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The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model
Christopher Semsarian1, Imran Ahmad, Michael Giewat
1Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Insights
Mutant sarcomere proteins disrupt calcium handling in the heart early in hypertrophic cardiomyopathy. Early diltiazem treatment prevented disease development in mice, suggesting a potential therapeutic strategy.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Inherited Cardiac Diseases
Background:
- Dominant mutations in sarcomere protein genes are a primary cause of hypertrophic cardiomyopathy (HCM).
- HCM is characterized by ventricular wall thickening, myocyte hypertrophy, and disarray.
- Understanding early molecular events is crucial for developing preventative strategies.
Purpose of the Study:
- To investigate the early consequences of sarcomere protein mutations on cardiac function.
- To determine the role of sarcoplasmic reticulum calcium (Ca2+) handling in the pathogenesis of HCM.
- To evaluate the therapeutic potential of L-type Ca2+ channel blockers in preventing HCM.
Main Methods:
- Studied mice with an Arg403Gln missense mutation in the alpha cardiac myosin heavy chain (alphaMHC(403/+)).
- Assessed sarcoplasmic reticulum Ca2+ levels, calsequestrin, ryanodine receptor expression, and phosphorylation.
- Administered the L-type Ca2+ channel inhibitor diltiazem early in the disease course.
Main Results:
- Reduced sarcoplasmic reticulum Ca2+ and diminished calsequestrin levels were observed prior to histological changes.
- Decreased ryanodine receptor expression and increased phosphorylation indicated sarcoplasmic reticulum Ca2+ dysregulation.
- Early diltiazem treatment normalized protein levels and prevented the development of cardiac pathology.
Conclusions:
- Disruption of sarcoplasmic reticulum Ca2+ homeostasis is an early pathogenic event in sarcomere protein mutation-induced HCM.
- Early intervention with Ca2+ channel blockers may prevent the clinical manifestation of HCM.
- Targeting Ca2+ handling offers a promising therapeutic avenue for inherited cardiomyopathies.
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.
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