Substrate-associated cues, such as mechanical and topographic, profoundly influence cellular response. However, much of the foundational research employs static or isolated effects. The direction and timescale of these mechanical effects on emergent cellular responses remain largely unexplored. Tools to examine how time-varying substrate-associated stimuli drive physiological and pathological processes can unlock the next level of mechanobiological insight. Here, we use micro-patterned magnetorheological elastomers (MREs) that can rapidly stiffen and soften in response to an external magnetic field, allowing for a more rigorous investigation of the effects of mechanical (stiffness) and contact-guided (topographic) stimulation on neonatal rat cardiomyocyte orientation and alignment. By integrating dynamic control of mechanical stiffness that can be temporally tuned and reversed, we can rigorously test the effects of load by (1) pre-conditioning under identical conditions and (2) acutely changing in vitro biomechanics to mimic clinically relevant phenomenology, such as myocardial infarction properly. This approach allows us to study the impact of load on cellular responses in a more realistic and controlled manner.