HPC for Simulation and Modelling of Cardiac Infarction for the Development of Novel and Effective Treatment

Transcription

1 HPC for Simulation and Modelling of Cardiac Infarction for the Development of Novel and Effective Treatment Thomas Franz Chris Barnard Division of Cardiothoracic Surgery, Programme for the Enhancement of Research Capacity - Research Office, Centre for Research in Computational and Applied Mechanics University of Cape Town; Centre for High Performance Computing

2 Acknowledgements Dr Neil Davies Prof Daya Reddy Dr Sebastian Skatulla Dr Greg Mitchell Dr Jun Liao Dr Bruce Spottiswoode Prof Ernesta Meintjes PhD Students Karen Kadner* Mazin Sirry Fulufhelo Masithulela Renee Miller Ritesh Rama Post-docs Dr Jeroen Kortsmit* Dr Dieter Legner Laura Dubuis MSc Students Renee Miller* James Mbewu* Ritesh Rama* Muhammad Saleh* Peter Wise Kevin Sack Mohammed Essack Jules Lancee (*completed) CHPC Kevin Colville Eric Mbele BSc Students Jesse Macadangdang* Gesant Abed* Devin Dollery* Tshenolo Tau* Dale Lewis* Aniel Prosper* Siddhartha Ram* Bruce Phelp* Kelebogile Motili* Mogoma Senthumule Wayde Herman Rimon Muchehiwa 1

3 WHO: World Health Statistics Geneva,

4 Myocardial Infarct (MI) 3

5 Changes in the Heart Healthy Infarcted 4

6 Therapies for MI Acorn CSD Aim: Prevention of adverse remodelling of the heart Cell delivery therapy Injection of cells with carrier medium into infarcted region of the heart Positive outcomes Mechanisms unclear 5

7 Infarct Thickness & Cardiac Function 1 Month after Infarction * p<0.05 n=7-9 6

8 Questions on Injection Therapy Contribution to mechanical and biological properties of the heart Properties of injectable biomaterials Timing of delivery Injection site Injection volume 7

9 Canine Biventricular Cardiac Model Myofibre representation Constitutive models Passive strain energy function Active contraction model Coupling to Windkessel circulation model (Nielsen et al. 1991) Antero-apical infarct: 22% LV wall Infarct wall thinning Post-infarct LV dilation 100% (Kortsmit, Davies, Miller, Franz)

10 Hydrogel Injectates Gel inclusion in infarct region Volume: 9.4 ml (7.1% of LV wall) Transmural distribution 8 thin layers Single bulk layer Kadner et al, Biomaterials, 2012

11 Time after coronary occlusion Study Design and Ventricular Function Case C Functional Parameters V 0 (ml) SV (ml) EF (%) Healthy Control H Ischemic Infarct II layered gel II + L bulk gel II + B Scarred Dilated Infarct SDI layered gel SDI + L bulk gel SDI + B

12 Stress and Strain in Infarct Region End-diastolic Myofibre Strain End-diastolic Myofibre Stress End-systolic Myofibre Strain End-systolic Myofibre Stress

13 Main Findings Functional Improvement More pronounced in scarred dilated infarct (still dilated LV cavity volume volume overload) Layered injectate superior at early infarct stage Bulk injectate superior at late infarct stage Infarct Stress and Strain Layered injectates better than bulk for all infarct stages Greatest benefits Stresses at end-diastole (filling) Strains at end-systole (ejection)

14 Meshless parallelised code (SESKA) Geometry: Rat LV, truncated ellipsoid Vol.-fraction : 100.0% / 0.0% / 0.0% 84.2% / 15.8% / 0.0% 71.0% / 15.8% / 13.2% (Healthy / Infarct / B-Zone) Material: Healthy: Omens et al. (2002) Infarct: Stiffness x 0.5 Injection: Neo-Hookean B.C.: Endocardium fixed at the base Loading: Diastolic pressure (Legner, Skatulla, Mbewu, Rama, Sack, Mothibi, Reddy)

15 Fibre Strain Infarct + Injectate Infarct Healthy

16 Constitutive Properties of Infarcts (Sirry, Liao, Davies, Franz) 15

17 Stress (Pa) Infarct Stress-Strain Relationships circumferential 28d longitudinal 28d d 7d 14d 7d d 0d Strain 16

18 Inverse FE Modelling 17

19 Cardiac Regeneration Mechanical Stimuli in Cardiac Environment Cell Differentiation Cell Proliferation Gene Expression

20 Cell-specific Geometrical Modelling Confocal microscopy images Slicing through sample 3D Cell geometry (Lancee, Davies, Dubuis, Franz)

21 Cell-specific Finite Element Model Microscope images Cytoskeleton 3D Reconstruction Cytoplasm Nucleus Cell membrane Stretching FEM Nucleus Focal adhesion Elastic substrate (Dubuis, Davies, Green, Franz)

22 Cell Deformation Bottom View 3D cell-specific FEM Cytoplasm, nucleus, membrane Focal adhesion Physiological stretch loading Top View

23 FSI Model Simulating blood flow around a cell: Fluid structure interaction

24 Tensile Strain in Fibroblast 3D view of nucleus 3D view on cell 3D Cross-sectional view

25 In Progress: Endothelial Cell Model