Asali, Salma

Bryant, Jennifer A.

Chin, Calvin

Ching, Jenny Chong Pek

Han, Yiying

Jaufeerally, Fazlur

Jin, Xuanyi

Lam, Carolyn S. P.

Lee, Sheldon

Liew, Oi Wah

Loh, Seet Yoong

Packer, Milton

Richards, A. Mark

Sim, David

Soon, Dinna

Tay, Wan Ting

Tromp, Jasper

van Veldhuisen, Dirk J.

van Woerden, Gijs

English

ARTS repository - University of Groningen

   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 21-06-2022..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Epicardial fat in heart failure with reduced versus preserved ejection fraction

   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-10-2023..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 10-09-2023..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 05-06-2022..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 04-06-2022..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 11-09-2023..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

University of Groningen

   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-04-2023..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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   University of GroningenEpicardial fat in heart failure with reduced versus preserved ejection fractionTromp, Jasper; Bryant, Jennifer A.; Jin, Xuanyi; van Woerden, Gijs; Asali, Salma; Han, Yiying;Liew, Oi Wah; Ching, Jenny Chong Pek; Jaufeerally, Fazlur; Loh, Seet YoongPublished in:European Journal of Heart FailureDOI:10.1002/ejhf.2156IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Tromp, J., Bryant, J. A., Jin, X., van Woerden, G., Asali, S., Han, Y., Liew, O. W., Ching, J. C. P.,Jaufeerally, F., Loh, S. Y., Sim, D., Lee, S., Soon, D., Tay, W. T., Packer, M., van Veldhuisen, D. J., Chin,C., Richards, A. M., & Lam, C. S. P. (2021). Epicardial fat in heart failure with reduced versus preservedejection fraction. European Journal of Heart Failure, 23(5), 835-838. https://doi.org/10.1002/ejhf.2156CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-11-2022..................................................................................................................................................................................................................................................................................................................................................................................................................................RESEARCH LETTERSdoi:10.1002/ejhf.2156Online publish-ahead-of-print 30 March 2021Epicardial fat in heart failurewith reduced versuspreserved ejection fractionEpicardial adipose tissue (EAT) plays impor-tant physiological and pathological rolesin the regulation of myocardial function.By sharing the same microcirculation asthe myocardium, EAT may maintain cardiachealth via mechanical, metabolic, thermo-genic and paracrine functions1; on the otherhand, EAT inflammation in obesity maymediate myocardial dysfunction and heartfailure (HF).1 Prior studies reported con-flicting associations between EAT and HF(Table 1).2–6 Importantly, the method ofmeasuring EAT may impact results. Magneticresonance imaging (MRI) allows measurementof whole heart EAT volume or mass, whereasTable 1 Overview of studies on epicardial fat in heart failure with reduced and preserved ejection fraction with majorfindingsStudy design Sample size Method Major findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .HFpEFObokata et al. (2017)6 Retrospective,single centreHFpEF: 195Controls: 71Echocardiography:EAT thicknessEAT increased in patients with HFpEF comparedto controlsVan Woerden et al.(2018)2Prospective, singlecentreHFpEF: 64Controls: 20MRI: EAT volume EAT increased in patients with HFpEF comparedto controls and related to markers ofinflammationHaykowsky et al.(2018)3Prospective, singlecentreHFpEF: 100Controls: 61MRI: EAT volume EAT reduced compared to controls andassociated with greater peak VO2 max inHFpEFHFrEFDoesch et al. (2010)4 Retrospective,single centreHF: 66Controls: 32MRI: EAT volume EAT and EAT/LVMi ratio reduced compared tocontrolsHFrEF and HFpEFWu et al. (2020)5 Prospective, singlecentreHFrEF: 34HFpEF: 164Controls: 108MRI: EAT mass EAT increased in patients with HFrEF andHFpEF compared to controlsTromp (2021) Prospective,multicentreHFrEF: 204HFpEF: 47Controls: 113MRI: EAT massEchocardiography:EAT thicknessEAT mass increased, but EAT/LVM ratio andEAT thickness reduced in HFrEF and HFpEFIncrease in EAT associated with worsefunctional parameters and markers of fibrosisin HFpEF compared to HFrEFEAT, epicardial adipose tissue; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVM, left ventricular mass; LVMi, leftventricular mass index; MRI, magnetic resonance imaging; VO2, oxygen consumption.echocardiography only allows measurementof EAT thickness over the free wall of theright ventricle. None of the prior studiesincluded both MRI and echocardiographicmeasurements of EAT, as well as both HFwith preserved (HFpEF) and reduced ejec-tion fraction (HFrEF) compared to controlswithout HF from the same population.Magnetic resonance imaging images wereavailable for 457 participants, of whom 93were excluded due to artefacts on MRI causedby either cardiac surgery or pericardial effu-sion. Patients could be included as inpatientsor outpatients. We compared EAT mass byMRI (EATMRI) and EAT thickness by echocar-diography (EATEcho) in 251 prospectivelyrecruited patients with a validated diagnosisof HF (18% HFpEF, left ventricular ejectionfraction ≥50%) and 113 community-basedcontrols without HF, all of whom underwentsimultaneous cardiac MRI and echocardiogra-phy by standardized protocol in a nationwidestudy. Controls without HF were identifiedfrom a door-to-door census, and invitedto participate. Patients with severe valvulardisease, previous cardiac surgery and pericar-dial effusion leading to artefacts on MRI wereexcluded. EATMRI was assessed from a stan-dard short-axis stack of balanced steady-statefree precession cine MRI images acquiredacross the right and left ventricles usingCVI42 release 5.9.3 (Circle CardiovascularImaging, Calgary, Canada) software. Cardiacvolumes, left ventricular mass (LVM) andglobal longitudinal strain (GLS) were deter-mined by standard MRI methods. Native andpost-contrast (15 min post-administrationof 0.1 mmol/kg of gadobutrol) myocardialT1 mapping sequences acquired in basaland mid short-axis slices were used to esti-mate extracellular volume (ECV). Areas ofmacro-scar were excluded, in keeping withcurrent guidelines.7 EATEcho thickness wasdefined as the echo-free space betweenmyocardium and pericardium layer in theparasternal long or short-axis view on two-dimensional transthoracic echocardiography(GE Healthcare, Milwaukee, WI, USA).© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................836 Research lettersFigure 1 Box plots of (A) epicardial fat mass stratified to control (n =113), heart failure with reduced ejection fraction (HFrEF, n = 204), andheart failure with preserved ejection fraction (HFpEF, n = 47). (B) Epicardial fat thickness on echocardiography stratified to control (n =103),HFrEF (n = 146), and HFpEF (n = 24). (C) Epicardial fat mass/left ventricular mass ratio stratified to control (n = 113), HFrEF (n = 204), andHFpEF (n = 47). (D) Association of epicardial fat mass with global longitudinal strain (GLS) stratified to HFrEF (n = 202) and HFpEF (n = 47). (E)Association of epicardial fat mass with ECV stratified to HFrEF (n = 144) and HFpEF (n = 27). ECV, extracellular volume; LVMi, left ventricularmass index.© 2021 European Society of Cardiology.............................................................................................................................................................................................................................................................................................................................................................................................................................................................................Research letters 837Differences between groups were testedusing the Chi-square test, Kruskal–Wallistest or one-way analysis of variance whenappropriate. The association between EATMRImass and functional/structural parameters onMRI was tested using linear regression anal-ysis correcting for age, sex, ethnicity, bodymass index (BMI), history of diabetes mellitusand atrial fibrillation. All tests were per-formed two-sided and P-values of <0.05 wereconsidered statistically significant. EATMRIwas available in 364 participants, EATEchoin 273 participants, and ECV in 171 (68%)out of 251 patients. Statistical analyses wereperformed with STATA 16.0 (Stata Corp,College Station, TX, USA) and R version4.0.2.Patients with HFrEF were younger(55±11 years) and patients with HFpEFolder (63± 12 years) compared to con-trols (59±10 years, P< 0.001). Of the 113non-HF controls, 44% were men, com-pared to 82% in HFrEF and 65% in HFpEF(P< 0.001). BMI was higher in patientswith HFpEF (median 30 kg/m2) comparedto HFrEF (median 26 kg/m2) and controls(median 24 kg/m2). Compared to controls,EATMRI mass was higher in HFpEF and high-est in HFrEF (medians 80, 90 and 107 g,respectively; P< 0.001; Figure 1A). Afteradjustment for confounders, EATMRI masswas increased in HFrEF (P< 0.001), andsimilar in HFpEF compared to controls. Incontrast, EATEcho thickness was lowest inHFrEF (median 0.7 cm) compared to controlsand HFpEF (P< 0.03; Figure 1B). To recon-cile the discrepancy between EATMRI massand EATEcho thickness results, we indexedEATMRI mass for heart size, recognizing thata larger heart, with larger epicardial surface,would be expected to have higher overallEATMRI mass (in contrast to EATEcho thicknesslocalized at the right ventricular wall). Afterindexation for LVM, the EATMRI/LVMMRI ratiowas lower in HFpEF and HFrEF comparedto controls (Figure 1C); this remained sig-nificant after multivariable adjustment. Inpatients with HF, greater EATMRI mass wasassociated with worse left ventricular GLS(β = −0.21, P = 0.001). This associationwas stronger in HFpEF compared to HFrEF(HFpEF: β = −0.48, P = 0.003 vs. HFrEF:β = −0.15, P = 0.016, Pinteraction = 0.005;Figure 1D), independent of clinical covariates.After exclusion of outliers for GLS (>0%),the interaction term between HF subtype(HFrEF/HFpEF) and GLS for epicardial fatremained significant. Furthermore, greaterEATMRI mass was associated with highercardiac ECV in HFpEF (β = 0.63, P = 0.034)but not in HFrEF (Pinteraction < 0.001;Figure 1E).In this prospective study of HFpEF andHFrEF compared to community-basedcontrols, studied with both MRI and echocar-diographic measurements of EAT, we foundthat (i) total EATMRI mass was increased inHFrEF and HFpEF, while the EATMRI/LVMMRIratio and EATEcho thickness were reducedin HFrEF and HFpEF compared to controlswithout HF; (ii) increased EATMRI mass wasmore strongly associated with left ventric-ular dysfunction (GLS) and fibrosis (ECV)in HFpEF than HFrEF. Our findings are con-sistent with some prior reports showingan increase in epicardial fat mass or vol-ume in HFpEF and/or HFrEF compared tocontrols2,5,6; but not others, which showa reduction of epicardial fat in patientswith HFpEF.3,4 We extend on previous find-ings by including data on EAT thicknesson echocardiography; and EAT mass, andECV on MRI in the same patients. Previousconflicting reports might be explained bydifferences in inclusion criteria and mea-surement methods; for instance, Haykowskyet al.3 exclusively included patients with aBMI of ≥30 kg/m2 who may have had obesity-related hypervolaemic HF. In the presentstudy, the reduction in EATMRI/LVMMRI ratioand EATEcho thickness, most prominent inHFrEF, suggests possible thinning of theepicardial fat pad out of proportion to theincrease in heart size. Indeed, in HFrEF,intramyocardial fat is reduced while beingincreased in HFpEF compared to controls.5EAT, as a depot of white adipocytes rich inenergy, can serve as a metabolic reservoirunder conditions of increased myocardialenergy demand which may become depletedin HF.8 In contrast, specifically in inflam-matory HFpEF, EAT may be a focal sourceof inflammatory cytokines, causing fibrosisand stiffening of the myocardium leading tofunctional impairment.1 Our study providessupportive evidence for this hypothesis inshowing a stronger association of increasedEAT mass with left ventricular dysfunctionand fibrosis in HFpEF than HFrEF. Yet, ourcross-sectional design precludes conclusionsregarding causality, and our findings warrantvalidation in future large prospective studiesincluding assessments of both the qualityand quantity of EAT. We did not excludepatients with cachexia or thyroid disease, andexcluded patients with artefacts on MRI orevidence of pericardial effusion, which mighthave influenced our results. More men thanwomen consented to participate in our study,leading to possible participation bias.In conclusion, we provide evidence of EATthinning despite increase in total EAT massin HF, most pronounced in HFrEF. Greatertotal EAT is more closely associated withworse functional parameters and markers ofmyocardial fibrosis in HFpEF than in HFrEF.These data highlight the possible divergentrole(s) of EAT in the pathophysiology ofHFrEF and HFpEF.FundingThe Asian neTwork for Translational Researchand Cardiovascular Trials (ATTRaCT) issupported by the Agency for Science, Tech-nology and Research (A*STAR) BiomedicalResearch Council program (SPF2014/003,SPF2014/004, SPF2014/005) and NationalMedical Research Council’s Heart Fail-ure: Markers and Management grant(NMRC/CG/014/2013).Conflict of interest: C.S.L. is supportedby a Clinician Scientist Award from theNational Medical Research Council of Sin-gapore; has received research support fromBoston Scientific, Bayer, Roche Diagnostics,AstraZeneca, Medtronic, and Vifor Pharma;has served as consultant or on the AdvisoryBoard/Steering Committee/Executive Com-mittee for Boston Scientific, Bayer, RocheDiagnostics, AstraZeneca, Medtronic, ViforPharma, Novartis, Amgen, Merck, JanssenResearch & Development LLC, Menarini,Boehringer Ingelheim, Novo Nordisk, AbbottDiagnostics, Corvia, Stealth BioTherapeu-tics, JanaCare, Biofourmis, Darma, AppliedTherapeutics, MyoKardia, Cytokinetics,WebMD Global LLC, Radcliffe Group Ltdand Corpus; and serves as co-founder andnon-executive director of eKo.ai. J.T hasreceived personal grants and speaker feesfrom Olink Proteomics and Roche Diag-nostics. M.P. reports receiving consultingfees from Abbvie, Akcea, Actavis, Amgen,AstraZeneca, Bayer, Boehringer Ingelheim,Cardiorentis, Daiichi Sankyo, Gilead, Johnson& Johson, NovoNordisk, Pfizer, Relypsa,Sanofi, Synthetic Biologics, and Theravance.D.J.v.V. reports receiving fees for serving on asteering committee and travel support fromARCA Biopharma and Corvia Medical. Allother authors have nothing to disclose.Jasper Tromp1,2,3†, Jennifer A. Bryant1†,Xuanyi Jin1,3, Gijs van Woerden3,Salma Asali1, Han Yiying1,Oi Wah Liew4,Jenny Chong Pek Ching4,Fazlur Jaufeerally2, Seet Yoong Loh5,David Sim1, Sheldon Lee6,© 2021 European Society of Cardiology.......................................................................................................................................................................................................................................838 Research lettersDinna Soon7, Wan Ting Tay1,Milton Packer8, Dirk J. van Veldhuisen3,Calvin Chin1, A. Mark Richards4,9, andCarolyn S.P. Lam1,2,3∗1National Heart Centre Singapore, Singapore,Singapore; 2Duke-NUS Medical School, Singapore,Singapore; 3Department of Cardiology, Universityof Groningen, University Medical CenterGroningen, Groningen, The Netherlands;4Cardiovascular Research Institute (CVRI),National University Heart Centre Singapore(NUHS), Singapore, Singapore; 5Tan Tock SengHospital, Singapore, Singapore; 6Changi GeneralHospital, Singapore, Singapore; 7Khoo Teck PuatHospital, Singapore, Singapore; 8Department ofClinical Sciences, University of Texas SouthwesternMedical Center, Dallas, TX, USA; and9Christchurch Heart Institute, University of Otago,Dunedin, New Zealand*Email: carolyn.lam@duke-nus.edu.sg†These authors contributed equally.References1. Rao VN, Fudim M, Mentz RJ, Michos ED, FelkerGM. Regional adiposity and heart failure withpreserved ejection fraction. Eur J Heart Fail2020;22:1540–1550.2. van Woerden G, Gorter TM, Westenbrink BD,Willems TP, van Veldhuisen DJ, Rienstra M. Epi-cardial fat in heart failure patients with mid-rangeand preserved ejection fraction. Eur J Heart Fail2018;20:1559–1566.3. Haykowsky MJ, Nicklas BJ, Brubaker PH, HundleyWG, Brinkley TE, Upadhya B, Becton JT, NelsonMD, Chen H, Kitzman DW. Regional adipose distri-bution and its relationship to exercise intolerancein older obese patients who have heart failurewith preserved ejection fraction. JACC Heart Fail2018;6:640–649.4. Doesch C, Haghi D, Flüchter S, Suselbeck T,Schoenberg SO, Michaely H, Borggrefe M, Papavas-siliu T. Epicardial adipose tissue in patients withheart failure. J Cardiovasc Magn Reson 2010;12:40.5. Wu CK, Lee JK, Hsu JC, Su MY, Wu YF, Lin TT,Lan CW, Hwang JJ, Lin LY. Myocardial adiposedeposition and the development of heart failurewith preserved ejection fraction. Eur J Heart Fail2020;22:445–454.6. Obokata M, Reddy YN, Pislaru SV, Melenovsky V,Borlaug BA. Evidence supporting the existence of adistinct obese phenotype of heart failure with pre-served ejection fraction. Circulation 2017;136:6–19.7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J,Nezafat R, Salerno M, Schelbert EB, Taylor AJ,Thompson R, Ugander M, van Heeswijk RB,Friedrich MG. Clinical recommendations for car-diovascular magnetic resonance mapping of T1, T2,T2* and extracellular volume: a consensus state-ment by the Society for Cardiovascular MagneticResonance (SCMR) endorsed by the EuropeanAssociation for Cardiovascular Imaging (EACVI).J Cardiovasc Magn Reson 2017;19:75.8. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardialfat in the maintenance of cardiovascular health.Methodist Debakey Cardiovasc J 2017;13:20–24.© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Epicardial fat in heart failure with reduced versus preserved ejection fraction

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