Transcoronary Infusion of Cardiac Progenitor Cells in Hypoplastic Left Heart Syndrome: 3-year Follow-up of the TICAP Trial

Transcription

1 Transcoronary Infusion of Cardiac Progenitor Cells in Hypoplastic Left Heart Syndrome: 3-year Follow-up of the TICAP Trial Shunji Sano, Shuta Ishigami, Takuya Goto, Daiki Ousaka, Suguru Tarui, Michihiro Okuyama, Sadahiko Arai, Kenji Baba, Shingo Kasahara, Shinichi Ohtsuki, Hidemasa Oh Okayama University, Okayama, Japan Department of Cardiovascular Surgery 1, Pediatrics 2, Regenerative Medicine, Center for Innovative Clinical Medicine AATS 95 th Annual Meeting,Seattle,2015

2 COI Disclosure The authors have no financial conflicts of interest to disclose concerning the presentation.

3 Long-term clinical outcome of hypoplastic left heart syndrome (HLHS) Semin Thorac Cardiovasc Surg. 2007;19(3): European Journal of Cardio- Thoracic Surgery 2014;46:

4 Cardiac regenerative therapy in recent years Non-Cardiac progenitors Cardiac progenitors Bone marrow cells Mesenchymal stem cells ips cells TOPCARE-AMI trial POSEIDON trial Skeletal myoblasts Cardiac progenitor cells Direct reprogramming MAGIC trial TICAP trial, PERSEUS trial SCIPIO trial CADUCEUS trial

5 TICAP (Transcoronary Infusion of CArdiac Progenitor cells) trial (Phase I) CDCs Objective The purpose of this clinical trial is to evaluate the feasibility and safety of cardiosphere-derived cell (CDC) infusion in children with HLHS. PERSEUS trial (Phase II) randomized study

6 Study design of TICAP phase 1 controlled trial 18 HLHS patients were eligible and enrolled 10 were constitutively allocated to receive CDC 3 exclude after surgery 1 : pacemaker implantation 1 : bacterial contamination 1 :lung infection 7 received CDCs, completed 3-year follow-up study 8 were prospectively assigned as control group 1 exclude Myocardial infarction after surgery 7 control patients completed 3-year follow-up study

7 Study timeline and procedures in this study Catheter and CDC infusion tissue harvesting intracoronary injection

8 Baseline characteristics in enrolled patients Control group (n=7) CDC-treated group (n=7) P value Age at operation 1.5 ± ± (years) Male sex 5 (71%) 4 (57%) 0.50 Body weight at 6.8 ± ± operation (kg) Morphology (HLHS) MA/AA 3 (43%) 3 (43%) 0.70 MS/AA 1 (14%) 2 (29%) 0.50 MA/AS 0 1 (14%) 0.50 MS/AS 2 (29%) Variant 1 (14%) 1 (14%) 0.77 BNP (pg/ml) 53.8 ± ±

9 Baseline characteristics in enrolled patients Control group (n=7) CDC-treated group (n=7) P value Surgical characteristics Norwood-Glenn 1 (14%) 1 (14%) 0.77 Bidirectional Glenn 4 (57%) 2 (29%) 0.29 TCPC 2 (29%) 4 (57%) 0.29 Concomitant procedures None 3 (43%) 3 (43%) 0.70 Arch augmentation 1 (14%) 1 (14%) 0.77 Tricuspid valve repair 1 (14%) 1 (14%) 0.77 Atrial septectomy 1 (14%) PA patch augmentation 1 (14%) 3 (43%) 0.28 CPB time (min) ± ± ACC time (min) 58.3 ± ±

10 Primary outcomes and adverse events during 36-month follow-up Control group (n=7) CDC-treated group (n=7) P value Adverse events Late failure NYHA class III-IV PLE/plastic bronchitis Takedown 0 0 Transplant 0 0 Death 0 0 Cardiopulmonary resuscitation SVT 0 0 Pacemaker implantation 0 0 Prolonged chest tube drainage Cirrhosis 0 0 Thromboembolic events 0 0 Stroke 0 0 Tumor formation 0 0

11 Adverse-event-free survival during 36-month follow-up

12 Incidence of catheter intervention during 36-month follow-up (N/person-year) Control CDC-treated P value group (n=7) group (n=7) Any type of unplanned catheter intervention APC coils Balloon angioplasty Pulmonary artery Aortic arch Fenestration

13 Freedom from catheter intervention during 36-month follow-up APC coil embolization All interventions

14 Myocardial ischemia and tumor marker analyses Tumor marker analyses at 36-month follow-up

15 RVEF on cmri (%) RVEDVI on cmri (ml/bsa 1.3 ) RVESVI on cmri (ml/bsa 1.3 ) Cardiac function analysis by cmri in CDC-treated and control patients RVEF RVEDVI RVESVI P=0.04 baseline months P=0.09 baseline months P=0.07 baseline months Between-group (control vs. CDC treated) comparisons, 2-way ANOVA was used to analyze the categorical independent variables between group and the time interaction term within group.

16 Cardiac function analysis by cmri during long-term follow-up baseline 1 year (+20%) 18 months (+18%) 36 months (+23%)

17 Ventricular stiffness and ventriculo-arterial coupling at final follow-up ventricular stiffness Ea/Ees

18 Heart failure status and somatic growth at 36-month follow-up BNP weight for age

19 Independent predictors of cardiac function improvements of CDC infusion age weight for age

20 Stronger regenerative ability of cardiac stem cells in young children (BBRC, 2007) (Circulation. 2012)

21 Independent predictors of cardiac function improvements of CDC infusion EF at baseline

22 Conclusions 1. Intracoronary infusion of autologous CDCs is feasible and safe to treat the children with hypoplastic left heart syndrome. 2. Improved ventricular function was maintained during 36 months of observation, which resulted in improvement of heart failure status in long term. 3. A phase 2(PERSEUS) trial is ongoing in our hospital to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes.

23 PERSEUS trial (n=34) Randomized assignment of patients 41 met initial eligibility criteria 7 excluded PERSEUS trial (n=34) 34 randomly assigned (1:1) 17 controls patients 17 CDCs-treated patients 5 pending analysis 17 control patients with 3-month F/U 12 CDCs-treated patients with 3-month F/U

24 Thank you very much! Hidemasa Oh Shuta Ishigami Suguru Tarui

25 Baseline characteristics of eligible patients in CDC and control groups (n=34) Control groups CDC-treated group (n=17) (n=17) Age at operation (ys) 2.7 ± ± 1.2 Male sex 11 8 Birth weight (g) 29511± ± 384 Body weight at operation (kg) 10.5± ± 2.4 Anatomic diagnosis Hypoplastic left heart syndrome 8 6 Non-HLHS 9 11 Moderate to severe TR 4 4 Ross score > grade III 4 4 BNP (pg/ml) 61.6 ± ± 38.4 History of Catheter interventions Type of surgical palliation Second-stage palliation 4 3 Third stage palliation 13 14

26 Ejection fraction on cmri (%) Ejection fraction on UCG (%) Ejection fraction on RVG (%) Cardiac function analysis in PERSEUS randomized-controlled study cardiac MRI UCG RVG P=0.12 P=0.02 P=0.16 P=0.006 P=0.42 P= controls CDCs controls 10 CDCs controls 10 CDCs baseline 3 months 3 baseline 3 months 3 months 0 0 baseline 3 months 3 baseline 3 months baseline 3 months 3 baseline 3 months 3