A network medicine approach to study comorbidities in heart failure with preserved ejection fraction

  • Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2013;10:401–10.

    Article 
    PubMed 

    Google Scholar 

  • Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017;14:591–602.

    Article 
    PubMed 

    Google Scholar 

  • Mishra S, Kass DA. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2021;18:400–23.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pandey A, Vaduganathan M, Arora S, Qamar A, Mentz RJ, Shah SJ, et al. Temporal trends in prevalence and prognostic implications of comorbidities among patients with acute decompensated heart failure: the ARIC study community surveillance. Circulation. 2020;142:230–43.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Simmonds SJ, Cuijpers I, Heymans S, Jones EAV. Cellular and molecular differences between HFpEF and HFrEF: a step ahead in an improved pathological understanding. Cells. 2020;9(1):242.

  • Palmiero G, Cesaro A, Vetrano E, Pafundi PC, Galiero R, Caturano A, et al. Impact of SGLT2 inhibitors on heart failure: from pathophysiology to clinical effects. Int J Mol Sci. 2021;22(11):5863.

  • Maron BA, Altucci L, Balligand J-L, Baumbach J, Ferdinandy P, Filetti S, et al. A global network for network medicine. NPJ Syst Biol Appl. 2020;6:29.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hu JX, Thomas CE, Brunak S. Network biology concepts in complex disease comorbidities. Nat Rev Genet. 2016;17:615–29.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Khan A, Uddin S, Srinivasan U. Comorbidity network for chronic disease: a novel approach to understand type 2 diabetes progression. Int J Med Inform. 2018;115:1–9.

    Article 
    PubMed 

    Google Scholar 

  • Guo M, Yu Y, Wen T, Zhang X, Liu B, Zhang J, et al. Analysis of disease comorbidity patterns in a large-scale China population. BMC Med Genomics. 2019;12(Suppl 12):177.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Aguado A, Moratalla-Navarro F, López-Simarro F, Moreno V. MorbiNet: multimorbidity networks in adult general population. Analysis of type 2 diabetes mellitus comorbidity. Sci Rep. 2020;10:2416.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hidalgo CA, Blumm N, Barabási A-L, Christakis NA. A dynamic network approach for the study of human phenotypes. PLoS Comput Biol. 2009;5: e1000353.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Goh K-I, Cusick ME, Valle D, Childs B, Vidal M, Barabási A-L. The human disease network. Proc Natl Acad Sci USA. 2007;104:8685–90.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lusis AJ, Weiss JN. Cardiovascular networks: systems-based approaches to cardiovascular disease. Circulation. 2010;121:157–70.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bousquet J, Anto JM, Sterk PJ, Adcock IM, Chung KF, Roca J, et al. Systems medicine and integrated care to combat chronic noncommunicable diseases. Genome Med. 2011;3:43.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shah SJ, Borlaug BA, Kitzman DW, McCulloch AD, Blaxall BC, Agarwal R, et al. Research priorities for heart failure with preserved ejection fraction: national heart, lung, and blood institute working group summary. Circulation. 2020;141:1001–26.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Joseph J, Liu C, Hui Q, Aragam K, Wang Z, Charest B, et al. Genetic architecture of heart failure with preserved versus reduced ejection fraction. Nat Commun. 2022;13:7753.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • GMS | GMDS 2012: 57. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e. V. (GMDS) | Webservice zur sicheren Pseudonymisierung durch Datentreuhänder. https://www.egms.de/static/en/meetings/gmds2012/12gmds121.shtml. Accessed 9 Dec 2022.

  • PheCode map. https://phewascatalog.org/phecodes_icd10. Accessed October 2021.

  • Wu P, Gifford A, Meng X, Li X, Campbell H, Varley T, et al. Mapping ICD-10 and ICD-10-CM Codes to Phecodes: Workflow Development and Initial Evaluation JMIR Med Inform. 2019;7(4):e14325.

  • Gasparini A. comorbidity: an R package for computing comorbidity scores. JOSS. 2018;3:648.

    Article 

    Google Scholar 

  • Traag VA, Waltman L, van Eck NJ. From Louvain to Leiden: guaranteeing well-connected communities. Sci Rep. 2019;9:5233.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Morbinet. https://shiny.odap-ico.org/morbinet/. Accessed October 2021.

  • HPO database. https://hpo.jax.org/app/. Accessed August 2021.

  • Köhler S, Gargano M, Matentzoglu N, Carmody LC, Lewis-Smith D, Vasilevsky NA, et al. The human phenotype ontology in 2021. Nucleic Acids Res. 2021;49:D1207–17.

    Article 
    PubMed 

    Google Scholar 

  • Greene D, Richardson S, Turro E. ontologyX: a suite of R packages for working with ontological data. Bioinformatics. 2017;33:1104–6.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Serrano MA, Boguñá M, Vespignani A. Extracting the multiscale backbone of complex weighted networks. Proc Natl Acad Sci USA. 2009;106:6483–8.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Koutra D, Vogelstein JT, Faloutsos C. DELTACON: a principled massive-graph similarity function. arXiv:1304.4657.

  • Czepluch FS, Wollnik B, Hasenfuß G. Genetic determinants of heart failure: facts and numbers. ESC Heart Fail. 2018;5:211–7.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51:D587–92.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cardiovascular Disease Knowledge Portal. https://cvd.hugeamp.org/phenotype.html?phenotype=HF. Accessed 8 Aug 2022.

  • Ramirez Flores RO, Lanzer JD, Holland CH, Leuschner F, Most P, Schultz J-H, et al. The Reference of the Transcriptional Landscape of Human End-Stage Heart Failure. https://doi.org/10.5281/zenodo.3797044.

  • Ramirez Flores RO, Lanzer JD, Holland CH, Leuschner F, Most P, Schultz J-H, et al. Consensus transcriptional landscape of human end-stage heart failure. J Am Heart Assoc. 2021;10: e019667.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • PheWAS catalog. Nat Biotechnol. 2013. https://phewascatalog.org/#. Accessed 26 Sep 2022.

  • Denny JC, Bastarache L, Ritchie MD, Carroll RJ, Zink R, Mosley JD, et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat Biotechnol. 2013;31:1102–10.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schiattarella GG, Altamirano F, Tong D, French KM, Villalobos E, Kim SY, et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature. 2019;568:351–6.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tong D, Schiattarella GG, Jiang N, May HI, Lavandero S, Gillette TG, et al. Female sex is protective in a preclinical model of heart failure with preserved ejection fraction. Circulation. 2019;140:1769–71.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lê S, Josse J, Husson F. FactoMineR: An R package for multivariate analysis. J Stat Softw. 2008;25(1):1–18.

  • Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33:1–22.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wright MN, Ziegler A. ranger: a fast implementation of random forests for high dimensional data inC++ and R. J Stat Softw. 2017;77:1–17.

    Article 

    Google Scholar 

  • Chmiel A, Klimek P, Thurner S. Spreading of diseases through comorbidity networks across life and gender. New J Phys. 2014;16: 115013.

    Article 

    Google Scholar 

  • Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, Ronzano F, Centeno E, Sanz F, et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2020;48:D845–55.

    PubMed 

    Google Scholar 

  • DisGeNET database. https://www.disgenet.org/downloads. Accessed August 2021.

  • Türei D, Valdeolivas A, Gul L, Palacio‐Escat N, Klein M, Ivanova O, et al. Integrated intra‐ and intercellular signaling knowledge for multicellular omics analysis. Mol Syst Biol. 2021;17:e9923.

  • Bioconductor – OmnipathR. https://www.bioconductor.org/packages/release/bioc/html/OmnipathR.html. Accessed August 2021.

  • HuRi. http://www.interactome-atlas.org/data/HI-union.tsv. Accessed August 2021

  • Luck K, Kim D-K, Lambourne L, Spirohn K, Begg BE, Bian W, et al. A reference map of the human binary protein interactome. Nature. 2020;580:402–8.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Buphamalai P, Kokotovic T, Nagy V, Menche J. Network analysis reveals rare disease signatures across multiple levels of biological organization. Nat Commun. 2021;12:6306.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Doll S, Dreßen M, Geyer PE, Itzhak DN, Braun C, Doppler SA, et al. Region and cell-type resolved quantitative proteomic map of the human heart. Nat Commun. 2017;8:1469.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Heart Proteome Map. http://maxqb.biochem.mpg.de/. Access ID:PXD006675. Accessed August 2021.

  • GTEX v8 DB. https://www.gtexportal.org/home/datasets#datasetTitleDiv1. Accessed October 2021.

  • Valdeolivas A, Tichit L, Navarro C, Perrin S, Odelin G, Levy N, et al. Random walk with restart on multiplex and heterogeneous biological networks. Bioinformatics. 2019;35:497–505.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43: e47.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013;14:128.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Korotkevich G, Sukhov V, Budin N, Shpak B, Artyomov MN, Sergushichev A. Fast gene set enrichment analysis. BioRxiv. 2016.

  • Ergatoudes C, Schaufelberger M, Andersson B, Pivodic A, Dahlström U, Fu M. Non-cardiac comorbidities and mortality in patients with heart failure with reduced vs. preserved ejection fraction: a study using the Swedish Heart Failure Registry. Clin Res Cardiol. 2019;108:1025–33.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cruz-Ávila HA, Vallejo M, Martínez-García M, Hernández-Lemus E. Comorbidity networks in cardiovascular diseases. Front Physiol. 2020;11:1009.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Klimek P, Aichberger S, Thurner S. Disentangling genetic and environmental risk factors for individual diseases from multiplex comorbidity networks. Sci Rep. 2016;6:39658.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Divo MJ, Casanova C, Marin JM, Pinto-Plata VM,de-Torres JP, Zulueta JJ, et al. COPD comorbidities network. Eur Respir J. 2015;46:640–50.

    Article 
    PubMed 

    Google Scholar 

  • Kustatscher G, Collins T, Gingras A-C, Guo T, Hermjakob H, Ideker T, et al. Understudied proteins: opportunities and challenges for functional proteomics. Nat Methods. 2022;19:774–9.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wesseling M, de Poel JHC, de Jager SCA. Growth differentiation factor 15 in adverse cardiac remodelling: from biomarker to causal player. ESC Heart Fail. 2020;7:1488–501.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Szumska D, Cioroch M, Keeling A, Prat A, Seidah NG, Bhattacharya S. Pcsk5 is required in the early cranio-cardiac mesoderm for heart development. BMC Dev Biol. 2017;17:6.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Warren SA, Terada R, Briggs LE, Cole-Jeffrey CT, Chien W-M, Seki T, et al. Differential role of Nkx2-5 in activation of the atrial natriuretic factor gene in the developing versus failing heart. Mol Cell Biol. 2011;31:4633–45.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Arasaratnam D, Bell KM, Sim CB, Koutsis K, Anderson DJ, Qian EL, et al. The role of cardiac transcription factor NKX2-5 in regulating the human cardiac miRNAome. Sci Rep. 2019;9:15928.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tayal U, Prasad S, Cook SA. Genetics and genomics of dilated cardiomyopathy and systolic heart failure. Genome Med. 2017;9:20.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu X, Shi G-P, Guo J. Innate immune cells in pressure overload-induced cardiac hypertrophy and remodeling. Front Cell Dev Biol. 2021;9: 659666.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Blanton RM, Carrillo-Salinas FJ, Alcaide P. T-cell recruitment to the heart: friendly guests or unwelcome visitors? Am J Physiol Heart Circ Physiol. 2019;317:H124–40.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Croquelois A, Domenighetti AA, Nemir M, Lepore M, Rosenblatt-Velin N, Radtke F, et al. Control of the adaptive response of the heart to stress via the Notch1 receptor pathway. J Exp Med. 2008;205:3173–85.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fernández-Ruiz I. Selective JAG1-NOTCH3 targeting shows potential for treating PAH. Nat Rev Cardiol. 2022;19:433.

    Article 
    PubMed 

    Google Scholar 

  • Zhao Q, Huang J, Wang D, Chen L, Sun D, Zhao C. Endothelium-specific CYP2J2 overexpression improves cardiac dysfunction by promoting angiogenesis via Jagged1/Notch1 signaling. J Mol Cell Cardiol. 2018;123:118–27.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yuan T, Krishnan J. Non-coding RNAs in cardiac regeneration. Front Physiol. 2021;12: 650566.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang J-K, Li Y, Zhao X-L, Liu Y-B, Tan J, Xing Y-Y, et al. Ablation of plasma prekallikrein decreases low-density lipoprotein cholesterol by stabilizing low-density lipoprotein receptor and protects against atherosclerosis. Circulation. 2022;145:675–87.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Dixit G, Blair J, Ozcan C. Plasma proteomic analysis of association between atrial fibrillation, coronary microvascular disease and heart failure. Am J Cardiovasc Dis. 2022;12:81–91.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lau ES, Paniagua SM, Zarbafian S, Hoffman U, Long MT, Hwang S-J, et al. Cardiovascular biomarkers of obesity and overlap with cardiometabolic dysfunction. J Am Heart Assoc. 2021;10: e020215.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eckenstaler R, Ripperger A, Hauke M, Petermann M, Hemkemeyer SA, Schwedhelm E, et al. A thromboxane A2 receptor-driven COX-2-dependent feedback loop that affects endothelial homeostasis and angiogenesis. Arterioscler Thromb Vasc Biol. 2022;42:444–61.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Butenas ALE, Rollins KS, Williams AC, Parr SK, Hammond ST, Ade CJ, et al. Thromboxane A2 receptors contribute to the exaggerated exercise pressor reflex in male rats with heart failure. Physiol Rep. 2021;9: e15052.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hariri E, Kakouros N, Bunsick DA, Russell SD, Mudd JO, Laws K, et al. Nonplatelet thromboxane generation is associated with impaired cardiovascular performance and mortality in heart failure. Am J Physiol Heart Circ Physiol. 2022;323:H248–55.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Alonso F, Dong Y, Génot E. Thrombomodulin, an unexpected new player in endothelial cell invasion during angiogenesis. Arterioscler Thromb Vasc Biol. 2021;41:1672–4.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Eidizadeh A, Schnelle M, Leha A, Edelmann F, Nolte K, Werhahn SM, et al. Biomarker profiles in heart failure with preserved vs. reduced ejection fraction: results from the DIAST-CHF study. ESC Heart Fail. 2023;10(1):200–10.

  • Zhang J, Zhou HJ, Ji W, Min W. AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis. Curr Atheroscler Rep. 2015;17:503.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huang Q, Qin L, Dai S, Zhang H, Pasula S, Zhou H, et al. AIP1 suppresses atherosclerosis by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2013;33:795–804.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sickinghe AA, Korporaal SJA, den Ruijter HM, Kessler EL. Estrogen contributions to microvascular dysfunction evolving to heart failure with preserved ejection fraction. Front Endocrinol (Lausanne). 2019;10:442.

    Article 
    PubMed 

    Google Scholar 

  • Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107:881–91.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Fu F, Doroudgar S. IRE1/XBP1 and endoplasmic reticulum signaling — from basic to translational research for cardiovascular disease. Curr Opin Physiol. 2022;28: 100552.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schiattarella GG, Altamirano F, Kim SY, Tong D, Ferdous A, Piristine H, et al. Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction. Nat Commun. 2021;12:1684.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li L, Zhao Q, Kong W. Extracellular matrix remodeling and cardiac fibrosis. Matrix Biol. 2018;68–69:490–506.

    Article 
    PubMed 

    Google Scholar 

  • Faul C. Cardiac actions of fibroblast growth factor 23. Bone. 2017;100:69–79.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Rodríguez C, Martínez-González J. The role of lysyl oxidase enzymes in cardiac function and remodeling. Cells. 2019;8(12):1483.

  • Agrawal V, Fortune N, Yu S, Fuentes J, Shi F, Nichols D, et al. Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension. Pulm Circ. 2019;9:2045894019878599.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gupta MP. Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure. J Mol Cell Cardiol. 2007;43:388–403.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yu J, Yang Y, Xu Z, Lan C, Chen C, Li C, et al. Long noncoding RNA ahit protects against cardiac hypertrophy through SUZ12 (suppressor of Zeste 12 protein homolog)-mediated downregulation of MEF2A (myocyte enhancer factor 2A). Circ Heart Fail. 2020;13: e006525.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tanaka K, Valero-Muñoz M, Wilson RM, Essick EE, Fowler CT, Nakamura K, et al. Follistatin like 1 regulates hypertrophy in heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2016;1:207–21.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Seki M, Powers JC, Maruyama S, Zuriaga MA, Wu C-L, Kurishima C, et al. Acute and chronic increases of circulating FSTL1 normalize energy substrate metabolism in pacing-induced heart failure. Circ Heart Fail. 2018;11: e004486.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Qin M, Huang H, Wang T, Hu H, Liu Y, Cao H, et al. Absence of Rgs5 prolongs cardiac repolarization and predisposes to ventricular tachyarrhythmia in mice. J Mol Cell Cardiol. 2012;53:880–90.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Li H, He C, Feng J, Zhang Y, Tang Q, Bian Z, et al. Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. Proc Natl Acad Sci USA. 2010;107:13818–23.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Al-Kindi SG, Buzkova P, Shitole SG, Reiner AP, Garg PK, Gottdiener JS, et al. Soluble CD14 and risk of heart failure and its subtypes in older adults. J Card Fail. 2020;26:410–9.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • De Franceschi N, Peuhu E, Parsons M, Rissanen S, Vattulainen I, Salmi M, et al. Mutually exclusive roles of SHARPIN in integrin inactivation and NF-κB signaling. PLoS ONE. 2015;10: e0143423.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lim S, Sala C, Yoon J, Park S, Kuroda S, Sheng M, et al. Sharpin, a novel postsynaptic density protein that directly interacts with the shank family of proteins. Mol Cell Neurosci. 2001;17:385–97.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Corker A, Neff LS, Broughton P, Bradshaw AD, DeLeon-Pennell KY. Organized chaos: deciphering immune cell heterogeneity’s role in inflammation in the heart. Biomolecules. 2021;12(1):11.

  • Essandoh K, Auchus RJ, Brody MJ. Cardiac decompensation and promiscuous prenylation of small GTPases in cardiomyocytes in response to local mevalonate pathway disruption. J Pathol. 2022;256:249–52.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Xu H, Shen Y, Liang C, Wang H, Huang J, Xue P, et al. Inhibition of the mevalonate pathway improves myocardial fibrosis. Exp Ther Med. 2021;21:224.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nishizawa H, Maeda N, Shimomura I. Impact of hyperuricemia on chronic kidney disease and atherosclerotic cardiovascular disease. Hypertens Res. 2022;45:635–40.

    Article 
    PubMed 

    Google Scholar 

  • Mátyás C, Németh BT, Oláh A, Török M, Ruppert M, Kellermayer D, et al. Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes. Eur J Heart Fail. 2017;19:326–36.

    Article 
    PubMed 

    Google Scholar 

  • Cornuault L, Rouault P, Duplàa C, Couffinhal T, Renault M-A. Endothelial dysfunction in heart failure with preserved ejection fraction: what are the experimental proofs? Front Physiol. 2022;13: 906272.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Simeunovic D, Odanovic N, Pljesa-Ercegovac M, Radic T, Radovanovic S, Coric V, et al. Glutathione transferase P1 polymorphism might be a risk determinant in heart failure. Dis Markers. 2019;2019:6984845.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Singh MM, Kumar R, Tewari S, Agarwal S. Association of GSTT1/GSTM1 and ApoE variants with left ventricular diastolic dysfunction in thalassaemia major patients. Hematology. 2019;24:20–5.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Nagamine T, Gillette B, Pakhomov A, Kahoun J, Mayer H, Burghaus R, et al. Multiscale classification of heart failure phenotypes by unsupervised clustering of unstructured electronic medical record data. Sci Rep. 2020;10:21340.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gulea C, Zakeri R, Quint JK. Model-based comorbidity clusters in patients with heart failure: association with clinical outcomes and healthcare utilization. BMC Med. 2021;19:9.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Woolley RJ, Ceelen D, Ouwerkerk W, Tromp J, Figarska SM, Anker SD, et al. Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction. Eur J Heart Fail. 2021;23:983–91.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Franssen C, Chen S, Hamdani N, Paulus WJ. From comorbidities to heart failure with preserved ejection fraction: a story of oxidative stress. Heart. 2016;102:320–30.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved ejection fraction in perspective. Circ Res. 2019;124:1598–617.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tam MC, Lee R, Cascino TM, Konerman MC, Hummel SL. Current perspectives on systemic hypertension in heart failure with preserved ejection fraction. Curr Hypertens Rep. 2017;19:12.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hicklin HE, Gilbert ON, Ye F, Brooks JE, Upadhya B. Hypertension as a road to treatment of heart failure with preserved ejection fraction. Curr Hypertens Rep. 2020;22:82.

    Article 
    PubMed 

    Google Scholar 

  • Vedin O, Lam CSP, Koh AS, Benson L, Teng THK, Tay WT, et al. Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study. Circ Heart Fail. 2017;10(6):e003875.

  • Reding KW, Cheng RK, Vasbinder A, Ray RM, Barac A, Eaton CB, et al. Lifestyle and cardiovascular risk factors associated with heart failure subtypes in postmenopausal breast cancer survivors. JACC CardioOncol. 2022;4:53–65.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Saiki H, Petersen IA, Scott CG, Bailey KR, Dunlay SM, Finley RR, et al. Risk of heart failure with preserved ejection fraction in older women after contemporary radiotherapy for breast cancer. Circulation. 2017;135:1388–96.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huang S, Cai T, Weber BN, He Z, Dahal KP, Hong C, et al. The association between inflammation, incident heart failure, and heart failure subtypes in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;75(5):1036–45.

  • Packer M. Link between synovial and myocardial inflammation: conceptual framework to explain the pathogenesis of heart failure with preserved ejection fraction in patients with systemic rheumatic diseases. Card Fail Rev. 2020;6:e10.

  • Gevaert AB, Boen JRA, Segers VF, Van Craenenbroeck EM. Heart failure with preserved ejection fraction: a review of cardiac and noncardiac pathophysiology. Front Physiol. 2019;10:638.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gao H, Patel S, Fohtung RB, Cawthon PM, Newman AB, Cauley JA, et al. Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults. J Am Geriatr Soc. 2023;71(3):742–55.

  • Sabbatini AR, Kararigas G. Menopause-related estrogen decrease and the pathogenesis of HFpEF: JACC review topic of the week. J Am Coll Cardiol. 2020;75:1074–82.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.

    Article 
    PubMed 

    Google Scholar 

  • Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol. 2022;19:100–16.

    Article 
    PubMed 

    Google Scholar 

  • Bortolotti M, Polito L, Battelli MG, Bolognesi A. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol. 2021;41: 101882.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Watanabe K, Watanabe T, Otaki Y, Shishido T, Murase T, Nakamura T, et al. Impact of plasma xanthine oxidoreductase activity in patients with heart failure with preserved ejection fraction. ESC Heart Fail. 2020;7:1735–43.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yoon S, Kim M, Lee H, Kang G, Bedi K, Margulies KB, et al. S-nitrosylation of histone deacetylase 2 by neuronal nitric oxide synthase as a mechanism of diastolic dysfunction. Circulation. 2021;143:1912–25.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • van Dam S, Võsa U, van der Graaf A, Franke L, de Magalhães JP. Gene co-expression analysis for functional classification and gene-disease predictions. Brief Bioinformatics. 2018;19:575–92.

    PubMed 

    Google Scholar 

  • Ata SK, Wu M, Fang Y, Ou-Yang L, Kwoh CK, Li X-L. Recent advances in network-based methods for disease gene prediction. Brief Bioinformatics. 2021;22(4):bbaa303.

  • Weiskopf NG, Rusanov A, Weng C. Sick patients have more data: the non-random completeness of electronic health records. AMIA Annu Symp Proc. 2013;2013:1472–7.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Wells BJ, Chagin KM, Nowacki AS, Kattan MW. Strategies for handling missing data in electronic health record derived data. EGEMS (Wash DC). 2013;1:1035.

    PubMed 

    Google Scholar 

  • Haneuse S, Daniels M. A general framework for considering selection bias in EHR-based studies: what data are observed and why? EGEMS (Wash DC). 2016;4:1203.

    PubMed 

    Google Scholar 

  • Farmer R, Mathur R, Bhaskaran K, Eastwood SV, Chaturvedi N, Smeeth L. Promises and pitfalls of electronic health record analysis. Diabetologia. 2018;61:1241–8.

    Article 
    PubMed 

    Google Scholar 

  • Pellikka PA, She L, Holly TA, Lin G, Varadarajan P, Pai RG, et al. Variability in ejection fraction measured by echocardiography, gated single-photon emission computed tomography, and cardiac magnetic resonance in patients with coronary artery disease and left ventricular dysfunction. JAMA Netw Open. 2018;1: e181456.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pieske B, Tschöpe C, de Boer RA, Fraser AG, Anker SD, Donal E, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40:3297–317.

    Article 
    PubMed 

    Google Scholar 

  • Triposkiadis F, Butler J, Abboud FM, Armstrong PW, Adamopoulos S, Atherton JJ, et al. The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J. 2019;40:2155–63.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sørensen HT. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol. 2011;11:83.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

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