Duchenne Muscular Dystrophy (DMD) is a severe, muscle-wasting genetic disorder that ultimately leads to heart failure. DMD is caused by the lack of dystrophin, a contractile protein that spans the actin cytoskeleton to the extracellular matrix. The disease is difficult to target by current gene therapy methods as the dystrophin transcript spans 14 kb, far exceeding the 4.7 kb packaging limit of AAV. Synthetic variants of dystrophin, called microdystrophins, have advanced to clinical trials. Microdystrophins contain key domains of dystrophin and have been successful in rescuing disease characteristics of the skeletal muscle; however, therapeutic efficacy in the heart remains controversial. To compare transgene designs, we used cardiomyocytes differentiated from human induced pluripotent stem cells (iPSC-CMs) to model the disease. DMD iPSC-CMs exhibit functional deficits characteristic of dystrophic cells, including poor calcium handling and compromised viability. This platform enables assessment of therapeutic efficacy of various gene therapy strategies in multiple genetic backgrounds in the molecular context of human cells. We compared three microdystrophin variants in DMD iPSC-CMs against minidystrophin, discovered in a Becker muscular dystrophy patient who survived into his seventies. We found that microdystrophins partially rescue disease phenotypes; however, the results are variable among genetic backgrounds. Bulk RNA-sequencing revealed that microdystrophins did not completely alter the transcriptional profiles of DMD iPSC-CMs to resemble a healthy profile. We show that minidystrophin better rescues DMD phenotypes, including improved calcium handling and viability. These findings suggest microdystrophins may have limited efficacy in DMD cardiomyocytes and that delivering larger dystrophin variants may be a better strategy to improve DMD patient outcomes.