Length-dependent hypercontractility decoupled from cellular adaptations is the initial phenotype in MYBPC3-haploinsufficient iPSC-derived engineered cardiac tissues

Hypertrophic cardiomyopathy (HCM) is often characterized by a complex landscape of secondary compensatory changes, making it difficult to distinguish primary events triggered by the underlying genetic variants. Here, using patient-derived iPSC-engineered heart tissues cultured in conditions minimizing external stimuli, we identify the initial phenotype of the HCM inducing variant MYBPC3-Q1061X. We demonstrate that initially MYBPC3 haploinsufficiency leads to robust, muscle length-dependent hypercontractility with emerging diastolic dysfunction at higher contraction rates. This phenotype is entirely decoupled from early transcriptional and metabolic stress responses, as evidenced by physiological phenotype and metabolite and cell type-specific transcriptional profiles. Mathematical modeling reveals that the hypercontractile phenotype can be translated to adult cardiac muscle with a small change in myosin availability, amplified by inherent cooperativity within the sarcomere that is instrumental in enhancing the force and the speed of the contraction cycle. Despite the apparent calcium sensitization, these sarcomeric changes do not affect excitation-contraction coupling or calcium buffering in this proximal stage. These results suggest that the primary biophysical defect in MYBPC3-haploinsufficiency manifests as a latent mechanical hypersensitivity that precedes secondary cellular remodeling and functional instability. This initial phenotype provides a window for preventive therapeutic intervention before the onset of permanent cellular remodeling in the heart.