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

A meta‐analysis of arrhythmia endpoints in randomized controlled trials of transendocardial stem cell injections for chronic ischemic heart disease

“…Similarly, Kandala et al performed a meta‐analysis of BMMNC vs control for patients with chronic ICMP and found that these cells were not associated with an increased risk of arrhythmic events. The same was true for the MSCs, which were not associated with an increase in the arrhythmic events in a short‐ or long‐term follow‐up and seemed to have a potential antiarrhythmic effect reported by Ramireddy et al…”

“…29 Safranow et al 30 patients with chronic ICMP and found that these cells were not associated with an increased risk of arrhythmic events. The same was true for the MSCs, which were not associated with an increase in the arrhythmic events in a short-or long-term follow-up 33 and seemed to have a potential antiarrhythmic effect reported by Ramireddy et al 34 Skeletal myoblast therapy has shown pro-arrhythmia responses, which was documented in clinical studies but not in controlled trials. [35][36][37][38][39] In the MAGIC trial, 7 the first double-blind placebo-controlled trial in patients with ICMP undergoing CABG, no statistical significant difference in VAs was observed between the treatment group and the placebo group, although the event rate was more than two times higher in the group that received the myoblasts.…”

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

“…19,20,37 Furthermore, our model could not explain pre-clinical and clinical observations, where hMSC delivery to the heart had no significant effect—or even favorable protective benefits—on the arrhythmogenicity of fibrotic cardiac tissue. 13,14,21,45 These discrepancies made it clear that some other mechanism of hMSC interaction with the myocardium, neglected in our original computational model, must be responsible for the inconsistencies with experimental data.…”

Mesenchymal Stem Cells for the Treatment of Idiopathic Pulmonary Fibrosis

“…MSCs are multipotent cells able to differentiate into a number of different cell lines and exert immunomodulatory, anti-proliferative, and anti-inflammatory effects. Their multipotency, migratory ability, and immunoprivileged state has led to extensive research efforts for therapeutic applications in several diseases including cardiac ischemia ( 35 – 39 ), ischemic acute renal failure ( 37 ), sepsis ( 40 ), autoimmune disorders ( 41 ), severe graft-vs. -host disease ( 42 ), pancreatic islet and renal glomerular repair in diabetes ( 43 ), fulminant hepatic failure ( 44 ), chronic lung diseases ( 45 – 48 ), and acute lung injury ( 49 – 53 ) (Table 2 ).…”