Researchers have created an initial 3-dimensional (3D) heart model from pulmonary arterial hypertension (PAH) patient cells to better study the disease. The study, published in Cells, used induced pluripotent stem cells (iPSCs) from a PAH patient to create a right heart dysfunction (RHD) model to further investigate the mechanisms of right ventricular overload.
During the study, cardiomyocytes derived from the PAH patient’s iPSCs (iPSC-CMs) were found to have a lower beating frequency and increased contraction and relaxation times compared to iPSC-CMs derived from a healthy control patient.
The PAH-derived cells were formed into 3D engineered heart tissues (EHTs) that also displayed increased contraction and relaxation times along with higher force compared to the control-derived cells.
“Under baseline spontaneous conditions, PAH-derived iPSC-CMs and EHTs show prolonged contraction compared with controls, as observed clinically in PAH patients,” the authors summarized.
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The PAH EHTs were also found to express higher levels of cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), and sarcomeric α-actinin (ACTN1) than the control-derived EHTs.
The EHTs first displayed measurable force production after 1 week of development and became stable after 1 month. The usual features of a failing right ventricle, such as cardiac hypertrophy, were not observed during the initial EHT design, however, so the researchers mimicked an increased afterload by using stiffer silicone posts to increase their resistance to deflection.
Many of the EHTs did not sustain this higher resistance and detached from the posts or became too thin and broke before 28 days. Due to these factors, no statistically significant difference was observed between the control and PAH EHTs with the stiffer posts despite observing differences in force, contraction time, and relaxation time.
The authors concluded, “This is the first version of a 3D model to study PAH-induced RHD. Further optimization will be performed and will consist of a multicellular model with a clear hypertrophic phenotype to represent a more complex 3D model to study PAH-induced RHD.”
Llucià-Valldeperas A, Smal R, Bekedam FT, et al. Development of a 3-dimensional model to study right heart dysfunction in pulmonary arterial hypertension: first observations. Cells. 2021;10(12):3595. doi:10.3390/cells10123595