Genetic Basis for Hypertrophic Cardiomyopathy: Implications for Diagnosis and Treatment

Abstract

Familial hypertrophic cardiomyopathy is a genetic disease defined by cardiac hypertrophy in the absence of an increased external load. It is the most common inherited cardiac disorder occurring in 1 in 500 individuals. Ten genes exhibiting over 200 mutations have been identified. However, about 75% are due to mutations in just three genes: e-myosin heavy chain, cardiac troponin T, and myosin binding protein-C. Certain phenotypes are more common with certain genes, such as the myosin binding protein-C gene, which induces the disease predominantly in the fifth or sixth decade of life. Genetic animal models in the mouse and rabbit have helped to elucidate the pathophysiology. The primary defect imparted by the specific mutation alters contractile function, which stimulates release of various growth factors that induce secondary cardiac hypertrophy and fibrosis. Placebo single-blinded studies in the mouse indicate that losartan reverses the phenotype; in the rabbit, simvastatin essentially reversed the phenotype after 12 weeks of therapy. Clinical trials are ongoing in human familial hypertrophic cardiomyopathy.

Familial Wolff‐Parkinson‐White Syndrome: A Disease of Glycogen Storage or Ion Channel Dysfunction?

“…1). 7–11 The activity of this kinase is increased as AMP levels increase during times of metabolic stress such as exercise or ischemia, and the primary role of AMPK is thought to be the phosphorylation of target proteins/enzymes in the metabolic pathway that increase the generation of ATP—consequently preserving energy supplies 7 . However, all of the targets for AMPK have presumably not been identified.…”

Cardiomyopathies

“…Interestingly, several of these nonsarcomeric pathogenic loci are also associated with other disease phenotypes; the same AMPK mutations involved in HCM cause an accumulation of cardiac glycogen, hence termed glycogen storage disease, and lead to severe electrophysiological abnormalities, particularly ventricular preexcitation (Wolff-Parkinson-White syndrome). 39 In HCM, there is significant genetic heterogeneity with over 200 different mutations in the 17 genes identified; 44 however, about 75% of cases with defined mutations have been estimated to be due to mutations in just three genes, the β-MHC MYH7 gene, the cardiac troponin T TNNT2 gene, and the myosin-binding protein C (MyBPC) MYBPC3 gene. 40,41 Furthermore, mutations in caveolin-3 cause limb-girdle muscular dystrophy (LGMD).…”