Finite afterload during asymmetrically cycled preload promotes fetal ventricular growth, maturation, and contractile function while suppressing fibrotic remodeling

Myocardial development requires precise modulation of its growth and maturation by the mechanical loads within cardiac cycle, including preload and afterload. However, the mechanisms by which these natural cardiac loads interact to simultaneously govern growth and maturation of the developing myocardium in both cellular and mesoscale levels remain poorly understood. Here, we developed a naturally engineered fetal ventricular tissue (NFVT) platform that enables the application of afterload under dynamic preload using cyclic stretching with an asymmetrical duty cycle (asymmetrically cycled preload) to better replicate the natural cardiac loading in chick NFVT. Our results showed that low afterload (LA) enhanced NFVT contractile function with sustained tissue growth and improved cardiomyocyte maturation while suppressing fibrosis phenotypes. These effects were associated with reduced YAP1 and NOTCH activation in cardiomyocytes and enhanced tissue architecture. In contrast, high afterload (HA) induced contractile impairment with fibrotic remodeling through activation of cardiomyocyte PIEZO1/YAP1 signaling and sustained fibroblast entanglement. TeaserLow afterload under asymmetrically cycled preload promotes NFVTs contractile function with sustained tissue growth and cardiomyocyte maturation while suppressing fibrosis phenotypes through regulation of cellular mechanotransduction, including minimal PIEZO1 expression and inhibited YAP1 and NOTCH activation in cardiomyocytes, and improvement of collective cellular organization.