Int J Stem Cells.  2020 Nov;13(3):364-376. 10.15283/ijsc20075.

Intramyocardial Transplantation of Umbilical Cord Mesenchymal Stromal Cells in Chronic Ischemic Cardiomyopathy: A Controlled, Randomized Clinical Trial (HUC-HEART Trial)

• Ulus AT
• Mungan C
• Kurtoglu M
• Celikkan FT
• Akyol M
• Sucu M
• Toru M
• Gul SS
• Cinar O
• Can A

• KMID: 2508910
• DOI: http://doi.org/10.15283/ijsc20075

Abstract

Background and Objectives
The HUC-HEART Trial (ClinicalTrials.gov Identifier: NCT02323477) was a controlled, prospective, phase I/II, multicenter, single-blind, three-arm randomized study of intramyocardial delivery of human umbilical cord-derived mesenchymal stromal cells (HUC-MSCs) combined with coronary artery bypass-grafting (CABG) in patients with chronic ischemic cardiomyopathy (CIC). The trial aimed to assess (i) the safety and the efficacy of cell transplantation during one-year follow-up, (ii) to compare the efficacy of HUC-MSCs with autologous bone-marrow- derived mononuclear cells (BM-MNCs) in the same clinical settings.
Methods and Results
Fifty-four patients who were randomized to receive HUC-MSCs (23×10⁶) (n=26) or BM-MNCs (70×10⁷) (n=12) in combination with CABG surgery. The control patients (n=16) received no cells/vehicles but CABG intervention. All patients were screened at baseline and 1, 3, 6, 12 months after transplantation. Forty-six (85%) patients completed 12 months follow-up. No short/mid-term adverse events were encountered. Decline in NT-proBNP (baseline∼ 6 months) in both cell-treated groups; an increase in left ventricular ejection fraction (LVEF) (5.4%) and stroke volume (19.7%) were noted (baseline∼6 or 12 months) only in the HUC-MSC group. Decreases were also detected in necrotic myocardium as 2.3% in the control, 4.5% in BM-MNC, and 7.7% in the HUC-MSC groups. The 6-min walking test revealed an increase in the control (14.4%) and HUC-MSC (23.1%) groups.
Conclusions
Significant findings directly related to the intramyocardial delivery of HUC-MSCs justified their efficacy in CIC. Stricter patient selection criteria with precisely aligned cell dose and delivery intervals, rigorous follow-up by detailed diagnostic approaches would further help to clarify the responsiveness to the therapy.

Keyword

Bone marrow MSC; Clinical trial; Ischemic cardiomyopathy; Stem cell therapy; Umbilical cord MSC

Figure

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  Fig. 1 (A) Subject throughput from enrollment (n=73) to data analysis (n=46). (B) A patient follow-up chart. BM-MNC: bone marrow mononuclear cells, HUC-MSC: human umbilical cord mesenchymal stromal cells, MI: myocardial infarction, CABG: coronary artery bypass grafting, ▲: cardiac evaluation including electrocardiography (ECG); echocardiography (Echo); Holter rhythm monitoring; 6-min walking test; cardiac enzymes (CK-MB, LDH, troponin I); 27-parameter blood tests, including complete blood count; 22-parameters biochemical tests; and NT-proBNP measurements, ■: MRI, SPECT and PET.

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  Fig. 2 Changes in LVEF (%) measured by MRI (A); SPECT (B); Echo (C), and calculated LVEF change ratio (ΔLVEF) at baseline and after 12-month follow-up (D). (A) LVEF significantly increased only in HUC-MSC group (p=0.004); did not significantly change in the control or BM-MNC groups (see, text for p values). (B) SPECT imaging presented significant LVEF increase both in BM-MNC (p=0.015) and HUC-MSC (p=0.044) groups. (C) LVEF (baseline to 6 month) detected using Echo, and was also found different only in HUC-MSC group (p=0.017). Mean LVEF (%) and confidence intervals (CI 95%) at certain time-points are given in the table below. (D) Cumulative LVEF change ratio in each patient (ΔLVEF) in MRI, SPECT, and Echo revealed no significance between groups (p=0.376; p=0.110, and p=0.765, respectively).

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  Fig. 3 Ratio of responder vs nonresponder and left ventricle measurements based on the segmental MRI evaluations. (A, B) represent the ratio of responder (green bars) vs nonresponder (red bars) due to the healing of wall motion (WM) and scar score (SS), respectively. (C) Wall thickness (WT) change (mm) showed no significant difference between the groups (χ2=2.400; p=0.301). (D) Myocardial mass (MM) change (grams) between the baseline and after the 12-month follow-up was not different within each group (p=0.850) or between groups (p=0.440). However, a striking MM increase (16±10.6 g) was noted only in HUC-MSC group, whereas MM decreased in the control and BM-MNC groups. Although none of the measured/calculated values based on the segmental analysis (wall motion, scar score, wall thickness and myocardial mass) exhibited significant difference among groups, these results demonstrated that a higher degree of healing effect in the HUC-MSC group (compare the values in the A∼D).

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  Fig. 4 Changes (percentage) in hibernating (A) and necrotic area (B) measured by PET. Cell-treated groups demonstrated a decrease in hibernating area; no significance difference was noted among groups or within each group. Varying and significant decreases were noted in the necrotic myocardium (baseline–12-month) as 2.3% in the control (Z=2.033; p=0.042), 4.5% in BM-MNC (Z=2.666; p=0.008), and 7.7% in the HUC-MSC (Z=3.517; p<0.001) groups. Graphics were drawn using median and error bars were given as IQR/2.

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  Fig. 5 Changes in 6-min walking distance (in meters) throughout the 12-month follow-up. Significant increase was noticed in the control (p=0.007) and HUC-MSC (p=0.037) groups only between baseline and at the end of the 12-month distances. Mean walked distances in meters and confidence intervals (CI 95%) at certain time points are given in the table below.

Reference

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