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

Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder resulting from mutations in genes encoding sarcomeric proteins(1,2). This typically i nduces hyperdynamic ejection(3), impaired relaxation, delayed early filling (4), myocyte disarray and fibrosis, and increased chamber end-systolic stif fness(5,6). To better understand the disease pathogenesis, early (primary) abnormalities must be distinguished from evolving responses to the genetic defect. We did in vivo analysis using a mouse model of FHC with an Arg403Gl n alpha-cardiac myosin heavy chain missense mutation(7) and used newly deve loped methods for assessing in situ pressure-volume relations(8). Hearts of young mutant mice (6 weeks old), which show no chamber morphologic or gros s histologic abnormalities, had altered contraction kinetics, with consider ably delayed pressure relaxation and chamber filling, yet accelerated systo lic pressure rise. Older mutant mice (20 weeks old), which develop fiber di sarray and fibrosis, had diastolic and systolic kinetic changes similar to if not slightly less than those of younger mice. However, the hearts of old er mutant mice also showed hyperdynamic contraction, with increased end-sys tolic chamber stiffness, outflow tract pressure gradients and a lower cardi ac index due to reduced chamber filling; all 'hallmarks' of human disease. These data provide new insights into the temporal evolution of FHC. Such da ta may help direct new therapeutic strategies to diminish disease progressi on.