Regional septal dysfunction in a three-dimensional computational model of focal myofiber disarray

MLC2v/ras transgenic mice display a phenotype characteristic of hypertrophi c cardiomyopathy, with septal hypertrophy and focal myocyte disarray. Exper imental measurements of septal wall mechanics in ras transgenic mice have p reviously shown that regions of myocyte disarray have reduced principal sys tolic shortening, torsional systolic shear, and sarcomere length. To invest igate the mechanisms of this regional dysfunction, a three-dimensional prol ate spheroidal finite-element model was used to simulate filling and ejecti on in the hypertrophied mouse left ventricle with septal disarray. Focally disarrayed septal myocardium was modeled by randomly distributed three-dime nsional regions of altered material properties based on measured statistica l distributions of muscle fiber angular dispersion. Material properties in disarrayed regions were modeled by decreased systolic anisotropy derived fr om increased fiber angle dispersion and decreased systolic tension developm ent associated with reduced sarcomere lengths. Compared with measurements i n ras transgenic mice, the model showed similar heterogeneity of septal sys tolic strain with the largest reductions in principal shortening and torsio nal shear in regions of greatest disarray. Average systolic principal short ening on the right ventricular septal surface of the model was -0.114 for n ormal regions and -0.065 for disarrayed regions; for torsional shear, these values were 0.047 and 0.019, respectively. These model results suggest tha t regional dysfunction in ras transgenic mice may be explained in part by t he observed structural defects, including myofiber dispersion and reduced s arcomere length, which contributed about equally to predicted dysfunction i n the disarrayed myocardium.