Development of a Subpulmonary Neoventricle from Engineered Heart Tissue for the Treatment of Univentricular Heart Defects

Background: Primary heart transplantation ruled out, the Fontan principle in all its variations is the only surgical treatment option for patients with single ventricle anatomy. With the systemic and pulmonary circulation connected in series, blood flows passively into the pulmonary vasculature. There is evidence from a chronic porcine model of cavopulmonary connection that even weak pulsatile stimuli positively affect vascular tone, endothelial function, and the development of pulmonary arteriovenous malformations. We aimed to generate a contractile subpulmonary neoventricle from engineered heart tissue (EHT) to treat patients with single ventricle anatomy in the future.

Method: We generated tubular EHTs (length: 18 mm, inner diameter: 6 mm, wall thickness: 1 mm) by casting human iPSC-derived cardiomyocytes (18 mio/mL) in a fibrin-based hydrogel around a silicon tube. After 24 hours under static conditions, a pulsatile flow through the silicon tube was initiated and continued until day 23.

Results: At days 8 to 14, the constructs started to beat macroscopically and remained stable in size and shape over the whole culture period. Spontaneous macroscopic contractions started between days 8 to 14 in a synchronized manner with a regular beating pattern. Isovolumetric pressure measurements demonstrated a coherent pulsatile wave formation with an average frequency of 77 beats/min and an average pressure of 0.2 mm Hg. Glucose consumption increased simultaneously over time, indicating CM viability and maturation. EHTs expressed the atrial (MLC2a) and ventricular (MLC2v) isoform of the myosin light chain. The alignment of cardiomyocytes was mainly longitudinally along the tubular wall, and some cardiomyocytes showed a mature, elongated phenotype.

Conclusion: In summary, our construct could be the basis for the future generation of a pressure-generating neoventricle to actively propel blood toward the pulmonary arteries in palliated patients with total cavopulmonary connection. However, to have a relevant impact, many limitations need to be overcome. Our primary constraint is the low pressure build-up in the construct, likely influenced by unfavorable CM alignment and maturity.

Publication History

Article published online:
03 February 2022