Clinical trials of cell therapy demonstrated mixed results regarding safety and efficacy, which have been reviewed elsewhere. 2–5
Early clinical trials of SkM transplantation demonstrated significant ventricular arrhythmias. 6–8
Recent trials with SkM transplants, however, reported lower incidence of ventricular arrhythmias 95–97
(but also see 98
). Mechanisms of cell therapies are complex and the reasons for a decreased incidence of ventricular arrhythmia in recent trials remains to be determined. For instance, prophylactic use of amiodarone may have reduced the incidence of arrhythmias.95
Among various types of SPC sources, infusion of selective types of BMMNCs seems to have provided modest improvement of cardiac function without serious pro-arrhythmic effects.99–101
However, the ability of such stem cells to generate cardiomyocytes is limited and thus the ameliorating effect is likely due to other beneficial mechanisms.2–3
Although other side effects of cell therapy, such as coronary restenosis and calcifications, occurred in a few studies, we will focus only on the discussion of arrhythmogenic potentials.
First, the prevalence of arrhythmic events increases with the severity of heart failure.102
Trials with SkM transplantations were mostly conducted in patients with left ventricular ejection fraction (LVEF) <36% and ventricular arrhythmias occurred more frequently post procedures. Whether these increased arrhythmic events were a reflection of the severity of underlying diseases or the result of intervention remains debatable. 103
Many recent trials with BMMNC, such as ASTAMI, 104
were conducted on patients with MI and a LVEF more than 40–45% (reviewed in 99–101
). This latter group of patients displays low incidence of arrhythmia-related events or death, 102
which may not allow a firm conclusion about arrhythmogenic risks due to lack of statistical power of these studies. Concomitant coronary revascularization, bypass-surgery and medications with anti-arrhythmic effects (such as beta blockers, statins, and ACE inhibitors) would further reduce the incidence of arrhythmias. 99
Consequently, a much larger number of patients with low arrhythmia-related events might be needed in future trials in order to obtain a firm conclusion that the procedure is safe.
Second, most trials applied electrocardiograms, or 24-hour Holter monitoring to determine arrhythmic events at follow-ups. These simple techniques may not be sufficient to detect arrhythmic events based on recent experience in defining the success of atrial fibrillation ablations. 106
Other monitoring techniques such as event monitors, insertable long-term recorders, microvolt T-wave alternans and invasive EP studies with programmed electrical stimulation (PES) protocols 107
should be included, especially for trials with SkM or ESC transplantations. If defibrillators (ICD) or pacemakers were implanted, the specifics of arrhythmia detection algorithms and types of detected arrhythmias should be reported. Inadequate device programming will underestimate arrhythmic events especially with concomitant use of amiodarone. In addition, lack of electrical therapy delivered from an ICD is not the same as lack of increased arrhythmic events. More detailed evaluation of the electrophysiological and arrhythmic consequences of cell-based therapies will improve future trial designs.
Third, human neonatal CMs take 6–10 years to reach adult form in terms of size, shape and gap junction distributions (see above). The developmental status of myocardial protein expression in most SPCs after transplantation in clinical trials is incompletely characterized. In one rare clinical instance, a postmortem study of a patient who received the BMMNC transplant revealed that pericytes just started expressing myocardial proteins at 11 months after cell therapy. 108
While the significance of this result remains to be established, it may suggest that longer follow-up times after cell transplantation are needed because of the extended time required for SPC-CMs to mature completely.
Fourth, most trials with positive outcomes did not provide evidence of true cardiomyogenesis from surviving SPCs. Even if cardiomyocyte differentiation from SPCs did occur, the frequency would expectedly be very low (discussed in 3
) with unclear EP maturation of these SPC-CMs. Moreover, positive outcomes reported from cell transplantation trials showing modest improvement in EF without increasing arrhythmic events might simply indicate that the beneficial effects of cell therapies are from mechanisms other than cardiomyogenesis. In fact, small numbers of surviving, immature SPC-CMs might explain the safety records of recent trials. If a sufficient number of injected cells were to survive and differentiate into immature cardiomyocytes (>10%, see above), they might be pro-arrhythmic. Therefore, the arrhythmogenic potential of cell therapies may depend on the balance between cell retention and cardiomyogenesis on one hand versus other beneficial mechanisms of donor cells on the other.