Bax, J.J.

Kuneman, J.H.

Leiden University Scholary Publications

Sex differences in coronary artery diseaseKuneman, J.H.; Bax, J.J.CitationKuneman, J. H., & Bax, J. J. (2021). Sex differences in coronary artery disease. NetherlandsHeart Journal, 29(10), 486-489. doi:10.1007/s12471-021-01619-x Version: Publisher's VersionLicense: Creative Commons CC BY 4.0 licenseDownloaded from: https://hdl.handle.net/1887/3279724 Note: To cite this publication please use the final published version (if applicable).CommentaryNeth Heart J (2021) 29:486–489https://doi.org/10.1007/s12471-021-01619-xSex differences in coronary artery diseaseJ. H. Kuneman · J. J. BaxAccepted: 5 August 2021 / Published online: 10 September 2021© The Author(s) 2021Cardiovascular disease, predominantly ischaemicheart disease, remains the leading cause of diseaseburden in men and women worldwide [1]. Overthe past decades, considerable evidence has beenreported on sex-related differences, in terms of preva-lence and severity of coronary artery disease (CAD)and outcomes. Among patients with suspected acuteor chronic coronary syndrome, women present morefrequently, and at older age, with different chest painsymptoms than men, and they have higher cardio-vascular risk profiles but less obstructive CAD [2, 3].Accordingly, concerns have been raised that womenare likely to receive suboptimal treatment for CADcompared with men.Coronary computed tomography angiography(CCTA) is an accurate diagnostic test for symptomaticpatients with suspected CAD [4]. It enables compre-hensive, noninvasive evaluation of CAD, includingcoronary anatomy and luminal narrowing, and quan-tification of atherosclerosis using advanced plaqueanalysis. A previous CCTA study demonstrated lesscalcified plaques and more noncalcified plaques inwomen than in men [5]. Moreover, it has been notedthat women have less coronary plaque burden ona per-patient level than men (with lower fibrous/fibrofatty plaque volume and total plaque volume)[6]. In addition, women show significantly slower pro-gression of coronary atherosclerosis on serial CCTAscans [7]. Yet, women with ischaemic heart diseasehave worse outcomes compared with men [8].J. H. Kuneman · J. J. Bax ()Department of Cardiology, Leiden University MedicalCenter, Leiden, The Netherlandsj.j.bax@lumc.nlJ. J. BaxTurku Heart Centre, University of Turku and TurkuUniversity Hospital, Turku, FinlandIn this issue, Arslan et al. report on sex-relateddifferences in the clinical presentation and CCTA re-sults and their effect on downstream outpatient test-ing among patients presenting with suspected acutecoronary syndrome (ACS) to the emergency depart-ment [9]. This subanalysis of the Better Evaluation ofAcute Chest Pain with Coronary Computed Tomog-raphy Angiography (BEACON) trial, in which CCTAwas evaluated against standard of care [10], included500 patients, of whom 47% were women. Study end-points were recorded within 30 days after the initialpresentation of suspected ACS and included coronaryangiography, coronary revascularisation, hospital ad-mission, length of stay, repeated emergency depart-ment visits and subsequent outpatient testing. Theauthors reported that women had a lower incidenceof obstructive CAD on CCTA compared with men, de-spite being older (56± 10 vs 53± 10 years, p<0.01) andless frequently using statins (18% vs 28%, p=0.01). Inaddition, women with suspected ACS were less fre-quently admitted to hospital and had less outpatienttesting if CCTA was used in the diagnostic work-up.The intriguing data presented by Arslan et al. arein line with current evidence and emphasise theapparent sex differences among patients presentingwith suspected ischaemic heart disease. Numerousreasons exist to explain the sex disparities in CAD,including, but not limited to, potential differences inpathophysiology as well as (patients’ and physicians’)disease perception. In general, the lower prevalenceof obstructive CAD in women versus men can be a re-assuring sign for the treating physician. Historically,the presence of less obstructive CAD in women hasbeen associated with lower referral rates for invasivecoronary angiography and a shift towards alternativeextra-cardiac diagnoses [11]. In the study [9], womenhad more non-obstructive CAD. Of note, 48% ofthe women who presented with suspected ACS at the486 Sex differences in coronary artery diseaseAdvertisement placed here.Houten 2021Advertisement placed here.Houten 2021Commentaryemergency department had no coronary artery steno-sis on CCTA (compared with 39% of men), which maybe an explanation for less downstream outpatienttesting in the female patients.Although data from a large study showed that pa-tients with non-obstructive CAD fared much betterthan those with obstructive CAD [11], the presence ofnon-obstructive CAD in women with anginal symp-toms may not necessarily be a reassuring sign. TheWomen’s Ischemia Syndrome Evaluation (WISE) studyreported that women with cardiac symptoms and noor minimal stenoses on invasive coronary angiogra-phy have a 2-fold and 4-fold increased risk of adversecardiovascular events, respectively, compared withasymptomatic women [12]. These observations, alongwith similar findings from other studies, may suggesta sex-specific pathophysiology for ischaemic heartdisease.It has been hypothesised that dysfunction of thecoronary microvasculature and endothelium con-tributes to the worse prognosis of symptomaticwomen in the absence of obstructive CAD [2]. Im-paired regulation of myocardial blood flow can be as-sessed by coronary flow reserve (CFR) on myocardialperfusion imaging. Reduced CFR may indicate mi-crovascular or endothelial dysfunction in the absenceof epicardial coronary stenosis [13]. In a study eval-uating symptomatic patients who were referred forinvasive coronary angiography, women with severelyimpaired CFR had a significantly increased risk of ad-verse cardiovascular events compared with men (haz-ard ratio 2.49, 95% confidence interval 1.16–5.38) [14].Arslan et al. observed that the use of CCTA in thework-up of patients with suspected ACS is feasible andis associated with less downstream outpatient test-ing in women [9]. However, whether this affects clin-ical outcomes or contributes to the underdiagnosisof ischaemic heart disease in women remains unan-swered. Long-term follow-up data may provide fur-ther insight into these sex differences in CAD.Conflict of interest The Department of Cardiology, Lei-den University Medical Center, Leiden, the Netherlandshas received unrestricted research grants from Abbot Vas-cular, Bayer, BioVentrix, GE Healthcare, Ionis, Medtronic,BIOTRONIK, Boston Scientific and Edwards Lifesciences.J.J. Bax has received speaker fees from Abbot Vascular.J.H. Kuneman has no relationships relevant to the contentsof this paper to disclose.Open Access This article is licensed under a Creative Com-mons Attribution 4.0 International License, which permitsuse, sharing, adaptation, distribution and reproduction inanymedium or format, as long as you give appropriate creditto the original author(s) and the source, provide a link tothe Creative Commons licence, and indicate if changes weremade. The images or other third party material in this articleare included in the article’sCreativeCommons licence, unlessindicated otherwise in a credit line to thematerial. If materialis not included in the article’s Creative Commons licence andyour intended use is not permitted by statutory regulation orexceeds the permitted use, you will need to obtain permis-sion directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.References1. Roth GA, Mensah GA, Johnson CO, et al. Global burdenof cardiovascular diseases and risk factors, 1990–2019:update from the GBD 2019 study. J Am Coll Cardiol.2020;76:2982–3021.2. Crea F, Battipaglia I, Andreotti F. Sex differences in mech-anisms, presentation andmanagement of ischaemic heartdisease. Atherosclerosis. 2015;241:157–68.3. ReynoldsHR, ShawLJ,Min JK, et al. Associationof sexwithseverityofcoronaryarterydisease, ischemia,andsymptomburden in patients with moderate or severe ischemia:secondary analysis of the ISCHEMIA randomized clinicaltrial. JAMACardiol. 2020;5:773–86.4. TheSCOT-HEARTInvestigators. CTcoronary angiographyin patients with suspected angina due to coronary heartdisease (SCOT-HEART): an open-label, parallel-group,multicentretrial. Lancet. 2015;385:2383–91.5. Pundziute G, Schuijf JD, van Velzen JE, et al. Assessmentwithmulti-slicecomputed tomographyandgray-scaleandvirtual histology intravascular ultrasound of gender-spe-cific differences in extent and composition of coronaryatherosclerotic plaques in relation to age. Am J Cardiol.2010;105:480–6.6. Conte E, Dwivedi A,Mushtaq S, et al. Age- and sex-relatedfeatures of atherosclerosis from coronary computed to-mography angiography in patients prior to acute coronarysyndrome: results from the ICONIC study. Eur Heart JCardiovascImaging. 2021;22:24–33.7. Gu H, Gao Y, Wang H, et al. Sex differences in coro-naryatherosclerosisprogressionandmajoradversecardiacevents in patients with suspected coronary artery disease.JCardiovascComputTomogr. 2017;11:367–72.8. Baldassarre LA, Raman SV, Min JK, et al. Noninvasiveimaging to evaluate women with stable ischemic heartdisease. JACCCardiovascImaging. 2016;9:421–35.9. Arslan M, Schaap J, Moelker A, et al. Coronary CT an-giography for suspected acute coronary syndrome: sex-associateddifferences. NethHeart J. 2021;https://doi.org/10.1007/s12471-021-01607-1.10. Dedic A, Lubbers MM, Schaap J, et al. Coronary CTangiographyfor suspectedACSintheeraofhigh-sensitivitytroponins: randomized multicenter study. J Am CollCardiol. 2016;67:16–26.11. Min JK, Dunning A, Lin FY, et al. Age- and sex-related dif-ferences inall-causemortality riskbasedoncoronarycom-puted tomography angiography findings results from theInternationalMulticenterCONFIRM(CoronaryCTAngiog-raphy Evaluation for Clinical Outcomes: An InternationalMulticenter Registry) of 23,854 patients without knowncoronaryarterydisease. JAmCollCardiol. 2011;58:849–60.12. GulatiM,Cooper-DeHoffRM,McClureC,etal. Adversecar-diovascularoutcomesinwomenwithnonobstructivecoro-nary artery disease: a report from the Women’s IschemiaSyndrome Evaluation Study and the St JamesWomen TakeHeartProject. ArchInternMed. 2009;169:843–50.13. Uusitalo V, Saraste A, Kajander S, et al. The associationbetween coronary flow reserve and development of coro-narycalcifications: a follow-upstudy for 11years inhealthyyoungmen. EurHeartJCardiovascImaging. 2013;14:812–8.14. Taqueti VR, Shaw LJ, Cook NR, et al. Excess cardiovas-cular risk in women relative to men referred for coronaryangiography is associated with severely impaired coro-nary flow reserve, not obstructive disease. Circulation.2017;135:566–77.Sex differences in coronary artery disease 489

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