[HTML][HTML] An abnormal Ca2+ response in mutant sarcomere protein–mediated familial hypertrophic cardiomyopathy

D Fatkin, BK McConnell, JO Mudd… - The Journal of …, 2000 - Am Soc Clin Investig
D Fatkin, BK McConnell, JO Mudd, C Semsarian, IGP Moskowitz, FJ Schoen, M Giewat…
The Journal of clinical investigation, 2000Am Soc Clin Investig
Dominant-negative sarcomere protein gene mutations cause familial hypertrophic
cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and
dyspnea that can result in sudden death. We report here that a murine model of FHC
bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated
with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy,
worsened histopathology, and was at risk for early death. Despite distinct pharmacologic …
Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.
The Journal of Clinical Investigation