Abstract
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.
Highlights
Heart failure is an emerging epidemic of ever-increasing incidence as the population ages, with severe morbidity and a 5-year mortality rate of 50% [1]
Calcium transients were compared between recordings taken from early (4–14 days) and late Engineered heart tissue (EHT) (29–42 days)
More mature calcium handling characteristics were obtained from late EHTs (Figure 1E), including faster time to peak measurements, faster 50% calcium transient decay measurements, and faster 75% calcium transient decay times
Summary
Heart failure is an emerging epidemic of ever-increasing incidence as the population ages, with severe morbidity and a 5-year mortality rate of 50% [1]. EHTs are effective in small animal models of heart disease, with improvements in cellular retention, vascularization, scar size, and heart function without the development of pathological ventricular arrhythmia [6, 7]. These results show promise; these studies were predominantly conducted in small animal models with heart physiology dissimilar to humans and EHTs of an inappropriate size (10 × 1 mm with 1–7 × 106 cells) [6]. While scale-up to NHPs (or other large animal models, such as dog or pig) is essential for a tissue engineering therapeutic strategy, the cost and ethical problems prevent detailed hypothesis testing and improvement of the method
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