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.

Mechanical stress concealed force enhancement and ionic transient membrane potential and metabolism in akinesia of stress cardiomyopathy

“…The passive mechanical properties of the myocardium partially recovered to their initial value in the muscle bearing the sustained stretch, reflecting a series of combinations of viscous elements and spring structures in the muscle fibers. The viscoelastic load is length-independent and dominates the early diastolic restoring force [62] ; however, most compounds in recovering passive tension are involved in the contraction filament-events. Muscle tension continues to rise slowly in this secondary phase [70] .…”

“…In active contraction, the muscle thin filaments in the fully activated state form overlapping arrays of opposite polarity in the center of the sarcomere [61] , while ramp stretch or slack muscle fiber create an overbalance in the cross-bridge interaction, which further creates an immediate response of myogenic force enhancement (please refer Figure 3A of Chiu 1982) [62] . Most enhancement responses are from myofilament compartment shortening during muscle contraction in an isometric state and from tolerating the sustained steady stretch (please refer Figure 2E of Chiu 1982) [63] .…”

“…Most enhancement responses are from myofilament compartment shortening during muscle contraction in an isometric state and from tolerating the sustained steady stretch (please refer Figure 2E of Chiu 1982) [63] . The lengthening scale determines the enhancement strengthening, while the lengthening ramp velocity determines the enhancement lasting time (please refer to Figure 5 of Chiu 1982) [62] . These further seals the trend of passive tension decay from the exponential nature of the elastic structure (springs) (Figure 10) [62] .…”

“…The lengthening scale determines the enhancement strengthening, while the lengthening ramp velocity determines the enhancement lasting time (please refer to Figure 5 of Chiu 1982) [62] . These further seals the trend of passive tension decay from the exponential nature of the elastic structure (springs) (Figure 10) [62] . Myocardial architecture rapid loss of elasticity at the apex in excessive dilatation Takotsubo cardiomyopathy.…”

Computational Analysis of Ventricular Mechanics in Hypertrophic Cardiomyopathy Patients

“…Specifically, mathematical models based on an idealized ellipsoidal LV geometry have been developed to investigate how regional strain is affected by myofiber disarray [34] and sarcomeric mutation [32]. A computational study has been conducted to quantify the effects of remodeling features associated with HCM by perturbing the heart geometry of a healthy volunteer that is used as a baseline [33]. These studies, however, do not consider the difference in LV mechanics between obstructive and non-obstructive HCM and patient-specific LV geometries that encapsulate the heterogeneous distribution of wall thickness associated with this disease.…”