Chronic stimulation of cardiac a1A-adrenergic receptors (a1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. This study tested the effects of chronic a1A-AR stimulation on human engineered heart tissue (EHT). EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. Using a paired experimental design, EHTs were cultured for 3 wk., mechanically tested, cultured again for 2 wk. with a1A-AR agonist A61603 (10 nM) or vehicle control, and retested after drug washout for 24-hr. Separate control experiments determined the effects of EHT age (3-5 wk.) or repeat mechanical testing. We found that chronic A61603 treatment caused a 25% increase of length-dependent activation (LDA) of contraction compared to vehicle treatment (n=7/group, P=0.035). EHT force was not increased after chronic A61603 treatment. However, after vehicle treatment, EHT force was increased 35% relative to baseline testing (n=7/group, P=0.022), suggesting EHT maturation. Control experiments suggested increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed the a1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways known to be activated by a1A-ARs, including the MAP kinase signaling pathway. In conclusion, chronic stimulation of the a1A-AR, a promising preclinical target for treating heart failure, gave mixed results in human EHTs. Chronic a1A-AR stimulation had a positive effect to increase LDA, but did not change EHT force. The translational significance of these findings requires further study.
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