First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction

Abstract

Background: Acute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization.

Objectives: This phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention.

Methods: Consenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period.

Results: Eight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline.

Conclusion: This pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.

Keywords: acute myocardial infarction; human pilot trial; intracoronary; intravenous; umbilical mesenchymal stem cell.

FIGURE 1

Study design and subject disposition. (A) Eligible patients who presented with first-ever ST elevation myocardial infarction (STEMI) were consecutively recruited. All of the subjects were hospitalized from the day of primary percutaneous coronary intervention (PCI), until the third day after IV infusion of UMSC01. IC infusion of UMSC01 was performed 4–5 days via the index culprit artery after successful revascularization. The day of IC infusion of UMSC01 was designed as Day 0 and IV infusion of UMSC01 was carried out on Day 2. After discharge, all subjects were followed up at 1, 3, 6, and 12 months for endpoint evaluation. (B) Between August 20, 2019, and August 2, 2020, we screened 10 patients with STEMI, of whom eight eligible patients provided written informed consent to participate in the clinical trial (NCT04056819). Two subjects withdrew consent during the follow-up period. Six subjects were followed up for the primary and secondary endpoints at 12 months. AE, adverse event; MACE, major adverse cardiovascular events; NT-pro-BNP, amino-terminal pro-brain natriuretic peptide.

FIGURE 2

Characterization of human umbilical cord-derived mesenchymal stem cells (UMSC01). (A) The clinical grade of UMSC01 was certified and identified by surface markers, which showed uniformly high expression (≥95%) of CD73, CD90, and CD105 but low expression (≤2%) of CD11b, CD34, CD45, CD19, and HLA-DR. (B) The potency assay for the capacity of in vitro differentiation into mesodermal lineages of adipocytes, chondrocytes, and osteocytes was confirmed by Oil-Red-O, Alcian-Blue and Alizarin-Red staining, respectively. Bar = 50 μm. CD, cluster of differentiation; HLA, human leukocyte antigen.

FIGURE 3

Comparison of NT pro-BNP levels between baseline and 12-month follow-up. (A) The serum level of NT pro-BNP of individual study patients shows a consistent declination pattern from baseline to 12-month follow-up. (B) The mean serum level of NT-proBNP decreased significantly at 12-month follow-up when compared to the value at baseline.

FIGURE 4

Regional left ventricular wall motion score (RLVWMS) and stroke volume evaluated by cardiac magnetic resonance imaging (CMRI). (A) The representative CMRIs of individual study patient at baseline and 12-month follow-up. The RLVWMS decreased (B) and the stroke volume increased (C) at 12-month follow-up compared to the baseline levels.