Atrial fibrillation (AF) is a common cardiac arrhythmia affecting over 6 million people in the U.S. Fatigue is a frequent symptom of AF, yet no underlying biological mechanisms have been identified in AF-related fatigue as in other chronic conditions such as cancer or HIV fatigue (inflammation, tissue injury). We aimed to identify biomarkers and correlates of AF-fatigue in ARIC participants.
Methods
Participants with AF from ARIC visit 5 (2011–2013) were included in the study. Multiple linear regression was used to estimate the association of high sensitivity troponin (hs-TnT), N-terminal fragment B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) levels with self-reported fatigue (SF-12 and PROMIS Fatigue Scale), depressive symptoms (Center for Epidemiological Studies Depression survey), and physical functioning (Short Physical Performance Battery) scores. All biomarkers underwent natural-log transformation.
Results
There were 446 participants (mean age: 78 y ± 5; 44% women). In adjusted analyses, NT-proBNP was associated with AF-fatigue (β: 0.11, 95% CI: 0.03, 0.19), increased depressive symptoms (β: 0.44, 95% CI: 0.19, 0.70), and decreased physical function (β: −0.48, 95% CI: −0.72, −0.23). Hs-TnT was also associated with elevated AF-fatigue (β: 0.24, 95% CI: 0.09, 0.39) along with decreased physical function (β: −1.19, 95% CI: -1.64, −0.75). No significant associations were found with hsCRP and fatigue.
Conclusion
Increased levels of cardiac injury biomarkers, depressive symptoms, and decreased physical function were associated with AF-fatigue. Inflammation was not associated with AF-fatigue; other physiological pathways, such as cardiac overload or myocardial injury may be more relevant in AF-fatigue.
AaronsonL. S.TeelC. S.CassmeyerV.NeubergerG. B.PallikkathayilL.PierceJ.PressA. N.WilliamsP. D.WingateA. (1999). Defining and measuring fatigue. Image-the journal of nursing scholarship, 31(1), 45–50. https://doi.org/10.1111/j.1547-5069.1999.tb00420.x
2.
Al-DakkakI.PatelS.McCannE.GadkariA.PrajapatiG.MaieseE. M. (2013). The impact of specific HIV treatment-related adverse events on adherence to antiretroviral therapy: A systematic review and meta-analysis. AIDS Care, 25(4), 400–414. https://doi.org/10.1080/09540121.2012.712667
3.
AlonsoA.AgarwalS. K.SolimanE. Z.AmbroseM.ChamberlainA. M.PrineasR. J.FolsomA. R. (2009). Incidence of atrial fibrillation in whites and african-Americans: The atherosclerosis risk in Communities (ARIC) study. American Heart Journal, 158(1), 111–117. https://doi.org/10.1016/j.ahj.2009.05.010
4.
AmeringerS.ElswickR. K.MenziesV.RobinsJ. L.StarkweatherA.WalterJ.GentryA. E.JalloN. (2016). Psychometric evaluation of the patient-reported outcomes measurement information system fatigue-short form across diverse populations. Nursing Research, 65(4), 279–289. https://doi.org/10.1097/nnr.0000000000000162
5.
BarrosoJ.BengtsonA. M.GaynesB. N.McGuinnessT.QuinlivanE. B.OgleM.HeineA.ThielmanN. M.PenceB. W. (2016). Improvements in depression and changes in fatigue: Results from the SLAM DUNC depression treatment trial. AIDS and Behavior, 20(2), 235–242. https://doi.org/10.1007/s10461-015-1242-4
6.
BarrosoJ.VossJ. G. (2013). Fatigue in HIV and AIDS: An analysis of evidence. Journal of the Association of Nurses in AIDS Care: Journal of the Association of Nurses in AIDS Care, 24(1 Suppl), S5–S14. https://doi.org/10.1016/j.jana.2012.07.003
7.
CellaD.ChoiS. W.CondonD. M.SchaletB.HaysR. D.RothrockN. E.YountS.CookK. F.GershonR. C.AmtmannD.DeWaltD. A.PilkonisP. A.StoneA. A.WeinfurtK.ReeveB. B. (2019). PROMIS® adult health profiles: Efficient short-form measures of seven health domains. Value in Health: The Journal of the International Society for Pharmacoeconomics and Outcomes Research, 22(5), 537–544. https://doi.org/10.1016/j.jval.2019.02.004
8.
ChangK. W.HsuJ. C.ToomuA.FoxS.MaiselA. S. (2017). Clinical applications of biomarkers in atrial fibrillation. The American Journal of Medicine, 130(12), 1351–1357. https://doi.org/10.1016/j.amjmed.2017.08.003
9.
ChungM. K.EckhardtL. L.ChenL. Y.AhmedH. M.GopinathannairR.JoglarJ. A.NoseworthyP. A.PackQ. R.SandersP.TrulockK. M. (2020). Lifestyle and risk factor modification for reduction of atrial fibrillation: A scientific statement from the American heart association. Circulation, 141(16), Article e750–e772. https://doi.org/10.1161/cir.0000000000000748
10.
ClarkD. M.PlumbV. J.EpsteinA. E.KayG. N. (1997). Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. Journal of the American College of Cardiology, 30(4), 1039–1045. https://doi.org/10.1016/s0735-1097(97)00254-4
11.
ColillaS.CrowA.PetkunW.SingerD. E.SimonT.LiuX. (2013). Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. The American Journal of Cardiology, 112(8), 1142–1147. https://doi.org/10.1016/j.amjcard.2013.05.063
12.
DaoudE. G.WeissR.BahuM.KnightB. P.BogunF.GoyalR.HarveyM.StrickbergerS. A.ManK. C.MoradyF. (1996). Effect of an irregular ventricular rhythm on cardiac output. The American Journal of Cardiology, 78(12), 1433–1436. https://doi.org/10.1016/s0002-9149(97)89297-1
13.
de LemosJ. A.DraznerM. H.OmlandT.AyersC. R.KheraA.RohatgiA.HashimI.BerryJ. D.DasS. R.MorrowD. A.McGuireD. K. (2010). Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA, 304(22), 2503–2512. https://doi.org/10.1001/jama.2010.1768
14.
FangaufS. V.Herbeck BelnapB.MeyerT.AlbusC.BinderL.DeterH. C.LadwigK. H.MichalM.RonelJ.RothenbergerA.SöllnerW.WachterR.WeberC. S.Herrmann-LingenC.SPIRR-CAD study group. (2018). Associations of NT-proBNP and parameters of mental health in depressed coronary artery disease patients. Psychoneuroendocrinology, 96, 188–194. https://doi.org/10.1016/j.psyneuen.2018.06.001
15.
FinkA. M.GonzalezR. C.LisowskiT.PiniM.FantuzziG.LevyW. C.PianoM. R. (2012). Fatigue, inflammation, and projected mortality in heart failure. Journal of Cardiac Failure, 18(9), 711–716. https://doi.org/10.1016/j.cardfail.2012.07.003
16.
FritschiC.QuinnL.HackerE. D.PenckoferS. M.WangE.ForemanM.FerransC. E. (2012). Fatigue in women with type 2 diabetes. The Diabetes Educator, 38(5), 662–672. https://doi.org/10.1177/0145721712450925
17.
GehiA. K.SearsS.GoliN.WalkerT. J.ChungE.SchwartzJ.WoodK. A.GuiseK.MounseyJ. P. (2012). Psychopathology and symptoms of atrial fibrillation: Implications for therapy. Journal of Cardiovascular Electrophysiology, 23(5), 473–478. https://doi.org/10.1111/j.1540-8167.2011.02264.x
18.
GuralnikJ. M.FerrucciL.PieperC. F.LeveilleS. G.MarkidesK. S.OstirG. V.StudenskiS.BerkmanL. F.WallaceR. B. (2000). Lower extremity function and subsequent disability: Consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. The journals of gerontology. Series A, Biological sciences and medical sciences, 55(4), M221–M231. https://doi.org/10.1093/gerona/55.4.m221
19.
GuralnikJ. M.SimonsickE. M.FerrucciL.GlynnR. J.BerkmanL. F.BlazerD. G.ScherrP. A.WallaceR. B. (1994). A short physical performance battery assessing lower extremity function: Association with self-reported disability and prediction of mortality and nursing home admission. Journal of Gerontology, 49(2), M85–M94. https://doi.org/10.1093/geronj/49.2.m85
20.
JanuaryC. T.WannL. S.CalkinsH.ChenL. Y.CigarroaJ. E.ClevelandJ. C.EllinorP. T.EzekowitzM. D.FieldM. E.FurieK. L.HeidenreichP. A.MurrayK. T.SheaJ. B.TracyC. M.YancyC. W. (2019). 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart rhythm society in collaboration with the society of thoracic surgeons. Circulation, 140(2), Article e125–e151. https://doi.org/10.1161/cir.0000000000000665
21.
JunghaenelD. U.ChristodoulouC.LaiJ. S.StoneA. A. (2011). Demographic correlates of fatigue in the US general population: Results from the patient-reported outcomes measurement information system (PROMIS) initiative. Journal of Psychosomatic Research, 71(3), 117–123. https://doi.org/10.1016/j.jpsychores.2011.04.007
22.
JurgensC. Y.LeeC. S.AycockD. M.Masterson CreberR.DenfeldQ. E.DeVonH. A.EversL. R.JungM.PucciarelliG.StreurM. M.KonstamM. A. (2022). State of the science: The relevance of symptoms in cardiovascular disease and research: A scientific statement from the American heart association. Circulation
23.
LeeK. A.GayC. L.LerdalA.PullingerC. R.AouizeratB. E. (2014). Cytokine polymorphisms are associated with fatigue in adults living with HIV/AIDS. Brain, Behavior, and Immunity, 40, 95–103. https://doi.org/10.1016/j.bbi.2014.02.017
24.
LeeK. A.JongS.GayC. L. (2020). Fatigue management for adults living with HIV: A randomized controlled pilot study. Research in Nursing & Health, 43(1), 56–67. https://doi.org/10.1002/nur.21987
25.
LinY. J.TsaoH. M.ChangS. L.LoL. W.TuanT. C.HuY. F.UdyavarA. R.TsaiW. C.ChangC. J.TaiC. T.LeeP. C.SuenariK.HuangS. Y.NguyenH. T.ChenS. A. (2010). Prognostic implications of the high-sensitive C-reactive protein in the catheter ablation of atrial fibrillation. The American Journal of Cardiology, 105(4), 495–501. https://doi.org/10.1016/j.amjcard.2009.10.019
26.
MarcusG. M.SmithL. M.OrdovasK.ScheinmanM. M.KimA. M.BadhwarN.LeeR. J.TsengZ. H.LeeB. K.OlginJ. E. (2010). Intracardiac and extracardiac markers of inflammation during atrial fibrillation. Heart Rhythm, 7(2), 149–154. https://doi.org/10.1016/j.hrthm.2009.10.004
27.
MaturaL. A.MaloneS.Jaime-LaraR.RiegelB. (2018). A systematic review of biological mechanisms of fatigue in chronic illness. Biological Research For Nursing, 20(4), 410–421. https://doi.org/10.1177/1099800418764326
28.
McCabeP. J.RhudyL. M.DeVonH. A. (2015). Patients' experiences from symptom onset to initial treatment for atrial fibrillation. Journal of Clinical Nursing, 24(5-6), 786–796. https://doi.org/10.1111/jocn.12708
29.
MuellerC.McDonaldK.de BoerR. A.MaiselA.ClelandJ. G. F.KozhuharovN.CoatsA. J. S.MetraM.MebazaaA.RuschitzkaF.LainscakM.FilippatosG.SeferovicP. M.MeijersW. C.Bayes-GenisA.MuellerT.RichardsM.JanuzziJ. L.Heart Failure Association of the EuropeanSociety of Cardiology. (2019). Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. European Journal of Heart Failure, 21(6), 715–731. https://doi.org/10.1002/ejhf.1494
30.
ParsonsT. J.SartiniC.WelshP.SattarN.AshS.LennonL. T.WannametheeS. G.LeeI. M.WhincupP. H.JefferisB. J. (2018). Objectively measured physical activity and cardiac biomarkers: A cross sectional population based study in older men. International Journal of Cardiology, 254, 322–327. https://doi.org/10.1016/j.ijcard.2017.11.003
31.
RadloffL. (1977). The CES-D scale: A self-report depression scale for research in the general population. Applied Psychological Measurement, 1(3), 385–401. https://doi.org/10.1177/014662167700100306
32.
SaeedA.NambiV.SunW.ViraniS. S.TaffetG. E.DeswalA.SelvinE.MatsushitaK.WagenknechtL. E.HoogeveenR.CoreshJ.de LemosJ. A.BallantyneC. M. (2018). Short-term global cardiovascular disease risk prediction in older adults. Journal of the American College of Cardiology, 71(22), 2527–2536. https://doi.org/10.1016/j.jacc.2018.02.050
33.
SaliganL. N.KimH. S. (2012). A systematic review of the association between immunogenomic markers and cancer-related fatigue. Brain, Behavior, and Immunity, 26(6), 830–848. https://doi.org/10.1016/j.bbi.2012.05.004
34.
SaliganL. N.OlsonK.FillerK.LarkinD.CrampF.YennurajalingamS.EscalanteC. P.del GiglioA.KoberK. M.KamathJ.PaleshO.MustianK.Multinational Association of Supportive Care in Cancer Fatigue Study Group-Biomarker Working Group. (2015). The biology of cancer-related fatigue: A review of the literature. Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer, 23(8), 2461–2478. https://doi.org/10.1007/s00520-015-2763-0
35.
SinghR.TeelC.SabusC.McGinnisP.KludingP. (2016). Fatigue in type 2 diabetes: Impact on quality of life and predictors. PLoS One, 11(11), Article e0165652. https://doi.org/10.1371/journal.pone.0165652
36.
StaerkL.PreisS. R.LinH.LubitzS. A.EllinorP. T.LevyD.BenjaminE. J.TrinquartL. (2020). Protein biomarkers and risk of atrial fibrillation: The FHS. Circulation. Arrhythmia and Electrophysiology, 13(2), Article e007607. https://doi.org/10.1161/circep.119.007607
37.
StewartA. L.HaysR. D.WareJ. E. (1988). The MOS short-form general health survey. Reliability and validity in a patient population. Medical Care, 26(7), 724–735. https://doi.org/10.1097/00005650-198807000-00007
38.
StreurM.RatcliffeS. J.BallJ.StewartS.RiegelB. (2017). Symptom clusters in adults with chronic atrial fibrillation. Journal of Cardiovascular Nursing, 32(3), 296–303. https://doi.org/10.1097/jcn.0000000000000344
39.
TsaoC. W.AdayA. W.AlmarzooqZ. I.AndersonC. A. M.AroraP.AveryC. L.Baker-SmithC. M.BeatonA. Z.BoehmeA. K.BuxtonA. E.Commodore-MensahY.ElkindM. S. V.EvensonK. R.Eze-NliamC.FugarS.GenerosoG.HeardD. G.HiremathS.HoJ. E.MartinS. S. (2023). Heart disease and stroke statistics-2023 update: A report from the American heart association. Circulation, 147(8), Article e93–e621. https://doi.org/10.1161/cir.0000000000001123
40.
WalkerK. A.WindhamB. G.PowerM. C.HoogeveenR. C.FolsomA. R.BallantyneC. M.KnopmanD. S.SelvinE.JackC. R.GottesmanR. F. (2018). The association of mid-to late-life systemic inflammation with white matter structure in older adults: The Atherosclerosis Risk in Communities Study. Neurobiology of Aging, 68, 26–33. https://doi.org/10.1016/j.neurobiolaging.2018.03.031
41.
WhiteheadL. (2009). The measurement of fatigue in chronic illness: A systematic review of unidimensional and multidimensional fatigue measures. Journal of Pain and Symptom Management, 37(1), 107–128. https://doi.org/10.1016/j.jpainsymman.2007.08.019
42.
WongC. X.LauD. H.SandersP. (2014). Atrial fibrillation epidemic and hospitalizations: How to turn the rising tide?Circulation, 129(23), 2361–2363. https://doi.org/10.1161/circulationaha.114.010073
43.
XiaoC.MillerA. H.FelgerJ.MisterD.LiuT.TorresM. A. (2017). Depressive symptoms and inflammation are independent risk factors of fatigue in breast cancer survivors. Psychological Medicine, 47(10), 1733–1743. https://doi.org/10.1017/s0033291717000150
44.
ZuzarteP.ScolaG.DuongA.KostiwK.FigueiraM. L.Costa-VitaliA. (2018). NT-proBNP is a potential mediator between reduced ejection fraction and depression in patients with heart failure. Journal of Psychiatric Research, 104, 8–15. https://doi.org/10.1016/j.jpsychires.2018.06.010
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
