PAPER IV - SYNOPSIS PRESENTATION

1. PAPER IV - SYNOPSIS PRESENTATION Title of the study: Coronary artery dimensions, myocardial bridging and their role in coronary artery disease among four states of South India- ‘single’ centered approach Divia Paul A PhD Scholar (Reg no.152/Jan 2015) Department of Anatomy Yenepoya Medical College Yenepoya University Co-Guide: Dr. Subramanyam.KH.O.D Department of Interventional Cardiology K.S Hegde Medical Academy Hospital Guide: Dr. Ramakrishna Avadhani Professor & H.O.D Department of Anatomy Yenepoya Medical College Yenepoya University

2. Contents of the presentation 1. Introduction and background 2. Literature survey I. Present status a. International b. National c. Local scenarios 3. Social relevance and uniqueness of the work . 4. Aim, objectives, hypothesis . 5. Methodology – Sample size, Sample size calculation, Selection criteria, Sampling technique, Ethical considerations .

3. Contd... 7. Research study plan in the form of flow chart . 8. Procedures for data collection, patient information form, format of informed consent. 9. Statistical analysis with detailed plan for the statistical analysis of the data . 10. Timeline of the project showing the duration of the study – Grant Chart. 11. Budget plan for the project. 12. References.

4. Introduction and background • Coronary artery vessels size varies among individuals and there is an evidence of some degree of variability among different geographic regions. • The calibre of coronary arteries, both main stems and larger branches, ranges between 1.5 to 5.5 mm at their origins. This is based on measurements of arterial casts or angiograms. • The diameters of the coronary arteries may increase up to the 30th year of life. (Standring S et al.; 2008) • The associated details about caliber of coronary artery among the Indian population are limited.

5. Contd... • The present study will help to reveal whether the ethnic variation of artery size holds ground. • The present study provide the first step towards developing a quantitative estimate of coronary artery by correlating it with gender differences and body mass index among population of south India. • It has been hypothesised that women having smaller coronary lumen can attribute to an increased risk of restenosis and repeated revascularisation after coronary angioplasty.

6. Contd... • However, data regarding the same is limited, contradicting or not reliable, hence, this study intends to provide sound data regarding whether gender differences exist in coronary vessel lumen. • Asians have higher levels of cardiovascular risk factors compared to Caucasians. Normal body mass index cut off values recommended for asians are lower than any other races or countries. • The present study correlates the body mass index and coronary artery dimensions to find out any association between them to be a precursor for coronary artery disease (CAD).

7. Contd... • Myocardial bridging (MB) has been implicated in coronary artery disease and its role has been found to be like a double edged sword. There is lack of clarity as to whether MB actually has a significant role to play in coronary artery disease (CAD). • Studies regarding this aspect have not shown consistent result as their sample sizes have been small. This study will aid in providing reliable data to study this association. • Cardiac dominance patterns and their correlations with atherosclerotic prominence give a better understanding of itsclinical significance. The present study outlooks the incidence percentages of right, left and co-dominance patterns in a broader aspect.

8. LITERATURE SURVEY CORONARY ARTERY DIMENSION AND VARIATIONS: STUDIES IN DIFFERENT GEOGRAPHICAL AREAS International scenarios • Mortality and morbidity rates are observed more in South Asians and they are considered as one of the high risk ethnic groups for the development of coronary artery disease (CAD). • The study group involved were selected South Asians and Caucasians who underwent the procedure of cardiac catheterization using the edge-detection method of quantitative coronary angiography at a similar period of time in the United States of America. • The South Asians showed the evidences of smaller proximal left anterior descending (LAD) luminal diameters, higher mean percent stenosis per vessel and number of subjects with double or triple vessel disease. (Hasan RK et al.; 2011)

9. Contd… • Outcome results of coronary artery bypass grafting (CABG) among South Asian patients in the UK are found to have a higher mortality rate than Caucasian patients. Coronary artery size and disease in matched South Asian and Caucasian men undergoing primary coronary artery bypass grafting were measured to prove this assumption by quantitative coronary angiography (QCA), showed little difference among both groups. (Zindrou D et al.; 2006) • British South Asian men had a different pattern of coronary artery disease when compared with European men. Reduced left anterior descending (LAD) diameter is associated with advanced disease in Europeans proved an indicative of ethnic differences in vascular remodelling compared to South Asians.(Tillin T et al.; 2008)

10. National scenarios • Normal dimensions of the coronary artery segments in Indian population obtained through quantitative coronary angiography procedure are made to compare with western estimates of coronary artery size. The results implied that coronary artery dimensions for at least some branches of the left coronary system are similar and of the right coronary appears greater in Indian population. These conclusions repudiate the general impression that Indians have smaller coronary arteries.(Saikrishna C et al.; 2006) • With Indian population having a high risk of coronary artery disease(CAD), it is imperative to find all factors that increase coronary disease severity. The prevalence of risk factors for CAD in an urban Indian population is high. Therefore, there is an urgent need to raise awareness of these risk factors ,so that individuals at high risk for future CAD can be managed effectively. (Sekhri T et al.; 2014)

11. Local scenarios • To define the presence of diffused diseases in coronary arteries,angiographically, the size of the non-stenosed arteries at such sites in the coronary tree must be known. The study was held in kerala, to prove the prediction of normal coronary dimensions may overcome the ineptitudes of judging the percentage stenosis in diffusely fragmented coronary artery diseases.(Sankar V et al.; 2005) • An increased prevalence of coronary artery disease (CAD) in south Indian population has been reported from chennai, with supporting study evidence. (Mohan V et al.; 2001)

12. MYOCARDIAL BRIDGING AND ITS IMPORTANCE • Three major coronary arteries customarily sequel along the epicardial surface of heart. Occasionally, short moieties of coronary artery douche into the myocardium for a vacillating distance which is termed as myocardial bridging. This has a prevalence of 5% to 12% among patients and is usually confined to the left anterior descending (LAD).(Alegria JR et al.; 2005) • The surrounding myocardium initiates an idiosyncratic atheroprotective hemodynamic microenvironment within bridges even though the mechanisms induced for this initiation uniqueness are largely unknown.(Chatzizisis YS et al.; 2009)

13. BODY MASS INDEX: RISKS AND CUT-OFF VALUES – GENDER, RACE DIFFERENCES • Developing appropriate anthropometric measures to assess obesity is important for the identification and prevention of the development of obesity-related disorders. (Yang J-j et al.; 2007) • Body mass index (BMI) has been recommended by the world health organisation (WHO) to classify body weight. The current cut-off point recommended by WHO is ≥25 kg/m2 for not being overweight and ≥30 kg/ m2 for not being classified as obese. (WHO Expert Consultation. Lancet ; 2004) • Gender significantly impacts proximal left anterior descending (LAD) and right coronary artery (RCA) size and differences in coronary artery dimensions. This can explain some gender-related risk with coronary artery revascularization,accentuating the priority of considering multiple subsidizing factors. (Dickerson JA et al.; 2010)

14. Contd... • Differences in disease outcomes between women and men can be related to vascular biological factors such as a smaller vessel size and functional differences of smooth muscle cells in the vessel wall. This causes smaller atheroma burden and slower progression of coronary artery disease in women.(Jacobs AK; 2009) • The median age for the appearance of myocardial infarction is higher in women and also, it must be emphasized that they are known worldwide to have a poor prognosis compared to men. (Mak KH et al.; 2004) • Women have higher mortality rates than men after coronary angioplasty. Differences in the size of the vessel involved may moderately account for the same. The decrease in target vessel size will be associated with increased risk of restenosis and repeat revascularization. (Cantor WJ et al.; 2002)

15. CARDIAC DOMINANCE • The right coronary artery (RCA) is dominant in 85% of patients and nondominant in 15% of patients in which the left circumflex artery (LCx) is the dominant vessel. The remaining patients have RCA that gives rise to the PDA (posterior descending artery), with LCx artery providing all the posterolateral branches is termed as balanced or co-dominant circulation. (Mann DL et al.; 2014) • Complex anatomy of the coronary artery system can accurately be depicted by 64-slice computed tomographic angiography (CTA). The coronary artery system was right dominant in 76%, left dominant in 9.1% and co-dominant in 14.8% of the cases. (Kosar P et al.; 2009)

16. SOCIAL RELEVANCE OF THE STUDY • The present study helps to acquire precise knowledge of the expected normal lumen diameter at a given coronary anatomic location which could be more useful than the traditional percent stenosis assessments. • Coronary stenting in the treatment of patients with small vessels isstill a causative factor for recurrent restenosis in patients. • The study helps the interventional cardiologists and cardiac surgeons to treat the patient by a bed to needle approach rather than a bed to scalpel approach. • The study may also help them not to merely presume the artery size with a concept of ethnic variation.

17. Contd... • The size of the coronary artery with or without a myocardial bridge (MB) may have a major role to play in the causation of coronary artery disease (CAD). • Cardiac dominance patterns and their correlations with atherosclerotic prominence give a better understanding of its clinical significance. • This could further aid in changing the approach of intervention on the patients, which in turn may help the patient to return to a normal life faster than the routine restrictions and precautions after a coronary bypass surgery. • Surgical procedures could be avoided. All these would lead to lower cost of coronary care, faster recuperation, and better quality of life for the patients; both physically and economically.

18. Aim To study the coronary artery vessel size with and without myocardial bridging and its association with other factors causing coronary artery disease among South Indian population.

19. Objectives i. To assess coronary artery vessel morphology in patients with and without myocardial bridging. ii. To find if gender differences exist in coronary artery measurements. iii. To find the possible association of body mass index with vessel dimensions. iv. To find the distribution of normal and tunneled segments among diseased and non-diseased coronary arteries. v. To find an association between cardiac dominance and artery stenosis involvement.

20. HYPOTHESIS Do coronary artery dimensions with or without myocardial bridging vary among Indian population ???????????? Hypothesis will be validated by considering the present study data as a representative data and comparing it with pooled datas from world wide.

21. Methods and Materials i. Study Design: A cross sectional study will be conducted. ii. Study Setting: • In order to get the correct representation of the South Indian population, all four states will be used for data collection. • Hospitals will be selected according to the number of cardiac patients identified by them. • The collection of samples depends upon the report of sanction for the same from ethical committee of the preselected hospitals. • More number of hospitals from each state will be included if sufficient samples are not achieved under stipulated period .

22. Contd… iii. Hospitals selected for the study are: 1. K.S Hegde Medical Acedemy, Derlakkatte, Mangalore, Karnataka.  2. Amrita School of Medicine , Ponnekkara, Kochi, Kerala. 3. Madras Medical Mission Hospital, Chennai, Tamilnadu. 4. Care hospital , Hyderabad, Andhra Pradesh. iv. Study subjects: • Patients who visit the cardiology outpatient department as a part of their routine cardiac checkups will be selected as study subjects, if they undergo a coronary angiography procedure due to variation in the normal cardiac parameters. • The selection criteria to be enrolled for a coronary angiograp- hy procedure will be strictly subjected to the guideline protocols.

23. Contd… INCLUSION CRITERIA: • All patients who undergo angiogram procedure as a part of their routine diagnosis will be selected for the study purpose after obtaining informed consent. EXCLUSION CRITERIA: • Patients with congenital heart disease, rheumatic heart disease, and cardiomyopathies will be excluded from the study. • Patients with previous history of myocardial infarction and recanalised, normal looking coronary arteries will also be exclu- ded.

24. Contd… v. Sample size and its calculation • Four thousand samples are estimated statistically for conducting the study. Sample size determination • Minimum sample size required is 3855 cases. Taking the sample size as 4000 as the samples can be up to 10% more than of the estimated sample size. • Level of significance = 5% • Effect size = 0.015 • Prevalence =12%(Alegria JR et al.; 2005) • The sample size was estimated by consulting a statistician and using the statistical software G* Power 3.0.10. • The estimated sample size has to be divided by four as the study is conducted in four South Indian states =4000/4=1000 cases per state.

25. Contd… vi. Sampling technique  • Convenience sampling will be done as all eligible cases which fulfil the inclusion criteria during the definite time period of the study will be selected as samples. • Patients will be approached at the cath lab prior to angiogram procedure.

26. METHODOLOGY A. ETHICAL CONSIDERATIONS B. ANGIOGRAPHY PROCEDURE a. Preparation of the patient b. Vascular Access c. Catheters d. Selection Criteria for Target Vessels e.Angiographic projections f. Angiogram reports C. CALCULATION OF BODY MASS INDEX D. DATA COLLECTION E. INDIVIDUAL SEGMENT MEASUREMENT ASSESSING PATTERNS

27. A. ETHICAL CONSIDERATIONS a) Approval of the Institutional Ethics Committee of Yenepoya University , as well as ethical committees of each of the four hospitals identified for the study , will be obtained followed by permission of the Director/ Medical Superintendant of the hospital. b) ) Patient information sheets will be provided to the patients for the better understanding of the research study. Informed written consent will be obtained from the patients who are willing to participate in the study. As the study is conducted in four south Indian states, local language translation of the consent form which has been translated by the language experts will be provided and explained to the patient. c) Confidentiality of the patients will be maintained and they will be assured that their participation and non participation in the study would have no bearing on their treatment at the hospital.

28. B. ANGIOGRAPHY PROCEDURE a. Preparation of the patient: • Elective coronary arteriography should be performed alone or in conjunction with right- heart catheterization or contrast-enhanced left ventriculography. • When co-morbid conditions, such as congestive heart failure, diabetes mellitus or renal insufficiency, if present, should be stable at the time of the procedure. • A baseline electrocardiogram, electrolyte and renal function tests, complete blood cell count, and coagulation panel should be reviewed before coronary arteriography.(Mann DL et al.; 2014)

29. Contd… b. Vascular Access • A variety of vascular approaches are available for coronary arteriography. • They are femoral artery approach, brachial artery approach, and radial artery approach. • The selection of the vascular access depends on operator and patient preferences, anticoagulation status and presence of peripheral vascular disease. c. Catheters • Diagnostic catheters developed for coronary arteriography are generally constructed from polyethylene and polyurethane with a fine wire braid within the wall to allow advancement and direc- tional control (torque) and to prevent kinking.

30. Contd… • Access for coronary angiography can be established by percutaneoustransfemoral route using the Seldinger technique. • The outer diameter size of the catheters ranges from 4F to 8F, but 5F and 6 F catheters are used most commonly for diagnostic arteriography. • An arterial (5F/6F) sheath should be inserted into the femoral artery and selective coronary catheterization has to be carried out with 4F/5F Judkins or Amplatz right and left coronary catheters. • All radiographic agents contain iodine, which effectively absorbs x-rays in the energy range of the angiographic imaging system.(Mann DL et al.; 2014)

31. Contd… • Selective hooking of the coronary ostium need to be performed and 7-8ml non ionic contrast (Iohexol 350mg/ml) has to be administrated by hand injection. • In the protocol followed for image acquisition, simultaneous digital and cine-angiographic acquisition has to be performed in two projections using the 20.5x20.5cm Flat Panel Detector. • Images are then acquired for each coronary artery segment in two orthogonal views and the mean of the two values should be taken for statistical analysis.

32. INTRA CORONARY CATHETER Figure 1: Intracoronary catheter

33. Contd… d. Selection Criteria for Target Vessels ( Haase J et al.; 1993) • Standard angiographic views(Ishikawa Y et al.; 2009), (Dhawan J et al.; 1995), ( Lip GY et al.; 1999) will be obtained and quantitative coronary angiography (QCA) will carried out on longest possible disease-free segments of coronary arteries which were uniformly distended and contrast filled, free of tortousity or kinking without overlap. • The vessels will be assessed in an end diastolic frame. Patients with normal coronary arteries as well as artery segments free from stenosis on angiograms will be included for calibration assessment.

34. Contd… e. Angiographic projections EPICRANIAL VIEW LEFT ANTERIOR OBLIQUE RIGHT ANTERIOR OBLIQUE VIEW VIEW (CRANIAL) (CRANIAL) PLANE LEFT ANTERIOR VIEW PLANE RIGHT ANTERIOR VIEW LEFT ANTERIOR OBLIQUE RIGHT ANTERIOR OBLIQUE VIEW VIEW (CAUDAL) (CAUDAL) EPICAUDAL VIEW Figure 2: Cranial and caudal angulated views of angiography

35. Contd… f. Angiogram reports • Coronary angiogram reports will be obtained after taking the patient consent from the cardiology out patient department of hospitals, cath labs and non-communicable disease (NCD) clinics of Kerala, Tamil Nadu, Karnataka and Andhra Pradesh / Telengana (four South Indian states). • The consent form will be printed in four South Indian languages and ethical clearance from hospitals of each state involved in the study will be taken separately.

36. C. CALCULATION OF BODY MASS INDEX • Body-mass index (BMI), will be calculated as weight in kilograms divided by height in metres squared (kg/m2). • As a measure of relative weight, BMI is easy to obtain. This is an acceptable proxy for thinness and fatness. It has been directly related to health risks and death rates in many populations(Low S- et al.; 2009). The suggested categories for Asian populations are as follows: • Less than 18·5 kg/m2 – underweight. • 18·5–23 kg/m2 - normal / increasing but acceptable risk. • 23–27·5 kg/m2 - over weight / increased risk. • 27·5 kg/m2 or more - obesity / higher high risk (WHO - Expert Consultation. Lancet ; 2004).

37. Contd… • Weight of the patient will be measured by digital weighing machine with crystal display which is manufactured by Health Genie Company named as Health Genie digital weighing scale HD-221; silver pattern. Measured values will be recorded as such with decimals without approximating it into highest or lowest decimal values. • The height of the patient will be measured by the height measuring scale manufactured by Gadget Hero’s company with inches and centimetre calibrations. Namely, gadget Hero’s height measuring scale/ tape/ stature meter (200cm/78 inch), wall mounted type.

38. D. DATA COLLECTION • Four thousand angiogram reports will be collected and studied for the following parameters; • Right and left coronary artery and its main branches vessel morphology measured at ostium and proximal segment by stenosis analysis programme using the automated coronary analysis package of the Innova 2100 IQ Cath and at a AW4.4 workstation and Siemens QCA – Scientific coronary analysis. • Patients anthropometric measurements will be done using the fore mentioned relevant equipments in the methodology and BMI is calculated. Body mass index is calculated by the relevant for- mula using patient’s height and weight measurements.

39. Contd… • Diameter and length of bridging segment with the mean diameter and the length of main coronary artery with bridging will be measured. To assess the whether narrowing is present in the bridging segment. • Cardiac dominance and artery stenosis involvement among each pattern will be recorded. • Clinical outcome in means of percentage of stenosis in patients with bridging or without bridging along with the vessel dimensions of the same will be assessed.

40. E. INDIVIDUAL SEGMENT MEASURENT ASSESSING PATTERNS a. Left main coronary artery (LMCA) b. Left anterior descending branch of coronary artery (LAD) c. Left circumflex branch of coronary artery (LCx) d. Right coronary artery (RCA) e. Measurement of a bridged segment f. Coronary Dominance patterns and assessment g. Observation from the angiogram data

41. Figure 3: Left main coronary artery (LMCA)

42. Table 1: Measurement parameters for left main coronary artery (LMCA)

43. A B Figure 4: Left anterior descending branch of coronary artery (LAD) (A) and Diagonal branch (B)

44. Table 2: Measurement parameters for left anterior descending branch of coronary artery (LAD)

45. A B Figure 5: Left circumflex branch of coronary artery (LCx) (A) and Obtuse marginal branch (B)

46. Table 3: Measurement parameters for left circumflex branch of coronary artery (LCx)

47. Figure 6: Right coronary artery (RCA)

48. Table 4: Measurement parameters for right coronary artery (RCA)

49. A B Figure 7: Diastolic (A) and Systolic (B) phase of Bridging

50. A B Figure 8: Length of Bridged segment (A) and bridged left anterior descending artery (LAD) length (B)