Matthew Gounis PhD - PDF document

1 Matthew Gounis, PhD Associate Professo
Matthew Gounis, PhD Associate Professor, Department of Radiology Director, New England Center for Stroke Research SVIN – November 2014 Flow Dynamics: Using Patient Data to Guide Treatment Di

2 sclosures • Research Grants (last
sclosures • Research Grants (last 36 months): – NINDS, NIBIB, NIA, NCI – Philips Healthcare – Fraunhofer Institute – Boston Scientific – Stryker Neurovascular – Codman Neurovasc

3 ular – Neurointerventional Therapeut
ular – Neurointerventional Therapeutics – Rapid Medical – Concentric Medical – eV3 Neurovascular – Covidien – Stryker/Biosystems – Thrombolytic Scientific – Senofi - aventis

4 – Neuravi – Surpass Medical –
– Neuravi – Surpass Medical – Silk Road – Lazarus Effect • Consulting (fee - per - hour, last 36 months): – Stryker Neurovascular – Codman Neurovascular – Soteira – Su

5 rpass Medical Inc (CRO) – Surpass Me
rpass Medical Inc (CRO) – Surpass Medical Ltd Important Questions • Hemodynamics long - believed to be critical component of aneurysm pathogenesis • Can we use patient - specific analysis

6 of hemodynamics to: – Determine whi
of hemodynamics to: – Determine which unruptured intracranial aneurysm is at high risk of rupture? – Determine efficacy of treatment? Hemodynamics: Aneurysm Pathogenesis • German and Black

7 , Circ Res 1955 • “…the ultimat
, Circ Res 1955 • “…the ultimate objective of an understanding of the stress - strain - time relationship of aneurysm rupture.” Rupture Risk Assessment J Xiang et al, JNIS 2014 Animal

8 Modeling • Cerebral aneurysms are ra
Modeling • Cerebral aneurysms are rare in species other than humans. • Reliable aneurysm formation requires vascular insult ( elastase , angiolathyrism ) • Reliable aneurysms made from HTN,

9 high flow conditions AND vascular in
high flow conditions AND vascular insult Handa et al. Stroke 1983 Sadasivan et al. Ann Biomed Eng 2013 Hypertension Atherosclerosis Infection Trauma Structural abnormalities Degradation

10 of internal elastic lamina Congenital
of internal elastic lamina Congenital Diseases 5% Acquired Diseases 95% Collagen disorders ADPKD Aneurysm formation Repair and stabilization Progressive degeneration and rupture Inflammation

11 Myeloperoxidase (MPO) • Potent anti
Myeloperoxidase (MPO) • Potent anti - microbial (respiratory burst) • Implicated in atherogenesis • ↑ MPO levels correlated with adverse CV outcomes Promise as a marker of inflammation

12 in the vascular wall Naruko et a
in the vascular wall Naruko et al. Circulation . 2002. Brennan et al. N Engl J Med . 2003. Nicholls et al. Arterioscler Thromb Vasc Biol. 2005 Targeting Contrast Agents • Enzyme - mediat

13 ed structural changes • Site - spe
ed structural changes • Site - specific accumulation upon activation Contrast Agent Lumen Lumen Querol et al. Org Lett. 2005. Querol et al. Org Biomol Chem . 2006. di - 5 - hydroxytryp

14 tamide GdDTPA Purpose 1. Identify
tamide GdDTPA Purpose 1. Identify MPO in human brain aneurysms 2. Develop clinically relevant MR molecular imaging approach for detection of MPO in an aneurysm model MPO Measurements from

15 Human Specimens • 54 y - o F, Incide
Human Specimens • 54 y - o F, Incidental + Family History SAH MPO Measurements from Human Specimens • 75 y - o F, SAH, Ruptured 7mm RT MCA IA • 46 y - o F, Incidental, 10 mm LT MCA IA M

16 PO Measurements from Human Specimens
PO Measurements from Human Specimens • 29 y - o F, Incidental, 14mm RT MCA UIA, No FH MPO and 5 Year Annual Rupture Risk Assessment (PHASES*) • 23 aneurysms from 19 pts collected • 3 r

17 uptured, 20 unruptured, mean diameter
uptured, 20 unruptured, mean diameter = 8.0mm • 10 UIA MPO+ (212 vs. 55 U/mg) * Greving et al. Lancet Neurol 2014, 13:59 Gounis et al, Stroke 2014, 45:1474 MPO as a Biomarker? n=20 n=5, p=0

18 .06, R 2 = 0.73 Gounis et al, Stroke
.06, R 2 = 0.73 Gounis et al, Stroke 2014, 45:1474 Molecular Imaging Approach Model of Aneurysm Inflammation • LPS injected into wall of aneurysm model Prior Data MSDE with IR • 3 Hours p

19 ost IV contrast administration Naïv
ost IV contrast administration Naïve LPS Modification Gounis et al, AJNR 2014, in press Molecular Imaging of Aneurysm Model In Vivo • Histology showed that the aneurysm model had 17.2 U

20 MPO per mg tissue and LPS - induced in
MPO per mg tissue and LPS - induced inflammation demonstrated large infiltration of MPO and macrophages with aneurysm wall as compared to naïve. Naïve, macrophages Naïve, MPO LPS, macrophages LPS,

21 MPO Gounis et al, AJNR 2014, in press
MPO Gounis et al, AJNR 2014, in press Conclusions • Preliminary evidence that human aneurysms at risk of rupture are MPO+ • Optimized sequence can reduce flow signal and maintain T1 contrast in

22 aneurysm model • MR imaging of a m
aneurysm model • MR imaging of a model of inflamed aneurysms with MPO - specific contrast agent shows significant quantitative increase in SNR change (p001) Patient - Specific Hemodynamic Analysis

23 and Treatment Efficacy (Flow Diversio
and Treatment Efficacy (Flow Diversion) Flow Mechanics Flow driven by Δ P Momentum Transfer Fundamental Goal: Design technology that can disrupt momentum transfer into the aneurysm producin

24 g exclusion from the circulation without
g exclusion from the circulation without occluding perforators/ jailed vessels In a Word(s)… • BETTER – in situ tissue engineering The Observation Neuroradiology 1992, AJNR 1994, 1995 Step

25 1: Aneurysm Thrombosis • Patient -
1: Aneurysm Thrombosis • Patient - Specific Hemodynamics is ONE - THIRD of Aneurysm Thrombosis Hull and Harris, Circulation 2013 Step 2: Tissue Engineering Wakhloo et al. AJNR 1994 50% Metal

26 Coverage 32 pores per diamond 50% M
Coverage 32 pores per diamond 50% Metal Coverage 2 pores per diamond Porosity and Mesh Density Porosity = Mesh Density Change in Hemodynamics ? PRESSURE SHEAR RATE PRE - STENT

27 POST - STENT Aenis, Stancampiano,
POST - STENT Aenis, Stancampiano, Wakhloo, Lieber Ann Biomed Eng 1997 Courtesy of Matthieu De Beule, FEops Braid angle 115 ° 72 wires 72 wires Courtesy of Matthieu De Beule, FEops

28 Mean Circulation: Function of FD Desi
Mean Circulation: Function of FD Design - 350 - 300 - 250 - 200 - 150 - 100 - 50 0 50 100 200 300 400 500 Time [ms] Circulation [mm 2 /s] No Device Divertor A Divertor

29 B 600 Sadasivan and Lieber, Stroke
B 600 Sadasivan and Lieber, Stroke 2010 Seong, Lieber, Wakhloo. J Biomech Eng 2007 Mean Circulation: Function of FD Design Seong, Lieber, Wakhloo. J Biomech Eng 2007 After FD implantation DSA

30 - Based Intra - Aneurysmal Flow DSA
- Based Intra - Aneurysmal Flow DSA (60 fps) Average flow (projected cm/s) DSA (60 fps) Average flow (projected cm/s) 0 16 Average flow (projected cm/s) Baseline Time (s) Time (s) 10

31 20 30 40 50 60 70 80 90
20 30 40 50 60 70 80 90 100 Warped Vessel 20 40 60 80 100 1 2 3 4 5 Arterial axis (mm) 40 20 0 1 2 3

32 4 5 Velocities (cm/
4 5 Velocities (cm/s) 6 4 2 0 1 2 3 4 5 Volume flow (ml/s) Optical Flow Tracker Vessel diameter (3DRA) Contrast wave m

33 ap 2D - 3D Registration Time (s
ap 2D - 3D Registration Time (s) 3D reconstruction DSA V. Mendes Pereira et al., AJNR 35 (2014): 156 - 163 AJNR 2014 35: 156 - 163 Arterial axis (mm) Apposition – Assu

34 med! • All models assumed device app
med! • All models assumed device apposition to PV wall • Non - binned, small FOV CE - CBCT (VasoCT) Flood et al JNIS 2014 Summary • Powerful tools now exist for rapid analysis of patient -

35 GEOMETRY - specific hemodynamic analys
GEOMETRY - specific hemodynamic analysis • Role of local hemodynamics in BOTH aneurysm pathogenesis and treatment efficacy is necessary, but not sufficient • Future research toward coupling hem

36 odynamics, vascular biology, AND hemato
odynamics, vascular biology, AND hematology for holistic understanding of aneurysm pathophysiology and treatment – Ajay Wakhloo, MD, PhD – Ajit Puri, MD – Juyu Chueh, PhD – Martijn van

37 der Bom, PhD – Kajo van der Marel, P
der Bom, PhD – Kajo van der Marel, PhD – Anna Kühn, MD, PhD – Sam Y. Hou, MD, PhD – Bo Hong, MD – Mary Howk, MS, CRC – Thomas Flood, MD, PhD – Erin Langan, BS – Olivia Brooks

38 – Conrad Bzura, BS – Chris Brooks
– Conrad Bzura, BS – Chris Brooks, PA – Mary Perras, NP – Shaokuan Zheng, PhD – Miklos Marosfoi, MD NECStR • UMass Collaborations – Marc Fisher, MD – Neil Aronin, MD – Ale

39 xei Bogdanov, PhD – Greg Hendricks,
xei Bogdanov, PhD – Greg Hendricks, PhD – Guanping Gao, PhD – Miguel Esteves, PhD – Linda Ding, PhD – Srinivasan Vedantham, PhD – John Weaver, MD • Collaborations – Alex Norbas

40 h, MD – BU – Thanh Nguyen, MD
h, MD – BU – Thanh Nguyen, MD - BU – Italo Linfante, MD - Baptist – Guilherme Dabus, MD - Baptist – Don Ingber, PhD – Harvard – Johannes Boltze, MD, PhD – Frauhofer

41 Institute In - Vitro Sequence Optimiz
Institute In - Vitro Sequence Optimization Optimization of: • Velocity encoded gradient echo imaging parameter (VENC) to suppress slow flow • Fat - saturation (SPIR) Vascular replica VENC

42 = 5 cm/s VENC = 2 cm/s VENC = 1 cm/s
= 5 cm/s VENC = 2 cm/s VENC = 1 cm/s VENC = 1 cm/s, No SPIR W/ GdDTPA - filled balloon Gounis et al, AJNR 2014, in press In - Vivo Sequence Testing • Rabbit model with elastase - induced R

43 CCA aneurysm. • Respiratory trigger
CCA aneurysm. • Respiratory triggering led to TR = 5 s. • Inversion recovery (IR) pulse added to achieve T1 - sensitivity. • IR delay optimized to minimize aneurysm wall signal Gounis et al