UNIVERSITY OF CINCINNATI

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1 UNIVERSITY OF CINCINNATI Date: 20-Jan-2009 I, Srikara Vishwanath Peelukhana, hereby submit this original work as part of the requirements for the degree of: Master of Science in Mechanical Engineering It is entitled: Effect of coronary collateral flow on diagnostic parameters: An In vitro study Student Signature: Srikara Vishwanath Peelukhana This work and its defense approved by: Committee Chair: Rupak Banerjee, PhD, PE Rupak Banerjee, PhD, PE Frank Gerner, PhD Frank Gerner, PhD William Gottliebson, PhD William Gottliebson, PhD 11/5/

2 INFLUENCE OF CORONARY COLLATERAL FLOW ON DIAGNOSTIC PARAMETERS: AN IN VITRO STUDY A thesis submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE in the Department of Mechanical Engineering, of the College of Engineering 2009 By Srikara Viswanath Peelukhana Bachelor of Technology (B.Tech.), Gayatri Vidya Parishad College of Engineering India. Committee Chair: Dr. Rupak K. Banerjee i

3 ABSTRACT Severity of blockages in the arteries of heart (Coronary stenosis) needs to be known for treatment of heart diseases. Visual techniques give an idea about the blockage, but they fail to quantify the severity of blockage, the flow obstruction and pressure variations caused (functional severity). So, functional severity of coronary stenosis is often assessed using diagnostic parameters. These parameters are evaluated from the combined pressure and/or flow measurements taken at the site of the stenosis. However, when there are interconnections between arteries supplying blood (functional collaterals) downstream to the stenosis, the coronary flow rate increases, and the pressure in the stenosed artery is altered. This effect of downstream collaterals on different diagnostic parameters is studied using a physiological representative in vitro flow loop, with a solution of glycerin and water mimicking the shearthinning properties of blood. The three diagnostic parameters tested are Fractional Flow Reserve (FFR), defined as the ratio of distal pressure and pressure proximal to the stenosis, Pressure Drop Coefficient (CDP) and Lesion Flow Coefficient (LFC), parameters that are formulated based on fluid dynamics involved in the stenosed artery. The latter two were discussed in recent publications by our group. They are evaluated for three different severities of stenosis and tested for possible misinterpretation in the presence of variable collateral flows: Maximum collateral flow, Intermediate collateral flow, and partially developed collateral flow. Pressure and flow measurements are taken without downstream collateral flow and for three different collateral flow developments mentioned above. The parameters are then calculated from these readings. In the case of intermediate stenosis (80% area blockage), FFR and LFC increased from 0.74 to 0.77 and 0.58 to 0.62 respectively for no collateral to fully developed collateral flow. ii

4 Also, CDP decreased from 47 to 42 for no collateral to fully developed collateral flow. These changes in diagnostic parameters might lead to erroneous postponement of coronary intervention. Thus, variability in diagnostic parameters for the same stenosis leads to misinterpretation of stenosis severity in the presence of operating downstream collaterals. iii

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6 ACKNOWLEDGEMENTS I would like to take this opportunity to thank everyone who directly or indirectly helped me in the completion of this thesis work. I would particularly like to thank my advisor, Dr. Rupak Banerjee for his patient help and expert advice in the conception and completion of this research work. I would also like to thank him for his valuable time on discussions regarding the numerous problems encountered during the course of the project. His insightful knowledge in this area of research has helped me a lot in overcoming the problems that are a part of the experimental research. I sincerely thank Dr.Frank Gerner, Professor, Department of Mechanical Engineering, and Dr. William Gottliebson, Assistant professor, University of Cincinnati, College of Medicine, for finding a time in their hectic schedules to attend my thesis defense as a part of the committee. I would also like to extend my thanks to all the members of Fluid Heat and Mass Transfer, BioMEMS lab who helped me with their valuable inputs on both the research and its presentation. v

7 TABLE OF CONTENTS List of Figures 1 List of Tables. 3 Nomenclature 4 Chapter 1: Outline 1.1: Outline of the Thesis. 5 Chapter 2: Background and Introduction 2.1: Anatomy of Heart : Blood circulation 8 2.3: Coronary circulation : Coronary stenosis : Coronary collaterals : Diagnosis : Motivation and Significance. 14 Chapter 3: Methods 3.1 Experimental set-up Data acquisition Diagnostic parameters: Definitions. 23 vi

8 Chapter 4: Results 4.1: Effect of collateral flow on pressure and flow measurement : Effect of collateral flow on diagnostic parameters Effect of collateral flow on FFR Effect of collateral on CDP and LFC Chapter 5: Discussion Chapter 6: Conclusion.. 39 Acknowledgement References vii

9 LIST OF FIGURES Figure 1: Anatomy of heart 7 Figure 2: Layers of heart 7 Figure 3: Blood flow through the heart...8 Figure 4: Image showing the coronary arteries 9 Figure 5: Angiographic image showing the LCA and its branches...10 Figure 6: Image showing a blocked artery Figure 7: Image showing the affected area due to blockage in LAD Figure 8: Figure showing a collateral conduit between LAD and LCX 12 Figure 9: Schematic showing the physiologically similar experimental set-up.17 Figure 10: Plot showing the viscosity comparison between A) Blood and water B) Blood and the experimental fluid...18 Figure 11: A) Schematic showing the transducer placement for checking the consistency of the input flow pulse B) Input flow pulses recorded for two different conditions Figure 12: Blown-up image showing the pressure ports on the intermediate and severe stenosis test-sections used in the experimental set-up Figure 13: A schematic showing transducer placement for pressure and flow measurements

10 Figure 14: Schematic showing the pressure measurements to calculate FFR...24 Figure 15: Schematic showing the different regions in the lesion geometry..25 Figure 16: X-Y plot showing the effect of collateral diameter on the collateral flow for different severities of stenosis Figure 17: X-Y plot showing the effect of collateral diameter on the total flow...31 Figure 18: Bar graph showing the effect of collateral flow on pressure drop across the stenosis for different severities of stenosis...32 Figure 19: Bar graph showing the effect of collateral flow on FFR for different severities of stenosis.33 Figure 20: Bar graph showing the effect of collateral flow on CDP for different severities of stenosis...35 Figure 21: Bar graph showing the effect of collateral flow on LFC for different severities of stenosis

11 LIST OF TABLES Table 1: Length, diameter, and area measurements of different stenosis test sections used in the experimental set-up...25 Table 2: Summary of variations in the pressure, flow, and diagnostic parameter for the four collateral flow conditions tested, in an intermediately stenosed artery 29 Table 3: Summary of variations in the pressure, flow, and diagnostic parameter for the four collateral flow conditions tested, in a moderately stenosed artery 29 Table 4: Summary of variations in the pressure, flow, and diagnostic parameter for the four collateral flow conditions tested, in a moderately stenosed artery 29 3

12 NOMENCLATURE P a = Pressure proximal to the stenosis, mmhg. P d = Pressure distal to the stenosis. mmhg. p = pressure drop across the stenosis, P d -P a, mmhg. P v =Central venous pressure, 0 mmhg. ρ = Density of the experimental fluid/blood = 1.05 g/cm 3. U e = Velocity in the proximal region, cm/s. U m = Velocity in the throat region, cm/s. A m = Area of the throat region, cm 2. A e = Area of the proximal region, cm 2. Q s = flow through the stenosed artery, ml/min. Q = total flow to myocardium, ml/min. Q c = Collateral flow (Q-Q s ), ml/min. λ = Time constant. n = Power law index. µ 0 = Zero shear viscosity. µ = Infinite shear viscosity. 4

13 CHAPTER 1 OUTLINE 1.1 Outline of the thesis The outline of the thesis work is given briefly in this section: Chapter 1 describes the whole layout of this work. In Chapter 2, a detailed background on the problem explaining the importance of the heart, heart failure, blockages leading to heart failure, the coronary flow circuit, diagnosis of the coronary blockages, collateral flows, and the possible effect of downstream collateral flow on the diagnostic parameters is given. Based on this background, the significance of the study is explained. In Chapter 3, the physiologically similar in vitro experimental set-up used to measure the pressure and flow readings is explained. The focus was on different issues that need to be addressed to get measurements as closer to the physiological values as possible. Then the diagnostic parameters used in the study are discussed in detail, with an emphasis on the trend observed in the parameters as the severity of the blockage increases. Chapter 4 describes the results obtained using the experimental set-up. First, the effect of different collateral flow values on pressure and flow measurements is analyzed. Then, the diagnostic parameters are checked for any possible misinterpretation and misdiagnosis, in the presence of downstream collaterals. Chapter 5 outlines the limitations of this study, and other factors that affect the diagnostic parameters. It also includes suggestion on how a better diagnosis can be achieved and what could be done to eliminate a possible misinterpretation. Chapter 6 concludes the work and mentions possible future work. 5

14 CHAPTER 2 BACKGROUND AND INTRODUCTION Our body needs circulation of blood to keep the metabolisms going. Heart is the pumping unit that drives the circulation. The heart itself needs blood to function. When the blood supply to the heart stops, it fails to function, leading to heart failure. Myocardial infarction (or heart failure), caused due to blockages in the coronary arteries, is one of the main health problems afflicting people. 451,236 people died of heart attack in the year 2004 (one in every five deaths). 1,200,000 new cases are reported every year in the United States alone. For more statistics and information please visit: A detailed explanation on the anatomy of the heart and the coronary circulation is given below. 2.1 Anatomy of heart The Heart is analogous to a pulsatile pump. It relentlessly drives blood to all the other organs in the body. Figure 1 shows a detailed anatomy of heart. It is divided into four chambers, two ventricles and two auricles or atriums. The Left ventricle and auricle are divided by bicuspid or mitral valves and the right ventricle and auricle are divided by tricuspid valves. Valves are essential for regulating the blood flow in the chambers of heart. They allow blood flow in only one direction, thereby allowing the separate flow of oxygenated and de-oxygenated blood. The heart is a dense muscle that comprises of three layers, MYOCARDIUM, EPICARDIUM and ENDOCARDIUM, surrounding the inner chambers and is enclosed in a fourth protective layer known as the pericardium (Figure 2). 6

15 Figure 1: Anatomy of heart ( Figure 2: Layers of heart ( 7

16 2.2 Blood Circulation The importance of heart valves will be apparent once the circulation of blood through the chambers of heart is considered. De-Oxygenated Blood from all the organs is brought into the right auricle by Vena cava. This blood travels to the right ventricle through the tricuspid valves. The valves allow the blood flow in only one direction. From the right ventricle, the blood travels to the lungs through pulmonary semi-lunar valve, which again regulates one-way flow. In the lungs, the blood gets oxygenated. The oxygenated blood flows back to the heart through the pulmonary artery, and is collected in the left auricle. It travels to left ventricle through the bicuspid valves. The oxygenated blood is then supplied to the whole body through aorta. A schematic of the blood flow through heart is shown below. Figure 3: Blood flow through the heart For this whole process to take place, the heart needs to continuously pump blood. The heart itself needs blood to stay functional and keep pumping. Though the heart is filled with 8

17 blood, the dense heart muscle (Myocardium) needs blood supply to function. This is achieved through coronary circulation. 2.3 Coronary circulation The arteries responsible for supplying blood to the muscle tissue of the heart are the coronary arteries. The coronary circulation mainly consists of the Right Coronary Artery (RCA), the Left Coronary Artery (LCA) which bifurcates into the Left Anterior Descending (LAD) and the Left Circumflex (LCX). The RCA supplies blood to the right ventricle (RV), in addition to supplying 25 to 35% of blood to the left ventricle (LV). The LCA, and its branches the LAD and the LCX, supply most of the blood to the LV. As seen above, LV is the part of the heart responsible for blood flow both to the systemic circulation (body) and heart. A blockage in LCA or the LAD causes ischemia in the left ventricle and leads to heart failure. So, Left coronary artery stenosis or LAD stenosis is often one of the main causes of myocardial ischemia. The focus of this research is mainly on the blockages occurring in the LAD. Figure 4: Image showing the coronary arteries ( 9

18 Figure 5: Angiographic image showing the LCA and its branches ( 2.4 Coronary stenosis Stenosis is the medical term for a blockage in any of the arteries. Blockages in arteries can be caused by many factors. Main causes for the blockages in artery are: 1. Atherosclerosis: This is caused due to blockages occurring due to plaque formation. Plaque can be formed due to many causes like Calcified deposits or excessive Cholesterol (lipid plaques), or due to blood clots. 2. Arteriosclerosis: This is caused due to hardening of arterial wall generally in older people. Lumen of the arteries expands in the systolic stage. Due to old age the arterial wall hardens and the lumen is constricted which leads to arteriosclerosis. This does not cause a blockage but is a chronic disease. 10

19 Stenosis prone areas in LAD include the branching arteries which causes the distal part to become the Zone of Perfusion. Zone of Perfusion is the part of area which gets affected due to the lack of blood when the artery gets blocked. It is always distal to the blockage in the artery. Figure 6: Image showing a blocked artery ( Figure 7: Image showing the affected area due to blockage in LAD Number 1 shows the blockage in LAD, Number 2 shows the zone of perfusion. ( 11

20 2.5 Coronary Collaterals Collateral arteries are small interconnections between a healthy artery and a stenosed artery (Figure 8). They are normally either non-existent or non-functional in a healthy artery. They become functional when there is a recurrent or severe stenosis in primary coronary arteries such as Left Coronary Artery (LCA), Left Circumflex (LCX), Left Anterior Descending (LAD) and Right Coronary Artery (RCA). Functional collaterals start supplying blood downstream to the stenosed coronary artery and reperfuse the microvasculature downstream to the stenosed artery. Numerous studies were done to predict the exact factors resulting in the coronary collateral flow, and to estimate the collateral flow as a contributor to the diseased artery (Rentrop et al 1988; Sasayama et al, 1992; Rockstroh et al, 2002; Koerselman et al, 2003; Fujita et al, 2004). Collateral conduit Figure 8: Figure showing a collateral conduit between LAD and LCX (Source: World Wide Web) 12

21 2.6 Diagnosis The main factor helpful in treating heart blockages is the diagnosis of the severity of the stenosis. In order to prevent the heart failure, the severity of the blockage (stenosis) needs to be assessed and a pertaining treatment is to be recommended. Over the years many methods have been developed to diagnose the stenosis in the arteries. The techniques can be divided into two categories depending on the method used. 1. Anatomical measurements: In this type of diagnosis the severity of Stenosis is determined by direct observation. Normal procedures include the CAT (Computerized Axial Tomography), CT (Computerized Tomography) scan, MRI scan (Magnetic resonance Imaging). Some other procedures use guide wire to diagnose the severity like the IVUS (Intra vascular Ultra sound), X-ray angiography or Fluoroscopy. Anatomic (angiography) endpoints are being widely used to assess the severity of the stenosis, but these often fail to delineate the functional (hemodynamic) severity of the stenosis (White et al, 1984). 2. Functional measurements: In this type of diagnosis, the pressure and flow characteristics of the blood across the stenotic area are calculated. Then the results are compared with their threshold values and depending on the deviation the severity of the stenosis is estimated. Many parameters have been defined over the years. Only three salient diagnostic parameters were evaluated in this study. The first one is Fractional Flow Reserve (FFR) (Pijls et al, 1993; Pijls et al, 1995; Lederman et al, 1997), which uses only pressure measurements. It is defined as the ratio of pressures distal and proximal to the stenosis. FFR is currently being used in clinical practice. Based on widely held clinical trials, a cut-off value of 0.75 was established (Pijls et al, 1993; Pijls et al, 1995; 13

22 Lederman et al, 1997) to make decisions on coronary interventions. If the value of FFR is greater than 0.75, coronary intervention is deferred whereas if the value is less than 0.75, a coronary intervention is recommended. The second parameter is Pressure Drop Coefficient (CDP), (Banerjee et al, 2008; Banerjee et al, 2007; Sinha Roy et al, 2007) which uses both pressure and flow measurements. The third one is Lesion Flow Coefficient (LFC) (Banerjee et al, 2008; Banerjee et al, 2007; Sinha Roy et al, 2007), which uses pressure and flow measurements combined with the geometry of the blockage. The last two parameters were formulated based on fundamental fluid dynamic principles in a stenosed artery. They have been published and are being investigated for clinical use (Banerjee et al, 2008; Banerjee et al, 2007; Sinha Roy et al, 2007). Like FFR, CDP and LFC have no current cut-off value. 2.7 Motivation and significance of the study Decisions on the treatment to prevent the heart failure are made depending on the severity of the blockage (stenosis). So, for a better treatment of the heart disease a better diagnosis of the severity of the blockage is required. As previously explained, Angiography is being widely used to diagnose the severity of the stenosis (White et al, 1984). But, it is limited in its diagnosis as it often fails to give the functional severity of the stenosis. So, diagnostic parameters are defined to get a better assessment of the stenosis severity (Pijls et al, 1993; Spaan et al, 2006; Kern et al, 2006). Depending on the value of the diagnostic parameters the functional severity of the stenosis is determined. The diagnostic parameters are calculated from pressure and flow measurements made at the site of the stenosis. The pressure and flow measurements made are dependent on the 14

23 transducer placement. Thus, parameters obtained from the pressure and flow measurements fail to account for different resistances in the coronary flow circuit, such as the operational downstream collateral conduits. As functional collateral vessels start supplying blood to the stenosed artery, the increased downstream flow causes an increase in the pressure values at the site of the stenosis. These increased pressure values, if not accounted for by the diagnostic parameters, will cause an error in judgment of the stenosis severity. Although estimations of the collateral flow has been made, such as the Pressure derived collateral flow index, Fractional Myocardial Index (FFR myo ) (Pijls et al, 1993; Pijls et al, 1995; Kern et al, 2006; Seiler et al, 1998; Seiler et al, 1999), these include measurement of wedge pressure, calculated at total coronary vessel occlusion, which is not so feasible in a clinical setting. Moreover, all the other previous studies on FFR, CDP, and LFC (Pijls et al, 1993; Pijls et al, 1995; Banerjee et al, 2007; Sinha Roy et al, 2007; Banerjee et al, 2008) doesn t include the effect of collateral flow on these parameters. So, a comprehensive study that focuses on the effect of the collateral flow on the diagnostic parameters is lacking. This study, therefore, has been carried out to check the misinterpretation that might result due to the presence of operating downstream collaterals. This is achieved using a physiologically similar in vitro experimental set-up. The misinterpretation was checked in three different parameters: 1. Fractional Flow Reserve (FFR) 2. Pressure Drop Coefficient (CDP) 3. Lesion Flow Coefficient (LFC) Each parameter was evaluated from pressure and flow measurements made in three different degrees of stenosis, using three different levels of collateral flow. 15

24 CHAPTER 3 METHODS To evaluate the effect of collaterals on the diagnostic parameters, a physiological representative in vitro experimental flow-loop is used. Pressure and flow readings obtained from this flow-loop for different collateral flows in different degrees of stenosis severity are used to evaluate the diagnostic parameters. 3.1 Experimental set-up For this study, the flow-loop used in our previous studies (Ashtekar et al 2007; Banerjee et al 2008) is modified to include the collateral flow. The selection of collateral diameters and the experimental set-up is based on previous in vitro experimental studies on coronary network involving collaterals (Pijls et al, 1993; Pijls et al, 1995; Seiler et al, 1998; Seiler et al, 1999; Wahl et al, 2000; Pohl et al, 2001; Werner et al, 2001; Billinger et al, 2002). The physiological similar in vitro experimental set-up is shown in Figure 9. The set-up is similar to the coronary flow network focusing on the Left Coronary Artery (LCA), Left Circumflex (LCX) and Left Anterior Descending (LAD). A Harvard apparatus pulsatile pump, representing left ventricle, is used to impart the required hyperemic (maximum) flow-rate (~ 200 ml/min) and desired heart-rate. A conduit representing the aorta originates from the pump; and it bifurcates into two arteries: one supplying fluid to the systemic circulation and the other to the LCA. The LCA bifurcates into the LCX and the LAD. The three stenosis (severe, intermediate, and moderate) test-sections are evaluated in the LAD, in the presence of downstream collaterals operating from the LCX to the LAD. Latex rubber tubing was used for all coronary arteries. 16

25 Figure 9: Schematic showing the physiologically similar experimental set-up. A compliance chamber is used in the flow circuit before the LCA bifurcation to maintain a consistent input pulse and pressure levels similar to the physiological values. Blood analog fluid: Blood is a non-newtonian fluid, i.e., the dynamic viscosity of blood changes with varying shear rate. Water is the main constituent of blood, but water has a constant viscosity at all shear rates. So, water mixed with some additives could induce the required non- Newtonian behavior to the solution. Glycerin controls the viscosity at infinite shear rates, and xanthum gum controls the non-newtonian behavior. So, a right mixture of water, glycerin, and xanthum gum will serve as a good blood-analog fluid for in vitro experiments (Brookshier et al, 1993). Based on previous studies by our research group, a combination of 80% Water, 20% glycerin, and 0.020% xanthum gum (Banerjee et al, 2007) is taken as starting mixture. 17

26 Figure 10: Figure showing the viscosity comparison between A) Blood and water B) Blood and Experimental fluid, 65% water, 35% Glycerin, 0.035% xanthum gum by weight. 18

27 The mixture is stirred for 8 hours before any viscosity measurements are done. After stirring, viscosities at higher and lower shear rates of the experimental fluid were measured using a Brookfield Viscometer and the experimental data points are used to fit a curve using the Carreau model equation: n 1 2 ( ) ( µ µ ) 1 ( λγ ) = µ µ & λ = Time constant. n = Power law index. µ 0 = Zero shear viscosity, cp. µ = Infinite shear viscosity, cp. γ& = Shear rate, 1/s. After a few trials with different combinations, a mixture of 65% water, 35% Glycerin and 0.035% xanthum gum was considered as the optimum composition, and used in the experimental set-up. A better match at the lower shear values could be obtained by the addition of water, and xanthum gum. But, that would elevate the high shear rate viscosities further, which is not desired. Figure 10 shows the comparison between the viscosities of the experimental fluid and blood. 3.2 Data acquisition Before the pressure and flow readings are taken in the experimental set-up, it needs to be confirmed that the input flow pulse is consistent.. The pulsatile pump parameters are set so that a flow of 200ml/min is maintained at no stenosis, no collateral conduit condition. This flow-rate is representative of hyperemic flow through a healthy coronary artery. This input flow pulse need to be maintained for all the test conditions. So, to check the uniqueness and consistency of 19

28 the input flow pulse, transducers are placed as shown in Figure 11A. The flow meter is connected to the LAD before the stenosis section. The consistency is checked in the LAD because it is the conduit in which the test-sections are placed. It is also the conduit being supplied with the collateral flow. The input pulse shouldn t be affected by these variations in the LAD as a change in input pulse will invalidate the whole set-up. Two flow pulses are recorded, one with the collateral channel closed and the other with the fully developed operating collateral (Figure 11B). The flow pulse is the volumetric flow (Y-axis) through the conduit varying with time (X-axis). It can be observed from the Figure 11B that both the flow pulses are identical, which shows that a consistent input flow pulse is maintained for all test conditions. Three different degrees of blockages, made of Lexan material, representing true stenosis geometry are used in the flow-loop (Figure 12): 1. 90% area blockage (severe stenosis) % area blockage (intermediate stenosis) % area, blockage (moderate stenosis). The various diameters of collateral conduits used to represent various levels of collateral flow are: 1. 3 mm diameter (maximum collateral flow) mm diameter (intermediate collateral flow) mm diameter (partially developed collateral flow). 20

29 Figure 11: A) Schematic showing the transducer placement for checking the consistency of the input flow pulse. B) Input flow pulses recorded for two different conditions.x-axis is the time (s), and Y-axis is the volumetric flow (Q), ml/min. 21

30 Figure 12: A blown-up picture showing the pressure ports on the intermediate and severe stenosis test sections. The DSA pressure scanner is connected to these ports to obtain pressure readings. Each stenosis severity is tested for four conditions: 1. No collateral flow. 2. Partial collateral flow (Collateral diameter = 1.5mm). 3. Intermediate collateral flow (Collateral diameter = 2mm). 4. Fully developed collateral flow (Collateral diameter = 3mm). Pressure and flow readings are taken using pressure scanner and flow transducers. A schematic of the transducer locations is shown in Figure 13. Pressure readings are taken across the stenosis using a DSA pressure scanner connected to the pressure ports on the stenosis test sections used (refer Figure 12). Two flow readings are taken in the LAD: Flow through the stenosed artery (Q s ), obtained by an ultrasound flow-cuff before the collateral from the LCX joins the LAD; and total flow (Q), measured by a transit-time ultrasound internal flow meter (Transonics Inc.) after the collateral from the LCX joins the LAD. Collateral flow (Q c ) is computed as the difference between Q and Q s i.e.,q c = Q - Q s 22

31 Figure 13: A schematic showing transducer placement for pressure and flow measurements 3.3 Diagnostic Parameters: Definitions The flow and pressure values measured experimentally are post-processed using macros written in Microsoft Visual Basic and analyzed in Microsoft Excel. Distal and proximal pressures are selected from the sixteen pressure values obtained across the stenosis. The three parameters evaluated are the Fractional Flow Reserve (FFR), the Pressure Drop Coefficient (CDP), and the Lesion Flow Coefficient (LFC). They are computed based on the formulae mentioned in the following pages. FFR: The FFR is defined as the ratio of distal pressure to the proximal pressure (Figure 14) in the stenosis at maximum vasodilation i.e., at hyperemic flow condition (Pijls et al, 1995; Lederman et al, 1997): Pd - Pv FFR = at hyperemic flow. Pa - Pv P a is the pressure proximal to the stenosis and measured at the aortic arch. 23

32 P v is the venous pressure 0 mmhg P d is pressure distal to the stenosis. Figure 14: Schematic showing the pressure measurements to calculate FFR Hyperemic flow is the flow through the arteries when a person is in agitated condition or exercising condition. It is an increased blood flow state. Obviously, the flow rate during the hyperemic flow is greater than the flow rate in basal flow. A Vaso-Constrictor drug is used to restrict the blood flow as it constricts the blood vessel and a Vaso-Dilator drug is used to dilate or increase the diameter of the blood vessel. So, in clinical practice, during the pressure and flow-rate measurements a Vaso-dilator is administered to increase the blood flow rate and induce the Hyperemic condition. Examples of Vasodilator drugs are Papaverine and Adenosine. In the experimental set-up used, all the readings are taken at hyperemic flow rate of 200ml/min maintained using pulsatile pump. The pressure readings are obtained from the pressure scanner. 24

33 Figure 15: Schematic showing the different regions in the lesion geometry. (Source: Banerjee et al, 2007) Parameter 65% area blockage 81% area blockage 90% area blockage Diameter of proximal region-d e (mm) Length of proximal region-l c (mm) Diameter of throat region-d m (mm) Length of throat region-l m (mm) Diameter of distal section-l r (mm) Length of distal section-d r (mm) Area of proximal region- A e (mm 2 ) Area of throat region-a m (mm 2 ) Area of distal region-a r (mm 2 ) Table 1: Length, diameter, and area measurements of the different stenosis test sections used. 25

34 As the severity of the blockage increases, from moderate to severe, the pressure value distal to the stenosis decreases. Due to this drop in distal pressure, the value of the FFR is expected to decrease as the severity of the stenosis increases. As mentioned previously, a cut-off value of 0.75 is established to differentiate between severe and moderate blockages. If FFR is greater than 0.75, the blockage is considered to be moderate, and coronary intervention is deferred. If FFR is less than 0.75, the blockage is considered severe, and a coronary intervention is recommended. Indecision might result when the value of FFR is near the cut-off value of 0.75, which normally occurs in the case of intermediate stenosis (80% area blockage), particularly if micro vascular disease coexists. CDP: The CDP and the LFC are defined based on the fundamental fluid dynamics. The lesion geometry details are shown in Figure 15 (Banerjee et al, 2007). Table 1 shows the area measurements of the stenosis test-sections. These values are used to calculate the velocity in different regions of the stenosis. CDP is calculated using the velocity value in the proximal region of the lesion: CDP = 0.5 p ρ 2 U e where, p = pressure drop across the stenosis U e = velocity in cm/sec ρ = density of the fluid in gm/ cubic cm The use of CDP, a functional parameter, depends on both the pressure and the flow values for assessing the stenosis severity. Pressure values are obtained from the pressure scanner, and the area of the proximal region (Table 1) is used to calculate the velocity from the flow values obtained experimentally. 26

35 As stenosis severity increases, the value of distal pressure as well as flow (velocity) decreases. Since p is the difference between proximal and distal pressures, p increases and flow decreases as stenosis severity increases. So, an increase in the value of CDP is expected as stenosis severity increases. LFC: The LFC (Banerjee et al, 2007; Sinha Roy et al, 2007) is a normalized parameter with values ranging from 0 to 1 and could also be useful, like CDP, under clinical setting. It combines the lesion geometry (Figure 15), i.e. anatomical endpoints (Wilson et al, 1988; Banerjee et al, 2003), and pressure and flow measurements, i.e. functional endpoints. It is defined using the velocity value in the throat region: LFC = p 1- k 2 ( 0.5 ρ ) U m where, k = A m /A e p = pressure drop across the stenosis A m = Area at the throat region A e = Area at the proximal region. U m = Velocity in the throat region. The area ratio is calculated from the test-section values (Table 1), pressure values are obtained from the pressure scanner. The velocity in the throat region is calculated using the flow value obtained from the experimental set-up, and test-section area in the throat region (Table 1). The value of LFC, where area ratio term (1-k) is in the numerator, is expected to increase as the severity of the stenosis increases. 27

36 CHAPTER 4 RESULTS The effect of collateral flow on pressure and flow readings is analyzed first. Then the diagnostic parameters computed from these readings are checked for misinterpretation. All the flow, pressure, and diagnostic parameter values are averaged from quantities obtained from three data sets. The readings are all taken for hyperemic flow condition. Table 2 shows the variation in the collateral flow, total flow, distal pressure, proximal pressure, and the diagnostic parameters in a severely stenosed artery. Table 3 and Table 4 show the variations in intermediate and moderately stenosed arteries, respectively. 4.1 Effect of collaterals on flow and pressure As the diameter of the collateral conduit increases, the value of collateral flow (Q c ) increases. This increase in Q c causes an increase in total flow (Q) (Q = Q s +Q c ). Increased flow downstream of the stenosis leads to a decrease in the pressure drop across the stenosis. The effect of increasing collateral diameters on Q c and Q for the three degrees of stenosis is shown in Figure 16 and Figure 17, respectively. The effect of different collateral flows on pressure drop is shown in Figure 18. The details of the effect of collateral flows in each degree of stenosis are discussed below. Severe stenosis: The hyperemic flow value (Q) through a severely stenosed artery when there is no collateral flow (Q c = 0) is 116 ml/min. The collateral flow elevates from 12 ml/min to 32 ml/min, a 2.7 fold increase, as diameter of the collateral conduit increases from partial to fully developed condition (Figure 16). Increase in Q c contributes to the total out-flow in the artery. 28

37 Diameter of the collateral mm (D) Distal pressure (Pd) mm Hg Proximal pressure (Pa) mm Hg Pressure drop (DelP) mm Hg Total flow (Q) ml/mi n Collateral flow (Qc) ml/min Fractional Flow reserve (FFR) Pressure Drop Coefficient (CDP) Lesion flow coefficient (LFC) Table 1: Detailed summary of all the pressure, flow, and diagnostic parameter variations for the four collateral flow conditions tested, in a severely stenosed artery. Diameter of the collateral mm (D) Distal pressure (Pd) mm Hg Proximal pressure (Pa) mm Hg Pressure drop (DelP) mm Hg Total flow (Q) ml/min Collateral flow (Qc) ml/min Fractional Flow reserve (FFR) Pressure Drop Coefficient (CDP) Lesion flow coefficient (LFC) Table 2: Detailed summary of all the pressure, flow, and diagnostic parameter variations for the four collateral flow conditions tested, in an intermediately stenosed artery. Diameter of the collateral mm (D) Distal pressure (Pd) mm Hg Proximal pressure (Pa) mm Hg Pressure drop (DelP) mm Hg Total flow (Q) ml/min Collateral flow (Qc) ml/min Fractional Flow reserve (FFR) Pressure Drop Coefficient (CDP) Lesion flow coefficient (LFC) Table 3: Detailed summary of all the pressure, flow, and diagnostic parameter variations for the four collateral flow conditions tested, in a moderately stenosed artery. 29

38 So, the value of Q elevates from 128 ml/min to 148 ml/min, a 15% increase, as the collateral flow increases from partial (D = 1.5 mm) to maximum (D = 3 mm) (Figure 17). Increased downstream pressure due to elevated flow leads to a reduction in p. The value of p decreases from 51 mmhg to 46 mmhg, an 11% decrease, as the collateral flow increases from partial to maximum condition (Figure 18). Figure 16: X-Y plot showing the effect of collateral diameter on the collateral flow for different severities of stenosis. Intermediate stenosis: The hyperemic flow value through intermediately stenosed artery when Q c = 0 is 148 ml/min. When the collateral conduit is partially developed, the collateral flow value is 6 ml/min. This value increases to 17 ml/min, a 3 fold increase, which is the maximum collateral flow (Figure 16). Thus, the value of Q elevates from 154 ml/min to 165 ml/min, a 7 % increase, as the collateral flow increases from partial to maximum condition 30

39 (Figure 17). Similarly, as the collateral flow elevates from partial to maximum condition, the value of p decreases from 24 mmhg to 22 mmhg, a 9% decrease (Figure 18). Moderate stenosis: The hyperemic flow value when Q c = 0 is 178 ml/min. When the collateral conduit is partially developed, the collateral flow value is 2 ml/min, which elevates to 6 ml/min, a 3 fold increase, as the collateral conduit becomes fully developed (Figure 16). So, the value of Q correspondingly increases from 179 ml/min to 184 ml/min as the collateral flow elevates from partial to maximum condition, a 3 % increase (Figure 17). The value of p, therefore, decreases from 11 mmhg to 10 mmhg as the collateral flow elevates from partial to maximum, a 10% decrease (Figure 18). Figure 17: X-Y plot showing the effect of collateral diameter on the total flow. 31

40 Figure 18: Bar graph showing the effect of collateral flow on pressure drop across the stenosis for different severities of stenosis Effect of collaterals on diagnostic parameters The trend followed by the parameters is dependent upon the way they are defined. In a particular stenosis, with increasing downstream collateral flow, the values of FFR and LFC increase while the value of CDP decreases Effect of collaterals on FFR Severe stenosis: The effect of increasing downstream collateral flow on FFR is shown in Figure 19. The value of FFR, for a severely stenosed artery, when Q c = 0 is This value increases to 0.51 and 0.55 respectively as the collateral flow elevates from partial to maximum 32

41 condition. This increase in parameter value in the presence of downstream collaterals may not lead to a misinterpretation of stenotic severity, as the FFR values are less than the cut-off value of Intermediate stenosis: The typical value of FFR when Q c = 0 is It increases to 0.75 and further to a value of 0.77 as the collateral flow elevates from partial (D = 1.5 mm) to maximum (D = 3 mm) condition. The values, as shown, vary along the cut-off value of This leads to a possible misdiagnosis, as the clinician might defer coronary intervention based on the fully developed collateral value of 0.77 while the severity of the stenosis remains the same. Figure 19: Bar graph showing the effect of collateral flow on FFR for different severities of stenosis 33

42 Moderate stenosis: The value of FFR when Q c = 0 is 0.875, which is greater than the cutoff value of This value increases to 0.88 and further to 0.89 as the collateral flow elevates from partial to maximum condition. There is an increase in the parameter value with increasing downstream collateral flow. However, this might not lead to a misinterpretation as the values are all above the cut-off value of Effect of collaterals on CDP and LFC CDP and LFC are computed using the pressure, flow, and lesion geometry values (shown previously in Table 1). The parameters have no present cut-off values. Figure 20 shows the change in CDP, and Figure 21 shows the variation of LFC in the presence of varying collateral flows. Severe stenosis: The value of CDP decreases as the collateral flow increases. The typical value of CDP when Q c = 0 is 177. It decreases to 166 and then to 149 as the collateral flow changes from partial (D = 1.5 mm) to maximum (D = 3 mm) condition. On the other hand, the value of LFC elevates as the collateral flow increases. The no collateral flow value is It increases to 0.63 and then to 0.67 as the collateral flow elevates from partial to maximum condition. This shows that misinterpretation of stenotic severity might result from both the CDP and the LFC with increasing downstream collateral flow. Intermediate stenosis: The above trend is observed for intermediate stenosis as well. The typical value of CDP when Q c = 0 is 47. It decreases to 46 and then to 42, as the collateral flow increases from partial to maximum condition. Similarly, the value of LFC value for no collateral flow is It increases to 0.59 in case of partially developed collateral flow, and then to 0.63 as the collateral flow becomes maximum. So, even in the case of intermediate 34

43 stenosis there might result a possible misinterpretation of the stenosis severity from CDP and LFC. Figure 20: Bar graph showing the effect of collateral flow on CDP in different severities of stenosis. Moderate stenosis: When there is no collateral operating, the value of CDP is 15. As the collateral flow increases from partial to fully developed flow, the value decreases from 14 to 13. Also, the value of LFC when Q c = 0 is This value increases from 0.48 to 0.51 as the collateral flow elevates from partial to maximum condition. Even in moderate stenosis, variability in CDP and LFC is detected, which might lead to a possible misinterpretation of the stenosis severity. 35

44 Figure 21: Bar graph showing the effect of collateral flow on LFC for different severities of stenosis. 36

45 CHAPTER 4 DISCUSSION The values of FFR, CDP, and LFC with no collateral, obtained in this study were compared with the previous works (Pijls et al, 1995; Sinha Roy et al, 2007; Banerjee et al, 2008). These previous studies don t consider the effect of downstream collateral flow on the diagnostic parameters. So, this present study which focuses on the effect of downstream collaterals on FFR, CDP, and LFC in an in vitro set-up was carried out. The variation of diagnostic parameters in the presence of collaterals might lead to some misinterpretation in the case of intermediate stenosis unless a prior knowledge of collateral flow is available. A lack of knowledge of collateral conduits and its effect on FFR might wrongly lead to the postponement of coronary interventional procedures, particularly in patients with intermediate stenosis. Also, the variability in CDP and LFC might also lead to misinterpretation of stenosis severity due to the effect of downstream collaterals. Other resistances, such as abnormal microvasculature, are difficult to simulate in an in vitro setup. Similarly, guide wire obstruction effect (Back et al, 1996, Banerjee et al, 1999, and Roy et al, 2005, Banerjee et al, 2008) and the eccentricity of guide wires and catheters (Banerjee et al, 2008) also influence pressure and flow measurements. In addition, dynamic factors, such as the heart-rate of the patient, contractility, and left ventricular pressure might also show an effect on the diagnostic parameters. In addition to the effect of downstream collateral flow, the above-mentioned factors which cannot be simulated in an in vitro setup need to be studied for better delineation of coronary stenosis. This study assumes the existence of developed collaterals, a priori. The collateral growth and development is a complex phenomenon involving diverse biological factors and pathways. 37

46 In humans, there are many factors that affect collateral development and growth, such as the severity and recurrence of stenosis, which has not been considered in this study (Rentrop et al, 1988;Carmeliet, 2000; Fujita et al, 2004; Schaper and Ito, 1996; D'Amore and Thompson, 1987). This study also presupposes the operation of only one collateral conduit. Depending on the severity and recurrence of the stenosis (Rentrop et al, 1988) there might be multiple collaterals operating that might further elevate the collateral flow. This factor needs to be further studied in a clinical setting. If extended for in vivo and clinical evaluation, this study, which determines the influence of downstream collateral flow on diagnosis of the severity of coronary stenosis, might aid in better diagnosis of coronary stenosis. There are a few available methods for coronary collateral quantification in clinical use. Coupled with myocardial contrast echocardiography (Sabia et al, 1992; Vogel et al, 2006) or Thallium-201 SPECT imaging data (Verani et al, 1992; Chouraqui et al, 2003), the diagnostic parameters discussed here might yield a better understanding of the effect of downstream collaterals and help in eliminating misinterpretation. 38

47 CHAPTER 5 CONCLUSION All the three diagnostic parameters, FFR, CDP and LFC, showed a change in the presence of functional downstream collaterals. CDP decreased, whereas FFR and LFC increased as the collateral flow increased, for the same severity of stenosis. In the case of intermediate stenosis, a higher value of FFR in the presence of collateral flow (value of 0.77) resulted in misinterpretation and possible misdiagnosis based on the cut-off value of Clinical evaluation of the influence of downstream collateral flow on diagnostic parameters will help in an improved determination of coronary stenosis severity. 39

48 ACKNOWLEDGEMENT This study has been partially funded by the American Heart Association (AHA), N and B. 40

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