Name: evaluation of capillary and other vessel contribution to macular perfusion density measured with optical coherence tomography angiography
Uploaded: 2022-02-18T13:15:00
Description: Watch this Scientific Journal Video about Evaluation of Capillary and Other Vessel Contribution to Macular Perfusion Density Measured with Optical Coherence Tomography Angiography at JoVE.com

The authors would like to thank Zeiss Mexico for the unrestricted support to use the Cirrus 6000 with AngioPlex equipment.

This protocol was approved by Sala Uno&#39;s human research ethics committee. See Video 1 for sections 1 and 2 and the Table of Materials for details about the equipment used in this study.
1. Retinal analysis in the OCTA device
<ol>
	<li>Select the menu for retinal analysis in the OCTA device.</li>
	<li>Select a 3 x 3 mm retinal map; select superficial if the OCTA device measures different capillary plexuses.</li>
	<li>Sele...

<ol>
	<li>Ong, J. X., Fawzi, A. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Perspectives+on+diabetic+retinopathy+from+advanced+retinal+vascular+imaging.">Perspectives on diabetic retinopathy from advanced retinal vascular imaging.</a> Eye. , (2022).</li><li>Tan, A. C. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+overview+of+the+clinical+applications+of+optical+coherence+tomography+angiography.">An overview of the clinical applications of optical coherence tomography angiography.</a> Eye. 32 (2), 262-286 (2018).</li><li>Elnahry, A. G., Ramsey, D. 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Report 1: Diabetic Retinopathy.</a> Translational Vision Science and Technology. 9, 34 (2020).</li><li>Xu, Q., Sun, H., Huang, X., Qu, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Retinal+microvascular+metrics+in+untreated+essential+hypertensives+using+optical+coherence+tomography+angiography.">Retinal microvascular metrics in untreated essential hypertensives using optical coherence tomography angiography.</a> Graefe's Archive for Clinical and Experimental Ophthalmology. 259 (2), 395-403 (2021).</li><li>Yeh, R. Y., Nischal, K. K., LeDuc, P., Cagan, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Written+in+blood:+applying+grammars+to+retinal+vasculatures.">Written in blood: applying grammars to retinal vasculatures.</a> Translational Vision Science &amp; Technology. 9, 36 (2020).</li><li>Corvi, F., Sadda, S. R., Staurenghi, G., Pellegrini, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Thresholding+strategies+to+measure+vessel+density+by+optical+coherence+tomography+angiography.">Thresholding strategies to measure vessel density by optical coherence tomography angiography.</a> Canadian Journal of Ophthalmology. 55 (4), 317-322 (2020).</li><li>Pathak, P., Panday, S. B., Ahn, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Artificial+neural+network+model+effectively+estimates+muscle+and+fat+mass+using+simple+demographic+and+anthropometric+measures.">Artificial neural network model effectively estimates muscle and fat mass using simple demographic and anthropometric measures.</a> Clinical Nutrition. 41 (1), 144-152 (2022).</li><li>OFee, K., Deych, E., Ciani, O., Brown, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+nonfatal+myocardial+infarction+as+a+surrogate+for+all-cause+and+cardiovascular+mortality+in+treatment+or+prevention+of+coronary+artery+disease:+a+meta-analysis+of+randomized+clinical+trials.">Assessment of nonfatal myocardial infarction as a surrogate for all-cause and cardiovascular mortality in treatment or prevention of coronary artery disease: a meta-analysis of randomized clinical trials.</a> JAMA Internal Medicine. 181 (12), 1575-1587 (2021).</li><li>Kushner-Lenhoff, S., Ashimatey, B. S., Kashani, A. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Retinal+vascular+reactivity+as+assessed+by+optical+coherence+tomography+angiography.">Retinal vascular reactivity as assessed by optical coherence tomography angiography.</a> Journal of Visualized Experiments: JoVE. (157), e60948 (2020).</li><li>Sousa, D. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+protocol+to+evaluate+retinal+vascular+response+using+optical+coherence+tomography+angiography.">A protocol to evaluate retinal vascular response using optical coherence tomography angiography.</a> Frontiers in Neuroscience. 13, 566 (2019).</li><li>Falavarjani, K. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+segmentation+error+correction+on+optical+coherence+tomography+angiography+measurements+in+healthy+subjects+and+diabetic+macular+oedema.">Effect of segmentation error correction on optical coherence tomography angiography measurements in healthy subjects and diabetic macular oedema.</a> British Journal of Ophthalmology. 104 (2), 162-166 (2020).</li><li>Warner, R. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Full-field+flicker+evoked+changes+in+parafoveal+retinal+blood+flow.">Full-field flicker evoked changes in parafoveal retinal blood flow.</a> Scientific Reports. 10 (1), 16051 (2020).</li><li>Zhang, Y. 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The contribution of vessels larger than capillaries to perfusion density changes in retinal vascular diseases before the development of retinopathy. It decreased in the inner region of patients with arterial hypertension and varied between fields in patients with diabetes. There are direct methods for measuring vascular reactivity in the retina, which depend on the exposure to a stimulus14,15. The measurement proposed in this paper uses two metrics, automatically...

Retinal circulation is the combination of arteriolar, capillary, and venular flow, whose contribution can vary to meet the oxygen needs of the different retinal layers. This circulation does not depend on the autonomous nervous system regulation and has been traditionally evaluated with fluorescein angiography, an invasive method that uses intravenous contrast to delineate retinal vessels. Sequential photographs allow the evaluation of arterial, arteriolar, venular, and venous circulation, as well as sites of capillary damage in retinal vascular diseases1.
A current method to measure the macular circulation is optical coherence tomography angiography (OCTA), which uses interferometry to obtain retinal images and can outline capillaries and larger retinal vessels2. Unlike fluorescein angiography, OCTA imaging is not influenced by macular xanthophyll pigment shadowing, allowing superior imaging of macular capillaries3. Other advantages of OCTA over fluorescein angiography are its noninvasiveness and higher resolution4.
OCTA devices measure the superficial capillary plexus at the parafovea in a 3 x 3 mm map, concentric to the foveal center (Figure 1). The equipment automatically measures vessel length density (the length of capillaries with circulation in the measured area) and perfusion density (the percentage of the measured area with circulation), which includes that of vessels larger than capillaries (Figure 2)5. Vessel density has a substantial contribution to perfusion density under physiological conditions. Some devices measure vessel density as a &#34;skeletonized vascular density&#34; and perfusion density as &#34;vessel/vascular density.&#34; Regardless of the device, there is usually a measurement for length (measured in mm/mm2 or mm-1) and another for the area with circulation (measured in %), which are generated automatically.
Vessel density can change in healthy people when exposed to darkness, flicker light6, or caffeinated drinks7 because of the neurovascular coupling that redistributes blood flow between the superficial, middle, and deep capillary plexuses according to the retinal layer with the highest activity. Any decrease in vessel density caused by this redistribution returns to baseline values after the stimulus ceases and does not represent capillary loss, a pathological change reported before retinopathy appears in vascular diseases such as diabetes8 or arterial hypertension9.
The decrease in capillaries could be compensated partially by arteriolar vasodilatation. Measuring only a percentage or perfused area does not provide any insight into whether there is vasodilatation, which can appear when capillaries reach a minimum threshold. Measuring vessel density would not help detect an increased circulation area resulting from vasodilatation. The contribution of arteriolar circulation to perfusion density can be estimated indirectly using a coefficient of determination between vessel density and perfusion density, and defining the percentage of the area with circulation that corresponds to capillaries or other vessels.
The rationale behind this technique is that regression analysis can identify the extent to which the changes of an independent numeric value result in changes of a dependent numeric value. In macular vessel imaging using OCTA, capillary circulation is an independent variable that influences the area with circulation because there are few larger vessels in the evaluated region. However, the parafovea has larger vessels that can dilate and change the percentage of the area with circulation, which cannot be identified directly by the current automated OCTA metrics. The advantage of using a coefficient of determination is that it measures a relationship between two existing metrics to produce two more: the percentage of the area with circulation that corresponds to capillaries, and the percentage that corresponds to other vessels. Both percentages can be measured directly using a pixel count with imaging software. However, the coefficient of determination can be calculated for a sample with the numbers that the OCTA devices generate automatically10,11.
Pathak et al. used a coefficient of determination to estimate lean muscle and fat mass from demographic and anthropometric measures using an artificial neural network. Their study found that their model had an R2 value of 0.92, which explained the variability of a large portion of their dependent variables12. O&#39;Fee and colleagues used a coefficient of determination to rule out nonfatal myocardial infarction as a surrogate for all-cause and cardiovascular mortality because they found an R2 of 0.01 to 0.21. Those results showed that the independent variable explained less than 80% of the changes of the dependent variables, set as a criterion of surrogacy (R2= 0.8)13.
The coefficient of determination is used to assess the effect of changes of a variable, a group of variables, or a model over the changes of an outcome variable. The difference between 1 and the R2 value represents the contribution of other variables to the changes of the outcome variable. It is uncommon to attribute the difference to a single variable because there are usually more than two contributing to the outcome. However, the proportion of the macular area that has circulation can only originate from the area covered by capillaries and from that covered by larger vessels, as larger vessels dilate more than capillaries. Moreover, reactive vasodilation is considered to most probably originate from retinal arterioles, because a reduced capillary circulation could decrease oxygen supply.
Only two sources contribute to a percentage of area with circulation in the macula: capillaries and vessels larger than them. The coefficient of determination between vessel density and perfusion density determines the contribution of capillaries to the area with circulation, and the remaining changes (the difference between 1 and the R2 value) represent the contribution of the only other variable that represents an area with circulation (that within larger retinal vessels). This paper describes the method of measuring this contribution in healthy people (group 1) and how it changes in patients with retinal vascular diseases: arterial hypertension without hypertensive retinopathy (group 2) and diabetes mellitus without diabetic retinopathy (group 3).

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Cirrus 6000 with Angioplex</td>
			<td>Carl Zeiss Meditec Inc., Dublin CA</td>
			<td>N/A</td>
			<td>3 x 3 vessel and perfusion density maps</td>
		</tr>
		<tr>
			<td>Excel</td>
			<td>Microsoft</td>
			<td>N/A</td>
			<td>spreadsheet</td>
		</tr>
		<tr>
			<td>Personal computer</td>
			<td>Generic</td>
			<td>N/A</td>
			<td>for running the calculations on the spreadsheet</td>
		</tr>
	</tbody>
</table>

evaluation of capillary and other vessel contribution to macular perfusion density measured with optical coherence tomography angiography

Parafoveal circulation of the superficial retinal capillary plexus is usually measured with vessel density, which determines the length of capillaries with circulation, and perfusion density, which calculates the percentage of the evaluated area that has circulation. Perfusion density also considers the circulation of vessels larger than capillaries, although the contribution of these vessels to the first is not usually evaluated. As both measurements are automatically generated by optical coherence tomography angiography devices, this paper proposes a method for estimating the contribution of vessels larger than capillaries by using a coefficient of determination between vessel and perfusion densities. This method can reveal a change in the proportion of perfusion density from vessels larger than capillaries, even when mean values do not differ. This change could reflect compensatory arterial vasodilatation as a response to capillary dropout in the initial stages of retinal vascular diseases before clinical retinopathy appears. The proposed method would allow the estimation of the changes in the composition of perfusion density without the need for other devices.

There were 45 subjects in group 1, 18 in group 2, and 36 in group 3. Table 1 shows the distribution of age and densities by group; only vessel and perfusion densities in group 1 were lower than in group 2. The coefficients of determination of center vessel and perfusion densities are shown in Figure 5. There was no significant difference between the groups.
The coefficient of determination between the inner vessel and perfusion densities was 0.818...

Watch this Scientific Journal Video about Evaluation of Capillary and Other Vessel Contribution to Macular Perfusion Density Measured with Optical Coherence Tomography Angiography at JoVE.com

Evaluation of Capillary and Other Vessel Contribution to Macular Perfusion Density Measured with Optical Coherence Tomography Angiography

We describe the evaluation of a coefficient of determination between vessel and perfusion density of the parafoveal superficial capillary plexus to identify the contribution of vessels larger than capillaries to perfusion density.

Parafoveal circulation of the superficial retinal capillary plexus is usually measured with vessel density, which determines the length of capillaries ...

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