Effects of Transendocardial Stem Cell Injection on Ventricular Proarrhythmia in Patients with Ischemic Cardiomyopathy: Results from the POSEIDON and TAC-HFT Trials

Abstract

Transendocardial stem cell injection in patients with ischemic cardiomyopathy (ICM) improves left ventricular function and structure but has ill-defined effects on ventricular arrhythmias. We hypothesized that mesenchymal stem cell (MSC) implantation is not proarrhythmic. Post hoc analyses were performed on ambulatory ECGs collected from the POSEIDON and TAC-HFT trials. Eighty-eight subjects (mean age 61 ± 10 years) with ICM (mean EF 32.2% ± 9.8%) received treatment with MSC (n = 48), Placebo (n = 21), or bone marrow mononuclear cells (BMC) (n = 19). Heart rate variability (HRV) and ventricular ectopy (VE) were evaluated over 12 months. VE did not change in any group following MSC implantation. However, in patients with ≥ 1 VE run (defined as ≥ 3 consecutive premature ventricular complexes in 24 hours) at baseline, there was a decrease in VE runs at 12 months in the MSC group (p = .01), but not in the placebo group (p = .07; intergroup comparison: p = .18). In a subset of the MSC group, HRV measures of standard deviation of normal intervals was 75 ± 30 msec at baseline and increased to 87 ± 32 msec (p =.02) at 12 months, and root mean square of intervals between successive complexes was 36 ± 30 msec and increased to 58.2 ± 50 msec (p = .01) at 12 months. In patients receiving MSCs, there was no evidence for ventricular proarrhythmia, manifested by sustained or nonsustained ventricular ectopy or worsened HRV. Signals of improvement in ventricular arrhythmias and HRV in the MSC group suggest a need for further studies of the antiarrhythmic potential of MSCs. Stem Cells Translational Medicine 2017;6:1366-1372.

Keywords: Cardiac arrhythmias; Cardiomyopathy; Heart failure; Stem cells; Ventricular tachycardia.

Figure 1

Change in log (ventricular ectopy/24 hours) from baseline to 12 months. Despite logarithmic transformation of the data, data remained skewed so nonparametric statistical analysis was used. There was no significant change in the acute phase after TESI or at 12 months post‐TESI in any of the three groups. Abbreviations: BMC, bone marrow mononuclear cells; MSC, mesenchymal stem cell.

Figure 2

Change in high‐burden ventricular ectopy runs (≥1 VE Run/24 hours) over 12 months. In a subgroup analysis of patients with ≥ 1 VE Run in a 24‐hour period, there was a significant decrease from baseline to 12 months in the MSC group, but not in the placebo group (p = .01). The BMC group was excluded due to an insufficient number of runs for comparison. Of note, an intergroup comparison between the placebo and MSC groups did not reach statistical significance with p = .18. The baseline to 12‐month analysis within each group was performed using Wilcoxon Signed‐Rank tests, and the Kruskal–Wallis test was used for intergroup comparison. Abbreviation: MSC, mesenchymal stem cell.

Figure 3

Change in heart rate variability (HRV) from baseline to 12‐month follow up. MSC patients (N = 21) from the POSEIDON trial were involved in HRV analysis. Changes in SDNN and RMSSD are shown. SDNN improved by 2% at 6 months (p = .19) and 16% at 12 months (p = .02). RMSSD improved by 13% at 6 months (p = .10) and 60% at 12 months (p = .01). Abbreviations: RMSSD, root mean square of the difference between coupling intervals of adjacent R‐R intervals; SDNN, standard deviation of all normal R‐R intervals.

Figure 4

Correlation between percentage change in scar size and percentage change in ventricular ectopy in MSC, BMC, and placebo groups. There is a significant correlation of percentage change in scar size to percentage change in ventricular ectopy in the MSC group (R ² = .17, p = .01) whereas there was no correlation found in the BMC group (R ² = .07, p = .38) or in the Placebo group (R ² = .03, p = .56). Abbreviations: BMC, bone marrow mononuclear cells; MSC, mesenchymal stem cell.