The pathogenesis of familial hypertrophic cardiomyopathy: Early and evolving effects from an α-cardiac myosin heavy chain missense mutation

摘要: Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder resulting from mutations in genes encoding sarcomeric proteins1,2. This typically induces hyperdynamic ejection3, impaired relaxation, delayed early filling4, myocyte disarray and fibrosis, increased chamber end-systolic stiffness5,6. To better understand the disease pathogenesis, (primary) abnormalities must be distinguished evolving responses to defect. We did vivo analysis using mouse model of FHC with an Arg403Gln α-cardiac myosin heavy chain missense mutation7, used newly developed methods for assessing situ pressure–volume relations8. Hearts young mutant mice (6 weeks old), which show no morphologic or gross histologic abnormalities, had altered contraction kinetics, considerably pressure relaxation filling, yet accelerated systolic rise. Older (20 develop fiber diastolic kinetic changes similar if not slightly less than those younger mice. However, hearts older also showed contraction, stiffness, outflow tract gradients lower cardiac index due reduced filling; all 'hallmarks' human disease. These data provide new insights into temporal evolution FHC. Such may help direct therapeutic strategies diminish progression.