Computational simulation of hypertrophic cardiomyopathy mutations in troponin I: influence of increased myofilament calcium sensitivity on isometric force, ATPase and [Ca2+]i.
J Biomech
; 40(9): 2044-52, 2007.
Article
em En
| MEDLINE
| ID: mdl-17140583
ABSTRACT
Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is characterized by ventricular hypertrophy, cardiac arrhythmias and increased risk of premature sudden death. FHC is caused by autosomal-dominant mutations in genes for a number of sarcomeric proteins; many mutations in Ca(2+)-regulatory proteins of the cardiac thin filament are associated with increased Ca(2+) sensitivity of myofilament function. Computational simulations were used to investigate the possibility that these mutations could affect the Ca(2+) transient and mechanical response of a myocyte during a single cardiac cycle. We used existing experimental data for specific mutations of cardiac troponin I that exhibit increased Ca(2+) sensitivity in physiological and biophysical assays. The simulated Ca(2+) transients were used as input for a three-dimensional half-sarcomere biomechanical model with filament compliance to predict the resulting force. Mutations with the highest Ca(2+) affinity (lowest K(m)) values, exhibit the largest decrease in peak Ca(2+) assuming a constant influx of Ca(2+) into the cytoplasm; they also prolong Ca(2+) removal but have little effect on diastolic Ca(2+). Biomechanical model results suggest that these cTnI mutants would increase peak force despite the decrease in peak [Ca(2+)](i). There is a corresponding increase in net ATP hydrolysis, with no change in tension cost (ATP hydrolyzed per unit of time-integrated tension). These simulations suggest that myofilament-initiated hypertrophic signaling could be associated with decreased [Ca(2+)](i), increased stress/strain, and/or increased ATP flux.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Simulação por Computador
/
Citoesqueleto de Actina
/
Cálcio
/
Adenosina Trifosfatases
/
Troponina I
/
Cardiomiopatia Hipertrófica Familiar
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article