Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
An Approach That Brings Out the Potential of Regenerative Therapies in Heart Failure
Yoshikazu KishinoShugo Tohyama
Author information
JOURNAL OPEN ACCESS FULL-TEXT HTML Advance online publication

Article ID: CJ-22-0781


Despite medical progress,1 endstage heart failure (HF) is a substantial contributor to the global burden of cardiovascular disease.2,3 Heart transplantation (HT) is the only radical treatment available today, but in Japan, a severe shortage of donor hearts limits the availability of HT as a therapeutic option. Currently, less than 100 patients have undergone HT, and the waiting period to register for transplantation is approximately 1,500 days.4 Given this scenario, cell therapies are expected to be an ideal therapeutic option to fill this unmet need.

Article p ????

Over the past 2–3 decades, HF cell therapies have been investigated using various cell types; for example, skeletal myoblasts, unfractionated mononuclear bone marrow cells, mesenchymal stromal cells (derived from bone marrow, umbilical cord, and adipose tissue), c-kit positive cardiac cells, CD34+ cells (released from the bone marrow and isolated from peripheral blood), pluripotent stem cells, chimeric antigen receptor T cells, and cardiosphere-derived cells.57 Of these cells, skeletal myoblasts are an easily accessible source of autologous precursor cells committed to a myogenic, functionally contractile phenotype. Myoblasts are resistant to ischemia, inflammation, and oxidative stress, and are able to form new myotubes within damaged myocardium. Moreover, the cell population releases paracrine factors that exert an antifibrotic effect and enhance cardiac performance and myocardial perfusion by stimulating local angiogenesis and establishing functionally and structurally mature arterial vascular networks. To date, several clinical studies have examined autologous myoblast-based cell therapies (Table).813 In the field of regenerative therapy, general statistical analysis of low event rates has been difficult to date because of low enrollment numbers and ethical issues. Previous clinical studies of myoblasts include several single-arm studies; as enrollment numbers were too small to detect a small number of clinically significant events, these were limited to validating effects on left ventricular function and quality of life. Furthermore, their efficacy results were heterogeneous and modest.

Table. Clinical Trials of Autologous Myoblast-Based Cell Therapies for the Treatment of Heart Failure
Study name Phase Cell type Cell numbers
size (n)
Key findings
LV volumes
QOL Other
MAGIC (2008)13 II
Skeletal myoblasts 40–80×107 Endomyocardial ICM with CABG indicated
LVEF 15–35%
NYHA class l–III
97 6 NS
(high dose)
NS Time to first MACE NS
Time to first ventricular
arrhythmia NS
CAuSMIC (2009)12 I
Skeletal myoblasts 3–60×107 Endomyocardial ICM
LVEF ≤40%
NYHA class ll–lV
23 12
NYHA class improved
MLHFQ improved
Arrhythmia NS
SEISMIC (2011)11 IIa
Skeletal myoblasts 15–80×107 Endomyocardial ICM
LVEF 20–45%
NYHA class ll–lll
40 6 NS
NYHA class NS
MARVEL-1 (2011)10 IIb/III
Skeletal myoblasts 40–80×107 Endomyocardial ICM
LVEF <35%
NYHA class ll–IV
20 6
Sawa et al (2015)8 II
single-arm, open-label)
Skeletal myoblast
30×107 Epicardial ICM
LVEF ≤35%
NYHA class lll–IV
7 6 Improved
(vs. baseline)
NYHA class improved
6MWT improved
(vs. baseline)
No serious arrhythmia
related to study drug
Gwizdala et al (2017)9 I
single-arm, open-label)
Cx-43 modified
skeletal muscle
derived stem cells
1×107 Endomyocardial ICM or NICM
LVEF ≤40%
NYHA class lI–IV
13 6 NS
(vs. baseline)
NYHA class improved
(vs. baseline)
One Cx43(−) subject suffered
from sustained VT required
ICD and amiodarone

−, not measured/reported; 6MWT, 6-minute walk test; CABG, coronary artery bypass grafting; Cx, connexin; EF, ejection fraction; ICD, implantable cardioverter defibrillator; ICM, ischemic cardiomyopathy; LV, left ventricular; MACE, major adverse cardiac events; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NICM, non-ischemic cardiomyopathy; NS, not statistically significant relative to comparator; NYHA, New York Heart Association; QOL, quality of life; SAE, severe adverse event; VT, ventricular tachycardia.

In this issue of the Journal, Miyagawa et al14 focused on restricted mean survival time (RMST) analysis as a breakthrough alternative method. RMST is a well-established yet underutilized analytical procedure that can be interpreted as the average event-free survival time up to a prespecified, clinically important time point.15 Graphically, it corresponds to the area under the Kaplan-Meier curve from the beginning of the study until the chosen time point. The RMST difference means gain or loss in the event-free survival time in the treatment vs. control groups during this period. Miyagawa et al used this method to verify the clinical effects of regenerative therapy by comparing data from a small single-arm trial (55 patients) to epidemiological data from a registry (937 participants).14 RMST analyses revealed that survival was significantly improved at 3 years (P=0.008) and 3.5 years (P=0.024) in the autologous myoblast patch (AMP) group than in the control group, whereas traditional Cox regression analyses revealed nonsignificant differences in survival between the 2 groups. Additionally, all-cause death in the AMP group was 45% lower than in the control group. This finding is impressive because the relative mean lost time (RMLT) ratio was 0.55 (AMP/control 0.21/0.38, 95% confidence interval 0.14–1.01) at 4 years after treatment. These results are useful and informative in the following ways: (1) the study is the first to show the efficacy of myoblast therapy on survival, although the difference in endpoint definitions between the groups should be taken into consideration; and (2) RMST analysis can show an early suppression effect on a few hard endpoints, likely due to the paracrine effect, which is undetected by traditional hazard ratio analyses.

Taken together, past research and the present study indicate that novel analysis methods, such as RMST, can facilitate clinical research on innovative technologies, including regenerative medicine, and help deliver treatments to patients suffering from intractable or rare diseases as quickly as possible. Further research is required to standardize the evidence and establish the utilization of cell therapy for HF in clinical practice.


S.T. is an advisor at Heartseed, Inc., and owns equity in Heartseed, Inc. Y.K. declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This article is licensed under a Creative Commons [Attribution-NonCommercial-NoDerivatives 4.0 International] license.