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 Surgery1 ,
Pediatrics2 , Regenerative Medicine, Center for
Innovative Clinical Medicine
AATS 95th Annual Meeting,Seattle,2015
COI Disclosure
The authors have no financial conflicts of interest to
disclose concerning the presentation.
Long-term clinical outcome of
hypoplastic left heart syndrome (HLHS)
Semin Thorac Cardiovasc Surg.
2007;19(3):238-44
European Journal of CardioThoracic Surgery 2014;46:465-473
Cardiac regenerative therapy in recent years
Non-Cardiac progenitors
2004
Cardiac progenitors
2008
2012
Bone marrow cells
Mesenchymal stem cells
TOPCARE-AMI trial
POSEIDON trial
Skeletal myoblasts
MAGIC trial
Cardiac progenitor cells
iPS cells
Direct
reprogramming
TICAP trial, PERSEUS trial
SCIPIO trial
CADUCEUS trial
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
Study design of TICAP phase 1 controlled trial
18 HLHS patients were
eligible and enrolled
▲
▲
1 exclude
Myocardial infarction
after surgery
▲
▲
7 received CDCs , completed
3-year follow-up study
8 were prospectively
assigned as control group
▲
▲
3 exclude after surgery
1 : pacemaker implantation
1 : bacterial contamination
1 :lung infection
▲
10 were constitutively allocated
to receive CDC
7 control patients completed
3-year follow-up study
Study timeline and procedures in this study
Catheter and
CDC infusion
tissue
harvesting
intracoronary
injection
Baseline characteristics in enrolled patients
Age at operation
(years)
Male sex
Body weight at
operation (kg)
Morphology (HLHS)
MA/AA
MS/AA
MA/AS
MS/AS
Variant
BNP (pg/ml)
Control
group (n=7)
CDC-treated
group (n=7)
P value
1.5 ± 1.7
2.1 ± 1.2
0.47
5 (71%)
6.8 ± 3.8
4 (57%)
9.2 ± 3.8
0.50
0.27
3 (43%)
1 (14%)
0
2 (29%)
1 (14%)
53.8 ± 27.3
3 (43%)
2 (29%)
1 (14%)
0
1 (14%)
53.1 ± 48.6
0.70
0.50
0.50
0.23
0.77
0.97
Baseline characteristics in enrolled patients
Control
CDC-treated P value
group (n=7) group (n=7)
Surgical characteristics
Norwood-Glenn
Bidirectional Glenn
1 (14%)
4 (57%)
1 (14%)
2 (29%)
TCPC
2 (29%)
4 (57%)
Concomitant procedures
None
3 (43%)
3 (43%)
Arch augmentation
1 (14%)
1 (14%)
Tricuspid valve repair
1 (14%)
1 (14%)
Atrial septectomy
1 (14%)
0
PA patch augmentation
1 (14%)
3 (43%)
CPB time (min)
100.3 ± 45.5 98.3 ± 49.1
ACC time (min)
58.3 ± 46.3 56.3 ± 40.6
0.77
0.29
0.29
0.70
0.77
0.77
0.50
0.28
0.94
0.93
Primary outcomes and adverse events
during 36-month follow-up
Adverse events
Late failure
NYHA class III-IV
PLE/plastic bronchitis
Takedown
Transplant
Death
Cardiopulmonary resuscitation
SVT
Pacemaker implantation
Prolonged chest tube drainage
Cirrhosis
Thromboembolic events
Stroke
Tumor formation
Control group
(n=7)
CDC-treated
group (n=7)
P value
2
1
1
0
0
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0.23
0.50
0.50
0.50
0.50
Adverse-event-free survival during
36-month follow-up
Incidence of catheter intervention during
36-month follow-up (N/person-year)
Any type of unplanned
catheter intervention
APC coils
Balloon angioplasty
Pulmonary artery
Aortic arch
Fenestration
Control
group (n=7)
1.43
CDC-treated
group (n=7)
0.52
P value
0.86
0.57
0.43
0.05
0.10
0.24
0.29
0.14
0.05
0.05
0.10
0.25
0.17
0.04
0.53
Freedom from catheter intervention
during 36-month follow-up
APC coil embolization
All interventions
Myocardial ischemia and tumor marker analyses
Tumor marker analyses at 36-month follow-up
Cardiac function analysis by cMRI
in CDC-treated and control patients
4040
3030
2020
1010
P=0.04
00
baseline
baseline
3636months
months
220
220
200
200
180
180
160
160
140
140
120
120
100
100
8080
6060
4040
2020
00
160
160
RVESVI on cMRI (mL/BSA1.3)
RVEDVI on cMRI (mL/BSA1.3)
RVEF on cMRI (%)
5050
RVESVI
RVEDVI
RVEF
P=0.09
baseline
baseline
months
3636months
140
140
120
120
100
100
8080
6060
4040
2020
P=0.07
00
baseline
baseline
3636months
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.
Cardiac function analysis by cMRI
during long-term follow-up
baseline
1 year
(+20%)
18 months
(+18%)
36 months
(+23%)
Ventricular stiffness and ventriculo-arterial
coupling at final follow-up
ventricular stiffness
Ea/Ees
Heart failure status and somatic growth
at 36-month follow-up
BNP
weight for age
Independent predictors of cardiac function
improvements of CDC infusion
age
weight for age
Stronger regenerative ability of cardiac stem cells
in young children
(BBRC, 2007)
(Circulation. 2012)
Independent predictors of cardiac function
improvements of CDC infusion
EF at baseline
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.
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
Thank you very much!
Hidemasa Oh
Shuta Ishigami
Suguru Tarui
Baseline characteristics of eligible patients in
CDC and control groups (n=34)
Age at operation (ys)
Male sex
Birth weight (g)
Body weight at operation (kg)
Anatomic diagnosis
Hypoplastic left heart syndrome
Non-HLHS
Moderate to severe TR
Ross score > grade III
BNP (pg/ml)
History of Catheter interventions
Type of surgical palliation
Second-stage palliation
Third stage palliation
Control groups
(n=17)
2.7 ± 1.5
11
29511± 414
10.5± 3.1
CDC-treated group
(n=17)
2.6 ± 1.2
8
2815 ± 384
10.3 ± 2.4
8
9
4
4
61.6 ± 59.7
13
6
11
4
4
61.9 ± 38.4
12
4
13
3
14
Cardiac function analysis in PERSEUS
randomized-controlled study
cardiac MRI
40 40
50
40
30 30
30
20 20
20
10 10
0 0
10
controls
CDCs
P=0.16
RVG
P=0.42
P=0.006
70 70
70
70 70
70
60 60
60
60 60
60
50 50
50
50 50
50
40 40
40
40 40
40
30 30
30
30 30
30
20 20
20
20 20
20
10 10
controls
10
CDCs
Ejection fraction on RVG (%)
Ejection fraction on cMRI (%)
50 50
P=0.02
Ejection fraction on UCG (%)
P=0.12
UCG
10 10
controls
10
P=0.005
CDCs
0 0
0
0 0
0
0
baseline
baseline 3 months
3 months
baseline
baseline 3 months
3 months
baseline
baseline 3 months
3 months
baseline
baseline 3 months
3 months
baseline
3 months
baseline 3 months
baseline 3 months
baseline
3 months