Abstract
The effects of two cardiomyopathy-associated mutations in regulatory sarcomere protein tropomyosin (Tpm) on heart function were studied with a new multiscale model of the cardiovascular system (CVS). They were a Tpm mutation, Ile284Val, associated with hypertrophic cardiomyopathy (HCM), and an Asp230Asn one associated with dilated cardiomyopathy (DCM). When the molecular and cell-level changes in the Ca2+ regulation of cardiac muscle caused by these mutations were introduced into the myocardial model of the left ventricle (LV) while the LV shape remained the same as in the model of the normal heart, the cardiac output and arterial blood pressure reduced. Simulations of LV hypertrophy in the case of the Ile284Val mutation and LV dilatation in the case of the Asp230Asn mutation demonstrated that the LV remodeling partially recovered the stroke volume and arterial blood pressure, confirming that both hypertrophy and dilatation help to preserve the LV function. The possible effects of changes in passive myocardial stiffness in the model according to data reported for HCM and DCM hearts were also simulated. The results of the simulations showed that the end-systolic pressure–volume relation that is often used to characterize heart contractility strongly depends on heart geometry and cannot be used as a characteristic of myocardial contractility.
Highlights
The inherited cardiac diseases, hypertrophic (HCM) and dilated (DCM) cardiomyopathies, can be caused by mutations in genes encoding sarcomere proteins expressed in heart muscle
Simulation of Hemodynamic Changes Caused by the Asp230Asn and Ile284Val Tpm Mutations Without the left ventricle (LV) Remodeling
To understand how the cell-level changes in mechanical properties of cardiac muscle caused by the Tpm mutations might affect the heart function, we simulated steady-state heartbeats at a rate of 60 heartbeats per min by the model with the default ‘normal’ LV size and shape [16,17], while the
Summary
The inherited cardiac diseases, hypertrophic (HCM) and dilated (DCM) cardiomyopathies, can be caused by mutations in genes encoding sarcomere proteins expressed in heart muscle. 31 mutations in the TPM1 gene encoding regulatory protein tropomyosin (Tpm) are associated with. HCM, DCM, or, more rear, left ventricular non-compaction [1,2,3]. HCM is characterized by a thickening of the left ventricular (LV) wall occurring in the absence of other diseases. This remodeling often results in a decrease in the volume of LV cavity and obstruction of the LV outflow tract. DCM is characterized by an increased volume of the LV cavity and a reduced ejection fraction in the absence of coronary artery diseases. Changes in passive mechanical properties of LV myocardium upon HCM and DCM were found [5,6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
