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<article article-type="brief-report" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xml:lang="EN">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cardiovasc. Med.</journal-id>
<journal-title>Frontiers in Cardiovascular Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cardiovasc. Med.</abbrev-journal-title>
<issn pub-type="epub">2297-055X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcvm.2023.1227532</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cardiovascular Medicine</subject>
<subj-group>
<subject>Brief Research Report</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Variation in left and right coronary artery physiology in patients with severe aortic stenosis</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes"><name><surname>Sabbah</surname><given-names>Muhammad</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="corresp" rid="cor1">&#x002A;</xref><uri xlink:href="https://loop.frontiersin.org/people/1202640/overview"/></contrib>
<contrib contrib-type="author"><name><surname>Engstr&#x00F8;m</surname><given-names>Thomas</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:href="https://loop.frontiersin.org/people/1443805/overview" /></contrib>
<contrib contrib-type="author"><name><surname>Olsen</surname><given-names>Niels Thue</given-names></name>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref><uri xlink:href="https://loop.frontiersin.org/people/2037897/overview" /></contrib>
<contrib contrib-type="author"><name><surname>L&#x00F8;nborg</surname><given-names>Jacob</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:href="https://loop.frontiersin.org/people/1200597/overview" /></contrib>
</contrib-group>
<aff id="aff1"><label><sup>1</sup></label><addr-line>The Heart Center, Rigshospitalet</addr-line>, <institution>Copenhagen University Hospital</institution>, <addr-line>Copenhagen</addr-line>, <country>Denmark</country></aff>
<aff id="aff2"><label><sup>2</sup></label><addr-line>Department of Biomedical Sciences</addr-line>, <institution>University of Copenhagen</institution>, <addr-line>Copenhagen</addr-line>, <country>Denmark</country></aff>
<aff id="aff3"><label><sup>3</sup></label><addr-line>Department of Cardiology</addr-line>, <institution>Copenhagen University Hospital&#x2014;Herlev and Gentofte</institution>, Gentofte, <country>Denmark</country></aff>
<author-notes>
<fn fn-type="edited-by"><p><bold>Edited by:</bold> Branko Dusan Beleslin, Clinical Center of Serbia, Serbia</p></fn>
<fn fn-type="edited-by"><p><bold>Reviewed by:</bold> William Kongto Hau, The Chinese University of Hong Kong, Hong Kong SAR, China Niya Mileva, Aleksandrovska University Hospital, Bulgaria</p></fn>
<corresp id="cor1"><label>&#x002A;</label><bold>Correspondence:</bold> Muhammad Sabbah <email>muhammadsabbah.ms@gmail.com</email></corresp>
</author-notes>
<pub-date pub-type="epub"><day>03</day><month>08</month><year>2023</year></pub-date>
<pub-date pub-type="collection"><year>2023</year></pub-date>
<volume>10</volume><elocation-id>1227532</elocation-id>
<history>
<date date-type="received"><day>23</day><month>05</month><year>2023</year></date>
<date date-type="accepted"><day>17</day><month>07</month><year>2023</year></date>
</history>
<permissions>
<copyright-statement>&#x00A9; 2023 Sabbah, Engstr&#x00F8;m, Olsen and L&#x00F8;nborg.</copyright-statement>
<copyright-year>2023</copyright-year><copyright-holder>Sabbah, Engstr&#x00F8;m, Olsen and L&#x00F8;nborg</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License (CC BY)</ext-link>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license>
</permissions>
<kwd-group>
<kwd>coronary flow reserve/methods</kwd>
<kwd>coronary physiology</kwd>
<kwd>aortic stenosis</kwd>
<kwd>thermodilution</kwd>
<kwd>microvascular</kwd>
</kwd-group><contract-num rid="cn001">&#x00A0;</contract-num><contract-num rid="cn002">NNF20SA0064340)</contract-num><contract-sponsor id="cn001">BRIDGE&#x2014;Translational Excellence Programme</contract-sponsor><contract-sponsor id="cn002">Novo Nordisk Foundation</contract-sponsor><counts>
<fig-count count="0"/>
<table-count count="1"/><equation-count count="0"/><ref-count count="5"/><page-count count="0"/><word-count count="0"/></counts><custom-meta-wrap><custom-meta><meta-name>section-at-acceptance</meta-name><meta-value>Coronary Artery Disease</meta-value></custom-meta></custom-meta-wrap>
</article-meta>
</front>
<body>
<p>It is widely accepted that severe aortic valve stenosis (AS) can cause exhaustion of coronary flow reserve (CFR), leading to angina pectoris despite the absence of obstructive coronary artery disease. However, it is not established whether CFR is uniformly affected in the left and right coronary arteries. We addressed the differences in coronary physiology between the left anterior descending artery (LAD) and right coronary artery (RCA) in patients with severe AS before aortic valve replacement, by performing pair-wise comparisons of coronary flow reserve (CFR), fractional flow reserve (FFR), absolute hyperemic flow (<italic>Q</italic>), and minimal microvascular resistance (<italic>R<sub>&#x03BC;</sub></italic>) in the LAD and RCA using intracoronary bolus and continuous saline thermodilution techniques (<xref ref-type="bibr" rid="B1">1</xref>). The patients in this analysis represent a subset from a previously published cohort in which the physiology of both the LAD and RCA was evaluated (<xref ref-type="bibr" rid="B1">1</xref>). Wilcoxon&#x0027;s signed rank test and paired <italic>t</italic>-test were used to test the differences in medians and means, respectively. Pearson&#x0027;s correlation coefficient was used to test the relationship between the difference in RCA&#x2013;LAD CFR and left ventricular mass. Two-tailed <italic>p</italic>-values &#x003C;0.05 were considered significant. IBM SPSS Statistics for Windows, version 28 (IBM Corp., Armonk, NY, USA), was used for statistical analyses.</p>
<p>A total of 27 patients were included in this analysis, of which 25 had a right-dominant system and two had a co-dominant system. The mean age was 74&#x2009;&#x00B1;&#x2009;8&#x2005;years, 11 (41&#x0025;) were women, and the left ventricular ejection fraction was 67&#x2009;&#x00B1;&#x2009;9&#x0025;. The aortic valve area was 0.72&#x2009;&#x00B1;&#x2009;0.19&#x2005;cm<sup>2</sup> with mean and peak gradients of 56&#x2009;&#x00B1;&#x2009;15&#x2005;mmHg and 87&#x2009;&#x00B1;&#x2009;24&#x2005;mmHg, respectively. Left ventricular hypertrophy (LVH) was present in 61&#x0025; of patients (<xref ref-type="bibr" rid="B2">2</xref>). CFR in the LAD was significantly lower than in the RCA (<xref ref-type="table" rid="T1">Table&#x00A0;1</xref>). Although FFR was lower in the LAD than that in the RCA, the difference in CFR between the LAD and RCA remained statistically significant when using CFR adjusted for epicardial pressure loss (i.e., CFR divided by FFR, <xref ref-type="table" rid="T1">Table&#x00A0;1</xref>). There was no correlation between the absolute RCA&#x2013;LAD CFR difference and the left ventricular mass indexed to body surface area, <italic>r</italic>&#x2009;&#x003D;&#x2009;&#x2212;0.011, <italic>p</italic>&#x2009;&#x003D;&#x2009;0.97. The resting transit time was significantly shorter in the LAD compared with that in the RCA, whereas hyperemic transit times were not significantly different (<xref ref-type="table" rid="T1">Table&#x00A0;1</xref>). Interestingly, absolute hyperemic flow and minimal microvascular resistance in the LAD and RCA were not significantly different (<xref ref-type="table" rid="T1">Table&#x00A0;1</xref>).</p>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p>Paired measurements of coronary physiological indices in the left anterior descending and right coronary artery in patients with severe aortic stenosis.</p></caption>
<table frame="hsides" rules="groups">
<colgroup>
<col align="left"/>
<col align="center"/>
<col align="center"/>
<col align="center"/>
</colgroup>
<thead>
<tr>
<th valign="top" align="left"/>
<th valign="top" align="center">LAD</th>
<th valign="top" align="center">RCA</th>
<th valign="top" align="center"><italic>p</italic>-Value</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">CFR</td>
<td valign="top" align="center">2.5 (1.4&#x2013;2.9)</td>
<td valign="top" align="center">4.1 (3.1&#x2013;5.0)</td>
<td valign="top" align="center">&#x003C;0.001</td>
</tr>
<tr>
<td valign="top" align="left">FFR</td>
<td valign="top" align="center">0.89 (0.84&#x2013;0.92)</td>
<td valign="top" align="center">0.95 (0.93&#x2013;0.97)</td>
<td valign="top" align="center">&#x003C;0.001</td>
</tr>
<tr>
<td valign="top" align="left">CFR adjusted for FFR</td>
<td valign="top" align="center">2.7 (1.5&#x2013;3.6)</td>
<td valign="top" align="center">4.3 (3.2&#x2013;5.5)</td>
<td valign="top" align="center">&#x003C;0.001</td>
</tr>
<tr>
<td valign="top" align="left"><italic>T</italic><sub>mn,rest</sub>, s</td>
<td valign="top" align="center">0.56&#x2009;&#x00B1;&#x2009;0.31</td>
<td valign="top" align="center">1.18&#x2009;&#x00B1;&#x2009;0.69</td>
<td valign="top" align="center">&#x003C;0.001</td>
</tr>
<tr>
<td valign="top" align="left"><italic>T</italic><sub>mn,hyperemia</sub>, s</td>
<td valign="top" align="center">0.24&#x2009;&#x00B1;&#x2009;0.11</td>
<td valign="top" align="center">0.29&#x2009;&#x00B1;&#x2009;0.16</td>
<td valign="top" align="center">0.15</td>
</tr>
<tr>
<td valign="top" align="left"><italic>Q</italic><sub>hyperemia</sub>, ml/min</td>
<td valign="top" align="center">267&#x2009;&#x00B1;&#x2009;101</td>
<td valign="top" align="center">255&#x2009;&#x00B1;&#x2009;130</td>
<td valign="top" align="center">0.75</td>
</tr>
<tr>
<td valign="top" align="left"><italic>R<sub>&#x03BC;</sub></italic>, WU</td>
<td valign="top" align="center">294 (203&#x2013;367)</td>
<td valign="top" align="center">319 (262&#x2013;451)</td>
<td valign="top" align="center">0.11</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="table-fn1"><p><italic>T</italic><sub>mn</sub>, mean transit time; <italic>Q</italic>, absolute volumetric flow; <italic>R<sub>&#x03BC;</sub></italic>, absolute microvascular resistance; WU, wood units.</p></fn>
<fn id="table-fn2"><p>A total of 27 paired coronary physiological measurements for the LAD and RCA of patients with severe aortic valve stenosis. Data are shown as median and interquartile range or mean&#x2009;&#x00B1;&#x2009;SD. CFR adjusted for FFR is calculated as CFR divided by FFR.</p></fn>
</table-wrap-foot>
</table-wrap>
<p>In healthy subjects, the coronary vascular bed is organized such that CFR is similar in the overall territory of all coronary arteries (<xref ref-type="bibr" rid="B3">3</xref>). The main finding of this study is that in severe AS, CFR is lower in the LAD compared with that in the RCA. This difference was not due to a difference in epicardial disease burden. Instead, our results indicate a higher resting flow in the LAD compared with that in the RCA, as shown once before with a Doppler-based approach (<xref ref-type="bibr" rid="B4">4</xref>). A possible explanation for this is that a proportion of RCA flow supplies the right ventricle which escapes the impact of AS, whereas the LAD exclusively supplies the pressure-loaded left ventricle and is thus taxed with a higher resting flow. In our previous work, we have shown that CFR in the LAD significantly increases 6 months after aortic valve replacement (<xref ref-type="bibr" rid="B5">5</xref>). Although changes in the RCA were not assessed in that study, it is conceivable that aortic valve replacement ultimately evens out the differences in CFR between the LAD and RCA found in this study.</p>
<p>In summary, CFR in the LAD is significantly lower than that in the RCA in patients with severe AS and right-dominant coronary systems. The difference is driven by a higher resting flow in the LAD compared with that in the RCA.</p>
</body>
<back>
<sec id="s1" sec-type="data-availability"><title>Data availability statement</title>
<p>The raw data supporting the conclusions of this article will be made available by the authors upon reasonable request.</p>
</sec>
<sec id="s2" sec-type="ethics-statement"><title>Ethics statement</title>
<p>The studies involving human participants were reviewed and approved by Videnskabsetisk Komit&#x00E9;, Region Hovedstaden, Denmark. The patients/participants provided their written informed consent to participate in this study.</p>
</sec>
<sec id="s3" sec-type="author-contributions"><title>Author contributions</title>
<p>MS contributed to the idea and drafted the manuscript. TE, JL, and NO contributed to the text and statistical analysis and revised the manuscript critically. All authors contributed to the article and approved the submitted version.</p>
</sec>
<sec id="s4" sec-type="funding-information"><title>Funding</title>
<p>This work was supported by the BRIDGE&#x2014;Translational Excellence Programme (<ext-link ext-link-type="uri" xlink:href="https://bridge.ku.dk">bridge.ku.dk</ext-link>) at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation (grant agreement no. NNF20SA0064340).</p>
</sec>
<sec id="s5" sec-type="COI-statement"><title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s6" sec-type="disclaimer"><title>Publisher&#x0027;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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</article>