Biomarker Correlates of Coronary Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction
2019; Lippincott Williams & Wilkins; Volume: 140; Issue: 16 Linguagem: Inglês
10.1161/circulationaha.119.042569
ISSN1524-4539
AutoresJasper Tromp, Camilla Hage, Wouter Ouwerkerk, Sandra Sanders‐van Wijk, Sara Svedlund, Antti Saraste, Ulrika Ljung Faxén, Maria Lagerström‐Fermér, Li-Ming Gan, Lars H. Lund, Sanjiv J. Shah, Carolyn S.P. Lam,
Tópico(s)Mechanical Circulatory Support Devices
ResumoHomeCirculationVol. 140, No. 16Biomarker Correlates of Coronary Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBBiomarker Correlates of Coronary Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction Jasper Tromp, MD, Camilla Hage, RN, PhD, Wouter Ouwerkerk, PhD, Sandra Sanders-van Wijk, MD, PhD, Sara Svedlund, MD, PhD, Antti Saraste, MD, PhD, Ulrika Ljung Faxén, MD, Maria Lagerstrom Fermer, PhD, MBA, Li-ming Gan, MD, Lars H. Lund, MD, PhD, Sanjiv J. Shah, MD and Carolyn S.P. Lam, MBBS, PhD Jasper TrompJasper Tromp National Heart Centre Singapore (J.T., W.O., C.S.P.L.). Department of Cardiology, University Medical Centre Groningen, University of Groningen, The Netherlands (J.T., C.S.P.L.). Duke-NUS Medical School Singapore (J.T., C.S.P.L.). , Camilla HageCamilla Hage Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (C.H., U.L.F., H.L.H.). GUCH, Arrhythmia and Heart Failure, Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden (C.H., H.L.H.). , Wouter OuwerkerkWouter Ouwerkerk National Heart Centre Singapore (J.T., W.O., C.S.P.L.). , Sandra Sanders-van WijkSandra Sanders-van Wijk Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL (S.S.-v.W., S.J.S.). Department of Cardiology, CARIM, Maastricht University Medical Center, The Netherlands (S.S.-v.W.). , Sara SvedlundSara Svedlund Department of Clinical Physiology, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Sweden (S.S.). , Antti SarasteAntti Saraste Heart Center, Turku University Hospital, University of Turku, Finland (A.S.). , Ulrika Ljung FaxénUlrika Ljung Faxén Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (C.H., U.L.F., H.L.H.). , Maria Lagerstrom FermerMaria Lagerstrom Fermer Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Sweden (M.L.F., L.-m.G.). , Li-ming GanLi-ming Gan Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Sweden (M.L.F., L.-m.G.). Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Sweden (L.-m.G.). Department of Cardiology, Sahlgrenska University Hospital, Sweden (L.-m.G.). , Lars H. LundLars H. Lund Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (C.H., U.L.F., H.L.H.). GUCH, Arrhythmia and Heart Failure, Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden (C.H., H.L.H.). , Sanjiv J. ShahSanjiv J. Shah Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL (S.S.-v.W., S.J.S.). and Carolyn S.P. LamCarolyn S.P. Lam Carolyn S.P. Lam, MBBS, PhD, National Heart Centre Singapore, 5 Hospital Dr, Singapore 169609, Singapore. Email E-mail Address: [email protected] National Heart Centre Singapore (J.T., W.O., C.S.P.L.). Department of Cardiology, University Medical Centre Groningen, University of Groningen, The Netherlands (J.T., C.S.P.L.). Duke-NUS Medical School Singapore (J.T., C.S.P.L.). The George Institute for Global Health, Sydney, Australia (C.S.P.L.). Originally published14 Oct 2019https://doi.org/10.1161/CIRCULATIONAHA.119.042569Circulation. 2019;140:1359–1361Reduced coronary flow reserve (CFR), reflecting coronary microvascular dysfunction, is common in heart failure with preserved ejection fraction (HFpEF)1 and can be caused by a number of factors, including extrinsic compression resulting from myocardial interstitial fibrosis, myocardial hypertrophy with insufficient microvascular supply, diffuse atherosclerosis, coronary microvascular inflammation, and elevated left ventricular (LV) filling pressures. Circulating biomarker correlates of CFR may provide important insights into underlying mechanisms of coronary microvascular dysfunction in HFpEF.Our aim was to uncover a biomarker profile specific to reduced CFR in HFpEF that is independent of myocardial hypertrophy, elevated cardiac filling pressures, atrial fibrillation, and epicardial coronary artery disease. Among 192 with blood samples available of the original 202 patients with a validated diagnosis of HFpEF (LV ejection fraction ≥40% without unrevascularized epicardial coronary artery disease) in the prospective multinational PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF),1 we measured 265 biomarkers using high-throughput proximity extension assays (Olink Proseek Multiplex CVD II and III, and inflammation 96×96 kits). We excluded 23 biomarkers that had >15% of values below the detection limit, leaving us with a total of 242 unique biomarkers for further analyses. CFR was measured with adenosine stress transthoracic Doppler echocardiography, and coronary microvascular dysfunction was defined as CFR <2.5. To assess the association between CFR and biomarkers, we used lasso penalized regression analyses including all biomarkers, age, sex, body mass index, creatinine, and study site. Multivariable regression analyses were performed to determine whether associations between biomarkers and CFR (as a continuous variable) were independent of smoking, LV mass index (cardiac hypertrophy), E/e' (elevated LV filling pressures), and history of atrial fibrillation, revascularized coronary artery disease, and hypertension. Protein–protein interaction networks were generated with the Genemania plug-in in Cytoscape version 3.6.1. Pathway overrepresentation analyses used data from the Gene Ontology network with a false discovery rate–corrected value of P<0.05 and the 242 biomarkers plus additional markers identified by Genemania as background. All analyses were performed with R version 3.4.0. A 2-sided value of P 0; Figure [A]), of which growth differentiation factor 15, osteoprotegerin, pulmonary surfactant-associated protein, angiotensin-converting enzyme 2, and insulin growth factor binding protein 1 showed the strongest associations. Two of these, tissue factor pathway inhibitor (P=0.18) and proprotein convertase subtilisin/kexin type 9 (P=0.20), lost significance in multivariable regression analyses. Of the 11 remaining biomarkers, 5 (in orange) were hits in our network (Figure [B]), which was then enriched with additional protein-protein interactions (blue). Pregnancy-associated plasma protein A (PAPP-A) formed an important hub in the network, suggesting greater biological importance, with similar results for PAPP-A when the analyses were restricted to patients with LV ejection fraction ≥50%. When the network is translated into biological pathways, those relating to cellular metabolism and physiological muscle hypertrophy were overrepresented (Figure [C]). Results were unchanged when we excluded biomarkers with either 10% or 20% of measurements below the limit of detection.Download figureDownload PowerPointFigure. Biomarkers associated with coronary microvascular dysfunction in PROMIS. A, Volcano plot showing biomarkers selected by lasso penalized regression analyses (red). The y axis shows the −log10 of the false discovery rate–corrected P value for the association of each individual biomarker with coronary microvascular dysfunction (coronary flow reserve <2.5) vs no coronary microvascular dysfunction. The x axis shows the log2 of the fold change of biomarker difference between patients with and without coronary microvascular dysfunction. B, Results of network analysis for the biomarkers independently associated with coronary microvascular flow reserve (orange) and those predicted in the network (blue). The size of the node reflects the edge betweenness of each biomarker. C, Bar graph depicting the top 10 overrepresented pathways with the −log10 of the false discovery rate–corrected P value on the x axis. ACE2 indicates angiotensin-converting enzyme 2; AGT, angiotensinogen; BNP, brain natriuretic protein; CMD, coronary microvascular dysfunction; CTSD, cathepsin D; Flt3L, FMS-like tyrosine kinase 3 ligand; GDF15, growth differentiation factor 15; IGF, insulin growth factor; IGFP, insulin growth factor binding protein; MMP10, matrix metalloproteinase 10; NPPB, natriuretic peptide precursor B; OPG, osteoprotegerin; PAPP-A, pregnancy-associated plasma protein A; PCSK9, proprotein convertase subtilisin/kexin type 9; PRG2, proteoglycan 2; PSPD, pulmonary surfactant-associated protein; SFTPC, surfactant protein D; THBS2, thrombospondin 2; and TFPI, tissue factor pathway inhibitor.PAPP-A emerged as a novel key hub in the network associated with reduced CFR in HFpEF, and it has been shown to be elevated in patients with unstable atherosclerosis and to be a predictor of cardiovascular events in patients with acute coronary syndrome through extracellular matrix degradation and interaction with insulin growth factor-1.2 Our findings extend the current paradigm of coronary microvascular dysfunction in HFpEF by suggesting that beyond microvascular inflammation,3 subclinical atherosclerosis may also play an important role. Limitations of this study include possible selection bias with regard to proteins measured and lack of data on how circulating proteins relate to proteins at the tissue level.In HFpEF, circulating biomarker profiles suggest that coronary microvascular dysfunction is related to subclinical atherosclerosis (via the PAPP-A pathway), potentially leading to cardiac hypertrophy and metabolic abnormalities.Sources of FundingPROMIS-HFpEF is an AstraZeneca-sponsored study. Dr Shah is supported by US National Institutes of Health grants (R01 HL107577, R01 HL127028, and R01 HL140731) and American Heart Association grants (16SFRN28780016 and 15CVGPSD27260148). Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore.DisclosuresDr Shah has received research grants from Actelion, AstraZeneca, Corvia, and Novartis and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Sanofi, Tenax, and United Therapeutics. Dr Lam has received research support from Boston Scientific, Bayer, Roche Diagnostics, Medtronic, and Vifor Pharma and has consulted for AstraZeneca, Bayer, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, and Takeda. Dr Saraste received research grants from Academy of Finland and Finnish Foundation for Cardiovascular Research and consulting fees from GE Healthcare, Novartis, Abbot, and AstraZeneca. Dr Hage has received consulting fees from Novartis and MSD. M.L. Fermer and Dr Gan are employees of AstraZeneca R&D. Dr Lund has received research grants from Novartis, Boehringer-Ingelheim, Vifor Pharma, and AstraZeneca, as well as consulting fees from Novartis, Merck, Boehringer-Ingelheim, Sanofi, Vifor Pharma, and AstraZeneca. The other authors report no conflicts.Footnoteshttps://www.ahajournals.org/journal/circData availability: The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.Guest Editor was Walter J. Paulus, MD.Carolyn S.P. Lam, MBBS, PhD, National Heart Centre Singapore, 5 Hospital Dr, Singapore 169609, Singapore. Email carolyn.[email protected]edu.sgReferences1. Shah SJ, Lam CSP, Svedlund S, Saraste A, Hage C, Tan RS, Beussink-Nelson L, Ljung Faxén U, Fermer ML, Broberg MA, et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF.Eur Heart J. 2018; 39:3439–3450. doi: 10.1093/eurheartj/ehy531CrossrefMedlineGoogle Scholar2. Bayes-Genis A, Conover CA, Overgaard MT, Bailey KR, Christiansen M, Holmes DR, Virmani R, Oxvig C, Schwartz RS. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes.N Engl J Med. 2001; 345:1022–1029. doi: 10.1056/NEJMoa003147CrossrefMedlineGoogle Scholar3. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.J Am Coll Cardiol. 2013; 62:263–271. doi: 10.1016/j.jacc.2013.02.092CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Arnold J, Kanagala P, Budgeon C, Jerosch-Herold M, Gulsin G, Singh A, Khan J, Chan D, Squire I, Ng L and McCann G (2022) Prevalence and Prognostic Significance of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction, JACC: Cardiovascular Imaging, 10.1016/j.jcmg.2021.11.022, 15:6, (1001-1011), Online publication date: 1-Jun-2022. González A, Richards A, Boer R, Thum T, Arfsten H, Hülsmann M, Falcao‐Pires I, Díez J, Foo R, Chan M, Aimo A, Anene‐Nzelu C, Abdelhamid M, Adamopoulos S, Anker S, Belenkov Y, Gal T, Cohen‐Solal A, Böhm M, Chioncel O, Delgado V, Emdin M, Jankowska E, Gustafsson F, Hill L, Jaarsma T, Januzzi J, Jhund P, Lopatin Y, Lund L, Metra M, Milicic D, Moura B, Mueller C, Mullens W, Núñez J, Piepoli M, Rakisheva A, Ristić A, Rossignol P, Savarese G, Tocchetti C, Van Linthout S, Volterrani M, Seferovic P, Rosano G, Coats A and Bayés‐Genís A (2022) Cardiac remodelling – Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology, European Journal of Heart Failure, 10.1002/ejhf.2493 Chandramouli C, Ting T, Tromp J, Agarwal A, Svedlund S, Saraste A, Hage C, Tan R, Beussink‐Nelson L, Lagerström Fermer M, Gan L, Lund L, Shah S and Lam C (2022) Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and preserved ejection fraction, European Journal of Heart Failure, 10.1002/ejhf.2435, 24:4, (681-684), Online publication date: 1-Apr-2022. 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Godo S, Takahashi J, Yasuda S and Shimokawa H (2021)(2021) Endothelium in Coronary Macrovascular and Microvascular Diseases, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000001089, 78:6S, (S19-S29) Hage C, Svedlund S, Saraste A, Faxén U, Benson L, Fermer M, Gan L, Shah S, Lam C and Lund L (2020) Association of Coronary Microvascular Dysfunction With Heart Failure Hospitalizations and Mortality in Heart Failure With Preserved Ejection Fraction: A Follow-up in the PROMIS-HFpEF Study, Journal of Cardiac Failure, 10.1016/j.cardfail.2020.08.010, 26:11, (1016-1021), Online publication date: 1-Nov-2020. Borlaug B (2020) Evaluation and management of heart failure with preserved ejection fraction, Nature Reviews Cardiology, 10.1038/s41569-020-0363-2, 17:9, (559-573), Online publication date: 1-Sep-2020. O'Meara E and Allen B (2019) Cardiac remodelling patterns and proteomics: the keys to move beyond ejection fraction in heart failure?, European Journal of Heart Failure, 10.1002/ejhf.1691, 22:7, (1156-1159), Online publication date: 1-Jul-2020. October 15, 2019Vol 140, Issue 16 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.042569PMID: 31609659 Originally publishedOctober 14, 2019 Keywordsheart failurePDF download Advertisement
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