Dataset Information

Causes of altered ventricular mechanics in hypertrophic cardiomyopathy: an in-silico study.

ABSTRACT:

Background

Hypertrophic cardiomyopathy (HCM) is typically caused by mutations in sarcomeric genes leading to cardiomyocyte disarray, replacement fibrosis, impaired contractility, and elevated filling pressures. These varying tissue properties are associated with certain strain patterns that may allow to establish a diagnosis by means of non-invasive imaging without the necessity of harmful myocardial biopsies or contrast agent application. With a numerical study, we aim to answer: how the variability in each of these mechanisms contributes to altered mechanics of the left ventricle (LV) and if the deformation obtained in in-silico experiments is comparable to values reported from clinical measurements.

Methods

We conducted an in-silico sensitivity study on physiological and pathological mechanisms potentially underlying the clinical HCM phenotype. The deformation of the four-chamber heart models was simulated using a finite-element mechanical solver with a sliding boundary condition to mimic the tissue surrounding the heart. Furthermore, a closed-loop circulatory model delivered the pressure values acting on the endocardium. Deformation measures and mechanical behavior of the heart models were evaluated globally and regionally.

Results

Hypertrophy of the LV affected the course of strain, strain rate, and wall thickening-the root-mean-squared difference of the wall thickening between control (mean thickness 10 mm) and hypertrophic geometries (17 mm) was >10%. A reduction of active force development by 40% led to less overall deformation: maximal radial strain reduced from 26 to 21%. A fivefold increase in tissue stiffness caused a more homogeneous distribution of the strain values among 17 heart segments. Fiber disarray led to minor changes in the circumferential and radial strain. A combination of pathological mechanisms led to reduced and slower deformation of the LV and halved the longitudinal shortening of the LA.

Conclusions

This study uses a computer model to determine the changes in LV deformation caused by pathological mechanisms that are presumed to underlay HCM. This knowledge can complement imaging-derived information to obtain a more accurate diagnosis of HCM.

SUBMITTER: Kovacheva E

PROVIDER: S-EPMC8296558 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RATIONALE:Truncation mutations in the MYBPC3 gene, encoding for cardiac myosin-binding protein C (MyBP-C), are the leading cause of hypertrophic cardiomyopathy (HCM). Whole heart, fiber and molecular studies demonstrate that MyBP-C is a potent modulator of cardiac contractility, but how these mutations contribute to HCM is unresolved. OBJECTIVES:To readdress whether MYBPC3 truncation mutations result in loss of MyBP-C content and/or the expression of truncated MyBP-C from the mutant allele and determine how these mutations effect myofilament sliding in human myocardium. METHODS AND RESULTS:Septal wall tissue samples were obtained from HCM patients undergoing myectomy (n = 18) and donor controls (n = 8). The HCM samples contained 40% less MyBP-C and reduced levels of MyBP-C phosphorylation, when compared to the donor control samples using quantitative mass spectrometry. These differences occurred in the absence of changes in the stoichiometry of other myofilament proteins or production of truncated MyBP-C from the mutant MYBPC3 allele. The functional impact of MYBPC3 truncation mutations on myofilament sliding was determined using a total internal reflection microscopy (TIRFM) single particle assay. Myosin-thick filaments containing their native complement of MyBP-C, and actin-thin filaments decorated with the troponin/tropomyosin calcium regulatory proteins, were isolated from a subgroup of the HCM (n = 4) and donor (n = 5) heart samples. The maximal sliding velocity of native thin filaments was enhanced within the C-zones of the native thick filaments isolated from the HCM samples, when compared to velocity within the C-zones of thick filaments isolated from the donor samples. Analytical modeling demonstrated that the 40% reduction in MyBP-C content was sufficient to enhance the myofilament sliding velocity, as observed in the TIRFM assay. CONCLUSIONS:HCM-causing MYBPC3 truncation mutations result in a loss of MyBP-C content that enhances maximal myofilament sliding velocities, only where MyBP-C is localized within the C-zone. These findings support therapeutic rationale for restoring normal levels of MyBP-C and/or dampening maximal contractile velocities for the treatment of human HCM.

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