Partial Pressure of Oxygen-Guided Adrenal Venous Sampling in Primary Aldosteronism

Partial Pressure of Oxygen-Guided Adrenal Venous Sampling in Primary Aldosteronism | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Partial Pressure of Oxygen-Guided Adrenal Venous Sampling in Primary Aldosteronism Kei Omata , View ORCID Profile Yuta Tezuka , Hiromitsu Tannai , View ORCID Profile Yoshikiyo Ono , Hiroki Kamada , Sota Oguro , Yoshihide Kawasaki , Akihiro Ito , Yuto Yamazaki , Hironobu Sasano , Takashi Suzuki , Tetsuhiro Tanaka , Kei Takase , Hideki Katagiri , View ORCID Profile Fumitoshi Satoh doi: https://doi.org/10.1101/2025.06.29.25330380 Kei Omata 1 Department of Diabetes, Metabolism, and Endocrinology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yuta Tezuka 1 Department of Diabetes, Metabolism, and Endocrinology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Yuta Tezuka Hiromitsu Tannai 2 Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yoshikiyo Ono 1 Department of Diabetes, Metabolism, and Endocrinology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Yoshikiyo Ono Hiroki Kamada 2 Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sota Oguro 2 Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yoshihide Kawasaki 3 Department of Urology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Akihiro Ito 3 Department of Urology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yuto Yamazaki 4 Department of Pathology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hironobu Sasano 4 Department of Pathology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Takashi Suzuki 4 Department of Pathology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tetsuhiro Tanaka 5 Department of Nephrology and Hypertension, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kei Takase 2 Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hideki Katagiri 1 Department of Diabetes, Metabolism, and Endocrinology, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: hideki.katagiri.e1{at}tohoku.ac.jp fumitoshi.satoh.b7{at}tohoku.ac.jp Fumitoshi Satoh 5 Department of Nephrology and Hypertension, Tohoku University Graduate School of Medicine, MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Fumitoshi Satoh For correspondence: hideki.katagiri.e1{at}tohoku.ac.jp fumitoshi.satoh.b7{at}tohoku.ac.jp Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract [Background] Primary aldosteronism (PA) is a leading cause of endocrine hypertension, characterized by the increased cardiovascular risks. Adrenal venous sampling (AVS) plays a pivotal role in optimization of treatment strategy for PA. However, technical challenges, such as anatomical variations and the small sizes of target vessels, often preclude us from appropriate cannulation to the adrenal veins. This study aimed to explore the distribution of partial pressure of oxygen (pO 2 ) in the adrenal and their neighboring veins, inspired by our awareness of lighter red color of adrenal venous blood than the others. [Methods] We enrolled 168 PA patients who underwent AVS at our center from 2021 to 2024. During AVS, we collected residual blood samples (0.2 mL for each) from bilateral adrenal, hepatic, inferior phrenic and external iliac veins both at baseline and under cosyntropin stimulation to perform blood gas analysis. Statistical analysis was conducted to evaluate the pO 2 distributions and its associations with clinical parameters. [Results] The pO 2 levels were significantly higher in bilateral adrenal veins than in their counterparts. The pO 2 levels tended to remain the same even after cosyntropin initiation, with its decrement only detected in the adrenal veins. In addition, the levels of partial pressure of carbon dioxide were lower in the adrenal veins than in the others. Of note, in the adrenal veins, pO 2 levels were significantly negatively correlated with ipsilateral levels of both aldosterone and cortisol. Finally, results of our present study firstly demonstrated the significance of evaluating pO 2 in identifying adrenal veins compatible to the selectivity index of cortisol, a standard criterion for successful cannulation. [Conclusion] This is the first study to examine the pO 2 dynamics in the human adrenal and non-adrenal veins, demonstrating its potential as a reliable tool for improving AVS cannulation success rates. Our findings also presented the oxygen consumption in the adrenal glands for steroidogenesis during cosyntropin stimulation. The pO 2 measurement is a faster, easier and less-expensive tool enhancing AVS techniques. Our findings could improve clinical practice and research towards the next stage of adrenocortical endocrinology. What is new? -The adrenal venous specimens appear lighter red than those from non-adrenal veins, which is considered to be due to significantly higher partial pressure of oxygen in the adrenal veins. -Cosyntropin stimulation results in decreased partial pressure of oxygen in the adrenal veins, indicating increased adrenal consumption of oxygen due to ACTH-driven steroid synthesis. What are the clinical implications? -Measurement of partial pressure of oxygen has a high ability for identifying adrenal veins compatible to the selectivity index of cortisol, a standard criterion for successful adrenal vein cannulation. -Venous blood gas analysis is a faster, easier and less-expensive tool for confirmation of successful cannulation to the adrenal veins when performing adrenal venous sampling. Introduction Primary aldosteronism (PA) is a leading cause of endocrine hypertension, accounting for 3-12% of all patients with hypertension in primary care settings 1 . A pile of evidence elucidated that PA frequently triggered cardiovascular disease (CVD) in both blood pressure (BP)- and mineralocorticoid-dependent manners: the enhanced risks of CVD in PA were reported as 1.67-1.77, 2.05, 2.03-2.58 and 2.68 times higher for coronary artery disease, heart failure, stroke and proteinuria, respectively, compared to those with essential hypertension (EH) 2 – 4 . In addition, PA could lead to a higher risk of mortality than EH 5 . PA-specific treatment, therefore, plays a pivotal role in mitigating the increased CVD risks as well as achieving better BP control 6 . Results of one meta-analysis revealed that adrenalectomy for unilateral PA resulted in 39% and 99% of complete clinical and biochemical outcomes, respectively, based on the PASO criteria 7 . Administration of mineralocorticoid receptor antagonists (MRAs) could also reverse the excess risks of developing comorbidities in bilateral PA, while the efficacy of medical treatment depends on MRA titration by physicians. Several clinical studies also reported medically-treated PA patients harboring persistent renin suppression had higher CVD incidences than those who achieved normal or elevated renin status after therapy 8 , 9 . Therefore, surgically-treated PA patients tend to have reduced events of major adverse CVD (odds ratio [OR], 0.55), atrial fibrillation (OR, 0.35) and mortality (OR, 0.33) than medically-treated patients 10 , 11 . Therefore, whether treatment is optimized for each PA subtype or not has a great impact on healthy life expectancy in the patients. Toward classification of PA patients, adrenal venous sampling (AVS) has been employed as a gold standard procedure to differentiate unilateral PA, surgery-curable form, from bilateral PA 6 . The techniques of AVS have been well developed, but still challenging due to the difficulties in cannulating adrenal veins. In fact, the success rate of bilateral adrenal venous cannulation was reported as 60-80% of all AVS cases 12 – 14 . A major cause of AVS failure is the difficulty in intraprocedural confirmation of adrenal venous cannulation. A couple of studies reported anatomical variation of right and left adrenal veins (RAV and LAV) 15 , 16 . The RAV normally flows into the inferior vena cava (IVC), whereas we reported that 20% of PA patients who underwent AVS had a common trunk of RAV and the accessory hepatic vein (HV) 15 . Those cases demonstrated various locations of the RAV orifice and angles between RAV and HV or IVC. The close proximity of the openings of the RAV and HV could therefore prevent successful RAV cannulation. Furthermore, on venograms, both veins could exhibit similar morphologies, leading to misidentification and sampling from the HV instead of the RAV. This is considered one of the causes of AVS failure. On the other hand, the LAV has been reported to form a common trunk with the inferior phrenic vein (IPV), draining blood from the diaphragm and stomach, before LAV flows into the left renal vein in more than 90% of the relevant cases 16 . Those anatomical features and individual differences sometimes resulted in misidentification of adrenal veins even in the experienced centers. Today, the selectivity index using cortisol levels in the target and the reference veins is globally used to judge whether adrenal veins are appropriately cannulated or not 17 . In order to improve the success rate of AVS, intraprocedural measurement of cortisol has been suggested in addition to preoperative imaging focusing on adrenal veins 18 , 19 . Recently, we have noticed the macroscopic color difference between blood specimens from the external iliac vein (EIV) and the adrenal vein in AVS. The red color of adrenal venous blood appeared to be lighter than those of the neighboring veins, including HV and EIV. Subsequent evaluation revealed that partial pressure of oxygen (pO 2 ) was higher in adrenal venous samples than in other venous samples, including HV and IVC. We, therefore, conducted the present study to prospectively investigate the pO 2 differences among blood obtained from adrenal veins and nearby veins, with a hypothesis that the pO 2 measurement is an indicator for successful cannulation of adrenal veins during the AVS procedure. Methods Ethical considerations This study protocol was developed in accordance with the tenets of Declaration of Helsinki and approved by Tohoku University Hospital institutional review board (2023-1-817). We obtained written informed consents from all the participants for the procedures for this study. Eligibility of the participants for this study In order to evaluate pO 2 differences among adrenal and the relevant veins, we included PA patients who underwent AVS for subtyping in our center from April 2021 to March 2024. Diagnosis of PA was performed as per the PA guidelines 20 , 21 . Briefly, hypertensive patients underwent evaluation of plasma renin and aldosterone after sufficient withdrawal of antihypertensive agents which interfere renin-angiotensin-system. Blood samples for renin and aldosterone evaluation were obtained after 30 minutes rest at supine position in the morning. Screening criteria for PA were defined as a higher plasma aldosterone concentration (PAC) than 6 ng/dL along with renin suppression (plasma renin activity [PRA] <1 ng/mL/h or its concentration [PRC] <4 pg/mL) 22 . Both PAC and PRC were measured by the recently developed chemiluminescent enzyme immunoassay 22 , while PRA by commercially available enzyme immunoassay. The diagnosis of PA was established based on the results of captopril challenge test (aldosterone-to-renin ratio >8.2 ng/dL per ng/mL/h after 50 mg captopril loading) and/or saline infusion test (PAC >1.2 ng/dL after 2 L saline injection) 20 , 23 . Those who had overt subclinical Cushing syndrome or other uncontrolled endocrinopathies, including thyroid dysfunction, were excluded for this study 24 . Blood pressure was measured after 5 minutes of rest with HEM 7120 (Omron Heathcare Co Ltd, Kyoto, Japan). Basic clinical information of the participants were collected by reviewing their medical records. Adrenal Imaging by computed tomography Non-contrast and four-phase dynamic contrast-enhanced computed tomography (CT) was primarily employed to evaluate adrenal nodules, adrenal veins and their neighboring veins using a 160-row multidetector CT system (Aquilion Precision; Canon Medical Systems, Otawara, Japan) 15 . The tube voltage was set to 120LkVp and the tube current to 310LmA. The scanner operated with a rotation time of 0.5 seconds and a pitch of 0.8. Transverse reconstructed images were acquired with a slice thickness and slice interval of 1Lmm, a matrix size of 512L×L512 pixels, and a field of view of approximately 320Lmm for all phases. Specifically, for the late arterial phase images, higher resolution was achieved with a slice thickness and interval of 0.25Lmm, a matrix size of 512L×L512 pixels, and a field of view of approximately 240Lmm. A non-ionic contrast agent, containing 300–370Lmg iodine/mL, was injected at a dose of 600Lmg I per patient body weight into a peripheral vein over 25 seconds. When the attenuation value reached a preset threshold (CT value on plain CT plus 50 Hounsfield Units) at the level of the abdominal aorta, early arterial-phase scanning automatically commenced 15 . Late arterial-phase scanning began 13 seconds after the completion of the first scan. Venous-phase and delayed-phase scanning started 70 seconds and 3 minutes, respectively, after the initiation of contrast injection. Subtyping using segmental AVS The procedure was performed by interventional radiologists, with endocrinologists in attendance. A 5LF or 7LF sheath was inserted into the bilateral femoral veins under ultrasonography guidance. A 5LF or 6.5LF diagnostic catheter for the left or right adrenal veins (Adselect, Hanaco Medical, Tokyo, Japan; MK adrenal type; Hanaco Medical, Tokyo, Japan) and a 2–2.9LF split-tip microcatheter (Goldcrest Neo microcatheter type OM, Medico’s Hirata, Osaka, Japan) were also utilized 25 – 27 . First, the LAV was cannulated with the catheter. Subsequently, the HV and RAV were cannulated with right adrenal catheter. Blood sampling was carefully conducted to obtain a minimum of 1.5 mL from RAV, HV and LAV (specially, from sites before and after IPV confluence, referred to LAV CV and LAV IPV , respectively.) and from right EIV (reference) using a microcatheter as needed. HV sampling was primarily performed from the middle or right HV, and occasionally from an accessory HV. Venous samples were also collected from the IPV when adrenal blood flow to the IPV was suspected. Bilateral AVS was completed within a short time frame. Subsequently, a 200Lμg intravenous bolus of cosyntropin (synthetic adrenocorticotropic hormone, ACTH) was administered, followed by a continuous infusion of 50Lμg/h via a peripheral vein 30 minutes later 25 – 28 . Fifteen minutes after the initiation of ACTH stimulation, sampling from the same sites and bilateral adrenal tributary veins was conducted. Heparinization was performed to prevent coagulation inside the catheter. Basically, oxygen was administrated at 2 L/min throughout the AVS procedure to keep oxygen saturation over 98%. The laterality of PA was determined based on the lateralized index under ACTH stimulation as previously reported 28 . Briefly, unilateral PA was identified in the case where the lateralized index, a quotient of the aldosterone/cortisol ratio obtained from the adrenal central vein of the dominant side divided by that of the other side, was higher than 2.6. Some cases were also categorized as unilateral PA by segmental AVS when the aldosterone/cortisol ratios were similar in bilateral adrenal central veins but significantly elevated only in a specific segment, often corresponding to a CT-detectable tumor. Successful cannulation to the adrenal veins were confirmed based on the selectivity index (the ratio of the cortisol level in the target vein divided by that of EIV >5) as well as angiography during AVS. Measurement of steroids and partial pressure of oxygen and carbon dioxide in AVS samples As routine diagnostic procedures of AVS, PAC and serum cortisol were measured employing commercially available assays, the chemiluminescent enzyme immunoassay (Lumipulse Presto Aldosterone; Fujirebio Inc., Tokyo, Japan) and the electro chemiluminescent immunoassay (Elecsys Cortisol-II; Roche Diagnostics, Rotkreuz, Switzerland), respectively. Assessment of both hormones was performed using blood samples from the adrenal veins and EIV, while only cortisol levels were measured in HV and IPV samples. For this study, we also performed blood gas analysis in residual venous samples collected from both adrenal veins, HV, IPV and EIV during AVS. The pO 2 and partial pressure of carbon dioxide (pCO 2 ) were measured employing ABL800 FLEX (Radiometer Medical A/S, Bronshoj, Denmark). Blood gas analysis was performed with 0.2 mL of residual samples immediately after collection of the blood samples during AVS. Gas analysis within 3 minutes confirmed that pO 2 stability remained within a 2% variation ( Figure S1 ). Statistical analysis We employed SPSS (version 28.0, Armonk, NY: IBM Corp) for all statistical analyses performed in this study. For clinical information, parametric and non-parametric variables were shown as mean ± standard deviation and median [an interquartile range], respectively. The comparison of blood pO 2 or pCO 2 levels between two veins or before and after ACTH stimulation was performed with the Wilcoxon signed-rank test. In cases with missing values, we excluded the cases with missing data only for the specific statistical analysis affected. The differences of pO 2 or pCO 2 between a target vein and EIV were shown as ΔpO 2 or pCO 2 , respectively, by subtracting their levels at EIV from those at a target vein. In addition, we employed Spearman’s correlation to reveal the associations between venous gas status and steroid production. Subsequently, the influence of clinical parameters on pO 2 levels was assessed with stepwise regression. Finally, receiver operating characteristic (ROC) curves were constructed to investigate the discriminative ability of pO 2 and pCO 2 levels in identifying adrenal veins, based on the cases in which target parameters were available for both the adrenal veins and their counterpart veins. The optimal cut-off value for ROC analysis was determined based on the Youden index. Statistical significance was set at p < 0.05 for all the statistical analysis performed in this study. Results We enrolled 179 PA patients whose baseline characteristics were summarized in Table S1 . Overall, 89 (49.7%) were men and the mean age and body mass index were 53.0 years old and 24.9 kg/m 2 , respectively. Adrenal imaging found unilateral and bilateral adrenal tumors in 100 (55.9%) and 17 (9.5%) patients, respectively. A combination of adrenal imaging and AVS confirmed the confluences of HV and RAV, and IPV and LAV in 30 (16.8%) and 176 (98.3%) of the patients, respectively. Based on segmental AVS, 104 (58.1%) patients were diagnosed with unilateral PA. Of these, 81 (77.9%) showed concordant laterality of hyperaldosteronism between adrenal imaging and segmental AVS, while others had bilateral adrenal tumors or no tumor on adrenals. Of the 179 PA patients, 11 (6.1%) didn’t receive oxygen support during AVS. The subsequent analysis focusing on pO 2 status was, therefore, limited to 168 patients who underwent AVS with oxygen supplementation to ensure accurate evaluation. Blood gas evaluation of venous samples obtained during AVS 1. Venous pO 2 levels before ACTH stimulation A representative image illustrating the color difference between blood specimens from the EIV and the adrenal vein is shown in Figure 1 . First, we measured blood pO 2 in the adrenal and neighboring veins without ACTH stimulation ( Figure 2A and Table S2 ). Among 168 PA patients, baseline blood samples from RAV, HV, EIV, IPV, LAV IPV and LAV CV were available for gas analysis in 158 (94.0%), 165 (98.2%), 168 (100%), 73 (43.4%), 86 (51.2%) and 166 (98.8%) cases, respectively. Consistent with the lighter red blood from the adrenal veins, both blood pO 2 levels were significantly higher in RAV and LAV CV than in EIV (66.3 [59.3, 76.1] and 66.5 [57.5, 76.2] mmHg vs. 43.2 [40.0, 47.0] mmHg, respectively; p <0.0001 for both). There was no significant difference of blood pO 2 between RAV and LAV CV ( p =0.07). Among the limited cases with available gas analysis in the adrenal tributary vein, there was no significant difference of pO 2 levels between the adrenal central and tributary veins ( Table S3 ). Similarly, pO 2 levels in RAV and LAV CV were significantly higher than those in their neighboring veins, HV and IPV, respectively (40.8 [37.6, 44.3] and 43.1 [35.5, 51.7] mmHg in HV and IPV, respectively; p <0.0001 for both) ( Table S2 ). Moreover, pO 2 levels were lower in HV than in EIV ( p <0.0001), while there was no significant difference of pO 2 between IPV and EIV. Thus, blood pO 2 levels in LAV decreased after IPV confluence (66.5 [57.5, 76.2] mmHg in LAV CV vs. 56.0 [50.3, 62.5] mmHg in LAV IPV , p <0.0001). The differences of pO 2 levels between the target veins and EIV,ΔpO 2 , were summarized in Figure 2B . The ΔpO 2 clearly demonstrated that blood pO 2 levels in RAV were higher than those in EIV in all available cases ( Figure 2B ). In addition, 164 out of 166 (98.8%) cases showed similar results between LAV CV and EIV pO 2 levels. Download figure Open in new tab Figure 1. Different blood colors of the external iliac vein (A) and the adrenal vein (B) obtained during adrenal venous sampling. Adrenal blood showed brighter red than the others. Download figure Open in new tab Figure 2. The pO 2 evaluation in the adrenal veins and their surrounding veins pO2, partial pressure of oxygen; RAV, right adrenal vein; HV, hepatic vein; EIV, external iliac vein; IPV, inferior phrenic vein; LAV IPV , left adrenal vein after the confluence of IPV; LAV CV , the central vein of left adrenal; BL, baseline; ACTH, cosyntropin stimulation. Δ pO2 was calculated by subtracting pO 2 levels at EIV from those at a target vein. Baseline pO 2 levels and calculated Δ pO 2 in the examined veins are shown in panel A and B. The pO 2 levels under cosyntropin stimulation and Δ pO 2 are depicted in panel C and D. The pO 2 levels are compared between baseline and under cosyntropin stimulation in panel E. ns, not significant. 2. Changes of venous pO 2 levels after ACTH stimulation Then, we evaluated blood pO 2 levels in the same veins under ACTH stimulation in 167 available cases ( Figure 2C and D , and Table S2 ). Blood pO 2 levels significantly decreased in RAV, from 66.3 [59.3, 76.1] mmHg to 56.6 [52.7, 62.8] mmHg ( p <0.0001), and LAV CV , from 66.5 [57.5, 76.2] mmHg to 58.2 [52.7, 63.8] mmHg ( p <0.0001) after ACTH injection ( Figure 2E ). In contrast, the pO 2 levels didn’t change in either HV, from 40.8 [37.6, 44.3] mmHg to 40.4 [37.8, 43.4] mmHg (not significant), or IPV, from 43.1 [35.5, 51.7] mmHg to 45.1 [34.3, 50.0] mmHg (not significant: Figure 2E ). In EIV, blood pO 2 levels slightly increased from 43.2 [40.0, 47.0] mmHg to 44.4 [41.2, 47.8] mmHg ( p =0.007). However, the dominance of blood pO 2 levels in the adrenal veins over those in examined non-adrenal veins was maintained even under ACTH stimulation ( Figure 2D ). Those trends of pO 2 distribution at baseline and after ACTH stimulation were similar even in 11 PA cases where O 2 was not administered during AVS ( Figure S2 ). However, there were significant differences of pO 2 levels between cases with and without oxygen administration, particularly in those of adrenal veins at baseline ( Table S4) . 3. Evaluation of venous pCO 2 levels before and after ACTH stimulation Notably, blood pCO 2 levels were significantly lower in the adrenal veins compared to their neighboring veins ( Figure 3A and B ). At baseline, the pCO 2 levels in RAV were lower than those in EIV and HV, measuring 41.6 [39.0, 43.7] mmHg in RAV versus 46.5 [43.7, 48.4] mmHg in EIV and 43.4 [40.8, 45.7] mmHg in HV ( p <0.0001 for both). Similarly, the pCO 2 levels were lower in LAV CV than in EIV and IPV, with values of 42.2 [39.9, 44.3] mmHg in LAV CV compared to 46.5 [43.7, 48.4] mmHg in EIV and 44.7 [42.6, 46.9] mmHg in IPV ( p <0.0001 for both). Following ACTH stimulation, blood pCO 2 levels significantly increased to 43.4 [41.3, 45.5] and 43.5 [41.2, 46.0] mmHg in RAV and LAV CV , respectively ( p <0.0001 for both). In addition, the initiation of ACTH resulted in a mild elevation of blood pCO 2 levels in HV, from 43.4 [40.8, 45.6] mmHg to 44.2 [41.1, 46.3] mmHg ( p =0.02), and IPV, from 44.7 [42.5, 46.9] mmHg to 45.2 [42.9, 48.2] mmHg ( p =0.001), but not EIV ( Figure 3B ). Download figure Open in new tab Figure 3. The pCO 2 evaluation in the adrenal veins and their surrounding veins pCO 2 , partial pressure of carbon dioxide; RAV, right adrenal vein; HV, hepatic vein; EIV, external iliac vein; IPV, inferior phrenic vein; LAV IPV , left adrenal vein after the confluence of IPV; LAV CV , the central vein of left adrenal; BL, baseline; ACTH, cosyntropin stimulation. Baseline pCO 2 levels in each vein are shown in panel A. Changes of pCO 2 levels after cosyntropin injection are summarized in panel B. #, p <0.05; **, p <0.01; ***, p <0.001; ****, p <0.0001; ns, not significant. 4. Influential factors on venous gas status in adrenal veins Intriguingly, in both adrenal veins, cortisol secretion was negatively correlated with pO 2 levels, both at baseline and under ACTH administration ( Figure 4A-F ). At baseline, the correlation between cortisol secretion and pO 2 was weak (Spearman r =-0.2265 and -0.2588, p =0.004 and 0.0008 in RAV and LAV CV , respectively) ( Figure 4A and 4D ), but became moderate after ACTH stimulation (Spearman r =-0.5142 and -0.5347, p <0.0001 for both in RAV and LAV CV , respectively) ( Figure 4B and 4E ). The cortisol increase, calculated as cortisol levels after ACTH stimulation divided by baseline levels, also showed a negative correlation with pO 2 changes between before and after ACTH initiation (Spearman r =-0.2645 and -0.2529, p =0.0009 and 0.001 in RAV and LAV CV , respectively) ( Figure 4C and 4F ). Similarly, PAC was also negatively correlated with pO 2 levels ( Figure 4G-L ). The correlations of pO 2 with PAC were similar to those with cortisol levels at baseline (Spearman r =-0.2221 and -0.2975, p =0.005 and <0.0001 in RAV and LAV CV , respectively) ( Figure 4G and 4J ), but relatively weaker under ACTH stimulation (Spearman r =-0.2183 and -0.2891, p =0.006 and 0.0002 in RAV and LAV CV , respectively) ( Figure 4H and 4K ). The aldosterone increase, calculated as PAC after ACTH stimulation divided by baseline levels, was also weakly but negatively correlated with the pO 2 changes (Spearman r =-0.1728 and -0.2087, p =0.03 and 0.007 in RAV and LAV CV , respectively) ( Figure 4I and 4L ). Furthermore, LAV CV showed a negative correlation between aldosterone-to-cortisol ratios and pO 2 (Spearman r =-0.2037 and -0.1525, p =0.009 and 0.05 at baseline and after ACTH stimulation, respectively), but not RAV (not significant). On the other hand, HV showed a positive correlation between cortisol levels and pO 2 only at baseline (Spearman r =0.2101, p =0.007), and IPV showed no correlation between them ( Figure S3) . In addition, no significant correlation was observed between pCO 2 and other parameters above in both adrenal veins and non-adrenal veins. Download figure Open in new tab Figure 4. Correlations between pO 2 and steroid production in the adrenal veins pO 2 , partial pressure of oxygen; RAV, right adrenal vein; LAV CV , the central vein of left adrenal. The pO 2 change was calculated by subtracting pO 2 levels under cosyntropin stimulation from their baseline levels. Cortisol or aldosterone increase was represented by dividing cortisol or aldosterone levels following cosyntropin injection by their baseline levels. The correlations between pO 2 and cortisol production in RAV and LAV CV are shown in panel A-C, and D-F, respectively. Panel A and D show the baseline evaluation, while panel B and E illustrate the parameters under cosyntropin stimulation. Changes in pO 2 and cortisol production after cosyntropin injection are displayed in panel C and F. For aldosterone, panel G-I and J-L represent the associations with pO 2 for RAV and LAV CV , respectively. The associations between pO 2 and aldosterone at baseline and following cosyntropin injection are shown in panel G and J, and H and K, respectively. Changes in pO 2 and aldosterone production after cosyntropin injection are evaluated in panel I and L. Finally, multiple regression analysis revealed that body mass index and ipsilateral PAC were negatively associated with pO 2 levels in RAV and LAV CV , regardless of ACTH stimulation ( Table 5S ). Additionally, age and ipsilateral cortisol secretion were confirmed as influential factors on pO 2 levels in LAV CV after ACTH stimulation and RAV for both statuses. Neither PA laterality nor the presence of an adrenal tumor was associated with pO 2 status. Application of blood gas analysis on detection of adrenal veins 1. ROC analysis of venous pO 2 in distinguishing adrenal veins Finally, we investigated the discriminative ability of venous pO 2 and pCO 2 in identifying adrenal veins ( Figure 5 ). At baseline, ROC curves demonstrated excellent performance of both actual pO 2 and ΔpO 2 in differentiating RAV from HV, comparable to the SI ( Figure 5A ). Optimal cutoff values for RAV detection based on the Youden index were determined as 1.64 (sensitivity 0.981, specificity 0.987), 50.9 mmHg (sensitivity 0.981, specificity 0.981) and 10.2 mmHg (sensitivity 0.942, specificity 0.981) for the SI, actual pO 2 and ΔpO 2 , respectively ( Table 1 ). For actual pO 2 , cutoff values of 45.2 and 57.3 mmHg showed a sensitivity of 1.000 and specificity of 1.000 for RAV detection, respectively. In addition, a higher ΔpO 2 values greater than 0.6 and 13.5 mmHg were associated with a sensitivity of 1.000 and a specificity of 1.000 for RAV, respectively, as well. After ACTH stimulation, a higher SI exceeding 9.4 demonstrated a sensitivity and specificity of 1.000 for RAV detection ( Figure 5B ). The evaluation of actual pO 2 and ΔpO 2 also proved helpful for RAV cannulation even under ACTH stimulation ( Table 1 ). An actual pO 2 greater than 47.2 mmHg exhibited a sensitivity of 0.955 and specificity of 0.929, while a ΔpO 2 greater than 3.9 mmHg demonstrated a sensitivity of 0.929 and specificity of 0.897. However, the performance of actual pO 2 and ΔpO 2 was inferior to that of the SI ( p <0.01). Download figure Open in new tab Figure 5. ROC analysis for the discriminative ability of pO 2 for the identification of adrenal veins The ability of partial pressure of oxygen (pO 2 ) to distinguish right adrenal vein from hepatic vein, or left adrenal vein from inferior phrenic vein, was assessed in panel A-B and C-D, respectively. Panel A (N=154) and C (N=73) illustrate the discriminative ability of pO 2 at baseline, while panel B (N=155) and D (N=72) show this ability under cosyntropin stimulation, respectively. Blue, red and green lines indicate selectivity index, actual pO 2 and Δ pO 2 , respectively. Δ pO 2 was calculated by subtracting pO 2 levels at external iliac vein from those at a target vein. View this table: View inline View popup Table 1. The discriminative ability of partial pressure of oxygen for adrenal veins Similarly, actual pO 2 and ΔpO 2 were useful indicators for LAV CV cannulation ( Figure 5C and D , and Table 1 ). In baseline gas analysis, optimal cutoff values of SI (>2.15), actual pO 2 (>52.7 mmHg) and ΔpO 2 (>13.9 mmHg) showed sensitivities of 0.904, 0.945 and 0.849, and specificities of 0.753, 0.808 and 0.836, respectively. Actual pO 2 and ΔpO 2 had larger AUCs than the SI ( Figure 5C ), though the differences were not statistically significant. ACTH stimulation clearly enhanced the discriminative ability of the SI in identifying LAV CV , while diminishing the performance of actual pO 2 and ΔpO 2 ( Figure 5D ). Throughout the investigation of blood gas analysis for AVS, the pCO 2 and ΔpCO 2 levels have less discriminative power in distinguishing the adrenal veins from the non-adrenal veins, despite showing significant differences in pCO 2 between those veins ( Figure S4 ). 2. Representative cases illustrating the potential of pO 2 as a guide in AVS Case 1: Discrimination of RAV from HV This was the PA case with a common trunk of RAV and HV. Enhanced CT pointed out the possibility of a confluence of RAV and HV prior to AVS ( Figure 6A ). For confirmation of the laterality of PA, we performed AVS in which venous angiography detected a candidate of RAV shown as Figure 6B . Blood samples for the assessment of pO 2 as well as steroids were collected by sequentially inserting a catheter into the superior and inferior branches of the vein to verify whether those veins were draining blood from the right adrenal gland ( Figure 6C and D ). The pO 2 level was higher in the inferior branch (69.9 mmHg) than in the superior branch (45.1 mmHg) comparable to the trend of SI ( Table 2 ). Under ACTH stimulation, the SI significantly elevated in the inferior branch (from 1.76 to 28.8), but not in the superior branch (from 1.09 to 1.34). Taken together with the findings of preoperative CT, we identified the inferior and superior branches as RAV and HV, respectively. The pO 2 levels maintained their dominance in RAV over HV even after ACTH injection. Download figure Open in new tab Figure 6. Adrenal imaging and venous angiography of representative cases Panel A-D and E-H show representative images of computed tomography and venous angiography from two men diagnosed with primary aldosteronism (Case 1 and 2), respectively. In Case 1, preoperative computed tomography revealed a confluence of the right adrenal vein and hepatic vein (A: Yellow and orange arrowheads indicate the right adrenal and the liver, respectively. A black arrow marks the accessory hepatic vein which flows into the right adrenal vein). Adrenal venous sampling confirmed this confluence (B). The right adrenal and hepatic veins were separately selected by a catheter (C and D, respectively) and the venous partial pressure of oxygen levels at baseline were measured as 69.9 and 45.1 mmHg, respectively. In Case 2, enhanced computed tomography visualized the left adrenal vein (E: yellow arrowheads). Adrenal venous sampling identified the left adrenal vein with three main branches (F). After exclusion of the proximal one as inferior phrenic vein, the middle and distal branches were individually cannulated for blood sampling (G and H, respectively), confirming the distal one as the left adrenal central vein based on the selectivity index. The blood partial pressure of oxygen level at baseline was measured as 37.1 mmHg in the middle vein and 57.7 mmHg in the distal vein. View this table: View inline View popup Download powerpoint Table 2. Venous parameters of representative cases illustrating pO 2 -guided adrenal venous sampling Case 2: Identification of LAV among several candidate veins The second case was a PA patient whose adrenal imaging detected a few candidates of LAV CV . Preoperative CT with contrast media clearly indicated LAV, with three main branches suspected to drain blood from the left adrenal gland ( Figure 6E ). We considered the proximal one coursing upward as IPV but couldn’t identify which of the two other veins was the LAV CV preoperatively. During AVS, we obtained blood samples from the two veins for the measurement of cortisol and pO 2 ( Figure 6F ). The SI and pO 2 levels were summarized in Table 2 . In the middle branch ( Figure 6G ), the SI and pO 2 level were 1.17 and 37.1 mmHg, respectively, while those parameters were higher in the distal branch (3.22 and 57.7 mmHg, respectively: Figure 6H ). After ACTH initiation, the SI increased to 2.27 and 41.9 in the middle and distal ones, respectively, resulting in confirmation of the distal vein as LAV CV . Discussion In our present study, we firstly demonstrated the difference of pO 2 status among the adrenal veins and their surrounding veins, which could be also clinically applicable for identification of adrenal veins in AVS. Of note, pO 2 status in adrenal veins was significantly negatively associated with steroid production from the adrenal tissue and body mass index. Venous gas analysis in both before and after ACTH stimulation indicated adrenal oxygen consumption for steroid hormone synthesis. Oxygen is one of the most critical elements for cellular activities. A sufficient supply of oxygen enables living cells to produce adenosine triphosphate, the primary energy source of the cells, and water through cellular respiration occurring in the mitochondria 29 . In the adrenal gland, this aerobic reaction also supports the ACTH-dependent steroidogenesis by enhancing the expression of steroidogenic enzymes using adenosine triphosphate 30 . Results of our present study also demonstrated that pO 2 levels in the adrenal veins were significantly higher than those in the other veins examined. These findings also suggest that adrenal consumption of oxygen is relatively small, compared to the organs such as the liver, stomach and lower limb. However, the differences in oxygen consumption between the adrenal glands and other organs have been rarely studied in both humans and animals. One exception is an animal study in which adrenal oxygen consumption was slightly lower than that of the liver in rabbits (2.53 ± 0.25 vs. 3.05 ± 0.77 μl/hr/mg dry weight) 31 . From another perspective, the adrenal glands are known to be highly vascularized. In humans, arterial blood supply to bilateral adrenal glands typically originates from the abdominal aorta, renal and phrenic arteries 32 . Animal studies previously demonstrated that the adrenal glands receive up to 0.5% of the total cardiac output 33 – 35 , while the adrenal glands are also one of the organs receiving the highest blood flow per unit of weight 34 . Therefore, the adrenal glands have an abundant supply of oxygen. In the adrenal cortex, oxygen is also involved in the steroidogenic process, particularly in oxidation reactions. Several steroidogenic enzymes, including aldosterone synthase, utilize oxygen within the mitochondria and the smooth endoplasmic reticulum during the transformation of cholesterol into steroid hormones 36 . In addition, chromaffin cells in the adrenal medulla also require oxygen for adrenaline synthesis during the hydroxylation step 37 . Those hormonal synthesis also generates reactive oxygen species, which are scavenged by antioxidant enzymes such as copper and zinc and manganese superoxide dismutase (SOD) 38 . In those SOD, copper and zinc-SOD played as a scavenger of toxic superoxide radicals generated during steroidogenesis, while manganese-SOD during catecholamine production 38 . Regarding adrenal oxygen consumption, a couple of animal studies reported that slices of dog and pig adrenal tissues exhibited baseline oxygen uptake rates of 84.4 and 86 mm 3 /100 mg weight/hr at baseline, respectively 39 , 40 . Both studies also demonstrated an increased oxygen uptake by 20-40 mm 3 /100 mg weight/hr following administration of ACTH 39 , 40 . In addition, oxygen availability has been identified as a regulatory factor in steroidogenesis 41 – 44 . An in vitro study using bovine adrenocortical cells demonstrated that low pO 2 conditions (80-90 torr) significantly decreased aldosterone production at baseline (-31%) and in response to angiotensin II (-45 to -55%), cAMP (-48 to - 54%) and ACTH (-13 to -33%), compared with normal pO 2 conditions (140-150 torr) 41 . Similarly, oxygen-dependent regulation of steroidogenesis has also been observed in human tissue experiments, particularly under stimulated conditions 44 . In accordance with those reports, we observed a set of decreased pO 2 and increased pCO 2 levels in the adrenal veins after cosyntropin administration. In addition, pO 2 changes before and after ACTH stimulation were significantly negatively correlated with production of both aldosterone and cortisol in the adrenal veins. Results of our present study are, therefore, interpreted as oxygen consumption during ACTH-dependent steroid synthesis in the adrenal glands. Those findings also suggested that the rich vascularization of the adrenal glands provides sufficient oxygen to support prompt steroid hormone synthesis in response to physiological demand. Consequently, the baseline pO 2 levels in the adrenal veins were considered higher than in other veins due to the relatively abundant oxygen supply. This characteristic was utilized in the current study to assess successful cannulation to the adrenal veins during AVS. Regarding the observed negative impact of body mass index on adrenal venous pO 2 levels, several clinical studies reported that obesity was associated with lower oxygen saturation, and lower maximal oxygen uptake during exercise 45 – 48 . The mechanisms underlying this association has been unclear, but the reduction of expiratory residual volume under obesity is considered as one of the contributing factors 49 . The possible association between adrenal oxygen consumption and the body size has remained unknown at this juncture and therefore, further studies are warranted to expand our understanding about the mechanisms of oxygen consumption in adrenal cortical cells and the influential factors. Notably, our study firstly indicated that pO 2 evaluation was a promising tool or pathfinder for identifying adrenal veins during AVS. Nearly 60 years have passed since AVS was first proposed for the subtype determination of PA 50 . However, cannulating the adrenal veins is still clinically challenging. Today, the combination of preprocedual imaging of adrenal veins and development of customized catheter has led to higher AVS success rates than before 15 , 28 . Nevertheless, intraprocedural judging whether the cannulated vessel is the target adrenal vein based on the angiography is sometimes difficult, particularly for operators with limited experience 18 . Successful cannulation to the adrenal veins is worldwide defined by achieving a higher SI with specific cutoff values that depend on sampling conditions and regions 17 , 20 , 21 , 28 . Recently, a new assay of cortisol with a shortened measurement time has been developed for the quick assessment of adrenal venous cannulation 18 . This immunochromatographic assay measures plasma cortisol concentrations quantitatively within 6 minutes, increasing successful AVS rates from 54% to 93% judged by the SI in a multi-center study 18 . With the findings from our present study, we propose another and an easy-to-use approach to the judgement of adrenal venous selection using pO 2 levels in the cannulated vein. Blood gas analyzers are widely available in hospitals, including inpatient unit, catheter laboratory and emergency room. Blood gas analysis needs only a small blood sample and can be completed within one minute. Our findings demonstrated that pO 2 levels are significantly higher in RAV and LAV CV than in their counterpart veins, HV and IPV, respectively, particularly under the baseline situation. The identical ability of pO 2 levels for the adrenal veins was compatible to the SI. Thus, AVS operators can easily and repeatedly use the technique to confirm whether the catheter is properly inserted into the adrenal veins until successful cannulation is achieved. The current study proposes pO 2 -guided AVS and provides a novel insight into adrenal oxygen consumption, while there are a few limitations to be considered for interpreting our findings. First, our AVS protocol includes oxygen administration to settle the patients’ breathing for the efficient performance of AVS. This medical procedure might alter the pO 2 levels in the examined veins and the cutoff values for the adrenal veins. Second, the cases where we assessed the pO 2 levels in IPV were limited due to the low clinical necessity, which influence the ROC curve for differentiating LAV CV from IPV. Finally, this is a single-center study, but not a multicenter study. A future study collaborating with multiple international centers is expected to clearly understand the utility of pO 2 assessment for PA subtyping. In conclusion, the first awareness of different blood colors between the adrenal and non-adrenal veins brought us to the current study, in which we successfully demonstrated the different distributions of pO 2 levels in the adrenal and their neighboring veins. Blood gas analysis is a faster, easier and less-expensive tool to identify the adrenal veins during AVS. From bedside to bench, we also observed oxygen consumption in the adrenal glands, referred to as “adrenal breathing”. Our findings should advance both clinical practice and research in the field of adrenal endocrinology. Sources of Funding This work was supported by JSPS KAKENHI Grant Number 23K15091 and YOKOYAMA Foundation for Clinical Pharmacology (YRY-2311). Disclosures KO has received JSPS KAKENHI Grant (23K15091). YT has received JSPS KAKENHI Grant (25K19407) and project support from YOKOYAMA Foundation for Clinical Pharmacology (YRY-2311). YT and YO have received project support from H.U. Group Research Institute and Fujirebio Inc. HK has received research funding from Sumitomo Pharma Co., Ltd., Kyowa Kirin Co., Ltd., Abbott Japan LLC, Nippon Boehringer Ingelheim Co., Ltd. and Murata Manufacturing Co., Ltd.. FS received grant support from the Ministry of Health, Labor and Welfare, Japan (No. H29-Nanji-Ippan-046) and research funding from Nippon Boehringer Ingelheim Co., Ltd.. All other authors declare no conflict of interest. Data availability Data presented in this study are available from the corresponding authors upon request. Supplemental Material Tables S1–S5 Figure S1-S4 Non-standard Abbreviations and Acronyms ACTH adrenocorticotropic hormone AVS adrenal venous sampling BP blood pressure CT computed tomography CVD cardiovascular disease EH essential hypertension EIV external iliac vein HV hepatic vein IVC inferior vena cava IPV inferior phrenic vein LAV left adrenal vein MRA mineralocorticoid receptor antagonist OR odds ratio PA primary aldosteronism PAC plasma aldosterone concentration PRA plasma renin activity PRC plasma renin concentration pCO 2 partial pressure of carbon dioxide pO 2 partial pressure of oxygen RAV right adrenal vein ROC receiver operating curve SI selectivity index SOD superoxide dismutase Acknowledgments We sincerely thank Shinichiro Hosaka and Satoko Kurosawa for their clinical management of PA patients. We also appreciate the technical assistance provided by Yasuko Tsukada and Kumi Kikuchi. 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