Abstract 12501: Abnormal Activation of TGFβ Signaling as a Pathogenesis of Left Ventricular Non-compaction Cardiomyopathy

Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and has a unique phenotype with characteristically extensive hypertrabeculation of the left ventricle, similar to the embryonic left ventricle, suggesting a developmental defect of the embryonic myocardium. However, in-depth investigation of this disease has been challenging due to the lack of animal models that can faithfully recapitulate the clinical phenotype of LVNC. In this study, we demonstrated that patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from LVNC patients carrying a mutation in cardiac transcription factor TBX20 recapitulated a developmental defect consistent with the LVNC phenotype at the single-cell level. We first performed genetic tests and identified two TBX20 mutations, Y317* and T262M from multiple members in a family with LVNC history and one isolated patient. We then utilized iPSC-CMs to show that increased transforming growth factor beta (TGFβ) signaling is one of the central mechanisms underlying the pathogenesis of LVNC caused by TBX20 mutation. LVNC iPSC-CMs demonstrated decreased proliferative capacity due to abnormal activation of TGFβ signaling (Figs. A-B). TBX20 regulated the expression of TGFβ signaling modifiers including ITGAV and the Smad cofactor, PRDM16, which is a known genetic cause of LVNC. Genome editing of PRDM16 in control iPSC-CMs led to proliferation defects as seen in LVNC iPSC-CMs. Inhibition of abnormal TGFβ signaling by TGFβ receptor-1 inhibitors or ITGAV inhibitor, or genetic correction of the TBX20 mutation using TALEN reversed the proliferation defects seen in LVNC iPSC-CMs (Figs. C-D). Our results demonstrate that iPSC-CMs are a useful tool for the exploration of novel mechanisms underlying poorly understood cardiomyopathies such as LVNC. Here we provide the first evidence of activation of TGFβ signaling as playing a role in the pathogenesis of LVNC.