Cardiomyopathy
An Approach That Brings Out the Potential of Regenerative Therapies in Heart Failure
2023 Volume 87 Issue 4 Pages 487-489
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2023 Volume 87 Issue 4 Pages 487-489
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.
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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.5–7 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).8–13 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.
| Study name | Phase | Cell type | Cell numbers transplanted |
Delivery route |
Patient population |
Sample size (n) |
Follow-up (months) |
Key findings | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| LVEF LV volumes |
Infarct/scar size |
QOL | Other | ||||||||
| MAGIC (2008)13 | II (multi-center, double-blind) |
Skeletal myoblasts | 40–80×107 | Endomyocardial | ICM with CABG indicated LVEF 15–35% NYHA class l–III |
97 | 6 | NS Improved (high dose) |
NS | – | Time to first MACE NS Time to first ventricular arrhythmia NS |
| CAuSMIC (2009)12 | I (single-center, open-label) |
Skeletal myoblasts | 3–60×107 | Endomyocardial | ICM LVEF ≤40% NYHA class ll–lV |
23 | 12 | – NS |
– | NYHA class improved MLHFQ improved |
Arrhythmia NS |
| SEISMIC (2011)11 | IIa (multi-center, open-label) |
Skeletal myoblasts | 15–80×107 | Endomyocardial | ICM LVEF 20–45% NYHA class ll–lll |
40 | 6 | NS – |
– | NYHA class NS MLHFQ NS 6MWT NS |
SAE NS |
| MARVEL-1 (2011)10 | IIb/III (multi-center, double-blind) |
Skeletal myoblasts | 40–80×107 | Endomyocardial | ICM LVEF <35% NYHA class ll–IV |
20 | 6 | – – |
– | 6MWT NS MLHFQ NS |
VT NS |
| Sawa et al (2015)8 | II (multi-center, single-arm, open-label) |
Skeletal myoblast sheets |
30×107 | Epicardial | ICM LVEF ≤35% NYHA class lll–IV |
7 | 6 | Improved Improved (vs. baseline) |
– | NYHA class improved 6MWT improved (vs. baseline) |
No serious arrhythmia related to study drug |
| Gwizdala et al (2017)9 | I (single-center, 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 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.
