Increased length-dependent activation of human engineered heart tissue after chronic ? 1A-adrenergic agonist treatment: testing a novel heart failure therapy

Chronic stimulation of cardiac oc1A-adrenergic receptors (oc1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. Human engineered heart tissues (EHTs) provide a means of quantifying the effects of chronic oc1A-AR stimulation on human cardiomyocyte physiology. EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. With a paired experi-mental design, EHTs were cultured for 3 wk, mechanically tested, cultured again for 2 wk with oc1A-AR agonist A61603 (10 nM) or vehi-cle control, and retested after drug washout for 24 h. 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 with 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 by 35% relative to baseline testing (n = 7/group, P = 0.022), suggesting EHT maturation. Control experiments suggested that increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed that the oc1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways known to be activated by oc1A-ARs, including the MAP kinase signaling pathway. In conclusion, increased LDA in human EHT after chronic A61603 treatment raises the possibility that chronic stimulation of the oc1A-AR might be beneficial for increasing LDA in human myocardium and might be beneficial for treating human heart failure by restoring LDA.NEW & NOTEWORTHY Chronic stimulation of oc1A-adrenergic receptors (oc1A-ARs) is known to mediate therapeutic effects in animal heart failure models. To investigate the effects of chronic oc1A-AR stimulation in human cardiomyocytes, we tested engineered heart tissue (EHT) created with iPSC-derived cardiomyocytes. RNA-seq analysis confirmed human EHT expressed oc1A- ARs. Chronic (2 wk) oc1A-AR stimulation with A61603 (10 nM) increased length-dependent activation (LDA) of contraction. Chronic oc1A-AR stimulation might be beneficial for treating human heart failure by restoring LDA.