A normative blood velocity model in the exchange microvessels for discriminating health from disease: Healthy controls versus COVID-19 cases.

A usual practice in medicine is to search for "biomarkers" which are measurable quantities of a normal or abnormal biological process. Biomarkers can be biochemical or physical quantities of the body and although commonly used statistically in clinical settings, it is not usual for them to be connected to basic physiological models or equations. In this work, a normative blood velocity model framework for the exchange microvessels was introduced, combining the velocity-diffusion (V-J) equation and statistics, in order to define the normative range (NR) and normative area (NA) diagrams for discriminating normal (normemic) from abnormal (hyperemic or underemic) states, taking into account the microvessel diameter D. This is different from the usual statistical processing since there is a basis on the well-known physiological principle of the flow diffusion equation. The discriminative power of the average axial velocity model was successfully tested using a group of healthy individuals (Control Group) and a group of post COVID-19 patients (COVID-19 Group).

The velocity-diffusion equation in the exchange microvessels.

In human and animal microvascular networks, the exchange microvessels are the capillaries and postcapillary venules where material transport between the circulating blood and tissue takes place. For small-size molecules, this material transport is done by the physical mechanism of diffusion through the endothelium wall and the diffusion rate J in relation to blood volume flow Q is described by the flow-diffusion (Q-J) equation. However, the volume flow is not easy to be measured in vivo. The objective of this work was to transform the classical flow-diffusion equation into a new form with axial velocity V as an independent variable instead of volume flow Q. The new form was called the velocity-diffusion (V-J) equation and has the advantage that V can be measured directly in vivo by optical imaging techniques. The V-J equation could have important applications in the calculation of the mass diffusion rate of various substances in vivo.

Optical Coherence Tomography Angiography (OCTA) of the eye: A review on basic principles, advantages, disadvantages and device specifications.

Optical Coherence Tomography Angiography (OCTA) is a relatively new imaging technique in ophthalmology for the visualization of the retinal microcirculation and other tissues of the human eye. This review paper aims to describe the basic definitions and principles of OCT and OCTA in the most straightforward possible language without complex mathematical and engineering analysis. This is done to help health professionals of various disciplines improve their understanding of OCTA and design further clinical research more efficiently. First, the basic technical principles of OCT and OCTA and related terminology are described. Then, a list of OCTA advantages and disadvantages, with a special reference to blood flow quantification limitations. Finally, an updated list of the basic hardware and software specifications of some of the commercially available OCTA devices is presented.

COVID-19 hemodynamic and thrombotic effect on the eye microcirculation after hospitalization: A quantitative case-control study.

BACKGROUND & OBJECTIVE: To quantify the hemodynamic and thrombotic effect of COVID-19 on the eye microcirculation of patients with thromboprophylaxis, shortly after hospital discharge. METHODS: This case-control study included 17 COVID-19 survivors (named "COVID-19 Group") and 17 healthy volunteers (named "Control Group"). Axial blood velocity (Vax) and percentage of occluded vessels (POV) were quantified by Conjunctival Video Capillaroscopy (CVC). Microvessels were identified and classified as "capillaries" (CAP), "postcapillary venules of size 1" (PC1), and "postcapillary venules of size 2" (PC2). RESULTS: The COVID-19 Group did not differ significantly in basic demographics from the Control Group. In the COVID-19 Group, there was a statistically significant (p < 0.001) reduction of Vax (39%, 49% and 47%, for CAP, PC1, and PC2, respectively) in comparison to the Control Group and a sizeable (p < 0.001) increase of POV (600%) in comparison to the Control Group. CONCLUSIONS: COVID-19 not only reduces significantly axial blood velocity in the capillaries and postcapillary venules of the eye but has also a devastating effect on microthrombosis (POV) despite thromboprophylaxis treatment. This gives a possible explanation for long COVID and a hint about the existence of a possibly unknown coagulation factor.

Blood flow velocity comparison in the eye capillaries and postcapillary venules between normal pregnant and non-pregnant women.

BACKGROUND: There is no consensus on how much and at what diameters the blood flow velocity changes in the female microcirculation during normal pregnancy. METHODS: A non-contact, digital slit-lamp biomicroscopy system was used to measure axial blood velocity (Vax) and diameter (D) in the conjunctival microcirculation of 28 normal non-pregnant women (Control Group), 17 women in the first semester of their normal pregnancy (Group 1) and 16 women in the third trimester of their normal pregnancy (Group 2). Blood volume flow (Q) was estimated from Vax and D. Microvessels were classified as "capillaries" (CAP) with D < 9 µm, "postcapillary venules of size 1" (PC1) with 9 ≤ D < 14 µm and "postcapillary venules of size 2" (PC2) with 14 ≤ D ≤ 24 µm. RESULTS: The women groups did not differ significantly in age, diastolic and systolic pressure and diameter of each size. Taking as baseline the capillary Vax of 0.51 mm/s of the Control Group, there was a statistically significant (p < 0.001) increase to 0.74 mm/s (45%) in Group 1 and to 0.95 mm/s (86%) in Group 2. This significant Vax increase in capillaries (CAP) was a consistent finding irrespective of the exact vessel size cut-off value for discriminating CAP from PC1. There was no statistical difference in Vax among groups at postcapillary venules of size 2 (PC2). Statistical conclusions for blood volume flows were similar to velocities. CONCLUSIONS: Normal pregnancy increases significantly axial blood velocity (Vax) in capillaries (CAP) with diameter <9 µm.

Deep tissue near infrared second derivative spectrophotometry for the assessment of claudication in peripheral arterial disease.

AIM: The purpose of this study was the application of a second derivative near infrared spectrophotometric (NIRS) technique to the human calf muscle in order to see if peripheral arterial disease (PAD) patients can be discriminated from control subjects, before, during and after a standard treadmill exercise test. METHODS: Three groups of human subjects were studied: group A consisted of 10 control subjects and groups B and C were formed by PAD patients classified as Fontaine's stage 2a (5 patients) and 2b (10 patients), respectively. The measurement protocol for all groups was 9.75 minutes of standing up (phase 1), 1 minute of exercise (phase 2) and 1 minute of rest (phase 3). Seven variables were defined at different times from the onset of the measurement protocol. RESULTS: All variables were significantly higher (p < 0.05) in group A in comparison to groups B and C. The level of significance was ten times higher (p < 0.005) at the onset (15 seconds) of the experiment and during phases 2 and 3. However, none of the variables in group B was significantly different from those in group C. CONCLUSIONS: It is shown for the first time that a second derivative NIRS technique can discriminate (p = 0.003) healthy subjects from PAD patients, in just 15 seconds of standing, with no exercise requirement. More experiments are required in order to uncover the full potential of the technique in the diagnosis of the PAD.

Pulsatility Index quantification in the human precapillary arterioles of the eye.

The Pulsatility Index (PI) was quantified for the first time in the human conjunctival pre-capillary arterioles in vivo. In 30 arterioles with diameters ranging between 6 and 12µm, from 15 healthy humans, peak to peak velocity ranged from 0.2 up to 4.8mm/s with a mean value equal to 1.4±0.2 (SE) mm/s. The PI ranged from 0.4 to 1.5 and the overall mean value was 0.8±0.1 (SE). The linear correlation between PI and diameter was practically zero (Spearman's correlation coefficient, rs≈0) for the range of arteriolar diameters examined here. In this work a first step was made towards the complete PI mapping of the human carotid arterial tree.

Wall shear stress in the human eye microcirculation in vivo, segmental heterogeneity and performance of in vitro cerebrovascular models.

Wall shear stress (WSS) is a very important hemodynamic parameter implicated in many physiological and pathological phenomena. In order to study these phenomena, it is more convenient to use in vitro models before testing on animals and humans. Dynamic in vitro cerebrovascular models are considered capable of simulating the in vivo hemodynamic conditions, but only few of them seem to meet the criteria for this task. It is now clear that in the human eye microcirculation a significant pulsation exists at the pre-capillary arterioles with average WSS values more than twice those in the venular side, for the same diameters. WSS heterogeneity is in support of segmental heterogeneity i.e. the endothelial phenotypic and functional difference among arterioles, capillaries and venules. In this review paper, the importance of WSS is described in detail and two more microvascular segments are proposed: a pre-capillary arteriolar and a post-capillary venular segment. The accurate hemodynamic simulation in all microvascular segments seems to be a prerequisite step in the development of dynamic in vitro blood brain barrier (BBB) models and microfluidic platforms on chip. Endothelial cells in the cardiovascular system seem to have sophisticated role acting like cardiovascular processing sensors (CPSs).

Correlation of axial blood velocity to venular and arteriolar diameter in the human eye in vivo.

The axial blood velocity (Vax) association with microvessel diameter (D) was studied at 104 different postcapillary venules (4 µm <  D <  24 µm) and 30 different precapillary arterioles (6 µm≤D≤12 µm) in the human conjunctiva of normal healthy humans. Venular diameter sizes were classified as "very small" (Group 1, 4.4 µm≤D <  8.9 µm), "small" (Group 2, 8.9 µm≤D <  13.8 µm), "medium" (Group 3, 13.8 µm≤D <  19.1 µm) and "large" (Group 4, 19.1 µm≤D≤23.5). The Spearman's correlation coefficient (rs) in all 4 venular groups was less than 0.36 and not statistically significant (n = 26, p≥0.08). Similar correlation results were observed for the arteriolar group (rs) ≈ 0) for the peak systolic, the average and the end systolic axial velocities. Vax was significantly (p <  0.001) lower in Group 1 in comparison to that in Group 2 and significantly (p <  0.01) lower in Group 2 in comparison to that in Group 3. However, Vax was not significantly lower in Group 3 in comparison to that in Group 4. Average Vax and standard deviation was 0.48 ± 0.13, 0.64 ± 0.16, 0.82 ± 0.25 and 0.88 ± 0.32 mm/s for Groups 1, 2, 3 and 4 respectively. The above results reinforce the importance of measuring D in microvascular hemodynamics. Higher diameters suggest higher axial velocities but Vax does not change significantly within the limits of each of the aforementioned groups.

The resistive index as a function of vessel diameter in the human carotid arterial tree.

The average resistive index (RI) as a function of the average vessel diameter (D) was studied in the human carotid arterial tree. Data were used from previously published research measurements taken from 505 different vessels of 371 healthy humans. When the RI from the carotid arteries was included in the data set the standard trend lines did not give efficient fits. However, when only data from the eye were used, the Neperian logarithmic function gave a best fit with a correlation coefficient r=0.99 and an absolute relative error less than 2.6%. This logarithmic model could be proved a valuable tool for both basic research and clinical practice in the human eye.

Elimination of motion, pulsatile flow and cross-talk artifacts using blade sequences in lumbar spine MR imaging.

The purpose of this study is to evaluate the ability of T2 turbo spin echo (TSE) axial and sagittal BLADE sequences in reducing or even eliminating motion, pulsatile flow and cross-talk artifacts in lumbar spine MRI examinations. Forty four patients, who had routinely undergone a lumbar spine examination, participated in the study. The following pairs of sequences with and without BLADE were compared: a) T2 TSE Sagittal (SAG) in thirty two cases, and b) T2 TSE Axial (AX) also in thirty two cases. Both quantitative and qualitative analyses were performed based on measurements in different normal anatomical structures and examination of seven characteristics, respectively. The qualitative analysis was performed by experienced radiologists. Also, the presence of image motion, pulsatile flow and cross-talk artifacts was evaluated. Based on the results of the qualitative analysis for the different sequences and anatomical structures, the BLADE sequences were found to be significantly superior to the conventional ones in all the cases. The BLADE sequences eliminated the motion artifacts in all the cases. In our results, it was found that in the examined sequences (sagittal and axial) the differences between the BLADE and conventional sequences regarding the elimination of motion, pulsatile flow and cross-talk artifacts were statistically significant. In all the comparisons, the T2 TSE BLADE sequences were significantly superior to the corresponding conventional sequences regarding the classification of their image quality. In conclusion, this technique appears to be capable of potentially eliminating motion, pulsatile flow and cross-talk artifacts in lumbar spine MR images and producing high quality images in collaborative and non-collaborative patients.

Wall shear stress quantification in the human conjunctival pre-capillary arterioles in vivo.

Blood volume flow (Q), wall shear rate (WSR) and wall shear stress (WSS) were quantified, for the first time, in the conjunctival pre-capillary arterioles of normal human volunteers with diameters (D) between 6 and 12 µm. The variation of the blood velocity throughout the cardiac cycle was taken into account using high speed video microcinematography. The dual effect of arteriolar diameter, firstly on the WSR and secondly on the dynamic viscosity of blood, was taken into account in the estimation of WSS. The average Q, WSR and WSS, throughout the cardiac cycle ranged from 13 to 202 pl/s, 587 to 3515 s(-1) and 1.7 to 21.1 N/m(2) respectively. The best fit power law equations, giving the increase of Q and the decrease of WSR and WSS with diameter, are presented for the systolic and diastolic phase as well as for the averages throughout the cardiac cycle. According to the WSS best fit equation, the average WSS decreases from 10.5 N/m(2) at D=6 µm down to 2.1 N/m(2) at D=12 µm.

Blood velocity pulse quantification in the human conjunctival pre-capillary arterioles.

Axial red blood cell velocity pulse was quantified throughout its period by high speed video microcinematography in the human eye. In 30 conjunctival precapillary arterioles (6 to 12 microm in diameter) from 15 healthy humans, axial velocities ranged from 0.4 (the minimum of all the end diastolic values) to 5.84 mm/s (the maximum of all the peak systolic values). With the velocity pulse properly quantified, two parameters can be estimated: (1) the average velocity of the pulse during a cardiac cycle AVV (average velocity value) and (2) the magnitude of the pulsation using Pourcelot's resistive index RI. These parameters are important for the estimation of other hemodynamic parameters such as the average volume flow and the average shear stress. The results of this study revealed that the AVV in the human precapillary arterioles ranged between 0.52 and 3.26 mm/s with a mean value for all microvessels of 1.66 mm/s+/-0.11(SE). The RI ranged between 35.5% and 81.8% with a mean value of 53.1%+/-2.2. Quantitative information was obtained for the first time on the velocity pulse characteristics just before the human capillary bed.

A velocity profile equation for blood flow in small arterioles and venules of small mammals in vivo and an evaluation based on literature data.

An empirical parametric equation with 2 bluntness parameters was introduced for describing the velocity profile of blood in the small arterioles and venules of small mammals, in vivo, with the basic approximations of the axisymmetric flow in cylindrical geometry, zero velocity at the wall and a blunter than parabolic flow profile. The purpose was to evaluate the usefulness of this equation in describing the velocity profile and in estimating the volume flow when only one velocity measurement is available near the vessel axis. The equation was tested on 17 velocity profiles (9 arteriolar and 8 venular) previously measured by particle image velocimetry (PIV) techniques, at diameters ranging from 17 to 38.6 microm. The correlation coefficients of each experimental profile were higher than 0.96. The average relative error-bias measured at 10 radial segments ranged between -5% to 1%, leading to an average relative volume flow estimation error for all the 17 velocity profiles of -1.8% with a standard deviation of 4.3%.

Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo.

Understanding the mathematical relationships of volume blood flow and wall shear stress with respect to microvessel diameter is necessary for the study of vascular design. Here, for the first time, volume flow and wall shear stress were quantified from axial red blood cell velocity measurements in 104 conjunctival microvessels of 17 normal human volunteers. Measurements were taken with a slit lamp based imaging system from the post capillary side of the bulbar conjunctiva in microvessel diameters ranging from 4 to 24 micrometers. The variation of the velocity profile with diameter was taken into account by using a profile factor function. Volume flow ranged from 5 to 462 pl/s with a mean value of 102 pl/s and gave a second power law best fitting line (r=0.97) deviating significantly from the third power law relation with diameter. The estimated wall shear stress declined hyperbolically (r=0.93) from a maximum of 9.55 N/m(2) at the smallest capillaries, down to a minimum of 0.28 N/m(2) at the higher diameter post capillary venules. The mean wall shear stress value for all microvessels was 1.54 N/m(2).

Volume flow estimation in the precapillary mesenteric microvasculature in vivo and the principle of constant pressure gradient.

Volume flow was estimated from axial erythrocyte velocity measurements in 30 mesenteric microvessels of 6 rabbits and was compared to Murray's law predictions. The diameters of capillaries and precapillary arterioles ranged between 5.6 and 12 microm. The significant pulsating flow component existing in these microvessels was taken into account by measuring instantaneous axial blood velocity throughout the course of a cardiac cycle and then averaging over the period. In addition, the effect of the velocity profile variation with diameter was taken into account, for the first time, by using a profile factor function. According to Murray's law, the relation between blood volume flow and diameter is governed by a 'cube' law. Curve fitting to volume flow and diameter data pairs for rabbits, showed a dependence of volume flow on diameter raised to the 4th power (with a correlation coefficient equal to 0.97). The above result supports the hypothesis that, in the precapillary part of microvasculature, the principle of constant longitudinal pressure gradient rather than the principle of minimum work may be valid.

Velocity pulse measurements in the mesenteric arterioles of rabbits.

The axial red blood cell velocity pulse was quantified throughout its period by a high-speed video microscopy method, using images of erythrocytes moving near the microvessel axis. In 10 mesenteric precapillary arterioles (8 to 12 microm in diameter) from six rabbits, axial velocities ranged from 0.46 (the minimum of all the end diastolic values) to 4.8 mm s(-1) (the maximum of all the peak systolic values). With the velocity pulse shape properly quantified, a correct estimation of the average velocity over time can be made and hence, appropriate quantification of blood flow. Average velocity ranged between 1.14 mm s(-1) (8 microm arterioles) and 1.98 mm s(-1) (9 microm arterioles). Also, with the velocity pulse shape known, an estimation of the magnitude of the pulsation can be made by introducing Pourcelot's resistive index (RI) in the microvascular haemodynamics (diameter less than 15 microm). The results of this study reveal that RI in the precapillary arterioles is quite high ranging between 0.56 (8 microm arterioles) and 0.74 (12 microm arterioles). Observing the velocity pulse diagrams in different diameters, quantitative information is obtained for the first time on how the velocity pulse shape flattens as it proceeds to the capillary bed.