Immunoglobulin Free Light Chains as Inflammatory Biomarkers of Atrial Fibrillation
2020; Lippincott Williams & Wilkins; Volume: 13; Issue: 11 Linguagem: Inglês
10.1161/circep.120.009017
ISSN1941-3149
AutoresAkira Matsumori, Toshio Shimada, Miho Shimada, Hideo Otani, Mark T. Drayson, Jay W. Mason,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculation: Arrhythmia and ElectrophysiologyVol. 13, No. 11Immunoglobulin Free Light Chains as Inflammatory Biomarkers of Atrial Fibrillation Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBImmunoglobulin Free Light Chains as Inflammatory Biomarkers of Atrial Fibrillation Akira Matsumori, MD, PhD Toshio Shimada, MD, PhD Miho Shimada, BS Hideo Otani, MD, PhD Mark T. Drayson, PhD Jay W. MasonMD Akira MatsumoriAkira Matsumori Correspondence to: Akira Matsumori, MD, PhD, Clinical Research Center, Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. Email E-mail Address: [email protected] https://orcid.org/0000-0002-9721-4659 Clinical Research Center, Kyoto Medical Center, Japan (A.M.). , Toshio ShimadaToshio Shimada Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan (T.S.). , Miho ShimadaMiho Shimada VCL Laboratory, Osaka, Japan (M.S.). , Hideo OtaniHideo Otani Cardiovascular Division, Tangofurusato Hospital, Kyotango, Japan (H.O.). , Mark T. DraysonMark T. Drayson Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom (M.T.D.). , Jay W. MasonJay W. Mason https://orcid.org/0000-0002-5713-9906 Department of Medicine, University of Utah Medical Center, Salt Lake City (J.W.M.). Originally published5 Oct 2020https://doi.org/10.1161/CIRCEP.120.009017Circulation: Arrhythmia and Electrophysiology. 2020;13:e009017It is important to develop a method to detect early or asymptomatic atrial fibrillation (AF). Abnormal atrial histology compatible with a diagnosis of myocarditis was uniformly found in patients with lone AF.1 Patients with AF exhibited a higher concentration of cytokines, higher NF-κB (nuclear factor κB) activity, and more severe lymphomonocyte infiltration than those in sinus rhythm.2 These observations collectively imply local immunologic inflammatory responses in the atria in AF.We found that circulating immunoglobulin free light chains (FLCs) were increased in mice with heart failure (HF) due to viral myocarditis.3 Recently, we found that FLC lambda was increased in the sera from patients with HF with myocarditis4 and diabetes5 in which inflammation is considered to play an important pathogenetic role. As FLCs could be a biomarker of activation of NF-κB, inflammation, and immune responses, we measured FLCs in patients with AF and patients with HF with sinus rhythm. The data that support the findings of this study are available from the corresponding author upon reasonable request.We tested the hypothesis that there are differences in concentrations of FLCs among patients with lone AF who were in AF when we took the samples (n=28, male 16, median age 76 years, interquartile range, 70.3–82.8), HF with sinus rhythm (n=16, male 11, age 75, 62.8–80.8), and age-matched healthy volunteers (n=28, male 21, age 74 years, 70.3–77 for AF, and n=16, age 74, 62.3–77.8 for HF). FLC kappa and lambda were assayed using frozen blood samples by a competitive-inhibition multiplex Luminex assay. Patients with amyloidosis, renal insufficiency, or autoimmune diseases were excluded. FLCs have benefits because they are very stable and do not change after long term storage or up to 3 freeze-thaw cycles4.This study was approved by an institutional review committee and the subjects gave informed consent.Separately after matching the lone AF (n=28) and HF (n=16) with sinus rhythm groups with the healthy volunteers (n=110) group by propensity score, using age and sex, all statistics were performed using JMP 14 (SAS Institute, Inc, Cary) and EZR v1. 37 RV 3.We used 0.2 as the optimal caliper in the matching. The median concentrations of circulating FLC kappa and lambda in patients with lone AF and HF with sinus rhythm were significantly different from the healthy volunteers group (all P<0.01, by nonparametric comparisons for all pairs using Wilcoxon rank-sum test, see Table). The area under the curve of the receiver operating characteristic curve analysis showed that FLC kappa or lambda was helpful in differentiating AF patients from healthy volunteers and that the cutoff value of FLC kappa or lambda may be beneficial to distinguish 2 groups (see Table).Table 1. Comparison of FLC Variables Between Patients With Atrial Fibrillation and Heart Failure With Sinus Rhythm vs Healthy VolunteersFLC variablesMedian (interquartile range)P valueROC-AUC [95% CI]Lone AF (n=28)HV (n=28)Kappa, mg/L19.85 (15.13–28.5)6.5 (5.24–18.3)0.00030.781 [0.65–0.91]Lambda, mg/L32.5 (20.33–44.13)11.3 (6.02–17.25)<0.00010.871 [0.77–0.97]HF with NSR (n=16)HV (n=16)Kappa, mg/L28.3 (16.13–49.43)6.45 (5.26–21.28)0.00110.84 [0.7–0.98]Lambda, mg/L44.55 (25.13– 65.25)12.5 (2.65–17.58)<0.00010.927 [0.84–1]AF indicates atrial fibrillation, FLC, free light chains; HF, heart failure; HV, healthy volunteers; NSR, normal sinus rhythm; and ROC-AUC, the area under the receiver operating characteristic curve vs HV.We recently showed that FLCs were independent biomarkers of the outcome of myocarditis. We observed significant associations with mortality of patients with myocarditis for FLC lambda and NT-proBNP (N-terminal pro-B-type natriuretic peptide), but not CRP (C-reactive protein).4Both HF with reduced ejection fraction (Table) and HF with preserved ejection fraction were associated with an increase in FLC lambda. We measured FLCs in patients with hypertrophic cardiomyopathy (diastolic dysfunction with ventricular hypertrophy). FLC lambda was significantly increased; 20.82 mg/L (16.84–30.36, n=43) compared with control, 8.63 mg/L (7.8–9.89, n=75, P<0.00001).In the current study, NT-proBNP was increased (785 pg/ml [551–1236]) but did not show a significant correlation with FLC lambda. Serum creatinine was 0.89 mg/dL (0.65–1.06) and estimated glomerular filtration rate was 59 mL/(min·1.73 m2) (47.5–66.75) and showed no significant correlations with FLC lambda (r=0.23, −0.16 respectively).However, NT-proBNP showed a significant correlation between creatinine and estimated glomerular filtration rate (r=0.6, −0.6, respectively, P<0.05). Thus, creatinine or estimated glomerular filtration rate influences FLC lambda less than NT-proBNP.Our recent study showed that the circulating level of FLC lambda was significantly higher in HF patients with myocarditis,4 and the FLC lambda findings in this study on HF patients were similar to the previous study. The current study showed that in AF, FLC kappa and lambda were increased, which suggests that the clones of B lymphocytes and plasma cells that produce FLC kappa and lambda may be activated in AF.The mechanism by which FLCs could cause AF remains to be clarified, but the inflammation associated with FLCs directly induce AF, or FLCs might cause a change in membrane fluidity, which, in turn, could alter ion channel function.NF-κB could be a target for new anti-inflammatory treatments for AF when FLCs are elevated, and FLCs could be a surrogate end point. Further study is necessary to clarify the role of FLCs in AF and whether FLCs could be included as one of the screening tests for AF.In a future larger study, we plan to examine potential confounders, such as severity of HF, gradations of renal function, ongoing infection or other inflammatory processes, and nutritional status.Nonstandard Abbreviations and AcronymsCRPC-reactive proteinFLCimmunoglobulin free light chainNF-κBnuclear factor κBNT-proBNPN-terminal pro-B-type natriuretic peptideSources of FundingNone.DisclosuresDr Drayson has shares in Abington Health and has been a paid consultant for them. The other authors report no conflicts.FootnotesFor Sources of Funding and Disclosures, see page 1393.Correspondence to: Akira Matsumori, MD, PhD, Clinical Research Center, Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. Email [email protected]kyoto-u.ac.jpReferences1. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation.Circulation. 1997; 96:1180–1184. doi: 10.1161/01.cir.96.4.1180CrossrefMedlineGoogle Scholar2. Qu YC, Du YM, Wu SL, Chen QX, Wu HL, Zhou SF. Activated nuclear factor-kappaB and increased tumor necrosis factor-alpha in atrial tissue of atrial fibrillation.Scand Cardiovasc J. 2009; 43:292–297. doi: 10.1080/14017430802651803CrossrefMedlineGoogle Scholar3. Matsumori A, Shimada M, Jie X, Higuchi H, Groot Kormelink T, Redegeld FA. Effects of free immunoglobulin light chains on viral myocarditis.Circ Res. 2010; 106:1533–1540. doi: 10.1161/CIRCRESAHA.110.218438LinkGoogle Scholar4. Matsumori A, Shimada T, Nakatani E, Shimada M, Tracy S, Chapman NM, Drayson MT, Hartz VL, Mason JW. Immunoglobulin free light chains as an inflammatory biomarker of heart failure with myocarditis.Clin Immunol. 2020; 217:108455. doi: 10.1016/j.clim.2020.108455CrossrefMedlineGoogle Scholar5. Matsumori A, Shimada T, Shimada M, Drayson MT. Immunoglobulin free light chains: an inflammatory biomarker of diabetes.Inflamm Res. 2020; 69:715–718. doi: 10.1007/s00011-020-01357-7CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails November 2020Vol 13, Issue 11Article InformationMetrics Download: 32 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.120.009017PMID: 33017540 Originally publishedOctober 5, 2020 Keywordsarrhythmiascardiomyopathybiomarkersinflammationheart failureinflammatory heart diseaseatrial fibrillationPDF download SubjectsInflammatory Heart DiseaseBiomarkersAtrial FibrillationHeart FailureInflammation
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