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A computational framework is developed to consider the concurrent growth and remodelling (G&R) processes occurring in the large pulmonary artery (PA) and right ventricle (RV), as well as ventricular–vascular interactions during the progression of pulmonary arterial hypertension (PAH). This computational framework couples the RV and the proximal PA in a closed-loop circulatory system that operates in a short timescale of a cardiac cycle, and evolves over a long timescale due to G&R processes in the PA and RV. The framework predicts changes in haemodynamics (e.g. 68.2% increase in mean PA pressure), RV geometry (e.g. 38% increase in RV end-diastolic volume) and PA tissue microstructure (e.g. 90% increase in collagen mass) that are consistent with clinical and experimental measurements of PAH. The framework also predicts that a reduction in RV contractility is associated with long-term RV chamber dilation, a common biomarker observed in the late-stage PAH. Sensitivity analyses on the G&R rate constants show that large PA stiffening (both short and long term) is affected by RV remodelling more than the reverse. This framework can serve as a foundation for the future development of a more predictive and comprehensive cardiovascular G&R model with realistic heart and vascular geometries.

Pulmonary arterial hypertension (PAH) is a complex disease involving increased resistance in the pulmonary arteries and subsequent right ventricular (RV) remodeling. Ventricular-arterial interactions are fundamental to PAH pathophysiology but are rarely captured in computational models. It is important to identify metrics that capture and quantify these interactions to inform our understanding of this disease as well as potentially facilitate patient stratification. Towards this end, we developed and calibrated two multi-scale high-resolution closed-loop computational models using open-source software: a high-resolution arterial model implemented using CRIMSON, and a high-resolution ventricular model implemented using FEniCS. Models were constructed with clinical data including non-invasive imaging and invasive hemodynamic measurements from a cohort of pediatric PAH patients. A contribution of this work is the discussion of inconsistencies in anatomical and hemodynamic data routinely acquired in PAH patients. We proposed and implemented strategies to mitigate these inconsistencies, and subsequently use this data to inform and calibrate computational models of the ventricles and large arteries. Computational models based on adjusted clinical data were calibrated until the simulated results for the high-resolution arterial models matched within 10% of adjusted data consisting of pressure and flow, whereas the high-resolution ventricular models were calibrated until simulation results matched adjusted data of volume and pressure waveforms within 10%. A statistical analysis was performed to correlate numerous data-derived and model-derived metrics with clinically assessed disease severity. Several model-derived metrics were strongly correlated with clinically assessed disease severity, suggesting that computational models may aid in assessing PAH severity.

IntroductionA 2-year-old female with hypoplastic left heart syndrome (HLHS)-variant, a complex congenital heart defect (CHD) characterized by the underdevelopment of the left ventricle, presented with complications following single ventricle palliation. Diagnostic work-up revealed elevated Fontan pathway pressures, as well as significant dilation of the inferior Fontan pathway with inefficient swirling flow and hepatic venous reflux. Due to the frail condition of the patient, the clinical team considered an endovascular revision of the Fontan pathway. In this work, we performed a computational fluid dynamics (CFD) analysis informed by data on anatomy, flow, and pressure to investigate the hemodynamic effect of the endovascular Fontan revision.MethodsA patient-specific anatomical model of the Fontan pathway was constructed from magnetic resonance imaging (MRI) data using the cardiovascular modeling software CardiovasculaR Integrated Modeling and SimulatiON (CRIMSON). We first created and calibrated a pre-intervention 3D-0D multi-scale model of the patient’s circulation using fluid-structure interaction (FSI) analyses and custom lumped parameter models (LPMs), including the Fontan pathway, the single ventricle, arterial and venous systemic, and pulmonary circulations. Model parameters were iteratively tuned until simulation results matched clinical data on flow and pressure. Following calibration of the pre-intervention model, a custom bifurcated endograft was introduced into the anatomical model to virtually assess post-intervention hemodynamics.ResultsThe pre-intervention model successfully reproduced the clinical hemodynamic data on regional flow splits, pressures, and hepatic venous reflux. The proposed endovascular repair model revealed increases of mean and pulse pressure at the inferior vena cava (IVC) of 6 and 29%, respectively. Inflows at the superior vena cava (SVC) and IVC were each reduced by 5%, whereas outflows at the left pulmonary artery (LPA) and right pulmonary artery (RPA) increased by 4%. Hepatic venous reflux increased by 6%.ConclusionOur computational analysis indicated that the proposed endovascular revision would lead to unfavorable hemodynamic conditions. For these reasons, the clinical team decided to forgo the proposed endovascular repair and to reassess the management of this patient. This study confirms the relevance of CFD modeling as a beneficial tool in surgical planning for single ventricle CHD patients.

Microstructural changes in the pulmonary arteries associated with pulmonary arterial hypertension (PAH) is not well understood and characterized in humans. To address this issue, we developed and applied a patient-specific inverse finite element (FE) modeling framework to characterize mechanical and structural changes of the micro-constituents in the proximal pulmonary arteries using in-vivo pressure measurements and magnetic resonance images. The framework was applied using data acquired from a pediatric PAH patient and a heart transplant patient with normal pulmonary arterial pressure, which serves as control. Parameters of a constrained mixture model that are associated with the structure and mechanical properties of elastin, collagen fibers and smooth muscle cells were optimized to fit the patient-specific pressure-diameter responses of the main pulmonary artery. Based on the optimized parameters, individual stress and linearized stiffness resultants of the three tissue constituents, as well as their aggregated values, were estimated in the pulmonary artery. Aggregated stress resultant and stiffness are, respectively, 4.6 and 3.4 times higher in the PAH patient than the control subject. Stress and stiffness resultants of each tissue constituent are also higher in the PAH patient. Specifically, the mean stress resultant is highest in elastin (PAH: 69.96, control: 14.42 kPa-mm), followed by those in smooth muscle cell (PAH: 13.95, control: 4.016 kPa-mm) and collagen fibers (PAH: 13.19, control: 2.908 kPa-mm) in both the PAH patient and the control subject. This result implies that elastin may be the key load-bearing constituent in the pulmonary arteries of the PAH patient and the control subject.

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization., Author summary We provide the first full presentation in the literature of CRIMSON, the Cardiovascular Integrated Modelling and Simulation Package. CRIMSON consists of a graphical user interface desktop computer program for creating geometric models of blood vessels from medical imaging scans, specifying parameters such as the stiffness of the artery walls, the resistance of connected vessels which are not visible on the scans, and determining the appropriate parameters for all aspects of the model. CRIMSON additionally consists of the Flowsolver, a high-performance computing package which simulates the flow of blood through the models created in the graphical user interface. Whilst several packages which can simulate blood flow exist, most target general fluid simulations, and this lack of specialisation means that blood flow simulation is harder to perform, and can require ad hoc (and potentially scientifically-limiting) workflow decisions. CRIMSON’s specialisation deals with these problems, as well as presenting a number of unique features which are unavailable elsewhere.

Ventricular-arterial coupling plays a key role in the physiologic function of the cardiovascular system. We have previously described a hybrid lumped-finite element (FE) modeling framework of the systemic circulation that couples idealized FE models of the aorta and the left ventricle (LV). Here, we describe an extension of the lumped-FE modeling framework that couples patient-specific FE models of the left and right ventricles, aorta and the large pulmonary arteries in both the systemic and pulmonary circulations. Geometries of the FE models were reconstructed from magnetic resonance (MR) images acquired in a pediatric patient diagnosed with pulmonary arterial hypertension (PAH). The modeling framework was calibrated with pressure waveforms acquired in the heart and arteries by catheterization as well as ventricular volume and arterial diameter waveforms measured from MR images. The calibrated model hemodynamic results match well with the clinically-measured waveforms (volume and pressure) in the LV and right ventricle (RV) as well as with the clinically-measured waveforms (pressure and diameter) in the aorta and main pulmonary artery. The calibrated framework was then used to simulate three cases, namely, (1) an increase in collagen in the large pulmonary arteries, (2) a decrease in RV contractility, and (3) an increase in the total pulmonary arterial resistance, all characteristics of progressive PAH. The key finding from these simulations is that hemodynamics of the pulmonary vasculature and RV wall stress are more sensitive to vasoconstriction with a 10% of reduction in the lumen diameter of the distal vessels than a 67% increase in the proximal vessel's collagen mass.

Objective:Suprarenal abdominal aortic coarctation (SAAC) alters flow and pressure patterns to the kidneys and is often associated with severe angiotensin-mediated hypertension refractory to drug therapy. SAAC is most often treated by a thoracoabdominal bypass (TAB) or patch aortoplasty (PA). It is currently unclear what effect these interventions have on renal flow and pressure waveforms. This study, using retrospective data from a patient with SAAC subjected to a TAB, undertook computational modeling to analyze aortorenal blood flow preoperatively as well as postoperatively after a variety of TAB and PA interventions. Methods:Patient-specific anatomic models were constructed from preoperative computed tomography angiograms of a 9-year-old child with an isolated SAAC. Fluid-structure interaction (FSI) simulations of hemodynamics were performed to analyze preoperative renal flow and pressure waveforms. A parametric study was then performed to examine the hemodynamic impact of different bypass diameters and patch oversizing. Results:Preoperative FSI results documented diastole-dominated renal perfusion with considerable high-frequency disturbances in blood flow and pressure. The postoperative TAB right and left kidney volumes increased by 58% and 79%, respectively, reflecting the increased renal artery blood flows calculated by the FSI analysis. Postoperative increases in systolic flow accompanied decreases in high-frequency disturbances, aortic pressure, and collateral flow after all surgical interventions. In general, lesser degrees of high-frequency disturbances followed PA interventions. High-frequency disturbances were eliminated with the 0% PA in contrast to the 30% and 50% PA oversizing and TAB interventions, in which these flow disturbances remained. Conclusions:Both TAB and PA dramatically improved renal artery flow and pressure waveforms, although disturbed renal waveforms remained in many of the surgical scenarios. Importantly, only the 0% PA oversizing scenario eliminated all high-frequency disturbances, resulting in nearly normal aortorenal blood flow. The study also establishes the relevance of patient-specific computational modeling in planning interventions for the midaortic syndrome. Clinical Relevance:We performed computational fluid dynamics modeling to assess aortorenal blood flow in a child with a suprarenal abdominal aortic coarctation and to test the performance of different surgical interventions. We discovered high-frequency disturbances in the renal arteries that could potentially trigger excessive renin release. Thoracoabdominal bypass and patch aortoplasty with oversizing did not remove these disturbances completely. This could explain why the hypertension cure rates of surgical repair of suprarenal abdominal aortic coarctation are suboptimal. In addition, this study establishes the relevance of computational fluid dynamics modeling as a valuable tool to analyze complex hemodynamics and to test the performance of different surgical interventions.