A Computational Cardiac Model for the Adaptation to Pulmonary Arterial Hypertension in the Rat

Abstract

Pulmonary arterial hypertension (PAH) imposes pressure overload on the right ventricle (RV), leading to RV enlargement via the growth of cardiac myocytes and remodeling of the collagen fiber architecture. The effects of these alterations on the functional behavior of the right ventricular free wall (RVFW) and organ-level cardiac function remain largely unexplored. Computational heart models in the rat (RHMs) of the normal and hypertensive states can be quite valuable in simulating the effects of PAH on cardiac function to gain insights into the pathophysiology of underlying myocardium remodeling. We thus developed high-fidelity biventricular finite-element RHMs for the normal and post-PAH hypertensive states using extensive experimental data collected from rat hearts. We then applied the RHM to investigate the transmural nature of RVFW remodeling and its connection to wall stress elevation under PAH. We found a strong correlation between the longitudinally-dominated fiber-level adaptation of the RVFW and the transmural alterations of relevant wall stress components. We further conducted several numerical experiments to gain new insights on how the RV responds both normally and in the post-PAH state. We found that the effect of pressure overload alone on the increased contractility of the RV is secondary to the effects of changes in the RV geometry and stiffness. Furthermore, our RHMs provided fresh perspectives on long-standing questions of the functional role of the interventricular septum in RV function. Specifically, we demonstrated that an inaccurate identification of the mechanical adaptation of the septum can lead to a significant underestimation of RVFW contractility in the post-PAH state. These findings showed that how integrated experimental-computational models can facilitate a more comprehensive understanding of the cardiac remodeling events during PAH.

Current Understanding of the Biomechanics of Ventricular Tissues in Heart Failure

“…Finally, with the combination of medical imaging and computational modeling such as finite element methods, it is also possible to estimate the ventricular material properties using 'inverse modeling' [77][78][79][80][81][82]. These computational methods are briefly reviewed in the works of [83][84][85].…”

Interactions Between Structural Remodeling and Hypertrophy in the Right Ventricle in Response to Pulmonary Arterial Hypertension

“…Although the nature of the pressure overload is a factor in the progression toward RV failure, studies suggest that the major predictive determinant of the prognosis of PAH is how the RV adapts [4]. Increase in regional RV free wall (RVFW) contractility, which consists of a hypertrophic response through sarcomerogenesis, as well as intrinsic changes in myocyte force generation, is considered to be an important adaptive remodeling to maintain stroke volume [2,5,6]. These changes are primarily caused by mechanical stimuli through a direct pressure overload and by activation of the neurohormonal system [7][8][9].…”

“…These changes are primarily caused by mechanical stimuli through a direct pressure overload and by activation of the neurohormonal system [7][8][9]. Parallel to these changes, structural remodeling in terms of fiber-level stiffening, as well as fiber reorientation and alignment, takes place [5,[10][11][12] that significantly contributes to the changes in both RV diastolic and contractile functions. At the organ level, a progressive RV dilation, considered to be a maladaptive (or decompensatory) response, is activated at later stages of PAH development to maintain the RV stroke volume once the increase in RVFW contractility is at its limit [5,9].…”

“…Parallel to these changes, structural remodeling in terms of fiber-level stiffening, as well as fiber reorientation and alignment, takes place [5,[10][11][12] that significantly contributes to the changes in both RV diastolic and contractile functions. At the organ level, a progressive RV dilation, considered to be a maladaptive (or decompensatory) response, is activated at later stages of PAH development to maintain the RV stroke volume once the increase in RVFW contractility is at its limit [5,9]. However, the exact determinants to identify the transition from adaptive to decompensated states remain elusive.…”

“…Recently, we developed high-fidelity biventricular finite element (FE) rodent heart models (RHMs), based on extensive data collected from rat hearts at control and post-PAH time points [5,10,33]. In this study, we extended our model to predict the time course of fiber-, tissue-, and organ-level adaptations of the RV under PAH from the control to post-PAH states.…”