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. 2020 Jun;19(3):1079-1089.
doi: 10.1007/s10237-019-01271-w. Epub 2019 Dec 7.

Predictions of hypertrophy and its regression in response to pressure overload

Kyoko Yoshida  1 , Andrew D McCulloch  2   3 , Jeffrey H Omens  2   3 , Jeffrey W Holmes  4   5   6   7
Affiliations

Predictions of hypertrophy and its regression in response to pressure overload

Kyoko Yoshida et al. Biomech Model Mechanobiol. 2020 Jun.

Abstract

Mechanics-based cardiac growth models can now predict changes in mass, chamber size, and wall thickness in response to perturbations such as pressure overload (PO), volume overload, and myocardial infarction with a single set of growth parameters. As these models move toward clinical applications, many of the most interesting applications involve predictions of whether or how a patient's heart will reverse its growth after an intervention. In the case of PO, significant regression in wall thickness is observed both experimentally and clinically following relief of overload, for example following replacement of a stenotic aortic valve. Therefore, the objective of this work was to evaluate the ability of a published cardiac growth model that captures forward growth in multiple situations to predict growth reversal following relief of PO. Using a finite element model of a beating canine heart coupled to a circuit model of the circulation, we quantitatively matched hemodynamic data from a canine study of aortic banding followed by unbanding. Surprisingly, although the growth model correctly predicted the time course of PO-induced hypertrophy, it predicted only limited growth reversal given the measured unbanding hemodynamics, contradicting experimental and clinical observations. We were able to resolve this discrepancy only by incorporating an evolving homeostatic setpoint for the governing growth equations. Furthermore, our analysis suggests that many strain- and stress-based growth laws using the traditional volumetric growth framework will have similar difficulties capturing regression following the relief of PO unless growth setpoints are allowed to evolve.

Keywords: Finite element model; Growth; Hypertrophy; Pressure overload; Reverse growth.

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Figures

Fig. 1
Fig. 1
a Canine biventricular finite element model coupled to a lumped-parameter circulation model of systemic and pulmonary circulation. b Inset of the finite element mesh demonstrating the incorporated myofiber anatomy and the local coordinate system
Fig. 2
Fig. 2
Model quantitatively matches the reported time course of hemodynamics for baseline (day −1.5), acutePO (day 0), forward growth (day 0–18), and at PO release (day 19.5). Figures show comparisons of the different simulated cases to data for a maximum LV pressure, b end-diastolic pressure, and c % shortening
Fig. 3
Fig. 3
Model quantitatively matches the reported time course of remodeling for baseline (day −1.5), acutePO (day 0), and forward growth (day 0–18). Figures show comparisons of the four different simulated cases to data for a end-diastolic diameter (EDD) and b end-diastolic wall thickness (EDWth). Following PO release, only the simulations with an evolving setpoint (Cases 3a and 3b) predicted regression of wall thickening (see text)
Fig. 4
Fig. 4
All cases of forward growth resulted in a similar quantitative match to experimental hemodynamics (maxP, EDP, and %short) and dimensions (EDWth and EDD) at the end of forward growth. Bar graphs show error as a fraction of the experimental standard deviation (z-score) at 18 days of forward growth. All predicted values were well within one standard deviation of the experimental mean (− 1 < z-score < 1) for all cases simulated
Fig. 5
Fig. 5
Matching PO release hemodynamics causes the elastic strains to return to baseline, triggering little-to-no regression in wall thickness. Each column represents one of the four cases simulated (see text). Top row: pressure–volume (PV) loops for baseline, acutePO, end of simulated forward growth, PO release, and end of simulated reverse growth. Second row: Ecross,max throughout the cardiac cycle for baseline, acutePO, and PO release for a midwall Gauss point on the lateral wall in the LV. Third row: contour plots of the thickening stimulus (st) immediately following PO release. Fourth row: unloaded grown geometry (colored in pink) at the end of forward growth (PO day 18) compared with the ungrown geometry (outline in black). All cases resulted in similar changes in the geometry. Bottom row: unloaded grown geometry (colored in pink) at the end of reverse growth (POrev day 18) compared with the ungrown geometry (outlined in black). Cases 1 and 2 did not lead to any changes in geometry compared with PO day 18, whereas Cases 3a and 3b resulted in a smaller heart compared to PO day 18
Fig. 6
Fig. 6
Increasing the duration and extent of forward growth due to PO does not significantly affect reverse growth predictions following simulated PO release. Solid line shows change in predicted EDWth for simulation Case 2 (fibrosis) over 54 days of forward growth followed by 54 days of continued simulation after PO release; symbols show data from Sasayama et al. (1976) during 18 days of forward growth following aortic constriction
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