Hemodynamic Impairment of Blood Pressure and Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Stenosis.

BACKGROUND: Hemodynamic impairment of blood pressure may play a crucial role in determining the mechanisms of stroke in symptomatic intracranial atherosclerotic stenosis). We aimed to elucidate this issue and assess the impacts of modifications to blood pressure on hemodynamic impairment. METHODS: From the Third China National Stroke Registry III, computed fluid dynamics modeling was performed using the Newton-Krylov-Schwarz method in 339 patients with symptomatic intracranial atherosclerotic stenosis during 2015 to 2018. The major exposures were translesional systolic blood pressure (SBP) drop and poststenotic mean arterial pressure (MAP), and the major study outcomes were cortex-involved infarcts and borderzone-involved infarcts, respectively. Multivariate logistic regression models and the bootstrap resampling method were utilized, adjusting for demographics and medical histories. RESULTS: In all, 184 (54.3%) cortex-involved infarcts and 70 (20.6%) borderzone-involved infarcts were identified. In multivariate logistic model, the upper quartile of SBP drop correlated with increased cortex-involved infarcts (odds ratio, 1.92 [95% CI, 1.03-3.57]; bootstrap analysis odds ratio, 2.07 [95% CI, 1.09-3.93]), and the lower quartile of poststenotic MAP may correlate with increased borderzone-involved infarcts (odds ratio, 2.07 [95% CI, 0.95-4.51]; bootstrap analysis odds ratio, 2.38 [95% CI, 1.04-5.45]). Restricted cubic spline analysis revealed a consistent upward trajectory of the relationship between translesional SBP drop and cortex-involved infarcts, while a downward trajectory between poststenotic MAP and borderzone-involved infarcts. SBP drop correlated with poststenotic MAP negatively (rs=-0.765; P<0.001). In generating hemodynamic impairment, simulating blood pressure modifications suggested that ensuring adequate blood pressure to maintain sufficient poststenotic MAP appears preferable to the reverse approach, due to the prolonged plateau period in the association between the translesional SBP drop and cortex-involved infarcts and the relatively short plateau period characterizing the correlation between poststenotic MAP and borderzone-involved infarcts. CONCLUSIONS: This research elucidates the role of hemodynamic impairment of blood pressure in symptomatic intracranial atherosclerotic stenosis-related stroke mechanisms, underscoring the necessity to conduct hemodynamic assessments when managing blood pressure in symptomatic intracranial atherosclerotic stenosis.

A clinical trial for computed tomography myocardial perfusion based non-invasive index of microcirculatory resistance (MPBIMR): rationale and trial design.

INTRODUCTION: Accurate and rapid assessment of the coronary microcirculation has become an important medical challenge. However, reliable and non-invasive quantitative methods to diagnose coronary microvascular disease (CMVD), select treatments for coronary artery disease (CAD), and therefore improve coronary microcirculation are lacking. Current detection methods have limitations. Therefore, we will assess whether a new detection method, the non-invasive index of microcirculatory resistance (IMR), based on computed tomography (CT) perfusion and hydrodynamics (CT-IMR), can effectively evaluate the function of coronary microvessels. METHODS: We will conduct a multicenter, randomized, open-label study, including a Phase I single-center and Phase II multicenter trial, to assess the accuracy of the non-invasive CT-IMR coronary measurement of microcirculation function. The study will enroll 295 patients who will undergo coronary CT angiography (CCTA), dynamic CT-myocardial perfusion imaging (CT-MPI), invasive coronary angiography (ICA), and invasive IMR. This study will identify the key influencing factors when calculating myocardial microcirculation perfusion and develop an accurate three-dimensional coronary reconstruction method and a non-invasive coronary IMR calculation method based on computational fluid dynamics (CFD). This will facilitate the development of a non-invasive system to detect and measure coronary microcirculation. CONCLUSION: The clinical trial for computed tomography myocardial perfusion based non-invasive index of microcirculatory resistance (MPBIMR) will establish the key influencing factors when calculating myocardial microcirculation perfusion and create a non-invasive CT-IMR calculation method based on CFD. This method may diagnose patients with simple coronary microvascular lesions and those with coronary microvascular lesions combined with coronary vascular lesions.

Evaluation of cerebrovascular hemodynamics in vascular dementia patients with a new individual computational fluid dynamics algorithm.

BACKGROUND: Cerebral hemodynamic disorders are involved in the occurrence and progression of vascular dementia (VaD), but the methods to detect hemodynamics remainmultifarious and uncertain nowadays. We aim to exploit a computational fluid dynamics (CFD) approach by static and dynamic parameters, which can be used to detect individual cerebrovascular hemodynamics quantitatively. METHODS: A patient-specific CFD model was constructed with geometrical arteries on the magnetic resonance angiography (MRA) and hemodynamic parameters on ultrasound Doppler, by which, the structural and simulated hemodynamic indexes could be obtained, mainly including the cerebral arterial volume (CAV), the number of visible arterial outlets, the total cerebral blood flow (tCBF) index and the total cerebrovascular resistance (tCVR) index. The hemodynamics were detected in subcortical vascular dementia (SVaD) patients (n = 38) and cognitive normal controls (CNCs; n = 40). RESULTS: Compared with CNCs, the SVaD patients had reduced outlets, CAV and tCBF index (all P ≤ 0.001), increased volume of white matter hyperintensity (WMH) and tCVR index (both P ≤ 0.01). The fewer outlets (OR = 0.77), higher Hachinski ischemic score (HIS) (OR = 3.65), increased tCVR index (OR = 1.98) and volume of WMH (OR = 1.12) were independently associated with SVaD. All hemodynamic parameters could differentiate the SVaD patinets and CNCs, especially the composite index calculated by outlets, tCVR index and HIS (AUC = 0.943). Fewer outlets and more WMH increased the odds of SVaD, which were partly mediated by the tCBF index (14.4% and 13.0%, respectively). CONCLUSION: The reduced outlets, higher HIS and tCVR index may be independent risk factors for the SVaD, and a combination of these indexes can differentiate SVaD patients and CNCs reliably. The tCBF index potentially mediates the relationships between hemodynamic indexes and SVaD. Although all simulated indexes only represented the true hemodynamics indirectly, this CFD model can provide patient-specific hemodynamic alterations non-invasively and conveniently.

Non-invasive assessment of intracranial wall shear stress using high-resolution magnetic resonance imaging in combination with computational fluid dynamics technique.

In vivo studies on association between wall shear stress (WSS) and intracranial plaque are deficient. Based on the three-dimensional T1-weighted high-resolution magnetic resonance imaging (3DT1 HR-MRI) data of patients with low-grade stenotic (<50%) atherosclerotic middle cerebral artery (MCA) and subjects with normal MCA, we built a three-dimensional reconstructed WSS model by computational fluid dynamics (CFD) technique. Three-dimensional registration of the CFD model to the HR-MRI was performed with projections based on the resolution and thickness of the images. The relationships between the WSS at each side of the vessel wall and plaque location were analyzed. A total of 94 MCA plaques from 43 patients and 50 normal MCAs were analyzed. In the normal MCAs, WSS was lower at the ventral-inferior wall than at the dorsal-superior wall (proximal segment, p < 0.001; middle segment, p < 0.001) and lower at the inner wall than at the outer wall of the MCA curve (p < 0.001). In atherosclerotic MCAs, similar low WSS regions were observed where plaques developed. The WSS ratio of the ventral-inferior wall to the dorsal-superior wall in atherosclerotic MCAs was lower than that in normal MCAs (p = 0.002). The WSSinner-outer ratio in atherosclerotic MCAs was lower than that in normal MCAs (p = 0.002). Low WSS was associated with MCA atherosclerosis formation and occurred mainly at the ventral-inferior wall, which was anatomically opposite the orifices of penetrating arteries, and at the inner wall of the MCA curve. Overall, the results were well consistent with the low WSS theory in atherosclerosis formation. The reconstructed WSS model is a promising novel method for assessing an individualized vascular profile once validated by further studies.

Personalized 0D-1D multiscale hemodynamic modeling and wave dynamics analysis of cerebral circulation for an elderly patient with dementia.

Senile dementia is associated with pronounced alterations in cerebral circulation. A fundamental understanding of intracranial hemodynamics and wave dynamics is essential for assessing dementia risk. Recent findings suggest that higher carotid artery wave intensity (WI) can predict future cognitive impairments in the elderly. However, wave power (WP) is more advantageous for assessing the risk of cognitive impairment and dementia because of its conservative form, which allows quantification of detailed WP distribution among the entire cerebrovascular network. Unfortunately, intracranial hemodynamics and wave dynamics in elderly patients with dementia remain poorly understood due to ethical issues and technical challenges. In this paper, we proposed a novel and easily achievable personalized methodology for the 0D-1D model of cerebral circulation using widely available clinical data on transcranial Doppler ultrasonography velocity, cerebral artery anatomy from magnetic resonance imaging, and brachial artery pressure. Using the proposed model, we simulated the cerebral blood flows and compared the wave dynamics between a healthy elderly subject and one living with dementia. Moreover, we performed a variance-based global sensitivity analysis to quantify the model-predicted WI and WP sensitivity to the uncertainties of model inputs. This provided more precise information for model personalization and further insights into the wave dynamics of cerebral circulation. In conclusion, the proposed personalized model framework provides a practical approach for patient-specific modeling and WI/WP analysis of cerebral circulation through noninvasive clinical data. The wave dynamics features of higher WI and lower WP in cerebral arteries may be an invaluable biomarker for assessing dementia risk.

Efficient parallel simulation of hemodynamics in patient-specific abdominal aorta with aneurysm.

Surgical planning for aortic aneurysm repair is a difficult task. In addition to the morphological features obtained from medical imaging, alternative features obtained with computational modeling may provide additional useful information. Though numerical studies are noninvasive, they are often time-consuming, especially when we need to study and compare multiple repair scenarios, because of the high computational complexity. In this paper, we present a highly parallel algorithm for the numerical simulation of unsteady blood flows in the patient-specific abdominal aorta before and after the aneurysmic repair. We model the blood flow with the unsteady incompressible Navier-Stokes equations with different outlet boundary conditions, and solve the discretized system with a highly scalable domain decomposition method. With this approach, a high resolution simulation of a full-size adult aorta can be obtained in less than an hour, instead of days with older methods and software. In addition, we show that the parallel efficiency of the proposed method is near 70% on a parallel computer with 2, 880 processor cores.

Expanding the coronary tree reconstruction to smaller arteries improves the accuracy of FFRCT.

OBJECTIVES: We attempted to improve the accuracy of coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) (FFRCT) by expanding the coronary tree in the computational fluid dynamics (CFD) domain. An observational study was performed to evaluate the effects of extending the coronary tree analysis for FFRCT from a minimal diameter of 1.2 to 0.8 mm. METHODS: Patients who underwent CCTA and interventional FFR were enrolled retrospectively. Seventy-six patients qualified based on the inclusion criteria. The three-dimensional (3D) coronary artery tree was reconstructed to generate a finite element mesh for each subject with different lower limits of luminal diameter (1.2 mm and 0.8 mm). Outlet boundary conditions were defined according to Murray's law. The Newton-Krylov-Schwarz (NKS) method was applied to solve the governing equations of CFD to derive FFRCT. RESULTS: At the individual patient level, extending the minimal diameter of the coronary tree from 1.2 to 0.8 mm improved the sensitivity of FFRCT by 16.7% (p = 0.022). This led to the conversion of four false-negative cases into true-positive cases. The AUC value of the ROC curve increased from 0.74 to 0.83. Moreover, the NKS method can solve the computational problem of extending the coronary tree to an 0.8-mm luminal diameter in 10.5 min with 2160 processor cores. CONCLUSIONS: Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFRCT. The NKS method can achieve favorable computational times for future clinical applications. KEY POINTS: • Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFRCT. • The NKS method applied in our study can effectively reduce the computational time of this process for future clinical applications.

Numerical Simulation of Blood Flows in Patient-specific Abdominal Aorta with Primary Organs.

The abdominal aorta is the largest artery in the abdominal cavity that supplies blood flows to vital organs through the complex visceral arterial branches, including the celiac trunk (the liver, stomach, spleen, etc.), the renal arteries (the kidneys) and the superior and inferior mesenteric arteries (the small and large intestine, pancreas, etc.). An accurate simulation of blood flows in this network of arteries is important for the understanding of the hemodynamics in various organs of healthy and diseased patients, but the computational cost is very high. As a result, most researchers choose to focus on a portion of the artery or use a low-dimensional approximation of the artery. In the present work, we introduce a parallel algorithm for the modeling of pulsatile flows in the abdominal aorta with branches to the primary organs, and an organ-based two-level method for calculating the resistances for the outflow boundary conditions. With this highly parallel approach, the simulation of the blood flow for a cardiac cycle of the anatomically detailed aorta can be obtained within a few hours, and the blood distribution to organs including liver, spleen and kidneys are also computed with certain accuracy. Moreover, we discuss the significant hemodynamic differences resulted from the influence of the peripheral branches. In addition, we examine the accuracy of the results with respect to the mesh size and time-step size and show the high parallel scalability of the proposed algorithm with up to 3000 processor cores.

A highly parallel simulation of patient-specific hepatic flows.

Computational hemodynamics is being developed as an alternative approach for assisting clinical diagnosis and treatment planning for liver diseases. The technology is non-invasive, but the computational time could be high when the full geometry of the blood vessels is taken into account. Existing approaches use either one-dimensional model of the artery or simplified three-dimensional tubular geometry in order to reduce the computational time, but the accuracy is sometime compromised, for example, when simulating blood flows in arteries with plaque. In this work, we study a highly parallel method for the transient incompressible Navier-Stokes equations for the simulation of the blood flows in the full three-dimensional patient-specific hepatic artery, portal vein and hepatic vein. As applications, we also simulate the flow in a patient with hepatectomy and calculate the S (PPG). One of the advantages of simulating blood flows in all hepatic vessels is that it provides a direct estimate of the PPG, which is a gold standard value to assess the portal hypertension. Moreover, the robustness and scalability of the algorithm are also investigated. A 83% parallel efficiency is achieved for solving a problem with 7 million elements on a supercomputer with more than 1000 processor cores.

A parallel non-nested two-level domain decomposition method for simulating blood flows in cerebral artery of stroke patient.

Numerical simulation of blood flows in patient-specific arteries can be useful for the understanding of vascular diseases, as well as for surgery planning. In this paper, we simulate blood flows in the full cerebral artery of stroke patients. To accurately resolve the flow in this rather complex geometry with stenosis is challenging and it is also important to obtain the results in a short amount of computing time so that the simulation can be used in pre- and/or post-surgery planning. For this purpose, we introduce a highly scalable, parallel non-nested two-level domain decomposition method for the three-dimensional unsteady incompressible Navier-Stokes equations with an impedance outlet boundary condition. The problem is discretized with a stabilized finite element method on unstructured meshes in space and a fully implicit method in time, and the large nonlinear systems are solved by a preconditioned parallel Newton-Krylov method with a two-level Schwarz method. The key component of the method is a non-nested coarse problem solved using a subset of processor cores and its solution is interpolated to the fine space using radial basis functions. To validate and verify the proposed algorithm and its highly parallel implementation, we consider a case with available clinical data and show that the computed result matches with the measured data. Further numerical experiments indicate that the proposed method works well for realistic geometry and parameters of a full size cerebral artery of an adult stroke patient on a supercomputers with thousands of processor cores.

The Hemodynamic Effect of Enhanced External Counterpulsation Treatment on Atherosclerotic Plaque in the Carotid Artery: A Framework of Patient-Specific Computational Fluid Dynamics Analysis.

Long-term enhanced external counterpulsation (EECP) therapy has been recommended for antiatherogenesis in recent clinical observations and trials. However, the precise mechanism underlying the benefits has not been fully clarified. To quantify the effect of EECP intervention on arterial hemodynamic environment, a framework of numerical assessment was introduced using a parallel computing algorithm. A 3D endothelial surface of the carotid artery with mild atherosclerotic plaque was constructed from images of magnetic resonance angiography (MRA). Physiologic boundary conditions were derived from images of the ultrasound flow velocity spectrum measured at the common carotid artery and before and during EECP intervention. Hemodynamic factors relating to wall shear stress (WSS) and its spatial and temporal fluctuations were calculated and analyzed, which included AWSS, OSI, and AWSSG. Measuring and computational results showed that diastole blood pressure, perfusion, and WSS level in carotid bifurcation were significantly increased during EECP intervention. Mean AWSS level throughout the model increased by 16.9%, while OSI level did not show a significant change during EECP. We thus suggested that long-term EECP treatment might inhibit the initiation and development of atherosclerotic plaque via improving the hemodynamic environment in the carotid artery. Meanwhile, EECP performance induced a 19.6% increase in AWSSG level, and whether it would influence the endothelial functions may need a further study. Moreover, the numerical method proposed in this study was expected to be useful for the instant assessment of clinical application of EECP .

Characteristics of Wall Shear Stress and Pressure of Intracranial Atherosclerosis Analyzed by a Computational Fluid Dynamics Model: A Pilot Study.

Background: Although wall shear stress (WSS) and pressure play important roles in plaque vulnerability, characteristics of the two indices in intracranial atherosclerosis (ICAS) have not been fully investigated yet. This study aimed to elucidate this issue by means of establishing a non-invasive computational fluid dynamics method with time-of-flight magnetic resonance angiography (TOF-MRA) of the whole cerebral artery. Materials and Methods: Subjects with symptomatic ICAS in the middle cerebral artery domain were enrolled, excluding those with concomitant internal carotid artery stenosis. Based on patient-specific TOF-MRA images for three-dimensional (3D) meshes and arterial blood pressure with patient-specific carotid artery ultrasonography for inlet boundary conditions, patients' three-dimensional hemodynamics were modeled by a finite element method governed by Navier-Stokes equations. Results: Among the 55 atherosclerotic lesions analyzed by this TOF-MRA based computational fluid dynamics model, the maximum WSS (WSSmax) was most frequently detected at the apex points and the upper half of the upstream sections of the lesions, whereas the maximum pressure was most often located at the lower half of the upstream sections. As the percent stenosis increases, the relative value of WSSmax and pressure drop increased with significantly increasing steep beyond 50% stenosis. Moreover, WSSmax was found to linearly correlate with pressure drop in ICAS. Conclusions: This study on ICAS revealed certain trends of longitudinal distribution of WSS and pressure and the influences of percent stenosis on cerebral hemodynamics, as well as the correlations between WSS and pressure drop. It represents a step forward in applying computational flow simulation techniques in studying ICAS and stroke, in a patient-specific manner.

Epicatechin isolated from Tripterygium wilfordii extract reduces tau-GFP-induced neurotoxicity in zebrafish embryo through the activation of Nrf2.

Tau plays important roles in the assembly and stabilization of the microtubule structure to facilitate axonal transport in mammalian brain. The intracellular tau aggregates to form paired helical filaments leading to neurodegenerative disorders, collectively called tauopathies. In our previous report, we established a zebrafish model to express tau-GFP to induce neuronal death, which could be directly traced in vivo. Recently, we used this model to screen 400 herbal extracts and found 45 of them to be effective on reducing tau-GFP-induced neuronal death. One of the effective herbal extracts is the Tripterygium wilfordii stem extract. HPLC analysis and functional assay demonstrated that epicatechin (EC) is the major compound of Tripterygium wilfordii stem extract to decrease the neurotoxicity induced by tau-GFP. Using a luciferase reporter assay in the zebrafish, we confirmed that EC could activate Nrf2-dependent antioxidant responses to significantly increase the ARE-controlled expression of luciferase reporter gene. These data suggest that EC from the Tripterygium wilfordii stem extract could diminish tau-GFP-induced neuronal death through the activation of Nrf2.

Multiple signaling factors and drugs alleviate neuronal death induced by expression of human and zebrafish tau proteins in vivo.

BACKGROUND: The axonal tau protein is a tubulin-binding protein, which plays important roles in the formation and stability of the microtubule. Mutations in the tau gene are associated with familial forms of frontotemporal dementia with Parkinsonism linked to chromosome-17 (FTDP-17). Paired helical filaments of tau and extracellular plaques containing beta-amyloid are found in the brain of Alzheimer's disease (AD) patients. RESULTS: Transgenic models, including those of zebrafish, have been employed to elucidate the mechanisms by which tau protein causes neurodegeneration. In this study, a transient expression system was established to express GFP fusion proteins of zebrafish and human tau under the control of a neuron-specific HuC promoter. Approximately ten neuronal cells expressing tau-GFP in zebrafish embryos were directly imaged and traced by time-lapse recording, in order to evaluate the neurotoxicity induced by tau-GFP proteins. Expression of tau-GFP was observed to cause high levels of neuronal death. However, multiple signaling factors, such as Bcl2-L1, Nrf2, and GDNF, were found to effectively protect neuronal cells expressing tau-GFP from death. Treatment with chemical compounds that exert anti-oxidative or neurotrophic effects also resulted in a similar protective effect and maintained human tau-GFP protein in a phosphorylated state, as detected by antibodies pT212 and AT8. CONCLUSIONS: The novel finding of this study is that we established an expression system expressing tau-GFP in zebrafish embryos were directly imaged and traced by time-lapse recording to evaluate the neurotoxicity induced by tau-GFP proteins. This system may serve as an efficient in vivo imaging platform for the discovery of novel drugs against tauopathy.

Identification and characterization of alternative promoters of zebrafish Rtn-4/Nogo genes in cultured cells and zebrafish embryos.

In mammals, the Nogo family consists of Nogo-A, Nogo-B and Nogo-C. However, there are three Rtn-4/Nogo-related transcripts were identified in zebrafish. In addition to the common C-terminal region, the N-terminal regions of Rtn4-n/Nogo-C1, Rtn4-m/Nogo-C2 and Rtn4-l/Nogo-B, respectively, contain 9, 25 and 132 amino acid residues. In this study, we isolated the 5'-upstream region of each gene from a BAC clone and demonstrated that the putative promoter regions, P1-P3, are functional in cultured cells and zebrafish embryos. A transgenic zebrafish Tg(Nogo-B:GFP) line was generated using P1 promoter region to drive green fluorescent protein (GFP) expression through Tol2-mediated transgenesis. This line recapitulates the endogenous expression pattern of Rtn4-l/Nogo-B mRNA in the brain, brachial arches, eyes, muscle, liver and intestines. In contrast, GFP expressions by P2 and P3 promoters were localized to skeletal muscles of zebrafish embryos. Several GATA and E-box motifs are found in these promoter regions. Using morpholino knockdown experiments, GATA4 and GATA6 were involved in the control of P1 promoter activity in the liver and intestine, while Myf5 and MyoD for the control of P1 and P3 promoter activities in muscles. These data demonstrate that zebrafish Rtn4/Nogo transcripts might be generated by coupling mechanisms of alternative first exons and alternative promoter usage.

Recapitulation of zebrafish sncga expression pattern and labeling the habenular complex in transgenic zebrafish using green fluorescent protein reporter gene.

Human synuclein family consists of alpha-, beta-, and gamma-synucleins. Here, we cloned three genes, sncb, sncga and sncgb from zebrafish. They encode beta-, gamma1-, and gamma2-synucleins, respectively. The zSyn-beta, zSyn-gamma1, and zSyn-gamma2 proteins display 69%, 47%, and 50% identity to human beta-synuclein and gamma-synuclein, respectively. By reverse transcriptase-polymerase chain reaction, we demonstrated that sncb and sncga mRNA were abundant in brain and eye, while sncgb expression was moderate in brain, kidney, ovary and testis. The 1.8-kb 5'-upstream/promoter region of the sncga gene was sufficient to direct green fluorescent protein (GFP) expression in the central nervous system and cranial ganglions. A transgenic line, Tg(sncga:GFP), was generated and its GFP expression is similar to that of endogenous sncga mRNA. Moreover, this line also labels the habenular complex and the domain of GFP expression is larger in the left than in the right habenula. Thus, this line can be used to study sncga gene regulation and for left-right asymmetry study in zebrafish brain.