. Gender 82

97 distribution of male to female patients is almost similar for all CAD risk factors except history of smoking with a male to female ratio of 10:1. However, this study has demonstrated that there is also no direct correlation between high calcium score of > 400 with the associated risk factors of developing CAD as the calculated p value is more than The findings conflicted with other study done by Pletcher et al. (55) which shows these associated risk factors are independent predictors of coronary artery calcification. This may be due to limitations encountered when conducting the study and will be discussed in the next chapter. Therefore, the results of this particular investigation cannot be taken into account and further studies needs to be conducted. The left anterior descending artery is more commonly affected by atherosclerotic plaques causing significant stenosis (taken as > 50% luminal narrowing) with a prevalence of 67.2% compared to the left circumflex artery (prevalence of 31.2%) or the right coronary artery (46.9%). Almost half of the arterial stenosis in the left anterior descending artery was severe with > 70% luminal narrowing at 48.4%. Majority of the patients that had underwent CCTA have either 1, 2 and/or 3 significant artery luminal narrowing with only 20.3% of patients with no significant coronary artery stenosis. Out of a total of 64 patients who underwent CCTA, 17.2% of these patients developed significant cardiac related chest pain suggesting an underlying acute coronary syndrome. About one third of the patients with a prevalence of 32.8% have undergone cardiac intervention which includes at least one of the following, a thrombolytic therapy, percutaneous intervention or CABG. Most of the patients had percutaneous intervention done with either angioplasty or arterial stent inserted at 61.6% compared to thrombolytic therapy or CABG at 19.2% each. The prevalence of patients with chest pain is slightly higher than the 83

98 patients without symptoms of chest pain undergoing at least 1 cardiac intervention at 45.5% and 30.2% respectively. However, there was no significant difference in prevalence of patients with chest pain compared to patients without symptoms of chest pain having at least 1 significant coronary artery stenosis at 81.8% and 79.2% respectively. We have only 1 case of cardiovascular event related death which was obtained from the questionnaire. It has remained controversial as to whether high calcium score of >400 affects the diagnostic performance of CCTA. According to Diederichsen et al. (38), the diagnostic capability of CCTA for patients with high calcium score of > 400 have significantly reduced and therefore has been suggested that these patients should not proceed with CCTA. However, according to Lau et al. (56), these particular patients with high calcium score have further increased the sensitivity without significantly affecting the specificity of CCTA in detecting CAD. Chen et al. (9) have concluded that a high calcium score did not reduced the accuracy and sensitivity of CCTA, but significantly reduced the specificity of the left anterior descending and left circumflex arteries. Other studies have also demonstrated that CCTA has a high sensitivity and accuracy in detecting significant CAD and even more so after the introduction of 64-slice CT scanner (57). For this study, a total of 35 patients with high calcium score were recruited and comparison was made between CCTA and ICA to determine the diagnostic accuracy of significant coronary artery stenosis in CCTA. The coronary calcium score for this cohort of patients were > 400 and ranges from to with a mean score of Specificity is defined as the ability for the CCTA to correctly identify patients without the disease while sensitivity is defined as the ability for the CCTA to identify patients with the disease. 84

99 According to this study, there was reduced sensitivity of CCTA in determining distal left circumflex artery stenosis at 50.0%; however the accuracy is significantly high at 84.0%. The overall sensitivity, specificity and accuracy in the rest of the coronary vessels were not significantly reduced in this group of patients with high calcium score ranging from 62.5% %, 54.2% % and 61.8% % respectively. There was also no significant difference with the ability of CCTA to determine significant coronary artery stenosis when compared to ICA apart from the proximal left anterior descending and left circumflex arteries with p value of and respectively (p < 0.05). From this study, we can conclude that the overall accuracy, sensitivity and specificity of CCTA in patients with high calcium score were not significantly reduced to suggest delaying CCTA with the exception of the distal left circumflex artery. The calculated NPV for all three major coronary arteries were high ranging from 72.7% %. However, PPV shows a wide range of value from 9.1% % and deemed not significant for this study. Coronary 3D-VIE is a relatively new reconstruction method which provides useful information regarding coronary plaques in relation to the location, plaque morphology as well as coronary wall changes and narrowing due to the existence of plaques within the coronary artery. The coronary wall changes and plaque appearance on VIE are related to the amount and types of plaques. There are three types of coronary plaques which can be grouped into calcified, non-calcified and mixed plaques (41). Preliminary findings were that the intraluminal plaques were clearly visualized on VIE and is thought to be more accurate than the conventional CCTA appearances as it is not affected by the blooming artefacts from the extensive coronary artery calcifications. These extensive calcifications decrease luminal visualization causing overestimation of the coronary artery stenosis and thereby reducing the diagnostic accuracy on CCTA. VIE concentrates on the 85

100 intraluminal appearance as compared to the extra luminal appearance on CCTA which makes it more accurate in determining the degree of coronary artery stenosis (42). This study involves the coronary 3D VIE reconstruction for 14 patients and comparison with ICA was made in determining significant coronary luminal stenosis. Specificity of LAD artery was significantly low at 20%, however the sensitivity and accuracy were high at 100% and 92.3% respectively. The sensitivity, specificity and accuracy for the left circumflex artery and right coronary artery were not significantly reduced. There was also no significance difference with the ability of VIE to determine significant coronary artery stenosis when compared to ICA in all the three major coronary arteries which are the left anterior descending artery (p = 0.125), left circumflex artery (p = 1.000) and right coronary artery (p = 1.000). Although the NPV values (90.0% %) of all three coronary arteries are higher than the PPV (66.7%), these results were significant and infers that the VIE is a useful tool in assessing coronary artery stenosis. Additional information can also be obtained when using VIE in determining the plaque morphology as well as its associated coronary wall changes. Initial assessment showed that the intraluminal plaques are clearly seen. However, the limitation of using VIE alone is the inability to accurately differentiate between the calcified and non-calcified plaques as both of these plaques have smooth protruding intraluminal appearance. This can be easily overcome with the aid of conventional CCTA to confirm the different types of plaques based on the measurable Hounsfield unit (42). Almost all calcified plaques demonstrate a smooth intraluminal appearance with an associated protruding sign on coronary 3D VIE. Figure 33 shows a calcified plaque with smooth intraluminal appearance on VIE. However, if the coronary artery is filled with heavily 86

101 calcified plaques, the coronary VIE will display an irregular intraluminal coronary wall changes. Figure 34 shows extensively calcified plaques with irregular intraluminal appearance on VIE. Non-calcified plaques usually demonstrate a smooth intraluminal appearance, while mixed calcified and non-calcified plaques commonly show an irregular intraluminal appearance on coronary VIE. Figure 35 shows mixed calcified and non-calcified plaques with irregular intraluminal appearance on VIE. The irregular intraluminal appearance in a mixed plaque is thought to be due to the coronary wall undergoing different stages of remodelling which are made up of the active inflammatory stage whereby lipid laden materials are being formed within the vessel walls and the chronic stage which involves the development of calcified plaques (41). Figure 33: CCTA and coronary VIE views of a calcified plaque at the LAD artery. (a) Curved planar reformatted CCTA image shows a calcified plaque (arrow) at the proximal LAD artery. (b) Coronary VIE demonstrates eccentric plaque in the coronary wall with smooth appearance. (41) 87

102 Figure 34: CCTA and coronary VIE views of extensively calcified plaques at the LAD artery. (a) Extensively calcified plaques (arrows) are shown at the LAD artery on curved planar reformatted CCTA. (b) Coronary VIE shows irregular wall changes (arrows) with significant lumen stenosis. (41) Figure 35: CCTA and coronary VIE views of mixed plaques at the LAD artery. (a) Mixed calcified (arrows) and non-calcified plaques are seen at the proximal LAD artery on curved planar reformatted CCTA. (b) Coronary VIE shows irregular wall changes with significant coronary stenosis caused by plaques. (41) 88

103 Correlation with VIE findings of the plaque morphology and coronary wall changes can assist in determining the extent of CAD, predicting the complications and prognosis as well as monitoring the treatment results. 89

104 CHAPTER SEVEN 7.0 LIMITATIONS OF STUDY AND FUTURE DEVELOPMENTS 7.1 LIMITATIONS OF STUDY We acknowledge that there were a few limitations with our study which needs to be addressed in order to obtain a more accurate outcome for future studies. Firstly, this study was a single centre, retrospective and prospective study, and the results obtained from this study may not necessarily reflect the general patient population or physician practice at other centres. Secondly, the study was conducted on a selected small number of patients (n=100) with high calcium score. This provided limited results as a larger number of patients are required to assess the correlation of CAD risk factors with high calcium score including determining the accuracy, sensitivity and specificity of CCTA and VIE in relation to coronary artery stenosis. Further study can also be done to verify the significance of calcium score in relation to the CAD risk factors by comparing with different subgroups of calcium scores i.e. 0, 1-10, , and >400. Another important limitation is the lack of clinical detail about the patients. While sufficient data was collected regarding the risk factors of CAD, certain data (diabetes mellitus, hypertension, dyslipidaemia, history of smoking) were only available from a questionnaire and not confirmed via initial follow-up. 90

105 Although the CCTA images were obtained from our centre, the post-processing and generation of 3D VIE images were done in Curtin University, Perth, Australia as we do not own the license for the particular software. It would be ideal if we could post process and interpret the data to obtain more information for the study and gather sufficient experience to conduct this practice in the future. 7.2 FUTURE DEVELOPMENTS In order to overcome the limitations of study listed above, collaboration with multiple medical centers and hospitals in the country for future studies are recommended to increase the sample size. This will provide more accurate results for the particular examination that reflect almost the entire population in the country. A more extensive involvement of the physician in future studies especially in providing an extensive clinical detail and the appropriate investigations will be helpful in obtaining a clear clinical picture of the patients involved thus improving the accuracy of the results. In the near future, we hope that our country will be able to own the software license for image post-processing and generation of 3D VIE images of the coronary arteries as well as acquire sufficient experience in performing this examination to improve the quality of the study. 91

106 CHAPTER EIGHT 8.0 CONCLUSION This study shows that a high calcium score did not significantly reduce the overall diagnostic accuracy of CCTA when compared to ICA. The sensitivity and specificity of CCTA was generally high with a good negative predictive value. However, blooming artefacts due to atherosclerotic calcifications predominantly at the proximal LAD artery and LCX artery may explain the significance difference of CCTA findings when compared to the ICA. The advantage of CCTA as a screening modality in low risk patients with chest pain for the assessment of CAD shows great potential. The evidence of the significant difference of CCTA findings has suggested that high risk patients with high calcium score > 400 should be referred for ICA for further evaluation. These patients would also benefit from immediate revascularization after a diagnostic ICA if required. Comparison between coronary VIE and using ICA as the gold standard showed that the overall sensitivity, specificity, PPV, NPV and accuracy was not significantly reduced. Moreover, the images obtained from VIE reconstruction was able to clearly demonstrate the intraluminal plaque appearance and associated coronary wall changes which is not possible from the conventional 2D and 3D visualizations. Therefore, VIE should be used as a complimentary approach in addition to CCTA to assist in clinical diagnosis, analysis of plaques, determining the extent of the disease and risk stratification of CAD. Further studies are needed in order to confirm the initial results. Other studies with correlation made between the coronary risk factors with the coronary plaques morphology are also essential to establish the prognostic value of CCTA using VIE as a complimentary tool in patients with suspected CAD. 92

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114 APPENDICES APPENDIX A QUESTIONNAIRES AN INVESTIGATION OF THE EFFECT OF HIGH CORONARY CALCIUM SCORE ON THE ASSESSMENT OF CORONARY ARTERY DISEASE USING CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY: AN INVESTIGATION OF CLINICAL VALUE OF 3D VIRTUAL INTRAVSCULAR ENDOSCOPY. Name:, DOB:,RN: Total cholesterol: mmol/l, LDL level: mmol/l, HDL level: mmol/l Blood pressure: mm/hg. Date of CTA coronary done: Indication of CTA: Is there any family history for premature cardiovascular events (history of myocardial infarction or stroke in first-degree relatives aged LESS THAN 65 years). YES NO: Do you smoke? YES NO: If yes, how long?: <5 years, <10 years, <15 years, > 20 years. Do you have diabetes mellitus? YES NO: If yes, how long?: <5 years, <10 years, <15 years, > 20 years. Do you have history of stroke? YES NO: If yes, how long?: <5 years, <10 years, <15 years, > 20 years. 100

115 Do you have any symptom for heart attack after CTA cardiac? No: Yes:, when is it occur? Duration from CTA cardiac and heart attack: If yes, what is/are the symptoms? Retrosternal pressure, squeezing: YES NO: Is it caused by exertion or emotional stress: YES NO: Relieved by sublingual GTN: YES NO: Relieved by rest: YES NO: If you were admitted for heart attack, what were the procedure/ intervention/management during admission? Medication (Thrombolytic therapy, i.e. streptokinase):yes NO Percutaneous coronary intervention: YES NO Coronary artery bypass surgery: YES NO Clinical outcome/ Final diagnosis (please tick ): Cardiac deaths Myocardial infarction/stemi Unstable anginas/ NSTEMI Revascularizations Date of phone call interview: Name of interviewer: 101

116 APPENDIX B PATIENT INFORMATION SHEET Please read the following information carefully, do not hesitate to discuss any questions you may have with your Doctor. Study Title AN INVESTIGATION OF THE EFFECT OF HIGH CORONARY CALCIUM SCORE ON THE ASSESSMENT OF CORONARY ARTERY DISEASE USING CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY: AN INVESTIGATION OF CLINICAL VALUE OF 3D VIRTUAL INTRAVSCULAR ENDOSCOPY. Introduction Coronary artery disease (CAD) is a known cause of mortality and morbidity with the disease reaching endemic proportions(1). It is the most important cause of death in Malaysia with the mortality rate of 20-25% in public hospitals. Due to technological advances in computed tomography (CT) scanner over the recent years, coronary computed tomographic angiography (CCTA) has emerged as a less invasive imaging modality for coronary artery assessment with high sensitivity and negative predictive value in determining the site and degree of coronary artery luminal stenosis. Despite the very high negative predictive value of CCTA, the diagnostic accuracy of CCTA is limited by the extensive coronary artery calcification (taken as coronary calcium score >400), resulting in blooming artefacts. However, recent studies have demonstrated the overall diagnostic accuracy for a coronary artery assessment in a patient with a high calcium score was not drastically impaired with no significant difference in sensitivity. 102

117 The CCTA offers extensive 2D axial and multiplanar reformatted images for the assessment of the coronary plaques. However, it is still lacking the direct intraluminal visualization of the coronary artery lumen as well as the assessment of the plaque if present. This limitation is can be overcome by using a 3D reconstruction tool known as 3D virtual intravascular endoscopy (3D VIE) which is able to provide a more extensive diagnostic evaluation of the coronary tree. With this imaging tool, a more accurate assessment can be done with regards to the plaque location in relation to the coronary ostium, plaque composition and coronary wall stenosis due to the presence of plaque within the coronary artery. In this study, we are exploring a new method of coronary artery assessment which was described above as 3D VIE. This new method is potentially beneficial as a supplementary tool to CCTA in improving diagnostic evaluation of patients with high CAC scores. What is the purpose of this study? The general objectives of this study are to evaluate the diagnostic values of CCTA for the assessment of coronary artery disease in patients with high calcium score in comparison with the conventional invasive coronary angiogram. The specific objectives of this study are to: a) To investigate the diagnostic value of 3D VIE in the visualisation of coronary wall changes due to the effect of coronary plaques in high CAC scores b) To correlate 3D VIE findings with conventional 2D and 3D visualisations in terms of the degree of coronary lumen stenosis or occlusion caused by high CAC scores 103

118 c) To explore the potential role of 3D VIE as a supplementary tool to conventional coronary CT angiography in improving diagnostic evaluation of patients with high CAC scores d) To investigate the relationship between the CCTA and the clinical outcome of these patients with high calcium score What are the procedures to be followed? During the CT examination day, you will be referred to the CT room (C1) at the Department of Biomedical Imaging, 2nd Floor, Menara Utama, UMMC. The radiologist or radiographer will explain the procedure to you, including the risks and benefits and answer any questions you may have. You will then be asked to sign a form giving your informed consent for the examination. Prior to the CT scan, a medical officer or nurse will insert an intravenous (IV) line into your vein. The IV tube is used for contrast injection during the CT scan. You will be placed on a CT scan table and positioned accordingly with the assistance of the radiographer. You will be made as comfortable as possible. The CT scan will start immediately after you are comfortably positioned. For the exam itself, which in most cases lasts just a few minutes, the radiographer will exit the room into the monitor console room which is located next to the CT scanner. The radiographer will inform you through a speaker when the exam is about to begin you may be asked to hold your breath briefly during a portion of the exam. At no time will the scanner itself touch you during the exam. Once the exam is complete, the radiographer will assist you to leave the CT room and you will be followed up / contacted by the researchers who take part in this study. 104

119 Who should not enter the study? Patients with coronary artery calcium score <400 and those with calcium score 400 and did not proceed with CCTA should be excluded from the study. What will be benefits of the study: (a) to you as the subject? You will be diagnosed using the latest imaging technique, dual-energy CT imaging and CT virtual endoscopy to assess the characteristics of your coronary artery as well as to estimate the risk factors for you to develop coronary artery diseases. (b) to the investigator? The data collected from this study will enable a reliable statistical test to be carried out to evaluate the diagnostic capability/value of CCTA and CT virtual intravascular endoscopy compared to conventional coronary angiography as well as to investigate the clinical outcome of patients with high calcium score. What are the possible drawbacks? There is no expected drawback from taking part in this study. Can I refuse to take part in the study? Sure, you can always withdraw yourself from the study at any time prior to the study. 105

120 Who should I contact if I have additional questions during the course of the study? Dr Woo Sze Yang, Final Year Masters of Radiology student, Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, Kuala Lumpur. Telephone number: address: jimmywoo_11@hotmail.com. Or Professor Dr Yang Faridah Abdul Aziz, Consultant Radiologist, Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, Kuala Lumpur. Telephone number: address: yangf@ummc.edu.my. 106

121 APPENDIX C CONSENT BY PATIENT FOR CLINICAL RESEARCH I,.. Identity Card No. (Name of Patient) of (Address) hereby agree to take part in the clinical research (clinical study) specified below: Title of Study: Effect of high coronary calcium score on the assessment of coronary artery disease using coronary computed tomography angiography: An investigation of the clinical value of 3D virtual intravascular endoscopy. The nature and purpose of which has been explained to me by Dr..... (Name & Designation of Doctor) and interpreted by..... (Name & Designation of Interpreter) to the best of his/her ability in. language/dialect. I have been told about the nature of the clinical research in terms of methodology, possible adverse effects and complications (as per patient information sheet). After knowing and understanding all the possible advantages and disadvantages of this clinical research, I voluntarily consent of my own free will to participate in the clinical research specified above. I understand that I can withdraw from this clinical research at any time without assigning any reason whatsoever and in such a situation shall not be denied the benefits of usual treatment by the attending doctors. Date:.. IN THE PRESENCE OF Signature or Thumbprint. (Patient) Name Identity Card No.. Designation.. Signature. (Witness for Signature of Patient) I confirm that I have explained to the patient the nature and purpose of the above-mentioned clinical research. Date. Signature (Attending Doctor) CONSENT BY PATIENT FOR CLINICAL RESEARCH R.N. Name Sex Age Unit 107

122 KEIZINAN OLEH PESAKIT UNTUK PENYELIDIKAN KLINIKAL Saya,.. (Nama Pesakit) No. Kad Pengenalan... beralamat. (Alamat) dengan ini bersetuju menyertai dalam penyelidikan klinikal (pengajian klinikal) disebut berikut: Tajuk Penyelidikan Effect of high coronary calcium score on the assessment of coronary artery disease using coronary computed tomography angiography: An investigation of the clinical value of 3D virtual intravascular endoscopy. yang mana sifat dan tujuannya telah diterangkan kepada saya oleh Dr. (Nama & Jawatan Doktor) mengikut terjemahan. (Nama & Jawatan Penterjemah) yang telah menterjemahkan kepada saya dengan sepenuh kemampuan dan kebolehannya di dalam Bahasa / loghat Saya telah diberitahu bahawa dasar penyelidikan klinikal dalam keadaan methodologi, risiko dan komplikasi (mengikut kertas maklumat pesakit). Selepas mengetahui dan memahami semua kemungkinan kebaikan dan keburukan penyelidikan klinikal ini, saya merelakan/mengizinkan sendiri menyertai penyelidikan klinikal tersebut di atas. Saya faham bahawa saya boleh menarik diri dari penyelidikan klinikal ini pada bila-bila masa tanpa memberi sebarang alasan dalam situasi ini dan tidak akan dikecualikan dari kemudahan rawatan dari doktor yang merawat. Tarikh:.. DI HADAPAN Tandatangan/Cap Jari (Pesakit) Nama No. K/P Jawatan... Tandatangan (Saksi untuk Tandatangan Pesakit) Saya sahkan bahawa saya telah menerangkan kepada pesakit sifat dan tujuan penyelidikan klinikal tersebut di atas. Tarikh:. Tandatangan.. (Doktor yang merawat) KEIZINAN OLEH PESAKIT UNTUK PENYELIDIKAN KLINIKAL No. Pend. Nama Jantina Umur Unit 108

123 CONSENT BY RESPONSIBLE RELATIVE FOR CLINICAL RESEARCH I,.. Identity Card No... (Name of responsible relative) of.. (Address) hereby agree that my relative I.C. No.. (Name) participate in the clinical research (clinical study) specified below:- Title of Study: Effect of high coronary calcium score on the assessment of coronary artery disease using coronary computed tomography angiography: An investigation of the clinical value of 3D virtual intravascular endoscopy. The nature and purpose of which has been explained to me by Dr.... (Name & Designation of Doctor) and interpreted by..... (Name & Designation of Interpreter) to the best of his/her ability in. language/dialect. I have been informed of the nature of this clinical research in terms of procedure, possible adverse effects and complications (as per patient information sheet). I understand the possible advantages and disadvantages of participating in this research. I voluntarily give my consent for my relative to participate in this research specified above. I understand that I can withdraw my relative from this clinical research at any time without assigning any reason whatsoever and in such situation, my relative shall not be denied the benefits of usual treatment by the attending doctors. Should my relative regains his/her ability to consent, he/she will have the right to remain in this research or may choose to withdraw. Relationship Signature or Date: to Patient. Thumbprint Name.. IN THE PRESENCE OF Identity Card No. Designation Signature (Witness) I confirm that I have explained to the patient s relative the nature and purpose of the abovementioned clinical research. Date Signature (Attending Doctor) CONSENT BY RESPONSIBLE RELATIVE FOR CLINICAL RESEARCH R.N. Name Sex Age Unit 109

124 KEIZINAN OLEH WARIS YANG BERTANGGUNGJAWAB UNTUK PENYELIDIKAN KLINIKAL Saya,.. Kad Pengenalan... (Nama Waris yang bertanggungjawab) beralamat. (Alamat) dengan ini bersetuju supaya saudara saya.. menyertai (Nama Pesakit) dalam penyelidikan klinikal (pengajian klinikal) disebut berikut: TajukPenyelidikan: Effect of high coronary calcium score on the assessment of coronary artery disease using coronary computed tomography angiography: An investigation of the clinical value of 3D virtual intravascular endoscopy. yang mana sifat dan tujuannya telah diterangkan kepada saya oleh Dr. mengikut terjemahan.. (Nama & Jawatan Penterjemah) (Nama & Jawatan Doktor)... yang telah menterjemahkan kepada saya dengan sepenuh kemampuan dan kebolehannya di dalam Bahasa / loghat Saya telah diberitahu bahawa dasar penyelidikan klinikal dalam keadaan metodologi, risiko dan komplikasi (mengikut kertas maklumat pesakit). Saya mengetahui dan memahami semua kemungkinan kebaikan dan keburukan penyelidikan klinikal ini. Saya merelakan/mengizinkan saudara saya menyertai penyelidikan klinikal tersebut di atas. Saya faham bahawa saya boleh menarik balik penyertaan saudara saya dalam penyelidikan klinikal ini pada bila-bila masa tanpa memberi sebarang alasan dalam situasi ini dan tidak akan dikecualikan dari kemudahan rawatan dari doktor yang merawat. Sekiranya saudara saya kembali berupaya untuk memberi keizinan, beliau mempunyai hak untuk terus menyertai kajian ini atau memilih untuk menarik diri. Tarikh: Pertalian Tandatangan/Cap Jari Waris dengan Pesakit.. yang bertanggungjawab DI HADAPAN Nama. No. K/P Jawatan..... Tandatangan (Saksi untuk Tandatangan Waris yang Bertanggungjawab) Saya sahkan bahawa saya telah menerangkan kepada waris yang bertanggungjawab sifat dan tujuan penyelidikan klinikal tersebut di atas. Tarikh:. KEIZINAN OLEH WARIS PESAKIT UNTUK PENYELIDIKAN KLINIKAL Tandatangan (Doktor yang merawat) No. Pend. Nama Jantina Umur Unit 110

125 APPENDIX D 111