The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy
in a mouse model
J Clin Invest, 109 (8):
1013-20 (April 2002)Semsarian, Christopher Ahmad, Imran Giewat, Michael Georgakopoulos,
Dimitrios Schmitt, Joachim P McConnell, Bradley K Reiken, Steven
Mende, Ulrike Marks, Andrew R Kass, David A Seidman, Christine E
Seidman, J G Research Support, Non-U.S. Gov't Research Support, U.S.
Gov't, P.H.S. United States The Journal of clinical investigation
J Clin Invest. 2002 Apr;109(8):1013-20..Abstract
Dominant mutations in sarcomere protein genes cause hypertrophic cardiomyopathy,
an inherited human disorder with increased ventricular wall thickness,
myocyte hypertrophy, and disarray. To understand the early consequences
of mutant sarcomere proteins, we have studied mice (designated alphaMHC(403/+))
bearing an Arg403Gln missense mutation in the alpha cardiac myosin
heavy chain. We demonstrate that Ca(2+) is reduced in the sarcoplasmic
reticulum of alphaMHC(403/+) mice, and levels of the sarcoplasmic
reticulum Ca(2+)-binding protein calsequestrin are diminished in
advance of changes in cardiac histology or morphology. Further evidence
for dysregulation of sarcoplasmic reticulum Ca(2+) in these animals
is seen in their decreased expression of the ryanodine receptor Ca(2+)-release
channel and its associated membrane proteins and in an increase in
ryanodine receptor phosphorylation. Early administration of the L-type
Ca(2+) channel inhibitor diltiazem restores normal levels of these
sarcoplasmic reticular proteins and prevents the development of pathology
in alphaMHC(403/+) mice. We conclude that disruption of sarcoplasmic
reticulum Ca(2+) homeostasis is an important early event in the pathogenesis
of this disorder and suggest that the use of Ca(2+) channel blockers
in advance of established clinical disease could prevent hypertrophic
cardiomyopathy caused by sarcomere protein gene mutations.