Multiscale Computational Analysis of Right Ventricular Mechanoenergetics

Abstract

Right ventricular (RV) failure, which occurs in the setting of pressure overload, is characterized by abnormalities in mechanical and energetic function. The effects of these cell- and tissue-level changes on organ-level RV function are unknown. The primary aim of this study was to investigate the effects of myofiber mechanics and mitochondrial energetics on organ-level RV function in the context of pressure overload using a multiscale model of the cardiovascular system. The model integrates the mitochondria-generated metabolite concentrations that drive intracellular actin-myosin cross-bridging and extracellular myocardial tissue mechanics in a biventricular heart model coupled with simple lumped parameter circulations. Three types of pressure overload were simulated and compared to experimental results. The computational model was able to capture a wide range of cardiovascular physiology and pathophysiology from mild RV dysfunction to RV failure. Our results confirm that, in response to pressure overload alone, the RV is able to maintain cardiac output (CO) and predict that alterations in either RV active myofiber mechanics or RV metabolite concentrations are necessary to decrease CO.

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

“…In this study a single animal model of RVF was explored. A recent study by our group evaluated the ability of the computational model to predict pathophysiology in three different experimental models of PH ( Pewowaruk et al, 2018 ). Here we focused on one PH model to enable in-depth investigation of the effect of a potential therapy.…”

“…The multiscale computational model does provide the ability to investigate interventricular interactions allowing for consideration of LV function as a key variable when experimental results are available. Recent work by our group has explored the impact of LV myocardial infarction on RV function using simulations ( Pewowaruk et al, 2018 ). Despite these limitations, this novel study highlights that impaired myocyte force generation previously shown to be a cellular feature of RVF appears to drive impaired hemodynamic function.…”

“…Developed by Tewari et al (2016b) , myofilament mechanoenergetics ( Tewari et al, 2016a , b ) drive biventricular contraction and relaxation ( Lumens et al, 2009 ) coupled to lumped parameter circulations ( Tewari et al, 2013 ). As recently described by Pewowaruk et al (2018) , in order to better represent diastolic ventricular physiology, a varying elastance atrial model was incorporated ( Senzaki et al, 1996 ), in which the atrial pressure changes that drive ventricular filling are calculated as…”

Current Understanding of the Right Ventricle Structure and Function in Pulmonary Arterial Hypertension

“…In silico modelling facilitates parametric analysis of the relative contribution of isolated remodeling events to RV dysfunction; something that would be otherwise time-consuming or impractical to measure experimentally. The multi-scale in silico models used to study RV function range from lumped parameter hemodynamic models of the pulmonary vasculature (Grant and Paradowski, 1987) to organ and tissue-level models incorporating 3D animal/patient-specific biventricular geometries (Finsberg et al, 2019), structurally detailed fiber-level models (Gomez et al, 2017), and cell/molecularlevel models coupling mitochondrial mechanoenergetics to cross-bridge cycling and cardiomyocyte contractile dynamics (Pewowaruk et al, 2018). For a detailed review on multi-scale modeling of RV-PA mechanics in PAH, please refer to the recent work by .…”

“…Pulmonary arterial hypertension has been shown to result in RV remodeling at different scales, from changes in organ-level hemodynamics to tissue stiffening, fiber reorientation, and altered myocyte contractility and mitochondrial energetics (Hill et al, 2014;Avazmohammadi et al, 2017a;Pewowaruk et al, 2018;Sharifi Kia et al, 2020). Mechanical stimuli play a key role in RV remodeling in response to pressure overload and biomechanical analysis of RV pathophysiology has drawn significant attention over the past years.…”