CPM Specifications Document Fontan - Exercise:

CPM Specifications Document Fontan - Exercise: OSMSC 0063_2000, 0063_3000, 0063_4000, 0064_2000, 0064_3000, 0064_4000, 0065_2000, 0065_3000, 0065_4000, 0075_2000, 0075_3000, 0075_4000, 0076_2000, 0076_3000, 0076_4000 May 1, 2013 Version 1 Open Source Medical Software Corporation 2013 Open Source Medical Software Corporation. All Rights Reserved.

1. Clinical Significance & Condition Congenital heart defects are structural abnormalities present at birth that disrupt normal blood flow through the heart, affecting 8 of every 1,000 newborns [1]. There are at least 18 documented types of congenital heart defects, including coarcataion of the aorta, single ventricle defects, and complete atrioventricular canal defect [2]. A large amount of anatomical variation is present within these individual congenital heart defect types. In a study that examined congenital heart disease in the general population, the prevalence of single ventricle defects was found to be 0.13 per 1000 children and 0.03 per 1000 adults [3]. Single ventricle defects cover a set of cardiac abnormalities that result in one of the two ventricles being underdeveloped. With one ventricle being of inadequate functionality or size, only one ventricle is available to pump the blood throughout the entire body. Some examples of single ventricle defects include: hypoplastic left heart syndrome, pulmonary atresia, tricuspid atresia, and double inlet left ventricle [2] [4]. Single ventricle heart patients are severely cyanotic at birth, and these conditions are fatal with no interventions. In order to provide adequate oxygenation, and separate the pulmonary and systemic blood supplies, the blood returning to the heart is surgically redirected to the pulmonary arteries, bypassing the heart. This surgical course typically consists of three staged surgeries, a Blalock Taussig (BT) shunt and/or Norwood procedure, a Glenn procedure, and finally a Fontan procedure (or total cavopulmonary connection, TCPC). The first stage is performed immediately after birth, and can vary among patients depending on the defect and the pulmonary resistances. A systemicpulmonary shunt (BT shunt, central shunt, or Sano shunt) is used to maintain adequate ventricle volume load and providing sufficient pulmonary blood flow. Figure 1 Systemic-pulmonary shunt for a single ventricle heart. This is accomplished by connecting a systemic artery, such as the brachocephalic artery, to the pulmonary arteries with a tube graft (Figure 1) [4] [5]. For situations where there is too much blood flow to the lungs, the pulmonary artery can be narrowed with a synthetic band to restrict blood flow [4]. In patients with aortic atresia, a neo-aorta is also constructed during the first stage of surgery. About 65-80% of hypoplastic left ventricles have been found to be related to aortic atresia in several reviews [6]. During reconstruction of a neoaorta, the distal stump of the pulmonary artery and homograft tissue are used to direct flow through the ascending aorta to the carotid and subclavian arteries [6, 7]. Figure 2 Glenn procedure. Arrows represent blood flow, with blue being deoxygenated blood, red being oxygenated blood, and purple being a mix of both. The second stage is typically completed between the ages of 2-6 months [5]. The Glenn procedure connects the superior vena cava to the right pulmonary artery in order to improve oxygenation and decrease ventricle volume load (Figure 2) [8]. If the patient had previously gone through a stage one procedure, it is removed during stage two [4]. Oxygen saturation in patients who have undergone the Glenn procedure typically is between 75-85% [4]. Another variation of the second stage is the hemi-fontan, where the pulmonary artery and superior vena cava are connected through the right atrium and closed off to the rest of heart with a patch. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 2

The third stage, a complete Fontan procedure, is typically completed between the ages of 1-5 years [5]. This final stage redirects the inferior vena cava to the pulmonary artery. In combination with the previous stage, deoxygenated blood bypasses the heart completely and is routed directly to the pulmonary artery so the single ventricle is only pumping oxygenated blood throughout the body. A complete Fontan procedure is typically done through a lateral tunnel or extracardiac method. A lateral tunnel Fontan incorporates the wall of the atrium with a baffle from the inferior vena cava to the pulmonary artery. On the other hand, an extracardiac Fontan connects the inferior vena cava to the pulmonary artery with a synthetic tube-shaped graft, bypassing the heart altogether (Figure 3) [4]. In both methods, a small hole, or fenestration, is often needed between the newly formed channel and the atrium to reduce pressure in the Fontan circuit [4] [5]. A complete Fontan procedure increases oxygen saturation to virtually normal levels [4]. Figure 3 Complete Fontan Circulation: Laterial Tunnel Fontan (leff), Extracardiac Fontan (right). Arrows represent blood flow, with blue being deoxygenated blood and red being oxygenated blood. 2. Clinical Data Patient-specific volumetric image data was obtained to create physiological models and blood flow simulations. Details of the imaging data used can be seen in Table 1. See Appendix 1 for details on image data orientation. Table 1 Patient-specific volumetric image data details (mm) OSMSC ID Modality Voxel Spacing Voxel Dimensions Physical Dimensions R A S R A S R A S 0063_X000 MR 1.0000 0.5469 0.5469 120 512 512 120 280 280 0064_X000 MR 1.5000 1.1719 1.1719 64 256 256 96 300 300 0065_X000 CT 0.3691 0.3691 0.5000 512 512 296 189 189 148 0075_X000 MR 1.5000 0.6836 0.6836 80 512 512 120 350 350 0076_X000 MR 1.5000 0.6836 0.6836 88 512 512 132 350 350 Available patient-specific clinical data collected for resting conditions can be seen in Table 2. OSMSC ID Age Gender BSA CI Table 2 Available patient-specific clinical data Aorta Psys (mmhg) Aorta Pdia (mmhg) Aorta Pavg (mmhg) IVC Pavg (mmhg) LPA Pavg (mmhg) RPA Pavg (mmhg) SVC Pavg (mmhg) 0063 3 M 0.63 3.8 80 50 63 11 10 10 11 0064 6 F 0.71 2.7 95 63 78 9 6 6 9 0065 5 F 0.68 2.8 - - - 11 7 9 11 0075 17 F 1.55 2.3 102 67 78 18 17 17 18 0076 27 F 0.68 3.8 140 95 108 15 14 14 15 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 3

3. Anatomic Model Description Anatomic models were created using customized SimVascular software (Simtk.org) and the image data described in Section 2. See Appendix 2 for a description of modeling methods. See Table 3 for a visual summary of the image data, paths, segmentations and solid model constructed. Table 3 Visual summary of image data, paths, segmentations and solid model. OSMSC ID Image Data Paths Paths and Segmentations Model OSMSC0063 Age: 3 Gender: M OSMSC0064 Age: 6 OSMSC0065 Age: 5 OSMSC0075 Age: 17 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 4

OSMSC0076 Age: 27 N/A N/A Details of anatomic models, such has number of outlets and model volume, can be seen in Table 4. Table 4 Anatomic Model details OSMSC ID Inlets Outlets Volume (cm 3 ) Surface Area (cm 2 ) Vessel Paths 2-D Segmentations 0063_X000 2 20 17.3673 90.6586 22 125 0064_X000 2 20 21.2094 106.402 23 100 0065_X000 4 23 26.3423 141.003 25 154 0075_X000 2 26 68.5137 262.946 28 160 0076_X000 2 20 46.5195 188.944 N/A N/A 4. Physiological Model Description In addition to the clinical data gathered for this model, several physiological assumptions were made in preparation for running the simulation. See Appendix 3 for details. 5. Simulation Parameters & Details 5. 1 Simulation Parameters See Appendix 4 and the peer-reviewed publication featuring these models [9] for information on the physiology and simulation specifications. Solver parameters can be seen in Table 5 Table 5 Solver Parameters OSMSC ID Time Steps per Cycle Time Stepping Strategy 0063_2000 4275 Fixed step - 4 0063_3000 4433 Fixed step - 4 0063_4000 5450 Fixed step - 4 0064_2000 4275 Fixed step - 3 0064_3000 6650 Fixed step - 3 0064_4000 5450 Fixed step - 3 0065_2000 4275 Fixed step - 3 0065_3000 4433 Fixed step - 3 0065_4000 5450 Fixed step - 3 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 5

0075_2000 4275 Fixed step - 3 0075_3000 3325 Fixed step - 3 0075_4000 5450 Fixed step - 3 0076_2000 4275 Fixed step - 4 0076_3000 4433 Fixed step - 4 0076_4000 5450 Fixed step - 4 5. 2 Inlet Boundary Conditions PC-MRI data was used to generate a flow waveform to be applied to the inlets of the computational fluid dynamics (CFD) model as the volumetric inflow rate (Q). A two-part polynomial model was used to account for the effects of respiration on pressures/flow rates and superimposed on the IVC PCMRI derived waveform [10]. No significant resspiration effects are seen in the SVC, internal jugular vien (IJV) and broncheocephilic cien (BrS) therefore the PCMRI derived waveform with no respiration model modification was used [10].These waveforms were then modified to represent light, moderate and heavy exercise (see Table 6 for physiological state of each simulation). See Figure 4 for a plot of total inflow for each model. See Table 7 for the period and cardiac output for each simulation. Table 6 Physiological Exercise State Simulated OSMSC ID Physiological Exercise State 0063_2000 Light 0063_3000 Moderate 0063_4000 Heavy 0064_2000 Light 0064_3000 Moderate 0064_4000 Heavy 0065_2000 Light 0065_3000 Moderate 0065_4000 Heavy 0075_2000 Light 0075_3000 Moderate 0075_4000 Heavy 0076_2000 Light 0076_3000 Moderate 0076_4000 Heavy 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 6

Table 7 Inflow details from waveforms seen in Figure 4 OSMSC ID Period (sec) Mean Flow (L/Min) Profile Type SVC IVC BrS IJV Total 0063_2000 1.71 1.27 1.73 - - 3.00 Parabolic 0063_3000 1.33 1.27 2.59 - - 3.86 Parabolic 0063_4000 1.09 1.90 3.42 - - 5.32 Parabolic 0064_2000 1.71 0.89 2.30 - - 3.19 Parabolic 0064_3000 1.33 0.89 3.41 - - 4.30 Parabolic 0064_4000 1.09 1.34 4.53 - - 5.87 Parabolic 0065_2000 1.71 0.49 2.20 0.09 0.28 3.05 Parabolic 0065_3000 1.33 0.49 3.26 0.09 0.28 4.11 Parabolic 0065_4000 1.09 0.73 0.14 0.41 4.35 5.63 Parabolic 0075_2000 1.71 1.11 3.76 - - 4.87 Parabolic 0075_3000 1.33 1.11 5.55 - - 6.66 Parabolic 0075_4000 1.09 1.67 7.45 - - 9.11 Parabolic 0076_2000 1.71 0.96 2.71 - - 3.67 Parabolic 0076_3000 1.33 0.97 4.05 - - 5.01 Parabolic 0076_4000 1.09 1.43 5.33 - - 6.77 Parabolic 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 7

Figure 4 Inflow waveforms in L/min 5. 3 Outlet Boundary Conditions RCR boundary conditions were applied to each outlet. Initial LPA/RPA flow splits were prescribed at 45/55, with a 20:40:40 split between the upper, middle, and lower lobes, respectively, for both the left and right pulmonary artery. Resistances values were decreased by 5%, 10% and 15% from calculated rest values to simulate light, moderate and heavy exercise, respectively. See Appendix 5 for more details on RCR calculations and Exhibit 1 for the values used in each simulation. 6. Simulation Results Simulation results were quantified for the last cardiac cycle. Paraview (Kitware, Clifton Park, NY), an opensource scientific visualization application, was used to visualize the results. A volume rendering of velocity magnitude for three time points during the cardiac cycle can be seen in Table 9 for each model. Table 8 Volume rendering velocity during max flow and min flow. OSMSC ID Max Flow Min Flow OSMSC0063 sub 2000 Age: 3 Gender: M OSMSC0063 sub 3000 Age: 3 Gender: M 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 10

OSMSC0063 sub 4000 Age: 3 Gender: M OSMSC0064 sub 2000 Age: 6 OSMSC0064 sub 3000 Age: 6 OSMSC0064 sub 4000 Age: 6 OSMSC0065 sub 2000 Age: 5 OSMSC0065 sub 3000 Age: 5 OSMSC0065 sub 4000 Age: 5 OSMSC0075 sub 2000 Age: 17 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 11

OSMSC0075 sub 3000 Age: 17 OSMSC0075 sub 4000 Age: 17 OSMSC0076 sub 2000 Age: 27 OSMSC0076 sub 3000 Age: 27 OSMSC0076 sub 4000 Age: 27 Surface distribution of time-averaged blood pressure (TABP), time-averaged wall shear stress (TAWSS) and oscillatory shear index (OSI) were also visualized and can be seen in Table 9. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 12

Table 9 Time averaged blood pressure (TABP), time-average wall shear stress (TAWSS), and oscillatory shear index (OSI) surface distributions OSMSC ID Time Averaged Pressure TAWSS OSI OSMSC0063 sub 2000 Age: 3 Gender: M OSMSC0063 sub 3000 Age: 3 Gender: M OSMSC0063 sub 4000 Age: 3 Gender: M OSMSC0064 sub 2000 Age: 6 OSMSC0064 sub 3000 Age: 6 OSMSC0064 sub 4000 Age: 6 OSMSC0065 sub 2000 Age: 5 OSMSC0065 sub 3000 Age: 5 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 13

OSMSC0065 sub 4000 Age: 5 OSMSC0075 sub 2000 Age: 17 OSMSC0075 sub 3000 Age: 17 OSMSC0075 sub 4000 Age: 17 OSMSC0076 sub 2000 Age: 27 OSMSC0076 sub 3000 Age: 27 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 14

7. References [1] National Heart Blood and Lung Institute, "Congenital Heart Defects," 1 July 2011. [Online]. Available: http://www.nhlbi.nih.gov/health/health-topics/topics/chd/. [Accessed January 2012]. [2] American Heart Association, "Common Types of Heart Defects," 2 May 2011. [Online]. Available: http://www.heart.org/heartorg/conditions/congenitalheartdefects/aboutcongenitalheartdefects/common- Types-of-Heart-Defects_UCM_307017_Article.jsp#.TwHuCNQS01I. [Accessed Januaray 2012]. [3] A. Marelli, A. Mackie, R. Ionescu-Ittu, E. Rahme and L. Pilote, "Congenital Heart Disease in the General Population: Changing Prevalence and Age Distribution," Circulation, vol. 115, pp. 163-172, 2007. [4] Cincinnati Children's, "Single Ventricle Anomalies and Fontan Circulation," March 2010. [Online]. Available: http://www.cincinnatichildrens.org/health/s/sv/. [Accessed January 2012]. [5] S. Nayak and P. Booker, "The Fontan Circulation," British Journal of Anaesthesia, vol. 8, no. 1, pp. 26-30, 2008. [6] A. M. Rudolph, "Aortic atresia, mitral atresia, and hypoplastic left ventricle," in Congenital Disease of the Heart: Clinical Physioloical Considerations, Hoboken, Blackwell Publishing, 2009, pp. 257-288. [7] Children's Hospital of Wisconsin, "Norwood Procedure of Hypoplastic Left Heart Syndrome," 2012. [Online]. Available: http://www.chw.org/display/router.asp?docid=21364#. [Accessed 24 May 2012]. [8] S. Yuan and H. Jing, "Palliative Procedures for Congenital Heart Defects," Archives of Cardiovascular Disease, vol. 102, pp. 549-557, 2009. [9] A. L. Marsden, I. E. Vignon-Clmentel, F. P. Chan, J. A. Feinstein and C. A. Taylor, "Effects of exercise and respiration on hemodynamics efficiency in CFD simulations of the total cavopulmonary connection," Annals of Biomedical Engineering, vol. 35, no. 2, pp. 250-263, 2007. [10] A. L. Marsden, M. Reddy, S. Shadden, F. Chan, C. Taylor and J. Feinstein, "A New Multiparameter Approach to Computational Simulation for Fontan Assessment and Redesign," Congenit Heart Dis., vol. 5, pp. 104-117, 2010. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 16

Exhibit 1: Simulation RCR Values Table 10 RCR Values for 0063 Simulations in cgs units ID Face Name 0063_2000 0063_3000 0063_4000 Rp C Rd Rp C Rd Rp C Rd 2 LPA_ul1_final 1127.88 2.31E-05 5643.97 1092.95 2.39E-05 5322.49 1057.86 2.48E-05 5001.17 3 LPA_ul2_final 1321.63 2.10E-05 6301.55 1281.03 2.18E-05 5940.93 1240.29 2.26E-05 5580.45 4 LPA_ulbr_final 1039.27 2.14E-05 6015.93 1006.24 2.21E-05 5677.64 973.09 2.29E-05 5339.46 5 LPA_ul_final 1039.25 2.14E-05 6015.78 1006.22 2.21E-05 5677.49 973.08 2.29E-05 5339.32 6 LPA_ml_final 1381.99 1.85E-05 6882.10 1339.00 1.92E-05 6490.13 1295.88 1.99E-05 6098.30 7 LML_final 1103.90 2.37E-05 5423.09 1070.13 2.45E-05 5113.33 1036.21 2.55E-05 4803.73 8 LMML_final 1524.26 1.33E-05 9340.23 1474.05 1.38E-05 8818.62 1423.71 1.43E-05 8297.14 9 LML2_final 1806.75 1.20E-05 11833.07 1750.53 1.24E-05 11171.40 1694.69 1.28E-05 10509.36 10 LPA_br1_final 1087.54 2.06E-05 6301.37 1052.60 2.13E-05 5947.42 1017.70 2.21E-05 5593.43 11 LPA 802.46 3.32E-05 4483.58 779.78 3.44E-05 4228.04 757.00 3.57E-05 3972.61 12 LPA_llbr_final 1792.28 1.06E-05 12951.34 1735.88 1.10E-05 12231.76 1679.33 1.13E-05 11512.33 13 RPA_br3_final 778.56 4.24E-05 3527.56 757.02 4.40E-05 3322.46 735.36 4.58E-05 3117.49 14 RPA_br2_final 1499.00 1.70E-05 7710.20 1461.84 1.79E-05 7262.67 1414.84 1.86E-05 6824.98 15 RPA_mmbr_final 1308.75 1.36E-05 8559.66 1262.89 1.40E-05 8086.13 1216.93 1.45E-05 7612.70 16 RUML2_final 1759.44 1.77E-05 7800.32 1706.71 1.84E-05 7349.90 1653.80 1.91E-05 6899.66 17 RPA_mm_final 1730.89 1.41E-05 9586.74 1676.83 1.46E-05 9045.14 1622.59 1.51E-05 8503.71 18 RPA_ml_final 895.62 2.95E-05 5160.09 869.40 3.05E-05 4867.59 842.90 3.16E-05 4575.36 19 RPA_mlbr_final 759.26 4.29E-05 3741.11 739.88 4.45E-05 3523.64 720.36 4.63E-05 3306.29 20 RPA_br1_final 565.82 6.13E-05 2432.84 550.23 6.37E-05 2290.61 534.56 6.63E-05 2148.45 21 RPA 542.90 6.95E-05 2329.48 529.02 7.21E-05 2192.18 515.03 7.51E-05 2054.99 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 17

Table 11 RCR Values for 0064 Simulations in cgs units ID Face Name 0064_2000 0064_3000 0064_4000 Rp C Rd Rp C Rd Rp C Rd 2 LUL2_final 2042.85 8.16E-06 13869.24 1967.25 8.42E-06 13107.36 1891.55 8.71E-06 12345.58 3 LUL2b_final 2587.57 5.04E-06 20610.13 2494.82 5.23E-06 19481.94 2395.29 5.40E-06 18360.54 4 LUL 1327.34 1.24E-05 9426.42 1280.32 1.28E-05 8907.45 1233.22 1.32E-05 8388.57 5 LUML2_final 2346.34 6.71E-06 17911.18 2258.21 6.92E-06 16933.12 2169.98 7.15E-06 15955.16 6 LPA_2_final 806.66 3.71E-05 4336.45 785.31 3.85E-05 4087.11 763.83 4.00E-05 3837.91 7 LPA_3_final 1088.38 2.40E-05 5280.54 1055.36 2.49E-05 4978.36 1022.19 2.59E-05 4676.32 8 LML 1139.07 2.24E-05 5749.67 1113.09 2.36E-05 5413.08 1077.18 2.45E-05 5086.43 9 LPA_4_final 888.49 2.98E-05 5080.51 862.63 3.08E-05 4792.21 836.46 3.19E-05 4504.23 10 LPA_final 751.77 4.10E-05 3470.49 730.04 4.25E-05 3269.99 708.21 4.42E-05 3069.60 11 PA_ex2_final 1800.86 1.51E-05 9040.73 1745.75 1.56E-05 8525.23 1690.45 1.62E-05 8009.92 12 RUL 848.89 3.46E-05 4523.91 825.94 3.58E-05 4264.07 802.87 3.72E-05 4004.37 13 RUL_3_final 1532.97 1.62E-05 8092.11 1485.04 1.68E-05 7633.45 1436.94 1.74E-05 7174.98 14 RUL4_final 3397.45 4.83E-06 22343.16 3286.60 5.02E-06 21099.24 3160.57 5.19E-06 19870.50 15 RUL_2_final 1072.31 2.02E-05 6488.00 1037.95 2.08E-05 6124.45 1003.23 2.16E-05 5761.26 16 RML_final 564.99 6.56E-05 2225.89 552.04 7.01E-05 2091.95 536.39 7.31E-05 1960.71 17 RML2_final 663.02 6.15E-05 2479.78 645.49 6.40E-05 2331.89 627.82 6.67E-05 2184.16 18 RMML_final 711.22 4.15E-05 3357.54 690.53 4.30E-05 3164.09 669.73 4.47E-05 2970.74 19 RLML_final 809.91 3.70E-05 4394.28 788.49 3.84E-05 4141.79 766.93 3.99E-05 3889.45 20 RLL_2 564.26 7.72E-05 2055.14 549.85 8.03E-05 1931.69 535.32 8.38E-05 1808.36 21 RPA_final 542.74 6.95E-05 2327.89 528.86 7.22E-05 2190.68 514.88 7.51E-05 2053.58 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 18

Table 12 RCR Values for 0065 simulations in cgs units ID Face Name 0065_2000 0065_3000 0065_4000 Rp C Rd Rp C Rd Rp C Rd 2 LUL2_final 1040.52 2.13E-05 6028.72 1007.42 2.21E-05 5689.75 974.21 2.29E-05 5350.89 3 LUL_final 849.57 3.64E-05 4482.30 827.24 3.77E-05 4224.01 804.76 3.92E-05 3965.87 4 LML2_final 901.23 2.93E-05 5222.75 874.73 3.03E-05 4926.94 847.97 3.14E-05 4631.38 5 LML_final 737.50 4.23E-05 3775.38 718.46 4.39E-05 3556.90 707.34 4.68E-05 3330.50 6 LUML_final 1223.09 2.16E-05 6099.03 1185.38 2.23E-05 5751.37 1155.46 2.36E-05 5395.91 7 LUML2_final 1223.15 2.16E-05 6099.55 1185.43 2.23E-05 5751.86 1155.51 2.36E-05 5396.37 8 LLL_final 978.56 2.13E-05 5991.97 947.01 2.20E-05 5656.65 915.36 2.28E-05 5321.43 9 LLL2_final 978.58 2.13E-05 5992.23 947.03 2.20E-05 5656.90 915.38 2.28E-05 5321.67 10 LPA_final 710.45 4.15E-05 3350.32 689.79 4.31E-05 3157.26 669.03 4.47E-05 2964.29 11 LLL3_final 1447.30 2.07E-05 6562.91 1403.30 2.15E-05 6185.32 1359.37 2.23E-05 5807.66 12 RUL2_final 1104.69 2.36E-05 5430.36 1070.88 2.45E-05 5120.22 1036.92 2.54E-05 4810.23 13 RUL_final 863.47 3.08E-05 4801.57 838.63 3.18E-05 4528.25 813.79 3.30E-05 4254.93 14 RPA_final 1739.28 9.18E-06 12039.52 1674.31 9.47E-06 11379.29 1609.38 9.80E-06 10719.02 15 RML4_final 1450.47 1.75E-05 7253.14 1405.12 1.81E-05 6840.41 1359.62 1.88E-05 6427.83 16 RML_final 735.90 3.71E-05 3932.11 715.15 3.84E-05 3707.18 694.17 3.99E-05 3482.48 17 RL1_final 720.73 6.27E-05 2541.10 702.12 6.53E-05 2388.03 683.40 6.82E-05 2235.08 18 RL1a_final 885.54 2.99E-05 5047.59 859.80 3.09E-05 4761.06 833.79 3.21E-05 4474.80 19 RL3b_final 1606.01 1.77E-05 7366.17 1557.07 1.84E-05 6942.89 1507.97 1.91E-05 6519.77 20 RL3_final 1606.01 1.77E-05 7366.17 1557.07 1.84E-05 6942.89 1507.97 1.91E-05 6519.77 21 RL2_new_final 745.78 3.33E-05 4153.46 722.84 3.45E-05 3918.55 699.81 3.58E-05 3683.73 22 RL2a_final 1079.24 2.43E-05 5196.75 1046.66 2.52E-05 4899.01 1013.94 2.61E-05 4601.42 23 RL1b_final 1380.18 1.85E-05 6865.63 1337.29 1.92E-05 6474.53 1294.26 1.99E-05 6083.57 24 RL3c_final 1617.80 1.50E-05 8733.40 1567.24 1.55E-05 8239.165 1516.50 1.61E-05 7745.10 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 19

Table 13 RCR values for 0075 simulations in cgs units ID Face Name 0075_2000 0075_3000 0075_4000 Rp C Rd Rp C Rd Rp C Rd 2 LUL2_new_final 1565.19 1.16E-05 11157.83 1515.13 1.2E-05 10538.26 1465.33 1.24E-05 9918.43 3 LUL_new_final 1365.81 2.06E-05 6542.53 1324.04 2.1E-05 6168.07 1282.35 2.21E-05 5793.53 4 LUML2_final 2318.02 7.17E-06 16157.93 2233.28 7.4E-06 15270.25 2148.40 7.66E-06 14382.71 5 LUML3_final 2317.94 7.17E-06 16157.10 2233.20 7.4E-06 15269.46 2148.33 7.66E-06 14381.97 6 LUML_final 1492.66 1.21E-05 10281.14 1441.89 1.3E-05 9712.23 1391.54 1.30E-05 9142.92 7 LML_final 1570.94 1.40E-05 9079.89 1520.37 1.4E-05 8569.89 1469.65 1.50E-05 8060.04 8 LML2_final 1795.61 8.14E-06 14463.67 1740.11 8.5E-06 13663.41 1676.09 8.75E-06 12871.68 9 LML4_final 1795.61 8.14E-06 14463.67 1740.11 8.5E-06 13663.41 1676.09 8.75E-06 12871.68 10 LML5_final 2244.96 6.95E-06 16786.08 2162.05 7.2E-06 15867.35 2085.04 7.47E-06 14942.73 11 LLL2_final 1739.40 9.18E-06 12040.75 1674.43 9.5E-06 11380.45 1609.49 9.79E-06 10720.12 12 LLL3_final 2244.96 6.95E-06 16786.08 2162.05 7.2E-06 15867.35 2085.04 7.47E-06 14942.73 13 LLL_final 1351.20 1.21E-05 11114.85 1307.26 1.2E-05 10502.69 1263.18 1.29E-05 9890.66 14 LPA_final 1108.07 2.36E-05 5461.48 1074.10 2.4E-05 5149.69 1039.98 2.53E-05 4838.05 15 RUL_final 1375.37 1.42E-05 8359.17 1328.51 1.5E-05 7893.68 1281.54 1.52E-05 7428.30 16 RULbr3_final 4312.73 2.86E-06 36565.91 4144.25 2.9E-06 34582.88 3975.60 3.04E-06 32600.03 17 RULbr2_final 3708.82 3.72E-06 29111.51 3568.79 3.8E-06 27524.15 3428.54 3.96E-06 25937.01 18 RULbr4_final 2336.25 7.13E-06 16349.11 2250.58 7.4E-06 15451.35 2164.77 7.61E-06 14553.72 19 RULbr_final 2609.19 4.72E-06 22750.89 2508.48 4.9E-06 21516.86 2407.66 5.02E-06 20282.94 20 RML5_final 1801.23 8.44E-06 14828.41 1739.80 8.7E-06 14014.59 1678.90 9.00E-06 13200.25 21 RML2_final 1743.22 1.57E-05 8565.60 1690.27 1.6E-05 8075.99 1637.13 1.69E-05 7586.55 22 RML3_final 1442.29 1.79E-05 7332.05 1397.63 1.9E-05 6914.90 1352.82 1.93E-05 6497.90 23 RML4_final 1121.06 2.33E-05 5581.09 1086.46 2.4E-05 5262.95 1051.70 2.50E-05 4944.96 24 RML_final 1344.17 1.22E-05 11016.72 1300.57 1.3E-05 10409.75 1256.85 1.30E-05 9802.90 25 RLL_final 861.87 3.08E-05 4784.07 837.13 3.2E-05 4511.65 812.36 3.31E-05 4239.26 26 RLL2_final 1354.14 1.21E-05 11155.81 1310.05 1.2E-05 10541.49 1265.82 1.29E-05 9927.29 27 RPA_final 767.98 4.60E-05 3327.93 747.32 4.8E-05 3133.02 726.41 4.97E-05 2938.36 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 20

Table 14 RCR Values for 0076 simulations in cgs units ID Face Name 0076_2000 0076_3000 0076_4000 Rp C Rd Rp C Rd Rp C Rd 2 LUL1 983.86 2.12E-05 6046.14 951.86 2.19E-05 5708.14 919.95 2.27E-05 5370.05 3 LUL2 2321.72 6.76E-06 17637.78 2234.86 6.98E-06 16674.14 2147.90 7.21E-06 15710.60 4 LML1 1116.33 2.34E-05 5537.47 1081.95 2.42E-05 5221.65 1047.43 2.51E-05 4905.97 5 LML2 1357.29 1.20E-05 11199.81 1313.04 1.24E-05 10583.16 1268.66 1.29E-05 9966.64 6 LML3 1879.68 7.55E-06 15602.22 1811.34 7.79E-06 14750.46 1742.90 8.05E-06 13898.80 7 LML4 1510.36 1.43E-05 8661.29 1460.78 1.48E-05 8175.52 1411.07 1.53E-05 7689.88 8 LLL1 1860.00 1.05E-05 12587.60 1799.99 1.08E-05 11887.21 1739.82 1.12E-05 11186.98 9 LLL2 858.14 3.31E-05 4738.31 834.72 3.43E-05 4467.18 811.17 3.56E-05 4196.18 10 LLL3 1221.75 2.16E-05 6086.60 1184.10 2.24E-05 5739.60 1154.24 2.37E-05 5384.81 11 RUL1 1662.93 8.63E-06 13287.22 1603.25 8.90E-06 12560.05 1542.28 9.20E-06 11834.17 12 RUL2 2156.23 7.25E-06 15802.57 2082.26 7.54E-06 14931.34 2002.13 7.79E-06 14066.27 13 RUL3 1764.11 8.69E-06 13832.04 1702.99 8.97E-06 13072.31 1640.70 9.27E-06 12313.75 14 RUL4 2380.73 6.63E-06 18293.17 2290.83 6.84E-06 17294.97 2200.82 7.07E-06 16296.88 15 RML1 1508.80 1.64E-05 8014.00 1462.02 1.70E-05 7559.58 1415.07 1.76E-05 7105.33 16 RML2 1083.32 2.42E-05 5234.18 1050.55 2.50E-05 4934.45 1017.63 2.60E-05 4634.87 17 RML3 775.95 3.96E-05 4057.65 755.38 4.10E-05 3823.82 734.69 4.26E-05 3590.11 18 RLL1 1751.07 1.45E-05 9202.43 1696.05 1.50E-05 8680.95 1640.84 1.56E-05 8159.66 19 RLL2 1100.12 2.38E-05 5388.38 1066.53 2.46E-05 5080.47 1032.80 2.56E-05 4772.70 20 RLL3 1443.11 1.33E-05 9280.49 1394.66 1.37E-05 8764.54 1346.09 1.42E-05 8248.71 21 RLL4 1263.26 2.09E-05 6338.64 1224.37 2.16E-05 5977.43 1185.54 2.24E-05 5616.16 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 21

Appendix 1. Image Data Orientation The RAS coordinate system was assumed for the image data orientation. Voxel Spacing, voxel dimensions, and physical dimensions are provided in the Right-Left (R), Anterior-Posterior (A), and Superior-Inferior (S) direction in all specification documents unless otherwise specified. 2. Model Construction All anatomic models were constructed in RAS Space. The models are generated by selecting centerline paths along the vessels, creating 2D segmentations along each of these paths, and then lofting the segmentations together to create a solid model. A separate solid model was created for each vessel and Boolean addition was used to generate a single model representing the complete anatomic model. The vessel junctions were then blended to create a smoothed model. 3. Physiological Assumptions Newtonian fluid behavior is assumed with standard physiological properties. Blood viscosity and density are given below in units used to input directly into the solver. Blood Viscosity: 0.04 g/cm s 2 Blood Density: 1.06 g/cm 3 4. Simulation Parameters Conservation of mass and Navier-Stokes equations were solved using 3D finite element methods assuming rigid and non-slip walls. All simulations were ran in cgs units and ran for several cardiac cycles to allow the flow rate and pressure fields to stabilize. 5. Outlet Boundary Conditions 5.1 Resistance Methods Resistances values can be applied to the outlets to direct flow and pressure gradients. Total resistance for the model is calculated using relationships of the flow and pressure of the model. Total resistance is than distributed amongst the outlets using an inverse relationship of outlet area and the assumption that the outlets act in parallel. 5.2 Windkessel Model In order to represent the effects of vessels distal to the CFD model, a three-element Windkessel model can be applied at each outlet. This model consists of proximal resistance (R p ), capacitance (C), and distal resistance (R d ) representing the resistance of the proximal vessels, the capacitance of the proximal vessels, and the resistance of the distal vessels downstream of each outlet, respectively (Figure 1). Figure 5 - Windkessel model 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 22

First, total arterial capacitance (TAC) was calculated using inflow and blood pressure. The TAC was then distributed among the outlets based on the blood flow distributions. Next, total resistance (R t ) was calculated for each outlet using mean blood pressure and PC-MRI or calculated target flow (R t =P mean /Q desired ). Given that R t =R p +R d, total resistance was distributed between R p and R d adjusting the R p to R t ratio for each outlet. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 23