HCM is characterized by an abnormality that involves excessive growth (hypertrophy). All of the mutant genes encode for proteins that comprise the sarcomere, which implicitly indicates a defect in contractility. Several in vitro and in vivo studies confirm that mutations in the ßMHC gene, troponin T, and MYBP-C1 impair contractility and induce release of growth factors that stimulate the phenotype of hypertrophy and fibrosis. The phenotype of FHCM has been induced in vitro and in vivo in genetic animal models. 13, 14 The main pathology of human FHCM disease is sarcomeric disarray, increased interstitial fibrosis, and cardiac hypertrophy. Sarcomere disarray is considered the hallmark of FHCM and has been observed consistently in genetic animal models13 after expression of ßMHC, troponin T, and MYBP-C mutations and most recently in the rabbit after expression of ßMHC. 15 In all of the genetic animal models, there is sarcomere disarray, increased interstitial fibrosis, and altered myocardial function; however, in the mouse there is very little if any hypertrophy. 14, 15 The heart of the mouse has αMHC, whereas the human heart has ßMHC. In contrast, cardiac myocytes of the rabbit have ßMHC similar to that of humans. The rabbit exhibits a phenotype that is virtually identical to that observed in human FHCM, which includes sarcomere disarray, increased interstitial fibrosis, hypertrophy, SCD, and impaired myocardial function. 15 The mutant protein has been shown to be incorporated into the cardiac myofibril in feline cardiomyocytes, 16 transgenic mice, 17 and transgenic rabbits. 15 Contractility of isolated skeletal muscles obtained18 from patients expressing mutant ßMHC exhibited impaired cell shortening. 13 Analysis of a 3D crystalline structure of skeletal myosin heavy chain showed that the ßMHC mutations involve several domains critical to contractility of the sarcomere, such as the actin binding site, ATP generation, or calcium sensitivity, 19 which could account for the in vitro observations of impaired contractility. Expression of the ßMHC mutant gene in intact feline cardiac myocytes showed sarcomeric disarray after 72 hours, 16 and expression of a troponin T mutation in cardiac feline myocytes was associated with impaired contractility after 24 to 48 hours, followed by sarcomere disarray in 72 hours. 20 The mutant troponin T expressed in adult cardiac rat myocytes21 exhibited decreased cell shortening and impaired contractility. In the intact genetic animal model of FHCM expressing a troponin T mutation, cardiac contractility was shown to be impaired before the development of sarcomere disarray. 22 Thus, the primary genetic defect appears to be impaired contractility, which triggers the release of growth factors that result in compensatory hypertrophy and fibroblast proliferation. 23 Upregulation of growth factors has been confirmed in FHCM mouse models24 and in humans with FHCM. 24 Furthermore, fetal isoforms of proteins expressed in pressureoverload hypertrophy are also expressed in human FHCM, including c-fos, c-jun, and c-myc25; atrial and brain natriuretic peptides26, 27; and endothelin I. 28 Environmental factors such as increased pressure also affect the FHCM phenotype and explain why it is restricted to the left ventricle despite equal abundance of the mutant protein in the right ventricle. Ventricular pressure as a stimulus for the hypertrophy is supported by the results of the 2-year follow-up of FHCM patients after elimination of their outflow tract gradient by septal alcohol injection, which induced a 30% reduction in wall thickness, cardiac mass, and myocardial collagen. 29