OU-MRU Vol.5 Jan 2015

Okayama University Medical Research Updates （OU-MRU）
Source: Okayama University, Center for Public Information
For immediate release: 28 January 2015
Okayama University research: Cell injections get to the heart of congenital defects(Okayama, 28 January 2015) Researchers at Okayama University and Okayama University
Hospital show that children suffering from a condition known as hypoplastic left heart
syndrome (HLHS) experienced some improvement in cardiac function in the months
following injection of CDCs.
Children suffering from a lethal congenital heart defect may benefit from injections of atype of stem cells – cardiosphere-derived cells (CDCs). A study conducted by researchers atOkayama University and Okayama University Hospital showed that children suffering from acondition known as hypoplastic left heart syndrome (HLHS) experienced some improvementin cardiac function in the months following injection of CDCs.
The left ventricle, aorta and related valvular components in the hearts of HLHS patients areunderdeveloped, with not enough cells being produced. Children born with the condition
may die if they do not receive immediate medical attention. They require surgery within afew days of birth and additional treatment is needed long-term to deal with the rightventricular-dependent circulation.
Previous studies had suggested that loss of a type of stem cell – progenitor cells which candifferentiate into a range of other cells – is responsible for lower replication of the heart
muscle cells. In their report of the research the Okayama researchers highlight that cardiac
progenitor cells in children are “more abundant, self-renewing, and multipotent than thosefound in adults,” and propose their use as a safe therapeutic strategy for patients with heart
failure.
The researchers monitored the heart functions in both a group of 7 patients that hadreceived cell injection and a control group of 7 patients who had not. As they conclude, “Ourprospective controlled study, the first paediatric phase 1 clinical trial of stem cell therapy forheart disease to our knowledge, suggests that intracoronary infusion of autologous cardiac
progenitor cells is a feasible and safe approach to treat children with HLHS.”
Background
Cardiosphere-derived cells
Tissue-specific stem progenitor cells can be found in the adult mammalian heart. Whencloned in suspension they form cardiospheres. The patient-derived CDCs used in the study
were tested prior to use to confirm expression of cardiac transcription factors and normal
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OU-MRU Vol.5 Jan 2015

chromosomes to avoid tumour formation after injection. Transcoronoray Injection was
successfully achieved in all patients with no adverse effects.
Cardiac function monitoring
The heart functions monitored by the researchers included right ventricular ejection fraction(RVEF), end-systolic volume (volume of blood at the maximum contraction point, ESV), andend-diastolic volume (volume of blood when at the maximum filling point, EDV), strokevolume and cardiac output. In addition the levels a type of peptide - brain natriuretic
peptide (BNP) were monitored. These peptides are secreted by the ventricles of the heart in
response to excessive stretching of the heart muscle cells.
Many of the parameters measured showed improvements in the group that had received
CDCs. In particular RVEF levels improved from 36.1 ± 7.5% at baseline to 42.7% ± 8.7% at 12
months. BNP levels were decreased 18 months after CDC injection compared with controls((26.3 ± 28.5 pg/mL vs. 68.6 ± 42.4 pg/mL).
The researchers associated the decrease in heart failure status in CDC-treated patients withthe decrease in BNP levels 18 months after CDC compared with the controls. In addition,right ventricular wall masses had decreased significantly and tissue growth was improved
suggesting long term benefits 3-18m months after CDC injection.
Study conclusions and limitations
Due to the rarity of the disease and the difficulty in recruiting a sample population the study
was small and non-randomized. With groups of just 7 patients the size of the study may
limit the ability to draw definite conclusions as to the safety and effectiveness of the using
CDC injections to treat HLHS patients. However the improved RVEP 18 months after CDC
CDC injection provides a positive proof of concept for the treatment.
Further studies are required to endorse the results. In addition the cell biologicalmechanisms for enhancing cardiac function are still not understood and a prognostic celltracking system may be required as new translational medicine for children.
Acknowledgments
We are indebted to the patients, the parents of the patients who gave their consent toparticipate in this trial, and the staff of the cardiac care unit and the catheterizationlaboratory at Okayama University Hospital.
This study was supported by grants from the Ministry of Health, Labour and Welfare (to HO),the Ministry of Education, Culture, Sports, Science and Technology (to HO), and theResearch Foundation of Okayama University Hospital (to SS and HO). The study funding
source had no role in study design, data collection, data analysis and interpretation, or inthe preparation of the manuscript.
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OU-MRU Vol.5 Jan 2015ReferenceShuta Ishigami, Shinichi Ohtsuki, Suguru Tarui, Daiki Ousaka, Takahiro Eitoku, Maiko Kondo,
Michihiro Okuyama, Junko Kobayashi, Kenji Baba, Sadahiko Arai, Takuya Kawabata, Ko
Yoshizumi, Atsushi Tateishi, Yosuke Kuroko, Tatsuo Iwasaki, Shuhei Sato, Shingo Kasahara,Shunji Sano and Hidemasa Oh “Intracoronary autologous cardiac progenitor cell transfer inpatients with hypoplastic left heart syndrome (TICAP): A prospective phase 1 controlledtrial” Circulation Research, (2015)
DOI: 10.1161/CIRCRESAHA.116.304671

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OU-MRU Vol.5 Jan 2015

Figure 1. Angiographic images of transcoronary infusion of CDCs into children with HLHS.
(A) Primary coronary angiography was performed prior to the CDC infusion. A 5 French
guiding catheter Launcher (Medtronic) was placed in the hypoplastic ascending aorta, which
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1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530 Japan© OKAYAMA University

OU-MRU Vol.5 Jan 2015

was connected to the newly reconstructed aortic arch by the Norwood procedure. SelectiveCDC transfer was performed into right (B), left ascending (C), and left circumferential (D)coronary arteries by a stop-flow technique (arrows). (E) Hand injection of contrast medium
demonstrates that the coronary arteries were unobstructed after CDC infusion.

Correspondence toProfessor Hidemasa Oh, M.D., Ph.D.
Department of Regenerative Medicine, Center for
Innovative Clinical Medicine, Okayama University
Hospital, Shikata-cho 2-5-1, Okayama city,Okayama 700-8558, Japan
E-mail: hidemasa@md.okayama-u.ac.jp

Further information
Okayama University
1-1-1 Tsushima-naka , Kita-ku , Okayama 700-8530, Japan
Planning and Public Information Division, Okayama University
E-mail: www-adm@adm.okayama-u.ac.jp
Website: http://www.okayama-u.ac.jp/index_e.html
Okayama Univ. e-Bulletin：http://www.okayama-u.ac.jp/user/kouhou/ebulletin/

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OU-MRU Vol.5 Jan 2015

Okayama University Medical Research Updates （OU-MRU）
Vol.1：Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells
from blood samples for genetic testing
Vol.2：Ensuring a cool recovery from cardiac arrest
Vol.3：Organ regeneration research leaps forward
Vol.4：Cardiac mechanosensitive integrator

About Okayama University
Okayama University is one of the largest
comprehensive universities in Japan withroots going back to the Medical Training
Place sponsored by the Lord of Okayama
and established in 1870. Now with 1,300
faculty and 14,000 students, the University
offers courses in specialties ranging frommedicine and pharmacy to humanities
and physical sciences. Okayama
University is located in the heart of Japan
approximately 3 hours west of Tokyo byShinkansen.

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