Rationale: Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, and characteristic cutaneous findings. NF1 patients also have an increased incidence of cardiovascular diseases, including obstructive vascular disorders and hypertension. The disease gene, NF1, encodes neurofibromin, a ubiquitously expressed protein that acts, in part, as a Ras-GAP (GTP-ase activating protein), downregulating the activity of activated Ras protooncogenes. In animal models, endothelial and smooth muscle expression of the disease gene is critical for normal heart development and the prevention of vascular disease, respectively.

Objective: To determine the role of NF1 in the postnatal and adult heart.

Methods and Results: We generated mice with homozygous loss of the murine homolog Nf1 in myocardium (Nf1mKO) and evaluated their hearts for biochemical, structural, and functional changes. Nf1mKO mice have normal embryonic cardiovascular development but have marked cardiac hypertrophy, progressive cardiomyopathy, and fibrosis in the adult. Hyperactivation of Ras and downstream pathways are seen in the heart with the loss of Nf1, along with activation of a fetal gene program.

Conclusions: This report describes a critical role of Nf1 in the regulation of cardiac growth and function. Activation of pathways known to be involved in cardiac hypertrophy and dysfunction are seen with the loss of myocardial neurofibromin.