Skip to main content
SpringerLink
Log in

Enhanced Levels of Adiposity, Stretch and Fibrosis Markers in Patients with Coexistent Heart Failure and Atrial Fibrillation

  • Original Article
  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

The coexistence of heart failure (HF) and atrial fibrillation (AF) worsens the prognosis of patients. We aimed to study the inflammation, metabolism, adiposity, and fibrosis markers on epicardial and subcutaneous fat and blood, and their relationship with HF and AF. Samples from 185 patients undergoing cardiac surgery were collected. Levels of multi-markers on fat biopsies and plasma were analyzed. Patients were grouped by HF or AF presence. Plasma adiposity markers were increased in AF patients, while increased stretch markers correlated with HF. Patients with both AF and HF had higher ANP and GDF-15 levels. After excluding AF patients, plasma FABP4 was identified as the main HF predictor. Fat biopsies from AF patients showed an enhanced inflammatory profile. Higher levels of adiposity markers are associated with AF or HF, and higher stretch and fibrosis markers with combined AF and HF, suggesting a role of adiposity-fibrosis pathway in HF and AF coexistence.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The used and analysed datasets of the current study are available from the corresponding author on reasonable request.

Abbreviations

HF:

Heart failure

AF:

Atrial fibrillation

CVD:

Cardiovascular disease

CAD:

Coronary artery disease

T2DM:

Type 2 diabetes mellitus

SAT:

Subcutaneous adipose tissue

EAT:

Epicardial adipose tissue

EATV:

Epicardial adipose tissue volume

ECG:

Electrocardiogram

FABP4:

Fatty binding protein 4

ANP:

Atrial natriuretic peptide

AGP:

Alpha-1 acid glycoprotein

TSP2:

Thrombospondin-2

GDF-15:

Growth differentiation factor 15

DEFA3:

α-Defensins 3

C5a:

Complement component 5a

Pref-1:

Preadipocyte factor 1

a-SMA:

Alpha smooth actin

Ct:

Cycle threshold

BMI:

Body mass index

AHT:

Arterial hypertension

DLP:

Dyslipidaemia

LVEF:

Left ventricular ejection fraction

ACEI:

Angiotensin converting enzyme inhibitors

MRA:

Mineralocorticoid receptor antagonist

a.u.:

Arbitrary unit

IQR:

Interquartile range

CI:

Confidence interval

References

  1. Dobrev D, Heijman J, Hiram R, Li N, Nattel S. Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology. Nat Rev Cardiol. 2023;20(3):145–67.

    Article  CAS  PubMed  Google Scholar 

  2. Murphy SP, Kakkar R, McCarthy CP, Januzzi JL. Inflammation in Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(11):1324–40.

    Article  PubMed  Google Scholar 

  3. Rao M, Wang X, Guo G, Wang L, Chen S, Yin P, et al. Resolving the intertwining of inflammation and fibrosis in human heart failure at single-cell level. Basic Res Cardiol. 2021;116(1):55.

    Article  PubMed  Google Scholar 

  4. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT, Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal anti-body to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107(25):3133–40.

    Article  CAS  PubMed  Google Scholar 

  5. Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, et al. Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail. 2017;10(11):e004373.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Batal O, Schoenhagen P, Shao M, Ayyad AE, Van Wagoner DR, Halliburton SS, et al. Left Atrial Epicardial Adiposity and Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2010;3(3):230–6.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006;74:443–77.

    Article  CAS  PubMed  Google Scholar 

  8. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91.

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Venteclef N, Guglielmi V, Balse E, Gaborit B, Cotillard A, Atassi F, et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J. 2015;36(13):795–805a.

    Article  CAS  PubMed  Google Scholar 

  10. Sugita Y, Ito K, Sakurai S, Sakai S, Kuno S. Epicardial adipose tissue is associated with cardiorespiratory fitness and hemodynamics among Japanese individuals of various ages and of both sexes. PLoS ONE. 2021;16(7):e0254733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fu X, Almenglo C, Fernandez ÁL, Martínez-Cereijo JM, Iglesias-Alvarez D, Duran-Muñoz D, et al. The Effect of Mineralocorticoid Receptor 3 Antagonists on Anti-Inflammatory and Anti-Fatty Acid Transport Profile in Patients with Heart Failure. Cells. 2022;11(8):1264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Izquierdo AG, Crujeiras AB, Casanueva FF, Carreira MC. Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later? Nutrients. 2019;11(11):2704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. López-Canoa JN, Couselo-Seijas M, Baluja A, González-Melchor L, Rozados A, Llorente-Cortés V, et al. Sex-related differences of fatty acid-binding protein 4 and leptin levels in atrial fibrillation. EP Europace. 2021;23(5):682–90.

    Article  Google Scholar 

  14. Ravera A, Santema BT, de Boer RA, Anker SD, Samani NJ, Lang CC, et al. Distinct pathophysiological pathways in women and men with heart failure. Eur J Heart Fail. 2022;24(9):1532–44.

    Article  CAS  PubMed  Google Scholar 

  15. DeBari MK, Abbott RD. Adipose Tissue Fibrosis: Mechanisms, Models, and Importance. Int J Mol Sci. 2020;21(17):6030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu C, Zhang H, Zhang J, Xie C, Fan C, Zhang H, et al. Inflammation and Fibrosis in Perirenal Adipose Tissue of Patients With Aldosterone-Producing Adenoma. Endocrinology. 2018;159(1):227–37.

    Article  CAS  PubMed  Google Scholar 

  17. Lawler HM, Underkofler CM, Kern PA, Erickson C, Bredbeck B, Rasouli N. Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects. J Clin Endocrinol Metab. 2016;101(4):1422–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Reggio S, Pellegrinelli V, Clément K, Tordjman J. Fibrosis as a Cause or a Consequence of White Adipose Tissue Inflammation in Obesity. Curr Obes Rep. 2013;2(1):1–9.

    Article  Google Scholar 

  19. Dietz JR. Mechanisms of atrial natriuretic peptide secretion from the atrium. Cardiovasc Res. 2005;68(1):8–17.

    Article  CAS  PubMed  Google Scholar 

  20. Wallén T, Landahl S, Hedner T, Hedner J, Hall C. Atrial peptides, ANP(1–98) and ANP(99–126) in health and disease in an elderly population. Eur Heart J. 1993;14(11):1508–13.

    Article  PubMed  Google Scholar 

  21. Anter E, Jessup M, Callans DJ. Atrial Fibrillation and Heart Failure. Circulation. 2009;119(18):2516–25.

    Article  PubMed  Google Scholar 

  22. Diaz J, Martinez F, Calderon JM, Fernandez A, Sauri I, Uso R, et al. Incidence and impact of atrial fibrillation in heart failure patients: real-world data in a large community. ESC Heart Fail. 2022;9(6):4230–9.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gopinathannair R, Chen LY, Chung MK, Cornwell WK, Furie KL, Lakkireddy DR, et al. Managing Atrial Fibrillation in Patients With Heart Failure and Reduced Ejection Fraction: A Scientific Statement From the American Heart Association. Cir Arrhythm Electrophysiol. 2021;14(6):e000078.

    Google Scholar 

  24. Kotecha D, Piccini JP. Atrial fibrillation in heart failure: what should we do? Eur Heart J. 2015;36(46):3250–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. van Woerden G, Gorter TM, Westenbrink BD, Willems TP, van Veldhuisen DJ, Rienstra M. Epicardial fat in heart failure patients with mid-range and preserved ejection fraction. Eur J Heart Fail. 2018;20(11):1559–66.

    Article  PubMed  Google Scholar 

  26. Iacobellis G. Epicardial adipose tissue in contemporary cardiology. Nat Rev Cardiol. 2022;19(9):593–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. García-Vega D, González-Juanatey JR, Eiras S. Diabesity in Elderly Cardiovascular Disease Patients: Mechanisms and Regulators. Int Mol Sci. 2022;23(14):7886.

    Article  Google Scholar 

  28. Golledge J, Clancy P, Hankey GJ, Norman PE. Relation Between Serum Thrombospondin-2 and Cardiovascular Mortality in Older Men Screened for Abdominal Aortic Aneurysm. Am J Cardiol. 2013;111(12):1800–4.

    Article  CAS  PubMed  Google Scholar 

  29. Wollert KC, Kempf T, Wallentin L. Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease. Clin Chem. 2017;63(1):140–51.

    Article  CAS  PubMed  Google Scholar 

  30. Gaul DS, Stein S, Matter CM. Neutrophils in cardiovascular disease. Eur Heart J. 2017;38(22):1702–4.

    Article  CAS  PubMed  Google Scholar 

  31. Horckmans M, Ring L, Duchene J, Santovito D, Schloss MJ, Drechsler M, et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J. 2017;38(3):187–97.

    CAS  PubMed  Google Scholar 

  32. Strassheim D, Dempsey EC, Gerasimovskaya E, Stenmark K, Karoor V. Role of Inflammatory Cell Subtypes in Heart Failure. J Immunol Rese. 2019;2019:2164017.

    Google Scholar 

  33. Kim S, Eliot M, Koestler DC, Wu WC, Kelsey KT. Association of Neutrophil-to-Lymphocyte Ratio With Mortality and Cardiovascular Disease in the Jackson Heart Study and Modification by the Duffy Antigen Variant. JAMA Cardiol. 2018;3(6):455–62.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Christensen HM, Frystyk J, Faber J, Schou M, Flyvbjerg A, Hildebrandt P, et al. α-Defensins and outcome in patients with chronic heart failure. Eur J Heart Fail. 2012;14(4):387–94.

    Article  CAS  PubMed  Google Scholar 

  35. Speidl WS, Exner M, Amighi J, Kastl SP, Zorn G, Maurer G, et al. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis. Eur Heart J. 2005;26(21):2294–9.

    Article  CAS  PubMed  Google Scholar 

  36. Guo RF, Ward PA. Role of C5a in inflammatory responses. Annu Rev Immunol. 2005;23:821–52.

    Article  CAS  PubMed  Google Scholar 

  37. Ruige JB, Assendelft WJ, Dekker JM, Kostense PJ, Heine RJ, Bouter LM. Insulin and risk of cardiovascular disease: a meta-analysis. Circulation. 1998;97(10):996–1001.

    Article  CAS  PubMed  Google Scholar 

  38. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373–498.

    Article  PubMed  Google Scholar 

  39. Gopinathannair R, Chen LY, Chung MK, Cornwell WK, Furie KL, Lakkireddy DR, et al. Managing Atrial Fibrillation in Patients With Heart Failure and Reduced Ejection Fraction: A Scientific Statement From the American Heart Association. Circ Arrhythm Electrophysiol. 2021;14(6):HAE0000000000000078.

    PubMed  Google Scholar 

  40. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart Disease and Stroke Statistics—2021 Update. Circulation. 2021;143(8):e254-743.

    Article  PubMed  Google Scholar 

  41. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss. Circulation. 2006;113(6):898–918.

    Article  PubMed  Google Scholar 

  42. Lavie CJ, Pandey A, Lau DH, Alpert MA, Sanders P. Obesity and Atrial Fibrillation Prevalence, Pathogenesis, and Prognosis: Effects of Weight Loss and Exercise. J Am Coll Cardiol. 2017;70(16):2022–35.

    Article  PubMed  Google Scholar 

  43. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946–52.

    Article  CAS  PubMed  Google Scholar 

  44. López-Canoa JN, Couselo-Seijas M, González-Ferrero T, Almengló C, Álvarez E, González-Maestro A, et al. The Role of Fatty Acid-Binding Protein 4 in the Characterization of Atrial Fibrillation and the Prediction of Outcomes after Catheter Ablation. Int J Mol Sci. 2022;23(19):11107.

    Article  PubMed  PubMed Central  Google Scholar 

  45. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–726.

    Article  CAS  PubMed  Google Scholar 

  46. Couselo-Seijas M, Lopez-Canoa JN, Fernandez ÁL, González-Melchor L, Seoane LM, Duran-Muñoz D, et al. Inflammatory and lipid regulation by cholinergic activity in epicardial stromal cells from patients who underwent open-heart surgery. J Cell Mol Med. 2020;24(18):10958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Denk S, Taylor RP, Wiegner R, Cook EM, Lindorfer MA, Pfeiffer K, et al. Complement C5a-Induced Changes in Neutrophil Morphology During Inflammation. Scand J Immunol. 2017;86(3):143–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang W, Cai D. Complement Components sC5b-9 and CH50 Predict Prognosis in Heart Failure Patients Combined With Hypertension. Am J Hypertens. 2020;33(1):53–60.

    Article  CAS  PubMed  Google Scholar 

  49. Packer M. Leptin-Aldosterone-Neprilysin Axis. Circulation. 2018;137(15):1614–31.

    Article  CAS  PubMed  Google Scholar 

  50. Buffolo F, Tetti M, Mulatero P, Monticone S. Aldosterone as a Mediator of Cardiovascular Damage. Hypertension. 2022;79(9):1899–911.

    Article  CAS  PubMed  Google Scholar 

  51. Koniari I, Artopoulou E, Mplani V, Mulita F, Alexopoulou E, Chourdakis E, et al. Atrial fibrillation in heart failure patients: An update on renin-angiotensin-aldosterone system pathway blockade as a therapeutic and prevention target. Cardiol J. 2023;30(2):312–26.

    Article  PubMed  Google Scholar 

  52. Ruan ZB, Gao RF, Wang F, Chen GC, Zhu JG, Ren Y, et al. Circulating Galectin-3 and Aldosterone for Predicting Atrial Fibrillation Recurrence after Radiofrequency Catheter Ablation. Cardiovasc Ther. 2022;2022:6993904.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank all the patients who participate in the study, all the institutions that have supported this project, ISCIII, CIBERCV (CB16/11/00226), Xunta de Galicia, IDIS, SERGAS and USC and all health professionals that have contributed to image acquisition, blood samples extraction by venipuncture and biopsies collection.

Funding

This study was supported by "Fondo de Investigaciones Sanitarias (PI16/01282 and PI19/01330) from Plan Estatal de I + D + I and cofounded by ISCIII-Subdirección general de evaluación y fomento de la investigación del fondo europeo de desarrollo regional (FEDER), Grupos de potencial crecemento, Xunta de Galicia (IN607B-2022/04). Xiaoran Fu has a predoctoral PFIS fellowship by ISCIII-Subdirección general de evaluación y fomento de la investigación del fondo europeo de desarrollo regional (FEDER).

Author information

Author notes

  1. Diego Iglesias-Álvarez

    Present address: University of Santiago de Compostela, Santiago de Compostela, Spain

  2. Moises Rodriguez-Manero and Sonia Eiras are contributed equally to this work.

Authors and Affiliations

  1. Translational Cardiology Group, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain

    Xiaoran Fu, Cristina Almenglo, Moises Rodriguez-Manero & Sonia Eiras

  2. University of Santiago de Compostela, Santiago de Compostela, Spain

    Xiaoran Fu

  3. Cardiovascular Area, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

    Diego Iglesias-Álvarez, Ana García-Campos, María Amparo Martínez-Monzonís, Jose Ramón Gonzalez-Juanatey & Moises Rodriguez-Manero

  4. CIBERCV, Madrid, Spain

    Ana García-Campos, María Amparo Martínez-Monzonís, Ángel Luis Fernandez, Jose Ramón Gonzalez-Juanatey, Moises Rodriguez-Manero & Sonia Eiras

  5. Heart Surgery Department, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

    José Manuel Martinez-Cereijo, Laura Reija & Ángel Luis Fernandez

  6. Medicine Department, University of Santiago de Compostela, Santiago de Compostela, Spain

    Jose Ramón Gonzalez-Juanatey

Authors
  1. Xiaoran Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diego Iglesias-Álvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana García-Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. María Amparo Martínez-Monzonís
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cristina Almenglo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José Manuel Martinez-Cereijo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laura Reija
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ángel Luis Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jose Ramón Gonzalez-Juanatey
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Moises Rodriguez-Manero
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sonia Eiras
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, X.F., S.E.; Methodology, X.F., D.I.-A, A.G.-C, M.A.M.-M, C.A., Á.L.F., J.M.M.-C., L.R.; Validation, X.F., A.G.-C., S.E.; Formal Analysis, X.F., S.E.; Investigation, X.F., S.E.; Resources, J.R.G.-J., M.R.-M., S.E.; Data Curation, X.F.; Writing-Original Draft Preparation, X.F., S.E.; Writing-Review and Editing, X.F., S.E., J.R.G.-J., M.R.-M.; Visualization, J.R.G.-J., M.R.-M., S.E.; Supervision, S.E.; Project Administration, S.E.; Funding Acquisition, J.R.G.-J., M.R.-M., S.E. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Sonia Eiras.

Ethics declarations

Ethics approval

The study was approved by the Galician Clinical Research Ethics Committee (protocol code 2019_439, 22/10/2019), and performed in line with the principles of the Declaration of Helsinki. No animal studies were carried out by the authors for this article.

Conflict of interest

The authors have no conflicts of interest to declare that are relevant to the content of this article.

Additional information

Associate Editor Rupak Mukherjee oversaw the review of this article.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, X., Iglesias-Álvarez, D., García-Campos, A. et al. Enhanced Levels of Adiposity, Stretch and Fibrosis Markers in Patients with Coexistent Heart Failure and Atrial Fibrillation. J. of Cardiovasc. Trans. Res. 17, 13–23 (2024). https://doi.org/10.1007/s12265-023-10454-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-023-10454-x

Keywords

Search

Navigation