Rol van Multimodale Beeldvorming in de Ontwikkeling van Cardiale Therapieën

Transcription

1 Rol van Multimodale Beeldvorming in de Ontwikkeling van Cardiale Therapieën Stefan P. Janssens, MD, PhD Department of Cardiovascular Diseases Gasthuisberg University Hospital KU-Leuven, Belgium No disclosures Kortrijk, 5 december, 2012

2 Multimodal Cardiac Imaging in Therapeutic Innovation for Ischemic Heart Disease Multimodal imaging of interventions in acute and chronic MI spoilt for choice? Challenges for future development: an integrated approach for new therapies in the failing heart? Challenges in training the next generation cardiologists

3 Восстановление кровотока после ТЛТ Chazov EI et al. Ter Arkh. 1976;48:8 19.

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5 Clinical Outcome in Acute and Chronic Ischemic Cardiomyopathy (%) VALIANT study (14,703 post-mi pts EF<35%, clin CHF) (%) 26% Bed rest Defibrill HD monitor ΒB GISSI-1 Con n= % over 20 years ASSENT-4 Prim PCI APEX-MI Control n=838 n= % Pre-CCU CCU Reperfusion Era 2006 Early Mortality in trials vs Real World experience! 1 y mortality 1 y death, re-mi, CHF rehosp Pfeffer et al. NEJM 2003

6 Critical Determinants for Post-infarction Myocardial Repair Biologicals? Drugs? Devices? Imaging modality? - Clot busters - Time = muscle

7 Surrogate Endpoints to Evaluate Innovative Cardiac Therapy? CRT biologicals Cell/gene transfer Surrogate Endpoints Perfusion Infarct / LV - Metabolism - remodeling Efficiency - PET - IC Doppler - MRI - SPECT, CT - MRI - MSCT - TTE/TDI - SPECT - PET - SPECT - stress / VO 2 - Cell Engraftment Contraction - MRI - Angio / MSCT - TTE/TDI/DSE - SPECT - PET, MRI

8 Improvements in LV Function analysis using MRI? 2D multi-breath-hold => single 3D breath-hold Definition of LA-LV boundary Endo- / Epicardial border delineation

9 Global LV Function and LV Remodeling 4 days 4 months 1 year

10 Endogenous Cardiac Repair after Myocardial Infarction How does infarcted myocardium remodel and change LV function over time? Baseline 4-6 mo mo Leuven Boost (g) Leuven ESV -Boost (ml/m2) -Leuven EDV -Boost (ml/m2) -Leuven EF -Boost (%) IS 5 years

11 Beyond TIMI-3 Flow Time-dependent Open Vessel Hypothesis Epicardial Flow Microvascular Flow Epicardial Flow Myocyte

12 Beyond Corrected Reperfusion of Epicardial Coronary Arteries Microvascular Flow Epicardial Flow Epicardial Flow

13 T2w-STIR-SE AAR Different Tissue Characteristics of MI based on MRI (T2-STIR & CE) Non MVO Infarct MVO Infarct Hemorrhagic Infarct CE-IR MRI ΔMRI (0-12 mo) EF, EDV= EF=, EDV EF, EDV Bogaert J & Janssens S, Eur Radiol 2007, EHJ 2009, Circ 2010

14 Ischemia Severity Determines Functional and Structural Remodeling in Reperfused STEMI ΔLV-EF (%) ΔVol (ml) Grade 2 Ischemia n=74 Grade 3 Ischemia n=64 + 4% ** 55 * 51 * ** Grade 2 (14% LV mass) Grade 3 (23% LV mass) EDV Grade 2 Grade 3 ESV Grade 2 Grade 3

15 LV Remodeling a.er Myocardial Infarc5on LVEDVi (ml/m 2 ) LVESVi (ml/m 2 ) Grade 2 Grade 3 Grade 2 Grade ** 20 * 0 0 baseline month 4 baseline month 4 baseline month 4 baseline month 4 Grade 2 Grade 3 P- value LVEF at baseline (%) 51±8 47± LVEF at 4 mo (%) 54±9 49± *** P<0.001 **P=0.002 *P=0.025

16 Infarct Size Determines Global and Regional Functional Recovery in Reperfused STEMI Change in LV-EF (%) Δ+ 3% P=0.003 SWT (%) Infarct P=0.01 Border P=0.003 Infarct Border P=NS P=NS P=NS Small Infarcts Large Infarcts (<17% LV mass) (>17% LV mass) n=29 n=29 Small Infarcts (<17% LV mass) n=29 Large Infarcts (>17% LV mass) n=29

17 Structure Function Analysis in Ischemic Cardiomyopathy Ischemia Necrosis I/R Remodeling Novel Therapies? Novel Therapies? Functional improvement Cardiac Protection - CMC dysfunction - apoptosis - CMC oxidant stress - inflammation - CMC perfusion - metabolism Cardiac Regeneration Infarct Healing - Biologicals? - AMTPs?

18 CLINICAL TRIALS in acute MI Study Design Patients Follow-Up Primary End Point Imaging Modality TOPCARE-AMI RCT 20 4 LVEF LV angiography Strauer et al NonRCT 20 3 LVEF LV angiography Bartunek et al NonRCT 35 4 Safety, LVEF LV angio, mibi-spect LEUVEN-AMI RCT LVEF +1.2% MRI BOOST RCT Safety, LVEF +2.8% MRI Zhan-Quan et al NonRCT 70 6 LVEF, LV volumes, WMSI Echocardiography MAGIC CELL3-DES NonRCT 56 6 LVEF MRI TCT-STAMI RCT 20 6 LVEF Echo, 201Tl-SPECT ASTAMI RCT LVEF +0.6% 99mTc-SPECT, MRI, echo REPAIR-AMI RCT LVEF +2.5% LV angiography Meluzin et al RCT Infarct zone systolic function sestamibi SPECT/FDG PET FINCELL RCT 80 6 LVEF LV angio, echo BALANCE NonRCT LVEF LV angiography MRI is the current «gold standard» for cardiac cell therapy REGENT RCT LVEF +3.0% MRI in AMI MYSTAR RCT 60 3 infarct size, LVEF 99m-Sestamibi-SPECT HEBE RCT Regional systolic function MRI Cao et al RCT LVEF Echo,, mibi-spect PROVACEL RCT 53 6 LVEF Echo, MRI Abdel-Latif et al, JACC 2007; 50: 1761; Janssens, Annu. Rev. Med :

19 Meta-Analysis: LV Ejection Fraction (n=499 BMC, n=477 Controls) Pooled difference 3.66% 95% CI [1.93% to 5.40%] P<0.001 ESV: ml 95% CI [-8.2 to ml] P=0.006 Infarct size: % 95% CI [-9.1 to %] P=0.003 Copyright restrictions may apply." Abdel-Latif, A. et al. Arch Intern Med 2007;167:

20 LV Remodeling and Infarct Wall Thickness Reduction after MI Change in EDVi (%) Reduction in Infarct WT (%) If SC transfer induces cardiomyogenesis, an effect on LV remodeling would be expected. % of akinesis-dyskinesis Infarct size (% LV mass) (R. McKay, Circulation 1986)

21 Meta-Analysis: LV End-diastolic Volume (n=499 BMC, n=477 Controls) Pooled difference -1.9 ml (P=NS) Copyright restrictions may apply." Abdel-Latif, A. et al. Arch Intern Med 2007;167:

22 Multimodal Cardiac Imaging in Therapeutic Innovation for Ischemic Heart Disease Multimodal imaging of interventions in acute and chronic MI spoilt for choice? Challenges for future development: an integrated approach for new therapies in the failing heart? Challenges in training the next generation cardiologists

23 Wall Motion Score Index and Ejection Fraction for Risk Stratification after AMI Predictors of mortality (forward Cox PHA) HR P Age (per 10y) 1.65 <.0001 Kilip Class 1.44 <.0001 (per 1 increase) WMSI 1.15 <.0001 (per 0.2 increase) (Moller et al. Am Heart J 2006;151:419-25)

24 Powerful Technology to Detect Biological Signals: MRI and TDI Analysis Infarct Transmurality & Segmental Contraction LV Coronary occlusion 20 min 60 min 3h >6h 0 AVO Baseline Strain Septum (%) AVC base! mid! apex! 0" AVO Strain Septum 4 months (%) AVC " " -30" " Time (ms)

25 BMC-mediated Functional Repair: Improved Regional Contraction in Dysfunctional Segments Improved contraction (%) P<0.05 for interaction * ES Strain (%) -20 Infarcted segments (n=232) Control BMSC 40 * -15 *** *** CONTROL BMC 0 Baseline 5 d 2 mo 4 mo 1 yr Lancet 2006; 367: Eur Heart J 2009; 30:662-70

26 BONAMI Trial SPECT myocardial viability at baseline and 3 mo after AMI n=101 post AMI LVEF <45% Reduced viability (resting Tl201-SPECT) Roncalli J et al. Eur Heart J 2011;32:

27 Will Intracoronary Infusion of BM-derived progenitor cells prolong the time to first occurrence of all-cause death in pts with reduced LVEF after successful reperfusion for AMI? Study design Central Reading TTE (EF 45%) Group 1: Control Baseline 3-5 d observation Randomisation 1:1 = day 0 N=1500 N=1500 N=3, IC BMC Infusion day 1,2,3 3 FU at day 30 Q 3 mo Telephone FU All-cause death N= mo. STEMI undergoing PCI within 24h EF >45% Group 2: BM- MNC N=1500 % drop-outs prior to randomization % drop-outs prior to final analysis

28 Multimodal Cardiac Imaging in Therapeutic Innovation for Ischemic Heart Disease Multimodal imaging of interventions in acute and chronic MI spoilt for choice? Challenges for future development: an integrated approach for new therapies in the failing heart? Challenges in training the next generation cardiologists

29 Netwerking Dienst Hart- en Vaatziekten Netwerk ZH, CME CAH KUL doctoral school Congenitale hartaandoeningen bij volwassenen Elektrofysiologie VMS portfolio Imaging Engineers IT, ARO support Klin. epidemiologie Ischemische valvulaire CMP Coagulopathieën HF - HTX Netwerk ZH, CME Radiologie, Nucl. gk CAH CME, LAG Netwerk ZH CAH CME, LAG Netwerk ZH

30 Cardiovascular Imaging Training Doelstelling: aanbieden van geintegreerde, multimodale imaging opleiding tijdens cardiologie curriculum en bevorderen van CV kwaliteitszorg TTE Duplex vasc MRI/MSCT SPECT/PET Level 3 Training Level 1 Training Beoogde realisatie: - level 1 training en accreditering Planning: - integratie ManaMa - proefproject academiejaar 2012 Randvoorwaarden: - ondersteuning radiologie en nucleaire gk - gemeenschappelijke projecten