Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be a
novel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more data
are needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5
mm) consisting of up to 20 million human induced pluripotent stem cell–derived cardiomyocytes
(hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarction
model was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs in
EHTs became more aligned over 28 days and had improved contraction kinetics and faster calcium
transients. Blinded echocardiographic analysis revealed a significant improvement in function in
infarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularization
from the host to the patch was observed at week 1 and stable to week 4, but electrical coupling
between patch and host heart was not observed. In vivo telemetry recordings and ex vivo
arrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTs
improved function and reduced scar size without causing arrhythmia, which may be due to the lack
of electrical coupling between patch and host heart.