Cellular Crosstalk Drives Hypertrophic Cardiomyopathy in LZTR1 Deficiency

LZTR1 deficiency causes Noonan syndrome (NS) and is associated with the manifestation of severe and early-onset hypertrophic cardiomyopathy (HCM). Although paracrine communication is thought to play a critical role in cardiac pathology, little is known about the underlying pathomechanism leading to the development of HCM and cardiac fibrosis in NS. In the present study, we used 2D and 3D iPSC models with LZTR1 deficiency to dissect the impact of non-cardiomyocytes in the development of NS-associated HCM and uncovered a cytokine-mediated intercellular crosstalk, predominantly activated in the disease state, as a major driver of cardiac hypertrophy and cardiac fibrosis.