Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) injected into the site of a myocardial infarction (MI) in macaque monkeys improves left ventricular function. However, the grafts can be associated with ventricular arrhythmias caused by abnormal electrical impulse generation.
Charles Murry and colleagues had previously shown that hESC-CMs can remuscularize the infarcted hearts of macaques, form electromechanical junctions with the native heart muscle, and beat in synchrony with the heart. The investigators sought to determine whether hESC-CMs could restore contractile function and by what mechanisms hESC-CMs might induce arrhythmias.
Large MIs were induced in macaques by 3-h occlusion of the left anterior descending coronary artery followed by reperfusion. The resulting transmural infarcts reduced left ventricular ejection fraction (LVEF) from ~69% at baseline to ~39% at 2 weeks after MI. Approximately 750 million hESC-CMs or vehicle placebo were administered 14 days after MI by surgically exposing the heart and injecting the cells into the infarct region and border zones.
At 1 month after injection, LVEF had improved significantly in the hESC-CM group compared with the control group (50.0% versus 40.5%; P < 0.05). Of the three macaques assessed at 3 months after injection, LVEF continued to improve in two animals that received hESC-CMs (66.0% and 61.0%), whereas LVEF remained impaired in a control animal (40.4%). “I’ve been in heart research since 1984,” says Murry, “and this is the largest improvement I’ve ever seen in function of an infarcted heart.”
Histological analysis revealed considerable maturation of cardiomyocyte grafts (image). At 4 weeks, cardiomyocytes were quite small and misaligned, but by 3 months, cardiomyocytes were larger, aligned, and had structures resembling transverse tubules.
Although no significant difference was noted in the number, duration, or severity of arrhythmias between the two groups either before or after injection, catheter-based electrophysiology mapping studies revealed that arrhythmias in control hearts arose from a small focus of re-entry, whereas those in the hESC-CM group had features of abnormal impulse generation.
Murry and colleagues are now working on two main areas: solving the arrhythmia problem and reducing the cardiomyocyte immune profile. “If our results are successful, we will have the first treatment (aside from heart transplantation) that can treat the root cause of heart failure — that is, cardiomyocyte deficiency.”
Liu, Y.-W. et al. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat. Biotech. 36, 597–605 (2018)
Menasché, P. et al. Cell therapy trials for heart regeneration — lessons learned and future directions. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-018-0013-0 (2018)
Hasimoto, H. et al. Therapeutic approaches for cardiac regeneration and repair. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-018-0036-6 (2018)
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Lim, G.B. Stem-cell therapy restores heart function after MI in macaques. Nat Rev Cardiol 15, 582 (2018). https://doi.org/10.1038/s41569-018-0062-4