An in silico study of the effects of cardiovascular aging on carotid flow waveforms and indexes in a virtual population.

Cardiovascular aging is strongly associated with increased risk of cardiovascular disease and mortality. Moreover, health and lifestyle factors may accelerate age-induced alterations, such as increased arterial stiffness and wall dilation, beyond chronological age, making the clinical assessment of cardiovascular aging an important prompt for preventative action. Carotid flow waveforms contain information about age-dependent cardiovascular properties, and their ease of measurement via noninvasive Doppler ultrasound (US) makes their analysis a promising tool for the routine assessment of cardiovascular aging. In this work, the impact of different aging processes on carotid waveform morphology and derived indexes is studied in silico, with the aim of establishing the clinical potential of a carotid US-based assessment of cardiovascular aging. One-dimensional (1-D) hemodynamic modeling was employed to generate an age-specific virtual population (VP) of N = 5,160 realistic carotid hemodynamic waveforms. The resulting VP was statistically validated against in vivo aging trends in waveforms and indexes from the literature, and simulated waveforms were studied in relation to age and underlying cardiovascular parameters. In our study, the carotid flow augmentation index (FAI) significantly increased with age (with a median increase of 50% from the youngest to the oldest age group) and was strongly correlated to local arterial stiffening (r = 0.94). The carotid pulsatility index (PI), which showed less pronounced age variation, was inversely correlated with the reflection coefficient at the carotid branching (r = -0.88) and directly correlated with carotid net forward wave energy (r = 0.90), corroborating previous literature where it was linked to increased risk of cerebrovascular damage in the elderly. There was a high correlation between corrected carotid flow time (ccFT) and cardiac output (CO) (r = 0.99), which was not affected by vascular age. This study highlights the potential of carotid waveforms as a valuable tool for the assessment of cardiovascular aging.NEW & NOTEWORTHY An age-specific virtual population was generated based on a 1-D model of the arterial circulation, including newly defined literature-based specific age variations in carotid vessel properties. Simulated carotid flow/velocity waveforms, indexes, and age trends were statistically validated against in vivo data from the literature. A comprehensive study of the impact of aging on carotid flow waveform morphology was performed, and the mechanisms influencing different carotid indexes were elucidated. Notably, flow augmentation index (FAI) was found to be a strong indicator of local carotid stiffness.

Simulated late gadolinium enhanced cardiac magnetic resonance imaging dataset from mechanical XCAT phantom including a myocardial infarct.

The late enhanced magnetic resonance image dataset in this article is simulated using a mechanistic cardiac phantom that includes an myocardial infarct. Settings of the image simulation pipeline are adjusted such that high- and low-resolution images, with and without slice alignment artifacts, are simulated. Our article on the influence of image artifacts on image-based models of the cardiac electrophysiology is based on this data (Kruithof et al., 2021). This dataset provides image-analysis researchers a reference to perform validation of their methods using the included high-resolution ground truth image, a resource that is often unavailable clinically.

Validation of an aging virtual population for the study of carotid hemodynamics.

The analysis of carotid ultrasound (US) flow, velocity, and diameter waveforms provides important information about cardiovascular and circulatory health. These can be used to derive clinical indices of atherosclerosis, vascular aging, and hemodynamic status. To derive clinical insight from carotid waveforms, it is essential to understand the relationship of the observed variability in morphology with the underlying hemodynamic status and cardiovascular properties. For this purpose, using a one-dimensional modeling approach, we have developed and validated a virtual population that is able to realistically simulate carotid waveforms of healthy subjects aged between 10 and 80 years old.Clinical Relevance-Our virtual population of carotid waveforms can support the interpretation of US patient data. It can be used, e.g., to investigate how waveform morphology and derived indices relate to individual arterial and cardiac properties.

Noninvasive detection of spatiotemporal activation-repolarization interactions that prime idiopathic ventricular fibrillation.

A comprehensive understanding of the interaction between triggers and electrical substrates leading to ventricular fibrillation (VF) and sudden cardiac arrest is lacking, and electrical substrates are difficult to detect and localize with current clinical tools. Here, we created repolarization time (RT) dispersion by regional drug infusion in perfused explanted human (n = 1) and porcine (n = 6) hearts and in a computational model of the human ventricle. Arrhythmia induction was tested with a single ventricular extrastimulus applied at the early or late RT region. Arrhythmias could only be induced from early RT regions. Vulnerability to VF increased with RT gradient steepness and with larger areas of early RT, but not with markers on the body-surface electrocardiogram. Noninvasive electrocardiographic imaging was performed in survivors of idiopathic VF (n = 11), patients with frequent premature ventricular complexes (PVCs) but no history of sudden cardiac arrest (n = 7), and controls (n = 10). In survivors of idiopathic VF, RT gradients were steeper than in controls, without differences in the clinical electrocardiogram, consistent with the ex vivo results. Patients with idiopathic VF also showed local myocardial regions with distinctly early-versus-late RT that were more balanced in size than in controls. Premature beats originated more often from the early RT regions in idiopathic VF survivors than in patients with frequent PVCs only. Thus, idiopathic VF emerges from the spatiotemporal interaction of a premature beat from an early-repolarization region with critical repolarization dispersion in that region. Electrocardiographic imaging can uncover the co-occurrence of these abnormalities.

CRIMSON: An open-source software framework for cardiovascular integrated modelling and simulation.

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.

Patient-Specific Modeling of Hemodynamics: Supporting Surgical Planning in a Fontan Circulation Correction.

Computational fluid dynamics (CFD) is a modeling technique that enables calculation of the behavior of fluid flows in complex geometries. In cardiovascular medicine, CFD methods are being used to calculate patient-specific hemodynamics for a variety of applications, such as disease research, noninvasive diagnostics, medical device evaluation, and surgical planning. This paper provides a concise overview of the methods to perform patient-specific computational analyses using clinical data, followed by a case study where CFD-supported surgical planning is presented in a patient with Fontan circulation complicated by unilateral pulmonary arteriovenous malformations. In closing, the challenges for implementation and adoption of CFD modeling in clinical practice are discussed.

Computational Fluid Dynamics and Aortic Thrombus Formation Following Thoracic Endovascular Aortic Repair.

BACKGROUND: We present the possible utility of computational fluid dynamics in the assessment of thrombus formation and virtual surgical planning illustrated in a patient with aortic thrombus in a kinked ascending aortic graft following thoracic endovascular aortic repair. METHODS: A patient-specific three-dimensional model was built from computed tomography. Additionally, we modeled 3 virtual aortic interventions to assess their effect on thrombosis potential: (1) open surgical repair, (2) conformable endografting, and (3) single-branched endografting. Flow waveforms were extracted from echocardiography and used for the simulations. We used the computational index termed platelet activation potential (PLAP) representing accumulated shear rates of fluid particles within a fluid domain to assess thrombosis potential. RESULTS: The baseline model revealed high PLAP in the entire arch (119.8 ± 42.5), with significantly larger PLAP at the thrombus location (125.4 ± 41.2, p < 0.001). Surgical repair showed a 37% PLAP reduction at the thrombus location (78.6 ± 25.3, p < 0.001) and a 24% reduction in the arch (91.6 ± 28.9, p < 0.001). Single-branched endografting reduced PLAP in the thrombus region by 20% (99.7 ± 24.6, p < 0.001) and by 14% in the arch (103.8 ± 26.1, p < 0.001), whereas a more conformable endograft did not have a profound effect, resulting in a modest 4% PLAP increase (130.6 ± 43.7, p < 0.001) in the thrombus region relative to the baseline case. CONCLUSIONS: Regions of high PLAP were associated with aortic thrombus. Aortic repair resolved pathologic flow patterns, reducing PLAP. Branched endografting also relieved complex flow patterns reducing PLAP. Computational fluid dynamics may assist in the prediction of aortic thrombus formation in hemodynamically complex cases and help guide repair strategies.

A mathematical model of coronary blood flow control: simulation of patient-specific three-dimensional hemodynamics during exercise.

This work presents a mathematical model of the metabolic feedback and adrenergic feedforward control of coronary blood flow that occur during variations in the cardiac workload. It is based on the physiological observations that coronary blood flow closely follows myocardial oxygen demand, that myocardial oxygen debts are repaid, and that control oscillations occur when the system is perturbed and so are phenomenological in nature. Using clinical data, we demonstrate that the model can provide patient-specific estimates of coronary blood flow changes between rest and exercise, requiring only the patient's heart rate and peak aortic pressure as input. The model can be used in zero-dimensional lumped parameter network studies or as a boundary condition for three-dimensional multidomain Navier-Stokes blood flow simulations. For the first time, this model provides feedback control of the coronary vascular resistance, which can be used to enhance the physiological accuracy of any hemodynamic simulation, which includes both a heart model and coronary arteries. This has particular relevance to patient-specific simulation for which heart rate and aortic pressure recordings are available. In addition to providing a simulation tool, under our assumptions, the derivation of our model shows that ß-feedforward control of the coronary microvascular resistance is a mathematical necessity and that the metabolic feedback control must be dependent on two error signals: the historical myocardial oxygen debt, and the instantaneous myocardial oxygen deficit.

Simulation of short-term pressure regulation during the tilt test in a coupled 3D-0D closed-loop model of the circulation.

Short-term fluctuations in arterial pressures arising from normal physiological function are buffered by a negative feedback system known as the arterial baroreflex. Initiated by altered biomechanical stretch in the vessel wall, the baroreflex coordinates a systemic response that alters heart rate, cardiac contractility and peripheral vessel vasoconstriction. In this work, a coupled 3D-0D formulation for the short-term pressure regulation of the systemic circulation is presented. Including the baroreflex feedback mechanisms, a patient-specific model of the large arteries is subjected to a simulated head up tilt test. Comparative simulations with and without baroreflex control highlight the critical role that the baroreflex has in regulating variations in pressures within the systemic circulation.

Magnetic cell delivery for peripheral arterial disease: A theoretical framework.

PURPOSE: Our aim was to compare different magnet arrangements for magnetic cell delivery to human lower leg arteries and investigate the theoretical targeting efficiency under realistic flow conditions as a possible treatment after angioplasty. Additionally the potential of scaling down or translating the magnetic actuation device for preclinical studies was explored. METHODS: Using finite element methods, the magnetic field distribution was calculated in 3D for the optimization of magnet arrangements. Computational fluid dynamics simulations were performed for the human posterior tibial artery with the geometry and boundary condition data derived from magnetic resonance imaging (MRI) studies. These simulations were used to trace the trajectories of cells for an optimized magnet arrangement. Additionally the behavior of cells close to the vessel wall was investigated using a fluid-structure interaction model. RESULTS: The optimal magnet for the lower leg arteries was a Halbach cylinder k3 variety (12 elements with 900 rotation steps for the magnetization orientation). With this magnet, numerical simulations predict a targeting efficiency of 6.25% could be achieved in the posterior tibial artery for cells containing 150 pg iron. Similar simulations, which were scaled down to rabbit dimensions while keeping the forces acting on a cell constant, lead to similar predicted targeting efficiencies. Fluid dynamic and fluid-structure interaction simulations predict that magnetically labeled cells within a 0.5% radii distance to the vessel wall would be attracted and remain at the wall under physiological flow conditions. CONCLUSIONS: First pass capture of magnetically labeled cells under pulsatile flow conditions in human lower leg arteries leads to low targeting efficiencies. However, this can be increased to almost 100% by stopping the blood flow for 5 min. A magnetic actuation device can be designed for animal models that generate magnetic forces achievable for cells in human leg arteries.