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1.
Math Biosci ; 377: 109292, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39243937

ABSTRACT

Vascular impairments, including compromised flow regulation, have been identified as significant contributors to glaucomatous disease. Recent studies have shown glaucoma patients with significantly reduced peripapillary, macular, and optic nerve head vessel densities occurring with early glaucomatous structural changes prior to detectable visual field loss. This study aims to quantify the potential impact of decreased vessel densities on retinal perfusion and oxygen metabolism. In our clinical observations, pre-perimetric glaucoma patients exhibited a 10-13 % reduction in vessel density compared to healthy individuals. Our theoretical model of the retinal vasculature is adapted in this study to assess the potential impact of this reduction in vessel density on retinal oxygenation. The model predicts a 1 % and 38 % decrease in mean oxygen saturation in retinal vessels immediately downstream of the capillaries when vessel density is decreased from its reference value by 10 % and 50 %, respectively. The impact of capillary loss on oxygen extraction fraction and the partial pressure of oxygen in retinal tissue is also predicted. Reductions in vessel density are simulated in combination with impaired flow regulation, and the resulting effects on saturation and flow are predicted. The model results showed a nonlinear relationship between vessel density and downstream saturation, indicating that larger decreases in the density of capillaries have a disproportionate impact on oxygenation. The model further demonstrates that the detrimental effects of minor vessel density reductions are exacerbated when combined with other vascular impairments.

2.
Invest Ophthalmol Vis Sci ; 65(11): 16, 2024 Sep 03.
Article in English | MEDLINE | ID: mdl-39250119

ABSTRACT

Purpose: To use neural network machine learning (ML) models to identify the most relevant ocular biomarkers for the diagnosis of primary open-angle glaucoma (POAG). Methods: Neural network models, also known as multi-layer perceptrons (MLPs), were trained on a prospectively collected observational dataset comprised of 93 glaucoma patients confirmed by a glaucoma specialist and 113 control subjects. The base model used only intraocular pressure, blood pressure, heart rate, and visual field (VF) parameters to diagnose glaucoma. The following models were given the base parameters in addition to one of the following biomarkers: structural features (optic nerve parameters, retinal nerve fiber layer [RNFL], ganglion cell complex [GCC] and macular thickness), choroidal thickness, and RNFL and GCC thickness only, by optical coherence tomography (OCT); and vascular features by OCT angiography (OCTA). Results: MLPs of three different structures were evaluated with tenfold cross validation. The testing area under the receiver operating characteristic curve (AUC) of the models were compared with independent samples t-tests. The vascular and structural models both had significantly higher accuracies than the base model, with the hemodynamic AUC (0.819) insignificantly outperforming the structural set AUC (0.816). The GCC + RNFL model and the model containing all structural and vascular features were also significantly more accurate than the base model. Conclusions: Neural network models indicate that OCTA optic nerve head vascular biomarkers are equally useful for ML diagnosis of POAG when compared to OCT structural biomarker features alone.


Subject(s)
Biomarkers , Glaucoma, Open-Angle , Intraocular Pressure , Nerve Fibers , Neural Networks, Computer , ROC Curve , Retinal Ganglion Cells , Tomography, Optical Coherence , Visual Fields , Humans , Glaucoma, Open-Angle/diagnosis , Glaucoma, Open-Angle/physiopathology , Tomography, Optical Coherence/methods , Male , Female , Retinal Ganglion Cells/pathology , Intraocular Pressure/physiology , Middle Aged , Prospective Studies , Nerve Fibers/pathology , Visual Fields/physiology , Aged , Optic Disk/pathology , Optic Disk/diagnostic imaging , Area Under Curve
3.
J Clin Med ; 13(14)2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39064230

ABSTRACT

Background/Objectives: To investigate macular vascular biomarkers for the detection of primary open-angle glaucoma (POAG). Methods: A total of 56 POAG patients and 94 non-glaucomatous controls underwent optical coherence tomography angiography (OCTA) assessment of macular vessel density (VD) in the superficial (SCP), and deep (DCP) capillary plexus, foveal avascular zone (FAZ) area, perimeter, VD, choriocapillaris and outer retina flow area. POAG patients were classified for severity based on the Glaucoma Staging System 2 of Brusini. ANCOVA comparisons adjusted for age, sex, race, hypertension, diabetes, and areas under the receiver operating characteristic curves (AUCs) for POAG/control differentiation were compared using the DeLong method. Results: Global, hemispheric, and quadrant SCP VD was significantly lower in POAG patients in the whole image, parafovea, and perifovea (p < 0.001). No significant differences were found between POAG and controls for DCP VD, FAZ parameters, and the retinal and choriocapillaris flow area (p > 0.05). SCP VD in the whole image and perifovea were significantly lower in POAG patients in stage 2 than stage 0 (p < 0.001). The AUCs of SCP VD in the whole image (0.86) and perifovea (0.84) were significantly higher than the AUCs of all DCP VD (p < 0.05), FAZ parameters (p < 0.001), and retinal (p < 0.001) and choriocapillaris flow areas (p < 0.05). Whole image SCP VD was similar to the AUC of the global retinal nerve fiber layer (RNFL) (AUC = 0.89, p = 0.53) and ganglion cell complex (GCC) thickness (AUC = 0.83, p = 0.42). Conclusions: SCP VD is lower with increasing functional damage in POAG patients. The AUC for SCP VD was similar to RNFL and GCC using clinical diagnosis as the reference standard.

4.
Microcirculation ; 31(3): e12849, 2024 04.
Article in English | MEDLINE | ID: mdl-38354046

ABSTRACT

OBJECTIVE: An improved understanding of the role of the leptomeningeal collateral circulation in blood flow compensation following middle cerebral artery (MCA) occlusion can contribute to more effective treatment development for ischemic stroke. The present study introduces a model of the cerebral circulation to predict cerebral blood flow and tissue oxygenation following MCA occlusion. METHODS: The model incorporates flow regulation mechanisms based on changes in pressure, shear stress, and metabolic demand. Oxygen saturation in cerebral vessels and tissue is calculated using a Krogh cylinder model. The model is used to assess the effects of changes in oxygen demand and arterial pressure on cerebral blood flow and oxygenation after MCA occlusion. RESULTS: An increase from five to 11 leptomeningeal collateral vessels was shown to increase the oxygen saturation in the region distal to the occlusion by nearly 100%. Post-occlusion, the model also predicted a loss of autoregulation and a decrease in flow to the ischemic territory as oxygen demand was increased; these results were consistent with data from experiments that induced cerebral ischemia. CONCLUSIONS: This study highlights the importance of leptomeningeal collaterals following MCA occlusion and reinforces the idea that lower oxygen demand and higher arterial pressure improve conditions of flow and oxygenation.


Subject(s)
Brain Ischemia , Hypertension , Humans , Infarction, Middle Cerebral Artery , Collateral Circulation/physiology , Cerebrovascular Circulation , Oxygen , Middle Cerebral Artery
5.
Acta Ophthalmol ; 102(3): e367-e380, 2024 May.
Article in English | MEDLINE | ID: mdl-37786359

ABSTRACT

PURPOSE: This study aims to characterize the dependence of measured retinal arterial and venous saturation on vessel diameter and central reflex in retinal oximetry, with an ultimate goal of identifying potential causes and suggesting approaches to improve measurement accuracy. METHODS: In 10 subjects, oxygen saturation, vessel diameter and optical density are obtained using Oxymap Analyzer software without diameter correction. Diameter dependence of saturation is characterized using linear regression between measured values of saturation and diameter. Occurrences of negative values of vessel optical densities (ODs) associated with central vessel reflex are acquired from Oxymap Analyzer. A conceptual model is used to calculate the ratio of optical densities (ODRs) according to retinal reflectance properties and single and double-pass light transmission across fixed path lengths. Model-predicted values are compared with measured oximetry values at different vessel diameters. RESULTS: Venous saturation shows an inverse relationship with vessel diameter (D) across subjects, with a mean slope of -0.180 (SE = 0.022) %/µm (20 < D < 180 µm) and a more rapid saturation increase at small vessel diameters reaching to over 80%. Arterial saturation yields smaller positive and negative slopes in individual subjects, with an average of -0.007 (SE = 0.021) %/µm (20 < D < 200 µm) across all subjects. Measurements where vessel brightness exceeds that of the retinal background result in negative values of optical density, causing an artifactual increase in saturation. Optimization of model reflectance values produces a good fit of the conceptual model to measured ODRs. CONCLUSION: Measurement artefacts in retinal oximetry are caused by strong central vessel reflections, and apparent diameter sensitivity may result from single and double-pass transmission in vessels. Improvement in correction for vessel diameter is indicated for arteries however further study is necessary for venous corrections.


Subject(s)
Oximetry , Oxygen , Humans , Retina/diagnostic imaging , Retinal Vessels/diagnostic imaging , Reflex
6.
J Glaucoma ; 32(11): 930-941, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37725789

ABSTRACT

PRCIS: Capillary and neuronal tissue loss occur both globally and with regional specificity in pre-perimetric glaucoma patients at the level of the optic nerve and macula, with perifovea regions affected earlier than parafovea areas. PURPOSE: To investigate optic nerve head (ONH) and macular vessel densities (VD) and structural parameters assessed by optical coherence tomography angiography in pre-perimetric open angle glaucoma (ppOAG) patients and healthy controls. MATERIALS AND METHODS: In all, 113 healthy and 79 ppOAG patients underwent global and regional (hemispheric/quadrants) assessments of retinal, ONH, and macular vascularity and structure, including ONH parameters, retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness. Comparisons between outcomes in ppOAG and controls were adjusted for age, sex, race, BMI, diabetes, and hypertension, with P <0.05 considered statistically significant. RESULTS: In ppOAG compared with healthy controls: RNFL thicknesses were statistically significantly lower for all hemispheres, quadrants, and sectors ( P <0.001-0.041); whole image peripapillary all and small blood vessels VD were statistically significantly lower for all the quadrants ( P <0.001-0.002), except for the peripapillary small vessels in the temporal quadrant (ppOAG: 49.66 (8.40), healthy: 53.45 (4.04); P =0.843); GCC and inner and full macular thicknesses in the parafoveal and perifoveal regions were significantly lower in all the quadrants ( P =0.000- P =0.033); several macular VD were significantly lower ( P =0.006-0.034), with the exceptions of macular center, parafoveal superior and inferior quadrant, and perifoveal superior quadrant ( P >0.05). CONCLUSIONS: In ppOAG patients, VD biomarkers in both the macula and ONH, alongside RNFL, GCC, and macular thickness, were significantly reduced before detectable visual field loss with regional specificity. The most significant VD reduction detected was in the peripheric (perifovea) regions. Macular and ONH decrease in VD may serve as early biomarkers of glaucomatous disease.


Subject(s)
Glaucoma, Open-Angle , Glaucoma , Optic Disk , Humans , Optic Disk/blood supply , Glaucoma, Open-Angle/diagnosis , Intraocular Pressure , Retinal Vessels , Visual Fields , Retinal Ganglion Cells , Biomarkers , Tomography, Optical Coherence/methods
7.
J Clin Med ; 12(4)2023 Feb 06.
Article in English | MEDLINE | ID: mdl-36835823

ABSTRACT

This study investigated the heterogeneity of ocular hemodynamic biomarkers in early open angle glaucoma (OAG) patients and healthy controls of African (AD) and European descent (ED). Sixty OAG patients (38 ED, 22 AD) and 65 healthy controls (47 ED, 18 AD) participated in a prospective, cross-sectional study assessing: intraocular pressure (IOP), blood pressure (BP), ocular perfusion pressure (OPP), visual field (VF) and vascular densities (VD) via optical coherence tomography angiography (OCTA). Comparisons between outcomes were adjusted for age, diabetes status and BP. VF, IOP, BP and OPP were not significantly different between OAG subgroups or controls. Multiple VD biomarkers were significantly lower in OAG patients of ED (p < 0.05) while central macular VD was lower in OAG patients of AD vs. OAG patients of ED (p = 0.024). Macular and parafoveal thickness were significantly lower in AD OAG patients compared to those of ED (p = 0.006-0.049). OAG patients of AD had a negative correlation between IOP and VF index (r = -0.86) while ED patients had a slightly positive relationship (r = 0.26); difference between groups (p < 0.001). Age-adjusted OCTA biomarkers exhibit significant variation in early OAG patients of AD and ED.

8.
Math Biosci ; 357: 108969, 2023 03.
Article in English | MEDLINE | ID: mdl-36702235

ABSTRACT

The retinal vascular network supplies perfusion to vital visual structures, including retinal ganglion cells responsible for vision. Impairments in retinal blood flow and oxygenation are involved in the progression of many ocular diseases, including glaucoma. In this study, an established theoretical hybrid model of a retinal microvascular network is extended to include the effects of local blood flow regulation on oxygenation. A heterogeneous representation of the arterioles based on confocal microscopy images is combined with a compartmental description of the downstream capillaries and venules. A Green's function method is used to simulate oxygen transport in the arterioles, and a Krogh cylinder model is applied to the capillary and venular compartments. Acute blood flow regulation is simulated in response to changes in pressure, shear stress, and metabolism. Model results predict that both increased intraocular pressure and impairment of blood flow regulation can cause decreased tissue oxygenation, indicating that both mechanisms represent factors that could lead to impaired oxygenation characteristic of ocular disease. Results also indicate that the metabolic response mechanism reduces the fraction of poorly oxygenated tissue but that the pressure- and shear stress-dependent response mechanisms may hinder the vascular response to changes in oxygenation. Importantly, the heterogeneity of the vascular network demonstrates that traditionally reported average values of tissue oxygen levels hide significant localized defects in tissue oxygenation that may be involved in disease processes, including glaucoma. Ultimately, the model framework presented in this study will facilitate future comparisons to sectorial-specific clinical data to better assess the role of impaired blood flow regulation in ocular disease.


Subject(s)
Glaucoma , Retina , Humans , Microcirculation/physiology , Retina/metabolism , Hemodynamics , Glaucoma/metabolism , Oxygen/metabolism
9.
Transpl Int ; 35: 10297, 2022.
Article in English | MEDLINE | ID: mdl-35479106

ABSTRACT

Introduction: The adoptive transfer of regulatory T cells (Tregs) has emerged as a method to promote graft tolerance. Clinical trials have demonstrated the safety of adoptive transfer and are now assessing their therapeutic efficacy. Strategies that generate large numbers of antigen specific Tregs are even more efficacious. However, the combinations of factors that influence the outcome of adoptive transfer are too numerous to be tested experimentally. Here, mathematical modeling is used to predict the most impactful treatment scenarios. Methods: We adapted our mathematical model of murine heart transplant rejection to simulate Treg adoptive transfer and to correlate therapeutic efficacy with Treg dose and timing, frequency of administration, and distribution of injected cells. Results: The model predicts that Tregs directly accumulating to the graft are more protective than Tregs localizing to draining lymph nodes. Inhibiting antigen-presenting cell maturation and effector functions at the graft site was more effective at modulating rejection than inhibition of T cell activation in lymphoid tissues. These complex dynamics define non-intuitive relationships between graft survival and timing and frequency of adoptive transfer. Conclusion: This work provides the framework for better understanding the impact of Treg adoptive transfer and will guide experimental design to improve interventions.


Subject(s)
Graft Rejection , T-Lymphocytes, Regulatory , Animals , Graft Rejection/prevention & control , Graft Survival , Humans , Mice , Transplantation Tolerance
10.
Microcirculation ; : e12738, 2021 Nov 15.
Article in English | MEDLINE | ID: mdl-34779082

ABSTRACT

OBJECTIVE: To incorporate chronic vascular adaptations into a mathematical model of the rat hindlimb to simulate flow restoration following total occlusion of the femoral artery. METHODS: A vascular wall mechanics model is used to simulate acute and chronic vascular adaptations in the collateral arteries and collateral-dependent arterioles of the rat hindlimb. On an acute timeframe, the vascular tone of collateral arteries and distal arterioles is determined by responses to pressure, shear stress, and metabolic demand. On a chronic timeframe, sustained dilation of arteries and arterioles induces outward vessel remodeling represented by increased passive vessel diameter (arteriogenesis), and low venous oxygen saturation levels induce the growth of new capillaries represented by increased capillary number (angiogenesis). RESULTS: The model predicts that flow compensation to an occlusion is enhanced primarily by arteriogenesis of the collateral arteries on a chronic time frame. Blood flow autoregulation is predicted to be disrupted and to occur for higher pressure values following femoral arterial occlusion. CONCLUSIONS: Structural adaptation of the vasculature allows for increased blood flow to the collateral-dependent region after occlusion. Although flow is still below pre-occlusion levels, model predictions indicate that interventions which enhance collateral arteriogenesis would have the greatest potential for restoring flow.

11.
Photonics ; 8(10)2021 Oct.
Article in English | MEDLINE | ID: mdl-36052288

ABSTRACT

Impaired blood flow and oxygenation contribute to many ocular pathologies, including glaucoma. Here, a mathematical model is presented that combines an image-based heterogeneous representation of retinal arterioles with a compartmental description of capillaries and venules. The arteriolar model of the human retina is extrapolated from a previous mouse model based on confocal microscopy images. Every terminal arteriole is connected in series to compartments for capillaries and venules, yielding a hybrid model for predicting blood flow and oxygenation throughout the retinal microcirculation. A metabolic wall signal is calculated in each vessel according to blood and tissue oxygen levels. As expected, a higher average metabolic signal is generated in pathways with a lower average oxygen level. The model also predicts a wide range of metabolic signals dependent on oxygen levels and specific network location. For example, for high oxygen demand, a threefold range in metabolic signal is predicted despite nearly identical PO2 levels. This whole-network approach, including a spatially nonuniform structure, is needed to describe the metabolic status of the retina. This model provides the geometric and hemodynamic framework necessary to predict ocular blood flow regulation and will ultimately facilitate early detection and treatment of ischemic and metabolic disorders of the eye.

12.
Math Biosci ; 329: 108476, 2020 11.
Article in English | MEDLINE | ID: mdl-32920096

ABSTRACT

Elevated intraocular pressure is the primary risk factor for glaucoma, yet vascular health and ocular hemodynamics have also been established as important risk factors for the disease. The precise physiological mechanisms and processes by which flow impairment and reduced tissue oxygenation relate to retinal ganglion cell death are not fully known. Mathematical modeling has emerged as a useful tool to help decipher the role of hemodynamic alterations in glaucoma. Several previous models of the retinal microvasculature and tissue have investigated the individual impact of spatial heterogeneity, flow regulation, and oxygen transport on the system. This study combines all three of these components into a heterogeneous mathematical model of retinal arterioles that includes oxygen transport and acute flow regulation in response to changes in pressure, shear stress, and oxygen demand. The metabolic signal (Si) is implemented as a wall-derived signal that reflects the oxygen deficit along the network, and three cases of conduction are considered: no conduction, a constant signal, and a flow-weighted signal. The model shows that the heterogeneity of the downstream signal serves to regulate flow better than a constant conducted response. In fact, the increases in average tissue PO2 due to a flow-weighted signal are often more significant than if the entire level of signal is increased. Such theoretical work supports the importance of the non-uniform structure of the retinal vasculature when assessing the capability and/or dysfunction of blood flow regulation in the retinal microcirculation.


Subject(s)
Models, Biological , Oxygen/metabolism , Retina/metabolism , Retinal Vessels/metabolism , Animals , Biological Transport, Active , Computer Simulation , Glaucoma, Open-Angle/etiology , Glaucoma, Open-Angle/physiopathology , Hemodynamics , Humans , Mathematical Concepts , Mice , Microcirculation/physiology , Oxygen Consumption , Regional Blood Flow/physiology
13.
Acta Ophthalmol ; 98(6): 559-571, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32248646

ABSTRACT

Abnormalities of the retinal blood supply have been widely implicated in primary open-angle glaucoma (POAG). Impaired blood supply to the retina and optic nerve head (ONH) may be a primary pathophysiologic mechanism contributing to POAG ('vascular hypothesis'). However, the decreased metabolic activity of atrophic tissue is itself known to induce both vascular changes and decreased blood flow due to reduced oxygen demand. Therefore, primary nonvascular factors could potentially induce glaucomatous atrophy, with subsequent secondary vascular pathology ('mechanical hypothesis'). Retinal oximetry holds great promise in the investigation of glaucoma pathogenesis, as it can provide useful data on retinal metabolic oxygen demand, especially when combined with measurements of retinal blood flow. This review surveys the research on retinal metabolism in POAG using spectroscopic retinal oximetry. The use of mathematical models in combination with oximetric data to investigate the role of retinal metabolism and oxygen supply in POAG is also discussed.


Subject(s)
Glaucoma, Open-Angle/physiopathology , Optic Disk/blood supply , Oxygen/blood , Regional Blood Flow , Retinal Vessels/physiopathology , Humans , Intraocular Pressure , Models, Theoretical , Oximetry/methods
14.
Microcirculation ; 27(4): e12610, 2020 05.
Article in English | MEDLINE | ID: mdl-31999392

ABSTRACT

OBJECTIVE: The development of earlier and less invasive treatments for peripheral arterial disease requires a more complete understanding of vascular responses following a major arterial occlusion. A mechanistic model of the vasculature of the rat hindlimb is developed to predict acute (immediate) changes in vessel diameters and smooth muscle tone following femoral arterial occlusion. METHODS: Vascular responses of collateral arteries and distal arterioles to changes in pressure, shear stress, and metabolism are assessed before and after occlusion. The effects of exercise are also simulated and compared with venous flow measurements from WKY rats. RESULTS: The model identifies collateral arteries as the primary contributors to flow compensation following occlusion. Increasing the number of capillaries has minimal effect on blood flow while increasing the number of collateral arteries significantly increases flow, since the primary site of resistance shifts upstream to the collateral arteries following occlusion. Despite significant collateral dilation, calf flow remains below pre-occlusion levels and the deficit becomes more severe with increased activity. CONCLUSIONS: Although unable to compensate fully for an occlusion, the model demonstrates the importance of the shear response in collateral arteries and the metabolic response in the distal microcirculation in acute adaptations to a major arterial occlusion.


Subject(s)
Arterial Occlusive Diseases/physiopathology , Hemodynamics , Microcirculation , Models, Cardiovascular , Peripheral Arterial Disease/physiopathology , Animals , Arteries/physiopathology , Arterioles/physiopathology , Disease Models, Animal , Hindlimb , Rats , Rats, Inbred WKY
15.
Prog Retin Eye Res ; : 100841, 2020 Jan 24.
Article in English | MEDLINE | ID: mdl-31987983

ABSTRACT

Alterations in ocular blood flow have been identified as important risk factors for the onset and progression of numerous diseases of the eye. In particular, several population-based and longitudinal-based studies have provided compelling evidence of hemodynamic biomarkers as independent risk factors for ocular disease throughout several different geographic regions. Despite this evidence, the relative contribution of blood flow to ocular physiology and pathology in synergy with other risk factors and comorbidities (e.g., age, gender, race, diabetes and hypertension) remains uncertain. There is currently no gold standard for assessing all relevant vascular beds in the eye, and the heterogeneous vascular biomarkers derived from multiple ocular imaging technologies are non-interchangeable and difficult to interpret as a whole. As a result of these disease complexities and imaging limitations, standard statistical methods often yield inconsistent results across studies and are unable to quantify or explain a patient's overall risk for ocular disease. Combining mathematical modeling with artificial intelligence holds great promise for advancing data analysis in ophthalmology and enabling individualized risk assessment from diverse, multi-input clinical and demographic biomarkers. Mechanism-driven mathematical modeling makes virtual laboratories available to investigate pathogenic mechanisms, advance diagnostic ability and improve disease management. Artificial intelligence provides a novel method for utilizing a vast amount of data from a wide range of patient types to diagnose and monitor ocular disease. This article reviews the state of the art and major unanswered questions related to ocular vascular anatomy and physiology, ocular imaging techniques, clinical findings in glaucoma and other eye diseases, and mechanistic modeling predictions, while laying a path for integrating clinical observations with mathematical models and artificial intelligence. Viable alternatives for integrated data analysis are proposed that aim to overcome the limitations of standard statistical approaches and enable individually tailored precision medicine in ophthalmology.

16.
Microcirculation ; 27(2): e12591, 2020 02.
Article in English | MEDLINE | ID: mdl-31520431

ABSTRACT

OBJECTIVE: There is currently a lack of clarity regarding which vascular segments contribute most significantly to flow compensation following a major arterial occlusion. This study uses hemodynamic principles and computational modeling to demonstrate the relative contributions of capillaries, arterioles, and collateral arteries at rest or exercise following an abrupt, total, and sustained femoral arterial occlusion. METHODS: The vascular network of the simulated rat hindlimb is based on robust measurements of blood flow and pressure in healthy rats from exercise and training studies. The sensitivity of calf blood flow to acute or chronic vascular adaptations in distinct vessel segments is assessed. RESULTS: The model demonstrates that decreasing the distal microcirculation resistance has almost no effect on flow compensation, while decreasing collateral arterial resistance is necessary to restore resting calf flow following occlusion. Full restoration of non-occluded flow is predicted under resting conditions given all chronic adaptations, but only 75% of non-occluded flow is restored under exercise conditions. CONCLUSION: This computational method establishes the hemodynamic significance of acute and chronic adaptations in the microvasculature and collateral arteries under rest and exercise conditions. Regardless of the metabolic level being simulated, this study consistently shows the dominating significance of collateral vessels following an occlusion.


Subject(s)
Arterial Occlusive Diseases/physiopathology , Capillaries/physiopathology , Femoral Artery/physiopathology , Hemodynamics , Hindlimb , Models, Cardiovascular , Animals , Arterioles/physiopathology , Hindlimb/blood supply , Hindlimb/physiopathology , Rats , Rats, Sprague-Dawley
17.
Math Biosci ; 305: 1-9, 2018 11.
Article in English | MEDLINE | ID: mdl-30149022

ABSTRACT

Impaired oxygen delivery and tissue perfusion have been identified as significant factors that contribute to the loss of retinal ganglion cells in glaucoma patients. This study predicts retinal blood and tissue oxygenation using a theoretical model of the retinal vasculature based on confocal microscopy images of the mouse retina. These images reveal a complex and heterogeneous geometry of vessels that are distributed non-uniformly into multiple distinct retinal layers at varying depths. Predicting oxygen delivery and distribution in this irregular arrangement of retinal microvessels requires the use of an efficient theoretical model. The model employed in this work utilizes numerical methods based on a Green's function approach to simulate the spatial distribution of oxygen levels in a network of retinal blood vessels and the tissue surrounding them. Model simulations also predict the blood flow rates and pressures in each of the microvessels throughout the entire network. As expected, the model predicts that average vessel PO2 decreases as oxygen demand is increased. However, the standard deviation of PO2 in the vessels nearly doubles as oxygen demand is increased from 1 to 8 cm3 O2/100 cm3/min, indicating a very wide spread in the predicted PO2 levels, suggesting that average PO2 is not a sufficient indicator of oxygenation in a heterogeneous vascular network. Ultimately, the development of this mathematical model will help to elucidate the important factors associated with blood flow and metabolism that contribute to the vision loss characteristic of glaucoma.


Subject(s)
Models, Biological , Oxygen/metabolism , Retina/metabolism , Animals , Computer Simulation , Glaucoma, Open-Angle/etiology , Glaucoma, Open-Angle/metabolism , Glaucoma, Open-Angle/pathology , Hemodynamics , Humans , Mathematical Concepts , Mice , Microcirculation , Regional Blood Flow , Retinal Vessels/metabolism , Retinal Vessels/pathology
19.
Front Immunol ; 7: 448, 2016.
Article in English | MEDLINE | ID: mdl-27872621

ABSTRACT

The quality of life of organ transplant recipients is compromised by complications associated with life-long immunosuppression, such as hypertension, diabetes, opportunistic infections, and cancer. Moreover, the absence of established tolerance to the transplanted tissues causes limited long-term graft survival rates. Thus, there is a great medical need to understand the complex immune system interactions that lead to transplant rejection so that novel and effective strategies of intervention that redirect the system toward transplant acceptance (while preserving overall immune competence) can be identified. This study implements a systems biology approach in which an experimentally based mathematical model is used to predict how alterations in the immune response influence the rejection of mouse heart transplants. Five stages of conventional mouse heart transplantation are modeled using a system of 13 ordinary differential equations that tracks populations of both innate and adaptive immunity as well as proxies for pro- and anti-inflammatory factors within the graft and a representative draining lymph node. The model correctly reproduces known experimental outcomes, such as indefinite survival of the graft in the absence of CD4+ T cells and quick rejection in the absence of CD8+ T cells. The model predicts that decreasing the translocation rate of effector cells from the lymph node to the graft delays transplant rejection. Increasing the starting number of quiescent regulatory T cells in the model yields a significant but somewhat limited protective effect on graft survival. Surprisingly, the model shows that a delayed appearance of alloreactive T cells has an impact on graft survival that does not correlate linearly with the time delay. This computational model represents one of the first comprehensive approaches toward simulating the many interacting components of the immune system. Despite some limitations, the model provides important suggestions of experimental investigations that could improve the understanding of rejection. Overall, the systems biology approach used here is a first step in predicting treatments and interventions that can induce transplant tolerance while preserving the capacity of the immune system to protect against legitimate pathogens.

20.
Surv Ophthalmol ; 61(2): 164-86, 2016.
Article in English | MEDLINE | ID: mdl-26498862

ABSTRACT

Impairments of autoregulation and neurovascular coupling in the optic nerve head play a critical role in ocular pathologies, especially glaucomatous optic neuropathy. We critically review the literature in the field, integrating results obtained in clinical, experimental, and theoretical studies. We address the mechanisms of autoregulation and neurovascular coupling in the optic nerve head, the current methods used to assess autoregulation--including measurements of optic nerve head blood flow (or volume and velocity)--blood flow data collected in the optic nerve head as pressure or metabolic demand is varied in healthy and pathologic conditions, and the current status and potential of mathematical modeling work to further the understanding of the relationship between ocular blood flow mechanisms and diseases such as glaucoma.


Subject(s)
Glaucoma/physiopathology , Homeostasis/physiology , Neurovascular Coupling/physiology , Optic Nerve Diseases/physiopathology , Blood Flow Velocity , Humans , Intraocular Pressure/physiology , Optic Disk/blood supply , Regional Blood Flow/physiology
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