Integrated modeling and simulation of recruitment of myocardial perfusion and oxygen delivery in exercise.

While exercise-mediated vasoregulation in the myocardium is understood to be governed by autonomic, myogenic, and metabolic-mediated mechanisms, we do not yet understand the spatial heterogeneity of vasodilation or its effects on microvascular flow patterns and oxygen delivery. This study uses a simulation and modeling approach to explore the mechanisms underlying the recruitment of myocardial perfusion and oxygen delivery in exercise. The simulation approach integrates model components representing: whole-body cardiovascular hemodynamics, cardiac mechanics and myocardial work; myocardial perfusion; and myocardial oxygen transport. Integrating these systems together, model simulations reveal: (1.) To match expected flow and transmural flow ratios at increasing levels of exercise, a greater degree of vasodilation must occur in the subendocardium compared to the subepicardium. (2.) Oxygen extraction and venous oxygenation are predicted to substantially decrease with increasing exercise level preferentially in the subendocardium, suggesting that an oxygen-dependent error signal driving metabolic mediated recruitment of flow would be operative only in the subendocardium. (3.) Under baseline physiological conditions approximately 4% of the oxygen delivered to the subendocardium may be supplied via retrograde flow from coronary veins.

Unraveling the Gordian knot of coronary pressure-flow autoregulation.

The coronary circulation has the inherent ability to maintain myocardial perfusion constant over a wide range of perfusion pressures. The phenomenon of pressure-flow autoregulation is crucial in response to flow-limiting atherosclerotic lesions which diminish coronary driving pressure and increase risk of myocardial ischemia and infarction. Despite well over half a century of devoted research, understanding of the mechanisms responsible for autoregulation remains one of the most fundamental and contested questions in the field today. The purpose of this review is to highlight current knowledge regarding the complex interrelationship between the pathways and mechanisms proposed to dictate the degree of coronary pressure-flow autoregulation. Our group recently likened the intertwined nature of the essential determinants of coronary flow control to the symbolically unsolvable "Gordian knot". To further efforts to unravel the autoregulatory "knot", we consider recent challenges to the local metabolic and myogenic hypotheses and the complicated dynamic structural and functional heterogeneity unique to the heart and coronary circulation. Additional consideration is given to interrogation of putative mediators, role of K+ and Ca2+ channels, and recent insights from computational modeling studies. Improved understanding of how specific vasoactive mediators, pathways, and underlying disease states influence coronary pressure-flow relations stands to significantly reduce morbidity and mortality for what remains the leading cause of death worldwide.

A comparative study of altered hemodynamics in iliac vein compression syndrome.

Introduction: Iliac vein compression syndrome (IVCS) is present in over 20% of the population and is associated with left leg pain, swelling, and thrombosis. IVCS symptoms are thought to be induced by altered pelvic hemodynamics, however, there currently exists a knowledge gap on the hemodynamic differences between IVCS and healthy patients. To elucidate those differences, we carried out a patient-specific, computational modeling comparative study. Methods: Computed tomography and ultrasound velocity and area data were used to build and validate computational models for a cohort of IVCS (N = 4, Subject group) and control (N = 4, Control group) patients. Flow, cross-sectional area, and shear rate were compared between the right common iliac vein (RCIV) and left common iliac vein (LCIV) for each group and between the Subject and Control groups for the same vessel. Results: For the IVCS patients, LCIV mean shear rate was higher than RCIV mean shear rate (550 ± 103 s-1 vs. 113 ± 48 s-1, p = 0.0009). Furthermore, LCIV mean shear rate was higher in the Subject group than in the Control group (550 ± 103 s-1 vs. 75 ± 37 s-1, p = 0.0001). Lastly, the LCIV/RCIV shear rate ratio was 4.6 times greater in the Subject group than in the Control group (6.56 ± 0.9 vs. 1.43 ± 0.6, p = 0.00008). Discussion: Our analyses revealed that IVCS patients have elevated shear rates which may explain a higher thrombosis risk and suggest that their thrombus initiation process may share aspects of arterial thrombosis. We have identified hemodynamic metrics that revealed profound differences between IVCS patients and Controls, and between RCIV and LCIV in the IVCS patients. Based on these metrics, we propose that non-invasive measurement of shear rate may aid with stratification of patients with moderate compression in which treatment is highly variable. More investigation is needed to assess the prognostic value of shear rate and shear rate ratio as clinical metrics and to understand the mechanisms of thrombus formation in IVCS patients.

lGeneralized super-resolution 4D Flow MRI-using ensemble learning to extend across the cardiovascular system.

4D Flow Magnetic Resonance Imaging (4D Flow MRI) is a non-invasive measurement technique capable of quantifying blood flow across the cardiovascular system. While practical use is limited by spatial resolution and image noise, incorporation of trained super-resolution (SR) networks has potential to enhance image quality post-scan. However, these efforts have predominantly been restricted to narrowly defined cardiovascular domains, with limited exploration of how SR performance extends across the cardiovascular system; a task aggravated by contrasting hemodynamic conditions apparent across the cardiovasculature. The aim of our study was to explore the generalizability of SR 4D Flow MRI using a combination of heterogeneous training sets and dedicated ensemble learning. With synthetic training data generated across three disparate domains (cardiac, aortic, cerebrovascular), varying convolutional base and ensemble learners were evaluated as a function of domain and architecture, quantifying performance on both in-silico and acquired in-vivo data from the same three domains. Results show that both bagging and stacking ensembling enhance SR performance across domains, accurately predicting high-resolution velocities from low-resolution input data in-silico. Likewise, optimized networks successfully recover native resolution velocities from downsampled in-vivo data, as well as show qualitative potential in generating denoised SR-images from clinicallevel input data. In conclusion, our work presents a viable approach for generalized SR 4D Flow MRI, with ensemble learning extending utility across various clinical areas of interest.

A multi-stage neural network approach for coronary 3D reconstruction from uncalibrated X-ray angiography images.

We present a multi-stage neural network approach for 3D reconstruction of coronary artery trees from uncalibrated 2D X-ray angiography images. This method uses several binarized images from different angles to reconstruct a 3D coronary tree without any knowledge of image acquisition parameters. The method consists of a single backbone network and separate stages for vessel centerline and radius reconstruction. The output is an analytical matrix representation of the coronary tree suitable for downstream applications such as hemodynamic modeling of local vessel narrowing (i.e., stenosis). The network was trained using a dataset of synthetic coronary trees from a vessel generator informed by both clinical image data and literature values on coronary anatomy. Our multi-stage network achieved sub-pixel accuracy in reconstructing vessel radius (RMSE = 0.16 ± 0.07 mm) and stenosis radius (MAE = 0.27 ± 0.18 mm), the most important feature used to inform diagnostic decisions. The network also led to 52% and 38% reduction in vessel centerline reconstruction errors compared to a single-stage network and projective geometry-based methods, respectively. Our method demonstrated robustness to overcome challenges such as vessel foreshortening or overlap in the input images. This work is an important step towards automated analysis of anatomic and functional disease severity in the coronary arteries.

Three-Dimensional Characterization of Aortic Root Motion by Vascular Deformation Mapping.

The aorta is in constant motion due to the combination of cyclic loading and unloading with its mechanical coupling to the contractile left ventricle (LV) myocardium. This aortic root motion has been proposed as a marker for aortic disease progression. Aortic root motion extraction techniques have been mostly based on 2D image analysis and have thus lacked a rigorous description of the different components of aortic root motion (e.g., axial versus in-plane). In this study, we utilized a novel technique termed vascular deformation mapping (VDM(D)) to extract 3D aortic root motion from dynamic computed tomography angiography images. Aortic root displacement (axial and in-plane), area ratio and distensibility, axial tilt, aortic rotation, and LV/Ao angles were extracted and compared for four different subject groups: non-aneurysmal, TAA, Marfan, and repair. The repair group showed smaller aortic root displacement, aortic rotation, and distensibility than the other groups. The repair group was also the only group that showed a larger relative in-plane displacement than relative axial displacement. The Marfan group showed the largest heterogeneity in aortic root displacement, distensibility, and age. The non-aneurysmal group showed a negative correlation between age and distensibility, consistent with previous studies. Our results revealed a strong positive correlation between LV/Ao angle and relative axial displacement and a strong negative correlation between LV/Ao angle and relative in-plane displacement. VDM(D)-derived 3D aortic root motion can be used in future studies to define improved boundary conditions for aortic wall stress analysis.

An ultrasound imaging and computational fluid dynamics protocol to assess hemodynamics in iliac vein compression syndrome.

OBJECTIVE: Elevated shear rates are known to play a role in arterial thrombosis; however, shear rates have not been thoroughly investigated in patients with iliac vein compression syndrome (IVCS) owing to imaging limitations and assumptions on the low shear nature of venous flows. This study was undertaken to develop a standardized protocol that quantifies IVCS shear rates and can aid in the diagnosis and treatment of patients with moderate yet symptomatic compression. METHODS: Study patients with and without IVCS had their iliac vein hemodynamics measured via duplex ultrasound (US) at two of the following three vessel locations: infrarenal inferior vena cava (IVC), right common iliac vein, and left common iliac vein, in addition to acquiring data at the right and left external iliac veins. US velocity spectra were multiplied by a weighted cross-sectional area calculated from US and computed tomography (CT) data to create flow waveforms. Flow waveforms were then scaled to enforce conservation of flow across the IVC and common iliac veins. A three-dimensional (3D), patient-specific model of the iliac vein anatomy was constructed from CT and US examination. Flow waveforms and the 3D model were used as a basis to run a computational fluid dynamics (CFD) simulation. Owing to collateral vessel flow and discrepancies between CT and US area measurements, flows in internal iliac veins and cross-sectional areas of the common iliac veins were calibrated iteratively against target common iliac flow. Simulation results on mean velocity were validated against US data at measurement locations. Simulation results were postprocessed to derive spatial and temporal values of quantities such as velocity and shear rate. RESULTS: Using our modeling protocol, we were able to build CFD models of the iliac veins that matched common iliac flow splits within 2% and measured US velocities within 10%. Proof-of-concept analyses (1 subject, 1 control) have revealed that patients with IVCS may experience elevated shear rates in the compressed left common iliac vein, more typical of the arterial rather than the venous circulation. These results encourage us to extend this protocol to a larger group of patients with IVCS and controls. CONCLUSIONS: We developed a protocol that obtains hemodynamic measurements of the IVC and iliac veins from US, creates patient-specific 3D reconstructions of the venous anatomy using CT and US examinations, and computes shear rates using calibrated CFD methods. Proof-of-concept results have indicated that patients with IVCS may experience elevated shear rates in the compressed left common iliac vein. Larger cohorts are needed to assess the relationship between venous compression and shear rates in patients with IVCS as compared with controls with noncompressed iliac veins. Further studies using this protocol may also give promising insights into whether or not to treat patients with moderate, yet symptomatic compression.

Oxygen-sensing pathways below autoregulatory threshold act to sustain myocardial oxygen delivery during reductions in perfusion pressure.

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. However, the mechanisms responsible for coronary autoregulation remain a fundamental and highly contested question. This study interrogated the local metabolic hypothesis of autoregulation by testing the hypothesis that hypoxemia-induced exaggeration of the metabolic error signal improves the autoregulatory response. Experiments were performed on open-chest anesthetized swine during stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg under normoxic (n = 15) and hypoxemic (n = 8) conditions, in the absence and presence of dobutamine-induced increases in myocardial oxygen consumption (MVO2) (n = 5-7). Hypoxemia (PaO2 < 40 mmHg) decreased coronary venous PO2 (CvPO2) ~ 30% (P < 0.001) and increased coronary blood flow ~ 100% (P < 0.001), sufficient to maintain myocardial oxygen delivery (P = 0.14) over a wide range of CPPs. Autoregulatory responsiveness during hypoxemia-induced reductions in CvPO2 were associated with increases of autoregulatory gain (Gc; P = 0.033) but not slope (P = 0.585) over a CPP range of 120 to 60 mmHg. Preservation of autoregulatory Gc (P = 0.069) and slope (P = 0.264) was observed during dobutamine administration ± hypoxemia. Reductions in coronary resistance in response to decreases in CPP predominantly occurred below CvPO2 values of ~ 25 mmHg, irrespective of underlying vasomotor reserve. These findings support the presence of an autoregulatory threshold under which oxygen-sensing pathway(s) act to preserve sufficient myocardial oxygen delivery as CPP is reduced during increases in MVO2 and/or reductions in arterial oxygen content.

A multiscale framework for defining homeostasis in distal vascular trees: applications to the pulmonary circulation.

Pulmonary arteries constitute a low-pressure network of vessels, often characterized as a bifurcating tree with heterogeneous vessel mechanics. Understanding the vascular complexity and establishing homeostasis is important to study diseases such as pulmonary arterial hypertension (PAH). The onset and early progression of PAH can be traced to changes in the morphometry and structure of the distal vasculature. Coupling hemodynamics with vessel wall growth and remodeling (G&R) is crucial for understanding pathology at distal vasculature. Accordingly, the goal of this study is to provide a multiscale modeling framework that embeds the essential features of arterial wall constituents coupled with the hemodynamics within an arterial network characterized by an extension of Murray's law. This framework will be used to establish the homeostatic baseline characteristics of a pulmonary arterial tree, including important parameters such as vessel radius, wall thickness and shear stress. To define the vascular homeostasis and hemodynamics in the tree, we consider two timescales: a cardiac cycle and a longer period of vascular adaptations. An iterative homeostatic optimization, which integrates a metabolic cost function minimization, the stress equilibrium, and hemodynamics, is performed at the slow timescale. In the fast timescale, the pulsatile blood flow dynamics is described by a Womersley's deformable wall analytical solution. Illustrative examples for symmetric and asymmetric trees are presented that provide baseline characteristics for the normal pulmonary arterial vasculature. The results are compared with diverse literature data on morphometry, structure, and mechanics of pulmonary arteries. The developed framework demonstrates a potential for advanced parametric studies and future G&R and hemodynamics modeling of PAH.

A magnetic resonance imaging-based computational analysis of cerebral hemodynamics in patients with carotid artery stenosis.

Management of asymptomatic carotid artery stenosis (CAS) relies on measuring the percentage of stenosis. The aim of this study was to investigate the impact of CAS on cerebral hemodynamics using magnetic resonance imaging (MRI)-informed computational fluid dynamics (CFD) and to provide novel hemodynamic metrics that may improve the understanding of stroke risk. CFD analysis was performed in two patients with similar degrees of asymptomatic high-grade CAS. Three-dimensional anatomical-based computational models of cervical and cerebral blood flow were constructed and calibrated patient-specifically using phase-contrast MRI flow and arterial spin labeling perfusion data. Differences in cerebral hemodynamics were assessed in preoperative and postoperative models. Preoperatively, patient 1 demonstrated large flow and pressure reductions in the stenosed internal carotid artery, while patient 2 demonstrated only minor reductions. Patient 1 exhibited a large amount of flow compensation between hemispheres (80.31%), whereas patient 2 exhibited only a small amount of collateral flow (20.05%). There were significant differences in the mean pressure gradient over the stenosis between patients preoperatively (26.3 vs. 1.8 mmHg). Carotid endarterectomy resulted in only minor hemodynamic changes in patient 2. MRI-informed CFD analysis of two patients with similar clinical classifications of stenosis revealed significant differences in hemodynamics which were not apparent from anatomical assessment alone. Moreover, revascularization of CAS might not always result in hemodynamic improvements. Further studies are needed to investigate the clinical impact of hemodynamic differences and how they pertain to stroke risk and clinical management.

Effects of non-Newtonian viscosity on arterial and venous flow and transport.

It is well known that blood exhibits non-Newtonian viscosity, but it is generally modeled as a Newtonian fluid. However, in situations of low shear rate, the validity of the Newtonian assumption is questionable. In this study, we investigated differences between Newtonian and non-Newtonian hemodynamic metrics such as velocity, vorticity, and wall shear stress. In addition, we investigated cardiovascular transport using two different approaches, Eulerian mass transport and Lagrangian particle tracking. Non-Newtonian solutions revealed important differences in both hemodynamic and transport metrics relative to the Newtonian model. Most notably for the hemodynamic metrics, in-plane velocity and vorticity were consistently larger in the Newtonian approximation for both arterial and venous flows. Conversely, wall shear stresses were larger for the non-Newtonian case for both the arterial and venous models. Our results also indicate that for the Lagrangian metrics, the history of accumulated shear was consistently larger for both arterial and venous flows in the Newtonian approximation. Lastly, our results also suggest that the Newtonian model produces larger near wall and luminal mass transport values compared to the non-Newtonian model, likely due to the increased vorticity and recirculation. These findings demonstrate the importance of accounting for non-Newtonian behavior in cardiovascular flows exhibiting significant regions of low shear rate and recirculation.

Patient-Specific Computational Modeling of Different Cannulation Strategies for Extracorporeal Membrane Oxygenation.

Institution of extracorporeal membrane oxygenation (ECMO) results in unique blood flow characteristics to the end-organ vascular beds. We studied the interplay between cardiac-driven and extracorporeal membrane oxygenation (ECMO)-driven flow to vascular beds in different ECMO configurations using a patient-specific computational fluid dynamics (CFD) analysis. A computational ECMO model (femoral artery cannulation [FAC]) was constructed using patient-specific imaging and hemodynamic data. Following model calibration, we augmented the 3D geometrical model to represent alternative ECMO configurations (ascending aorta cannulation [AAC] and subclavian artery cannulation [SAC]). We performed CFD analyses, including a novel virtual color-dye analysis to compare global and regional blood flow and pressure characteristics as well as contributions of cardiac and ECMO-derived flow to the various vascular beds. Flow waveforms at all the aortic branch vessels were pulsatile, despite low cardiac output and predominant nonpulsatile ECMO-driven hemodynamics. Virtual color-dye analysis revealed differential contribution of cardiac and ECMO-derived flow to the end-organ vascular beds in the FAC model, while this was more evenly distributed in the AAC and SAC models. While global hemodynamics were relatively similar between various ECMO configurations, several distinct hemodynamic indices, in particular wall shear stress and oscillatory shear patterns, as well as differential contribution of ECMO-derived flow to various vascular beds, showed remarkable differences. The clinical impact of this study highlighting the relevance of CFD modeling in assessment of complex hemodynamics in ECMO warrants further evaluation.

Computational modelling of multi-temporal ventricular-vascular interactions during the progression of pulmonary arterial hypertension.

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.

Left ventricular remodeling following aortic root and ascending aneurysm repair.

Objective: Adverse left ventricular remodeling due to a mismatch between stiffness of native aortic tissue and current polyester grafts may be under-recognized. This study was conducted to evaluate the impact of proximal aortic replacement on adverse remodeling of the left ventricle. Materials and methods: All aortic root and ascending aortic aneurysm patients were identified (n = 2,001, 2006-2019). The study cohort consisted of a subset of patients (n = 98) with two or more electrocardiogram (ECG)-gated CT angiograms, but without concomitant aortic valve disease or bicuspid aortic valve, connective tissue disease, acute aortic syndrome or prior history of aortic repair or mitral valve surgery. LV myocardial mass was measured from CT data and indexed to body surface area (LVMI). The study cohort was divided into a surgery group (n = 47) and a control group; optimal medical therapy group (OMT, n = 51). Results: The mean age was 60 ± 11 years (80% male). Beta-blocker use was significantly more frequent in the surgery group (89 vs. 57%, p < 0.001), whereas, all other antihypertensive drugs were more frequent in the OMT group. The average follow-up was 9.1 ± 4.0 months for the surgery group and 13.7 ± 6.3 months for the OMT group. Average LVMI at baseline was similar in both groups (p = 0.934). LVMI increased significantly in the surgery group compared to the OMT group (3.7 ± 4.1 vs. 0.6 ± 4.4 g/m2, p = 0.001). Surgery, baseline LVMI, age, and sex were found to be independent predictors of LVMI increased on multivariable analysis. Conclusion: Proximal aortic repair with stiff polyester grafts was associated with increased LV mass in the first-year post-operative and may promote long-term adverse cardiac remodeling. Further studies should be considered to evaluate the competing effects of aortic aneurysm related mortality against risks of long-term graft induced aortic stiffening and the potential implications on current size thresholds for intervention.

Mitochondrial oxidative stress contributes to diastolic dysfunction through impaired mitochondrial dynamics.

Diastolic dysfunction (DD) underlies heart failure with preserved ejection fraction (HFpEF), a clinical syndrome associated with aging that is becoming more prevalent. Despite extensive clinical studies, no effective treatment exists for HFpEF. Recent findings suggest that oxidative stress contributes to the pathophysiology of DD, but molecular mechanisms underpinning redox-sensitive cardiac remodeling in DD remain obscure. Using transgenic mice with mitochondria-targeted NOX4 overexpression (Nox4TG618) as a model, we demonstrate that NOX4-dependent mitochondrial oxidative stress induces DD in mice as measured by increased E/E', isovolumic relaxation time, Tau Glantz and reduced dP/dtmin while EF is preserved. In Nox4TG618 mice, fragmentation of cardiomyocyte mitochondria, increased DRP1 phosphorylation, decreased expression of MFN2, and a higher percentage of apoptotic cells in the myocardium are associated with lower ATP-driven and maximal mitochondrial oxygen consumption rates, a decrease in respiratory reserve, and a decrease in citrate synthase and Complex I activities. Transgenic mice have an increased concentration of TGFß and osteopontin in LV lysates, as well as MCP-1 in plasma, which correlates with a higher percentage of LV myocardial periostin- and ACTA2-positive cells compared with wild-type mice. Accordingly, the levels of ECM as measured by Picrosirius Red staining as well as interstitial deposition of collagen I are elevated in the myocardium of Nox4TG618 mice. The LV tissue of Nox4TG618 mice also exhibited increased ICaL current, calpain 2 expression, and altered/disrupted Z-disc structure. As it pertains to human pathology, similar changes were found in samples of LV from patients with DD. Finally, treatment with GKT137831, a specific NOX1 and NOX4 inhibitor, or overexpression of mCAT attenuated myocardial fibrosis and prevented DD in the Nox4TG618 mice. Together, our results indicate that mitochondrial oxidative stress contributes to DD by causing mitochondrial dysfunction, impaired mitochondrial dynamics, increased synthesis of pro-inflammatory and pro-fibrotic cytokines, activation of fibroblasts, and the accumulation of extracellular matrix, which leads to interstitial fibrosis and passive stiffness of the myocardium. Further, mitochondrial oxidative stress increases cardiomyocyte Ca2+ influx, which worsens CM relaxation and raises the LV filling pressure in conjunction with structural proteolytic damage.

Data-driven computational models of ventricular-arterial hemodynamics in pediatric pulmonary arterial hypertension.

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.

Multiscale model of the physiological control of myocardial perfusion to delineate putative metabolic feedback mechanisms.

Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural and metabolic mechanisms. Although several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the co-ordinated action of parallel regulatory mechanisms, we applied a multiscale modelling framework to analyse experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The modelling framework integrates a previously established lumped-parameter model of myocardial perfusion used to account for transmural haemodynamic variations and a simple vessel mechanics model used to simulate the vascular tone in each of three myocardial layers. Vascular tone in the resistance vessel mechanics model is governed by input stimuli from the myogenic, metabolic and autonomic control mechanisms. Seven competing formulations of the metabolic feedback mechanism are implemented in the modelling framework, and associated model simulations are compared with experimental data on coronary pressures and flows under a range of experimental conditions designed to interrogate the governing control mechanisms. Analysis identifies a maximally probable metabolic mechanism among the seven tested models, in which production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow. Finally, the identified model is validated based on comparisons of simulations with data on the myocardial perfusion response to conscious exercise that were not used for model identification. KEY POINTS: Although several competing hypotheses exist, we lack knowledge of specific nature of the metabolic mechanism(s) governing regional myocardial perfusion. Moreover, we lack an understanding of how parallel myogenic, adrenergic/autonomic and metabolic mechanisms work together to regulatory oxygen delivery in the beating heart. We have developed a multiscale modelling framework to test competing hypotheses against experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The analysis identifies a maximally probable metabolic mechanism among seven tested models, in which the production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow.

Comparative Study of Human and Murine Aortic Biomechanics and Hemodynamics in Vascular Aging.

Introduction: Aging has many effects on the cardiovascular system, including changes in structure (aortic composition, and thus stiffening) and function (increased proximal blood pressure, and thus cardiac afterload). Mouse models are often used to gain insight into vascular aging and mechanisms of disease as they allow invasive assessments that are impractical in humans. Translation of results from murine models to humans can be limited, however, due to species-specific anatomical, biomechanical, and hemodynamic differences. In this study, we built fluid-solid-interaction (FSI) models of the aorta, informed by biomechanical and imaging data, to compare wall mechanics and hemodynamics in humans and mice at two equivalent ages: young and older adults. Methods: For the humans, 3-D computational models were created using wall property data from the literature as well as patient-specific magnetic resonance imaging (MRI) and non-invasive hemodynamic data; for the mice, comparable models were created using population-based properties and hemodynamics as well as subject-specific anatomies. Global aortic hemodynamics and wall stiffness were compared between humans and mice across age groups. Results: For young adult subjects, we found differences between species in pulse pressure amplification, compliance and resistance distribution, and aortic stiffness gradient. We also found differences in response to aging between species. Generally, the human spatial gradients of stiffness and pulse pressure across the aorta diminished with age, while they increased for the mice. Conclusion: These results highlight key differences in vascular aging between human and mice, and it is important to acknowledge these when using mouse models for cardiovascular research.

A Combined Computational Fluid Dynamics and Arterial Spin Labeling MRI Modeling Strategy to Quantify Patient-Specific Cerebral Hemodynamics in Cerebrovascular Occlusive Disease.

Cerebral hemodynamics in the presence of cerebrovascular occlusive disease (CVOD) are influenced by the anatomy of the intracranial arteries, the degree of stenosis, the patency of collateral pathways, and the condition of the cerebral microvasculature. Accurate characterization of cerebral hemodynamics is a challenging problem. In this work, we present a strategy to quantify cerebral hemodynamics using computational fluid dynamics (CFD) in combination with arterial spin labeling MRI (ASL). First, we calibrated patient-specific CFD outflow boundary conditions using ASL-derived flow splits in the Circle of Willis. Following, we validated the calibrated CFD model by evaluating the fractional blood supply from the main neck arteries to the vascular territories using Lagrangian particle tracking and comparing the results against vessel-selective ASL (VS-ASL). Finally, the feasibility and capability of our proposed method were demonstrated in two patients with CVOD and a healthy control subject. We showed that the calibrated CFD model accurately reproduced the fractional blood supply to the vascular territories, as obtained from VS-ASL. The two patients revealed significant differences in pressure drop over the stenosis, collateral flow, and resistance of the distal vasculature, despite similar degrees of clinical stenosis severity. Our results demonstrated the advantages of a patient-specific CFD analysis for assessing the hemodynamic impact of stenosis.

Interventional Planning for Endovascular Revision of a Lateral Tunnel Fontan: A Patient-Specific Computational Analysis.

INTRODUCTION: A 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. METHODS: A 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. RESULTS: The 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%. CONCLUSION: Our 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.