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Abstract P2112: Human Genetics And Engineered Heart Tissues Link Frail
 MYH7
 Alleles To Delayed Maturation And Ventricular Noncompaction


 Background:
 Up to 1% of humans are born with a congenital heart defect. Among those defects is a condition known as left ventricular noncompaction (LVNC), which is defined as the ratio of trabeculated myocardium to compact myocardium exceeding 2.3:1. The process of compaction occurs when the layer of compact cardiomyocytes (CMs) proliferates, while CMs in the trabecular layer quiesce. This differential expansion of the CM layers reduces the trabecular invaginations into the cardiac lumen. Deficient compact CM proliferation or excessive trabecular CM proliferation converge on a similar presentation, collectively referred to as noncompaction. Family and population genetics studies have implicated deleterious variants in sarcomere genes as highly correlated with LVNC (PMID: 18506004, PMID: 3350056); specifically,
 MYH7
 truncations and missense variants that fall within the first 600 amino acids of the beta myosin heavy chain head region.
 
 
 Hypothesis:
 Reduced contractility in certain
 MYH7
 head domain missense or truncating variants disrupts cardiomyocyte terminal maturation, leading to excessive trabeculation.
 
 
 Results:
 We identified individuals and families with
 MYH7
 Lys234Asn and Arg243His. Variant carriers had LVNC often in the setting of dilated cardiomyopathy, similar to what has been described with
 MYH7
 truncations. We engineered
 MYH7
 truncations in human induced pluripotent stem cells (hiPSCs) which were differentiated into engineered heart tissues (EHTs) to model the developing heart. In EHTs with
 MYH7
 truncations contractility was reduced by 50%, EHT size increased by 17%, and CM proliferation increased by 40% in EHTs heterozygous for
 MYH7
 truncations (N=6 each).
 
 
 Conclusions and Future Directions:
 Our observations of impaired differentiation, reduced contractility, and decreased compaction are consistent with LVNC phenotypes. We propose a general model where diminished contractility delays sarcomere maturation, extending the proliferation time of trabecular cardiomyocytes and resulting in excessive trabeculae.
