Extended-volume image-derived models of coronary microcirculation.

OBJECTIVE: Recent advances in tissue clearing and high-throughput imaging have enabled the acquisition of extended-volume microvasculature images at a submicron resolution. The objective of this study was to extract information from this type of images by integrating a sequence of 3D image processing steps on Terabyte scale datasets. METHODS: We acquired coronary microvasculature images throughout an entire short-axis slice of a 3-month-old Wistar-Kyoto rat heart. This dataset covered 13 × 10 × 0.6 mm at a resolution of 0.933 × 0.933 × 1.866 µm and occupied 700 Gigabytes of disk space. We used chunk-based image segmentation, combined with an efficient graph generation technique, to quantify the microvasculature in the large-scale images. Specifically, we focused on the microvasculature with a vessel diameter up to 15 µm. RESULTS: Morphological data for the complete short-axis ring were extracted within 16 h using this pipeline. From the analyses, we identified that microvessel lengths in the rat coronary microvasculature varied from 6 to 300 µm. However, their distribution was heavily skewed toward shorter lengths, with a mode of 16.5 µm. In contrast, vessel diameters ranged from 3 to 15 µm and had an approximately normal distribution of 6.5 ± 2 µm. CONCLUSION: The tools and techniques from this study will serve other investigations into the microcirculation, and the wealth of data from this study will enable the analysis of biophysical mechanisms using computer models.

Personalized surgical planning for coronary bypass graft configurations using patient-specific computational modeling to avoid flow competition in arterial grafts.

Objectives: Flow competition between coronary artery bypass grafts (CABG) and native coronary arteries is a significant problem affecting arterial graft patency. The objectives of this study were to compare the predictive hemodynamic flow resulting from various total arterial grafting configurations and to evaluate whether the use of computational fluid dynamics (CFD) models capable of predicting flow can assist surgeons to make better decisions for individual patients by avoiding poorly functioning grafts. Methods: Sixteen cardiac surgeons declared their preferred CABG configuration using bilateral internal mammary and radial arteries for each of 5 patients who had differing degrees of severe triple vessel coronary disease. Surgeons selected both a preferred 'aortic' strategy, with at least one graft arising from the ascending aorta, and a preferred "anaortic" strategy which could be performed as a "no-aortic touch" operation. CT coronary angiograms of the 5 patients were coupled to CFD models using a novel flow solver "COMCAB." Twelve different CABG configurations were compared for each patient of which 4 were "aortic" and 8 were "anaortic." Surgeons then selected their preferred grafting configurations after being shown predictive hemodynamic metrics including functional assessment of stenoses (instantaneous wave-free ratio; fractional flow reserve), transit time flowmetry graft parameters (mean graft flow; pulsatility index) and myocardial perfusion. Results: A total of 87.5% (7/8) of "anaortic" configurations compared to 25% (1/4) of "aortic" configurations led to unsatisfactory grafts in at least 1 of the 5 patients (P = 0.038). The use of the computational models led to a significant decrease in the selection of unsatisfactory grafting configurations when surgeons employed "anaortic" (21.25% (17/80) vs. 1.25% (1/80), P < 0.001) but not "aortic" techniques (5% (4/80) vs. 0% (0/80), P = 0.64). Similarly, there was an increase in the selection of ideal configurations for "anaortic" (6.25% (5/80) vs. 28.75% (23/80), P < 0.001) but not "aortic" techniques (65% (52/80) vs. 61.25% (49/80), P = 0.74). Furthermore, surgeons who planned to use more than one unique "anaortic" configuration across all 5 patients increased (12.5% (2/16) vs. 87.5% (14/16), P<0.001). Conclusions: "COMCAB" is a promising tool to improve personalized surgical planning particularly for CABG configurations involving composite or sequential grafts which are used more frequently in anaortic operations.

A predictive patient-specific computational model of coronary artery bypass grafts for potential use by cardiac surgeons to guide selection of graft configurations.

Cardiac surgeons face a significant degree of uncertainty when deciding upon coronary artery bypass graft configurations for patients with coronary artery disease. This leads to significant variation in preferred configuration between different surgeons for a particular patient. Additionally, for the majority of cases, there is no consensus regarding the optimal grafting strategy. This situation results in the tendency for individual surgeons to opt for a "one size fits all" approach and use the same grafting configuration for the majority of their patients neglecting the patient-specific nature of the diseased coronary circulation. Quantitative metrics to assess the adequacy of coronary bypass graft flows have recently been advocated for routine intraoperative use by cardiac surgeons. In this work, a novel patient-specific 1D-0D computational model called "COMCAB" is developed to provide the predictive haemodynamic parameters of functional graft performance that can aid surgeons to avoid configurations with grafts that have poor flow and thus poor patency. This model has significant potential for future expanded applications.

It's clearly the heart! Optical transparency, cardiac tissue imaging, and computer modelling.

Recent developments in clearing and microscopy enable 3D imaging with cellular resolution up to the whole organ level. These methods have been used extensively in neurobiology, but their uptake in other fields has been much more limited. Application of this approach to the human heart and effective use of the data acquired present challenges of scale and complexity. Four interlinked issues need to be addressed: 1) efficient clearing and labelling of heart tissue, 2) fast microscopic imaging of human-scale samples, 3) handling and processing of multi-terabyte 3D images, and 4) extraction of structural information in computationally tractable structure-based models of cardiac function. Preliminary studies show that each of these requirements can be achieved with the appropriate application and development of existing technologies.

Reconstruction of coronary circulation networks: A review of methods.

Building anatomically accurate models of the coronary vascular system enables potentially deeper understandings of coronary circulation. To achieve this, (a) images at different levels of vascular network-arteries, arterioles, capillaries, venules, and veins-need to be obtained through suitable imaging modalities; and (b) from images, morphological and topological information needs to be extracted using image processing techniques. While there are several modalities that enable the imaging of large vessels, microcirculation imaging-capturing vessels having diameter lesser than 100 µm-has to date been typically confined to small regions of the heart. This spatially limited microcirculatory information has often been used within cardiac models, with the potentially erroneous assumption that it is representative of the whole organ. However, with the recent advancements in imaging and image processing, it is rapidly becoming feasible to acquire, process, and quantify microcirculation data at the scale of whole organ. In this review, we summarize the progress toward this goal followed through a presentation of the current state-of-the-art imaging and image processing techniques in the context of coronary microcirculation extraction, prominently but not exclusively, from small animals.

Decreasing Compensatory Ability of Concentric Ventricular Hypertrophy in Aortic-Banded Rat Hearts.

The cardiac system compensates for variations in physiological and pathophysiological conditions through a dynamic remodeling at the organ, tissue, and intracellular levels in order to maintain function. However, on longer time scales following the onset of ventricular pressure overload, such remodeling may begin to inhibit physiological function and ultimately lead to heart failure. This progression from compensatory to decompensatory behavior is poorly understood, in particular owing to the absence of a unified perspective of the concomitantly remodeling subsystems. To address this issue, the present study investigates the evolution of compensatory mechanisms, in response to overload, by integrating diffusion-tensor MRI, echocardiography, and intracellular and hemodynamic measurements within consistent computational simulations of aortic-banded rat hearts. This approach allows a comparison of the relative leverage of different cardiac properties (geometry, passive mechanical stiffness, fiber configuration, diastolic and peak calcium concentrations, calcium-binding affinity, and aortic impedance) to affect cardiac contraction. Measurements indicate that, following aortic banding, an ejection fraction (EF) of 75% was maintained, relative to control rats, despite significant remodeling of the left-ventricular wall thickness (increasing by ~90% over 4 weeks). Applying our framework, we identified the left-ventricular wall thickness (concentric hypertrophy) and the intracellular calcium dynamics as playing the dominant roles in preserving EF acutely, whereas the significance of hypertrophy decreased subsequently. This trend suggests an increasing reliance on intracellular mechanisms (average increase ~50%), rather than on anatomical features (average decrease ~60%), to achieve compensation of pump function in the early phase of heart failure.

Compensatory and decompensatory alterations in cardiomyocyte Ca2+ dynamics in hearts with diastolic dysfunction following aortic banding.

KEY POINTS: At the cellular level cardiac hypertrophy causes remodelling, leading to changes in ionic channel, pump and exchanger densities and kinetics. Previous studies have focused on quantifying changes in channels, pumps and exchangers without quantitatively linking these changes with emergent cellular scale functionality. Two biophysical cardiac cell models were created, parameterized and validated and are able to simulate electrophysiology and calcium dynamics in myocytes from control sham operated rats and aortic-banded rats exhibiting diastolic dysfunction. The contribution of each ionic pathway to the calcium kinetics was calculated, identifying the L-type Ca2+ channel and sarco/endoplasmic reticulum Ca2+ ATPase as the principal regulators of systolic and diastolic Ca2+ , respectively. Results show that the ability to dynamically change systolic Ca2+ , through changes in expression of key Ca2+ modelling protein densities, is drastically reduced following the aortic banding procedure; however the cells are able to compensate Ca2+ homeostasis in an efficient way to minimize systolic dysfunction. ABSTRACT: Elevated left ventricular afterload leads to myocardial hypertrophy, diastolic dysfunction, cellular remodelling and compromised calcium dynamics. At the cellular scale this remodelling of the ionic channels, pumps and exchangers gives rise to changes in the Ca2+ transient. However, the relative roles of the underlying subcellular processes and the positive or negative impact of each remodelling mechanism are not fully understood. Biophysical cardiac cell models were created to simulate electrophysiology and calcium dynamics in myocytes from control rats (SHAM) and aortic-banded rats exhibiting diastolic dysfunction. The model parameters and framework were validated and the fitted parameters demonstrated to be unique for explaining our experimental data. The contribution of each ionic pathway to the calcium kinetics was calculated, identifying the L-type Ca2+ channel (LCC) and the sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) as the principal regulators of systolic and diastolic Ca2+ , respectively. In the aortic banding model, the sensitivity of systolic Ca2+ to LCC density and diastolic Ca2+ to SERCA density decreased by 16-fold and increased by 23%, respectively, relative to the SHAM model. The energy cost of ionic homeostasis is maintained across the two models. The models predict that changes in ionic pathway densities in compensated aortic banding rats maintain Ca2+ function and efficiency. The ability to dynamically alter systolic function is significantly diminished, while the capacity to maintain diastolic Ca2+ is moderately increased.

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes.

Experimental data from human cardiac myocytes at body temperature is crucial for a quantitative understanding of clinically relevant cardiac function and development of whole-organ computational models. However, such experimental data is currently very limited. Specifically, important measurements to characterize changes in tension development in human cardiomyocytes that occur with perturbations in cell length are not available. To address this deficiency, in this study we present an experimental data set collected from skinned human cardiac myocytes, including the passive and viscoelastic properties of isolated myocytes, the steady-state force calcium relationship at different sarcomere lengths, and changes in tension following a rapid increase or decrease in length, and after constant velocity shortening. This data set is, to our knowledge, the first characterization of length and velocity-dependence of tension generation in human skinned cardiac myocytes at body temperature. We use this data to develop a computational model of contraction and passive viscoelasticity in human myocytes. Our model includes troponin C kinetics, tropomyosin kinetics, a three-state crossbridge model that accounts for the distortion of crossbridges, and the cellular viscoelastic response. Each component is parametrized using our experimental data collected in human cardiomyocytes at body temperature. Furthermore we are able to confirm that properties of length-dependent activation at 37°C are similar to other species, with a shift in calcium sensitivity and increase in maximum tension. We revise our model of tension generation in the skinned isolated myocyte to replicate reported tension traces generated in intact muscle during isometric tension, to provide a model of human tension generation for multi-scale simulations. This process requires changes to calcium sensitivity, cooperativity, and crossbridge transition rates. We apply this model within multi-scale simulations of biventricular cardiac function and further refine the parametrization within the whole organ context, based on obtaining a healthy ejection fraction. This process reveals that crossbridge cycling rates differ between skinned myocytes and intact myocytes.

Accurate and Standardized Coronary Wave Intensity Analysis.

OBJECTIVE: Coronary wave intensity analysis (cWIA) has increasingly been applied in the clinical research setting to distinguish between the proximal and distal mechanical influences on coronary blood flow. Recently, a cWIA-derived clinical index demonstrated prognostic value in predicting functional recovery postmyocardial infarction. Nevertheless, the known operator dependence of the cWIA metrics currently hampers its routine application in clinical practice. Specifically, it was recently demonstrated that the cWIA metrics are highly dependent on the chosen Savitzky-Golay filter parameters used to smooth the acquired traces. Therefore, a novel method to make cWIA standardized and automatic was proposed and evaluated in vivo. METHODS: The novel approach combines an adaptive Savitzky-Golay filter with high-order central finite differencing after ensemble-averaging the acquired waveforms. Its accuracy was assessed using in vivo human data. The proposed approach was then modified to automatically perform beat wise cWIA. Finally, the feasibility (accuracy and robustness) of the method was evaluated. RESULTS: The automatic cWIA algorithm provided satisfactory accuracy under a wide range of noise scenarios (≤10% and ≤20% error in the estimation of wave areas and peaks, respectively). These results were confirmed when beat-by-beat cWIA was performed. CONCLUSION: An accurate, standardized, and automated cWIA was developed. Moreover, the feasibility of beat wise cWIA was demonstrated for the first time. SIGNIFICANCE: The proposed algorithm provides practitioners with a standardized technique that could broaden the application of cWIA in the clinical practice as enabling multicenter trials. Furthermore, the demonstrated potential of beatwise cWIA opens the possibility investigating the coronary physiology in real time.

Beyond Bernoulli: Improving the Accuracy and Precision of Noninvasive Estimation of Peak Pressure Drops.

BACKGROUND: Transvalvular peak pressure drops are routinely assessed noninvasively by echocardiography using the Bernoulli principle. However, the Bernoulli principle relies on several approximations that may not be appropriate, including that the majority of the pressure drop is because of the spatial acceleration of the blood flow, and the ejection jet is a single streamline (single peak velocity value). METHODS AND RESULTS: We assessed the accuracy of the Bernoulli principle to estimate the peak pressure drop at the aortic valve using 3-dimensional cardiovascular magnetic resonance flow data in 32 subjects. Reference pressure drops were computed from the flow field, accounting for the principles of physics (ie, the Navier-Stokes equations). Analysis of the pressure components confirmed that the spatial acceleration of the blood jet through the valve is most significant (accounting for 99% of the total drop in stenotic subjects). However, the Bernoulli formulation demonstrated a consistent overestimation of the transvalvular pressure (average of 54%, range 5%-136%) resulting from the use of a single peak velocity value, which neglects the velocity distribution across the aortic valve plane. This assumption was a source of uncontrolled variability. CONCLUSIONS: The application of the Bernoulli formulation results in a clinically significant overestimation of peak pressure drops because of approximation of blood flow as a single streamline. A corrected formulation that accounts for the cross-sectional profile of the blood flow is proposed and adapted to both cardiovascular magnetic resonance and echocardiographic data.

Analysis of lead placement optimization metrics in cardiac resynchronization therapy with computational modelling.

AIMS: The efficacy of cardiac resynchronization therapy (CRT) is known to vary considerably with pacing location, however the most effective set of metrics by which to select the optimal pacing site is not yet well understood. Computational modelling offers a powerful methodology to comprehensively test the effect of pacing location in silico and investigate how to best optimize therapy using clinically available metrics for the individual patient. METHODS AND RESULTS: Personalized computational models of cardiac electromechanics were used to perform an in silico left ventricle (LV) pacing site optimization study as part of biventricular CRT in three patient cases. Maps of response to therapy according to changes in total activation time (ΔTAT) and acute haemodynamic response (AHR) were generated and compared with preclinical metrics of electrical function, strain, stress, and mechanical work to assess their suitability for selecting the optimal pacing site. In all three patients, response to therapy was highly sensitive to pacing location, with laterobasal locations being optimal. ΔTAT and AHR were found to be correlated (ρ < -0.80), as were AHR and the preclinical activation time at the pacing site (ρ ≥ 0.73), however pacing in the last activated site did not result in the optimal response to therapy in all cases. CONCLUSION: This computational modelling study supports pacing in laterobasal locations, optimizing pacing site by minimizing paced QRS duration and pacing in regions activated late at sinus rhythm. Results demonstrate information content is redundant using multiple preclinical metrics. Of significance, the correlation of AHR with ΔTAT indicates that minimization of QRSd is a promising metric for optimization of lead placement.

Impact of coronary bifurcation morphology on wave propagation.

The branching pattern of the coronary vasculature is a key determinant of its function and plays a crucial role in shaping the pressure and velocity wave forms measured for clinical diagnosis. However, although multiple scaling laws have been proposed to characterize the branching pattern, the implications they have on wave propagation remain unassessed to date. To bridge this gap, we have developed a new theoretical framework by combining the mathematical formulation of scaling laws with the wave propagation theory in the pulsatile flow regime. This framework was then validated in multiple species using high-resolution cryomicrotome images of porcine, canine, and human coronary networks. Results demonstrate that the forward well-matchedness (no reflection for pressure/flow waves traveling from the coronary stem toward the microcirculation) is a salient feature in the coronary vasculature, and this result remains robust under many scenarios of the underlying pulse wave speed distribution assumed in the network. This result also implies a significant damping of the backward traveling waves, especially for smaller vessels (radius, <0.3 mm). Furthermore, the theoretical prediction of increasing area ratios (ratio between the area of the mother and daughter vessels) in more symmetric bifurcations found in the distal circulation was confirmed by experimental measurements. No differences were observed by clustering the vessel segments in terms of transmurality (from epicardium to endocardium) or perfusion territories (left anterior descending, left circumflex, and right coronary artery).

Investigating a Novel Activation-Repolarisation Time Metric to Predict Localised Vulnerability to Reentry Using Computational Modelling.

Exit sites associated with scar-related reentrant arrhythmias represent important targets for catheter ablation therapy. However, their accurate location in a safe and robust manner remains a significant clinical challenge. We recently proposed a novel quantitative metric (termed the Reentry Vulnerability Index, RVI) to determine the difference between activation and repolarisation intervals measured from pairs of spatial locations during premature stimulation to accurately locate the critical site of reentry formation. In the clinic, the method showed potential to identify regions of low RVI corresponding to areas vulnerable to reentry, subsequently identified as ventricular tachycardia (VT) circuit exit sites. Here, we perform an in silico investigation of the RVI metric in order to aid the acquisition and interpretation of RVI maps and optimise its future usage within the clinic. Within idealised 2D sheet models we show that the RVI produces lower values under correspondingly more arrhythmogenic conditions, with even low resolution (8 mm electrode separation) recordings still able to locate vulnerable regions. When applied to models of infarct scars, the surface RVI maps successfully identified exit sites of the reentrant circuit, even in scenarios where the scar was wholly intramural. Within highly complex infarct scar anatomies with multiple reentrant pathways, the identified exit sites were dependent upon the specific pacing location used to compute the endocardial RVI maps. However, simulated ablation of these sites successfully prevented the reentry re-initiation. We conclude that endocardial surface RVI maps are able to successfully locate regions vulnerable to reentry corresponding to critical exit sites during sustained scar-related VT. The method is robust against highly complex and intramural scar anatomies and low resolution clinical data acquisition. Optimal location of all relevant sites requires RVI maps to be computed from multiple pacing locations.

The calcium-frequency response in the rat ventricular myocyte: an experimental and modelling study.

KEY POINTS: In the majority of species, including humans, increased heart rate increases cardiac contractility. This change is known as the force-frequency response (FFR). The majority of mammals have a positive force-frequency relationship (FFR). In rat the FFR is controversial. We derive a species- and temperature-specific data-driven model of the rat ventricular myocyte. As a measure of the FFR, we test the effects of changes in frequency and extracellular calcium on the calcium-frequency response (CFR) in our model and three altered models. The results show a biphasic peak calcium-frequency response, due to biphasic behaviour of the ryanodine receptor and the combined effect of the rapid calmodulin buffer and the frequency-dependent increase in diastolic calcium. Alterations to the model reveal that inclusion of Ca(2+) /calmodulin-dependent protein kinase II (CAMKII)-mediated L-type channel and transient outward K(+) current activity enhances the positive magnitude calcium-frequency response, and the absence of CAMKII-mediated increase in activity of the sarco/endoplasmic reticulum Ca(2+) -ATPase induces a negative magnitude calcium-frequency response. ABSTRACT: An increase in heart rate affects the strength of cardiac contraction by altering the Ca(2+) transient as a response to physiological demands. This is described by the force-frequency response (FFR), a change in developed force with pacing frequency. The majority of mammals, including humans, have a positive FFR, and cardiac contraction strength increases with heart rate. However, the rat and mouse are exceptions, with the majority of studies reporting a negative FFR, while others report either a biphasic or a positive FFR. Understanding the differences in the FFR between humans and rats is fundamental to interpreting rat-based experimental findings in the context of human physiology. We have developed a novel model of rat ventricular electrophysiology and calcium dynamics, derived predominantly from experimental data recorded under physiological conditions. As a measure of FFR, we tested the effects of changes in stimulation frequency and extracellular calcium concentration on the simulated Ca(2+) transient characteristics and showed a biphasic peak calcium-frequency relationship, consistent with recent observations of a shift from negative to positive FFR when approaching the rat physiological frequency range. We tested the hypotheses that (1) inhibition of Ca(2+) /calmodulin-dependent protein kinase II (CAMKII)-mediated increase in sarco/endoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, (2) CAMKII modulation of SERCA, L-type channel and transient outward K(+) current activity and (3) Na(+) /K(+) pump dynamics play a significant role in the rat FFR. The results reveal a major role for CAMKII modulation of SERCA in the peak Ca(2+) -frequency response, driven most significantly by the cytosolic calcium buffering system and changes in diastolic Ca(2+) .

Heterogeneous mechanics of the mouse pulmonary arterial network.

Individualized modeling and simulation of blood flow mechanics find applications in both animal research and patient care. Individual animal or patient models for blood vessel mechanics are based on combining measured vascular geometry with a fluid structure model coupling formulations describing dynamics of the fluid and mechanics of the wall. For example, one-dimensional fluid flow modeling requires a constitutive law relating vessel cross-sectional deformation to pressure in the lumen. To investigate means of identifying appropriate constitutive relationships, an automated segmentation algorithm was applied to micro-computerized tomography images from a mouse lung obtained at four different static pressures to identify the static pressure-radius relationship for four generations of vessels in the pulmonary arterial network. A shape-fitting function was parameterized for each vessel in the network to characterize the nonlinear and heterogeneous nature of vessel distensibility in the pulmonary arteries. These data on morphometric and mechanical properties were used to simulate pressure and flow velocity propagation in the network using one-dimensional representations of fluid and vessel wall mechanics. Moreover, wave intensity analysis was used to study effects of wall mechanics on generation and propagation of pressure wave reflections. Simulations were conducted to investigate the role of linear versus nonlinear formulations of wall elasticity and homogeneous versus heterogeneous treatments of vessel wall properties. Accounting for heterogeneity, by parameterizing the pressure/distention equation of state individually for each vessel segment, was found to have little effect on the predicted pressure profiles and wave propagation compared to a homogeneous parameterization based on average behavior. However, substantially different results were obtained using a linear elastic thin-shell model than were obtained using a nonlinear model that has a more physiologically realistic pressure versus radius relationship.

The relative role of patient physiology and device optimisation in cardiac resynchronisation therapy: A computational modelling study.

Cardiac resynchronisation therapy (CRT) is an established treatment for heart failure, however the effective selection of patients and optimisation of therapy remain controversial. While extensive research is ongoing, it remains unclear whether improvements in patient selection or therapy planning offers a greater opportunity for the improvement of clinical outcomes. This computational study investigates the impact of both physiological conditions that guide patient selection and the optimisation of pacing lead placement on CRT outcomes. A multi-scale biophysical model of cardiac electromechanics was developed and personalised to patient data in three patients. These models were separated into components representing cardiac anatomy, pacing lead location, myocardial conductivity and stiffness, afterload, active contraction and conduction block for each individual, and recombined to generate a cohort of 648 virtual patients. The effect of these components on the change in total activation time of the ventricles (ΔTAT) and acute haemodynamic response (AHR) was analysed. The pacing site location was found to have the largest effect on ΔTAT and AHR. Secondary effects on ΔTAT and AHR were found for functional conduction block and cardiac anatomy. The simulation results highlight a need for a greater emphasis on therapy optimisation in order to achieve the best outcomes for patients.

Non-invasive pressure difference estimation from PC-MRI using the work-energy equation.

Pressure difference is an accepted clinical biomarker for cardiovascular disease conditions such as aortic coarctation. Currently, measurements of pressure differences in the clinic rely on invasive techniques (catheterization), prompting development of non-invasive estimates based on blood flow. In this work, we propose a non-invasive estimation procedure deriving pressure difference from the work-energy equation for a Newtonian fluid. Spatial and temporal convergence is demonstrated on in silico Phase Contrast Magnetic Resonance Image (PC-MRI) phantoms with steady and transient flow fields. The method is also tested on an image dataset generated in silico from a 3D patient-specific Computational Fluid Dynamics (CFD) simulation and finally evaluated on a cohort of 9 subjects. The performance is compared to existing approaches based on steady and unsteady Bernoulli formulations as well as the pressure Poisson equation. The new technique shows good accuracy, robustness to noise, and robustness to the image segmentation process, illustrating the potential of this approach for non-invasive pressure difference estimation.

Measurement and modeling of coronary blood flow.

Ischemic heart disease that comprises both coronary artery disease and microvascular disease is the single greatest cause of death globally. In this context, enhancing our understanding of the interaction of coronary structure and function is not only fundamental for advancing basic physiology but also crucial for identifying new targets for treating these diseases. A central challenge for understanding coronary blood flow is that coronary structure and function exhibit different behaviors across a range of spatial and temporal scales. While experimental studies have sought to understand this feature by isolating specific mechanisms, in tandem, computational modeling is increasingly also providing a unique framework to integrate mechanistic behaviors across different scales. In addition, clinical methods for assessing coronary disease severity are continuously being informed and updated by findings in basic physiology. Coupling these technologies, computational modeling of the coronary circulation is emerging as a bridge between the experimental and clinical domains, providing a framework to integrate imaging and measurements from multiple sources with mathematical descriptions of governing physical laws. State-of-the-art computational modeling is being used to combine mechanistic models with data to provide new insight into coronary physiology, optimization of medical technologies, and new applications to guide clinical practice.

4D Blood Flow Reconstruction Over the Entire Ventricle From Wall Motion and Blood Velocity Derived From Ultrasound Data.

We demonstrate a new method to recover 4D blood flow over the entire ventricle from partial blood velocity measurements using multiple 3D+t colour Doppler images and ventricular wall motion estimated using 3D+t BMode images. We apply our approach to realistic simulated data to ascertain the ability of the method to deal with incomplete data, as typically happens in clinical practice. Experiments using synthetic data show that the use of wall motion improves velocity reconstruction, shows more accurate flow patterns and improves mean accuracy particularly when coverage of the ventricle is poor. The method was applied to patient data from 6 congenital cases, producing results consistent with the simulations. The use of wall motion produced more plausible flow patterns and reduced the reconstruction error in all patients.