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Serum relaxin level predicts recurrence of atrial fibrillation after radiofrequency catheter ablation

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Abstract

Relaxin, an emerging biomarker in heart failure, is involved in fibrosis and inflammation. The value of relaxin in predicting recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) is unknown and the subject of this study. We prospectively enrolled 248 consecutive patients with AF (paroxysmal in 127 and persistent in 121) who underwent RFCA at our center after measurement of circulating levels of relaxin by ELISA. Kaplan–Meier analysis with log-rank test and multivariate analysis were used to assess the association between pre-RFCA relaxin levels and post-RFCA AF recurrence at 18 months follow-up. At mean 16.3 ± 3.8 months post-RFCA, 195 (78.6%) patients maintained sinus rhythm, and their pre-RFCA relaxin level was lower than that in patients with AF recurrence (P < 0.001). From lowest to highest pre-RFCA relaxin level tertiles (T1; 82.10–< 234.36; T2; 234.36–< 342.26; and T3; 342.26–740.63 ng/L), AF recurrence rate increased significantly (8.5%, 20.5% and 34.9%, respectively; Kaplan–Meier analysis with log-rank test, χ2 = 18.44, P < 0.001). Using a cutoff of 285.4 ng/L, pre-RFCA relaxin level predicted AF recurrence during follow-up with sensitivity of 77.4% and specificity of 55.9% (area under the receiver operating characteristic curve = 0.71). On multivariate Cox proportional hazard model, relaxin level by tertile (T2, hazard ratio 2.678; 95% confidence interval 1.110–6.460; P = 0.028, and T3, hazard ratio 4.745; 95% confidence interval 2.075–10.854; P < 0.001, respectively compared with the T1) was the independent factor predicting recurrence. Elevated pre-RFCA relaxin level is associated with post-RFCA AF recurrence. A simple measurement of relaxin level therefore might help identify patients at high risk of AF recurrence after RFCA.

Clinical Trial Registration chictr.org.cn identifier: ChiCTR-OOC-15006130.

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Abbreviations

AF:

Atrial fibrillation

RFCA:

Radiofrequency catheter ablation

Ang II:

Renin–angiotensin–aldosterone system and angiotensin II

PaAF:

Paroxysmal atrial fibrillation

PeAF:

Persistent atrial fibrillation

ECG:

Electrocardiography

eGFR:

Estimated glomerular filtration rate

BNP:

Brain natriuretic peptide

LAD:

Left atrial diameter

LVMI:

Left ventricular mass index

ROC:

Receiver operating characteristic

CI:

Confidence interval

AUC:

Area under the ROC curve

HR:

Hazard ratio

OR:

Odds ratio

ECM:

Extracellular matrix

LA:

Left atrial

LDL-C:

Low-density lipoprotein cholesterol

LVEDD:

Left ventricular end-diastolic diameter

References

  1. Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J (2002) Structural correlate of atrial fibrillation in human patients. Cardiovasc Res 54:361–379

    Article  CAS  PubMed  Google Scholar 

  2. Sardu C, Santamaria M, Paolisso G, Marfella R (2015) microRNA expression changes after atrial fibrillation catheter ablation. Pharmacogenomics 16:1863–1877

    Article  CAS  PubMed  Google Scholar 

  3. Tan AY, Zimetbaum P (2011) Atrial fibrillation and atrial fibrosis. J Cardiovasc Pharmacol 57:625–629

    Article  PubMed  Google Scholar 

  4. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ Jr, Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Iesaka Y, Jackman W, Jalife J, Jais P, Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, Lindsay BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D (2012) 2012 HRS/EHRA/ECAS Expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 14:528–606

    Article  PubMed  Google Scholar 

  5. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J (1998) Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 339:659–666

    Article  PubMed  Google Scholar 

  6. Balk EM, Garlitski AC, Alsheikh-Ali AA, Terasawa T, Chung M, Ip S (2010) Predictors of atrial fibrillation recurrence after radiofrequency catheter ablation: a systematic review. J Cardiovasc Electrophysiol 21:1208–1216

    Article  PubMed  Google Scholar 

  7. Cao H, Xue L, Xu X, Wu Y, Zhu J, Chen L, Chen D, Chen Y (2011) Heat shock proteins in stabilization of spontaneously restored sinus rhythm in permanent atrial fibrillation patients after mitral valve surgery. Cell Stress Chaperones 16:517–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sotomi Y, Inoue K, Ito N, Kimura R, Toyoshima Y, Masuda M, Doi A, Iwakura K, Okamura A, Koyama Y, Date M, Fujii K (2013) Cause of very late recurrence of atrial fibrillation or flutter after catheter ablation for atrial fibrillation. Am J Cardiol 111:552–556

    Article  PubMed  Google Scholar 

  9. Cai L, Yin Y, Ling Z, Su L, Liu Z, Wu J, Du H, Lan X, Fan J, Chen W, Xu Y, Zhou P, Zhu J, Zrenner B (2013) Predictors of late recurrence of atrial fibrillation after catheter ablation. Int J Cardiol 164:82–87

    Article  PubMed  Google Scholar 

  10. Letsas KP, Weber R, Bürkle G, Mihas CC, Minners J, Kalusche D, Arentz T (2009) Pre-ablative predictors of atrial fibrillation recurrence following pulmonary vein isolation: the potential role of inflammation. Europace 11:158–163

    Article  PubMed  Google Scholar 

  11. Zhao Z, Ng CY, Liu T, Li H, Li G (2014) Relaxin as novel strategy in the management of atrial fibrillation: potential roles and future perspectives. Int J Cardiol 171:e72–e73

    Article  PubMed  Google Scholar 

  12. Mookerjee I, Unemori EN, Du XJ, Tregear GW, Samuel CS (2005) Relaxin modulates fibroblast function, collagen production, and matrix metalloproteinase-2 expression by cardiac fibroblasts. Ann N Y Acad Sci 1041:190–193

    Article  CAS  PubMed  Google Scholar 

  13. Zhou H, Qu X, Gao Z, Zheng G, Lin J, Su L, Huang Z, Li H, Huang W (2016) Relaxin level in patients with atrial fibrillation and association with heart failure occurrence: a STROBE compliant article. Medicine (Baltim) 95:e3664

    Article  CAS  Google Scholar 

  14. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH (2010) Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 31:2369–2429

    Article  Google Scholar 

  15. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P, ESC Committee for Practice Guidelines (CPG) (2012) 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 33:2719–2747

    Article  PubMed  Google Scholar 

  16. Nattel S, Opie LH (2006) Controversies in atrial fibrillation. Lancet 367:262–272

    Article  PubMed  Google Scholar 

  17. Beyerbach DM, Zipes DP (2004) Mortality as an endpoint in atrial fibrillation. Heart Rhythm 1:8–18

    Article  Google Scholar 

  18. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA (1995) Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92:1954–1968

    Article  CAS  Google Scholar 

  19. Allessie M, Ausma J, Schotten U (2002) Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 54:230–246

    Article  CAS  Google Scholar 

  20. Goudis CA, Kallergis EM, Vardas PE (2012) Extracellular matrix alterations in the atria: insights into the mechanisms and perpetuation of atrial fibrillation. Europace 14:623–630

    Article  PubMed  Google Scholar 

  21. Xu J, Cui G, Esmailian F, Plunkett M, Marelli D, Ardehali A, Odim J, Laks H, Sen L (2004) Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation. Circulation 109:363–368

    Article  CAS  Google Scholar 

  22. Mulukutla S, Althouse AD, Jain SK, Saba S (2018) Increased left atrial size is associated with higher atrial fibrillation recurrence in patients treated with antiarrhythmic medications. Clin Cardiol 41:825–829

    Article  PubMed  Google Scholar 

  23. Kohári M, Zado E, Marchlinski FE, Callans DJ, Han Y (2014) Left atrial volume best predicts recurrence after catheter ablation in patients with persistent and longstanding persistent atrial fibrillation. Pacing Clin Electrophysiol 37:422–429

    Article  PubMed  Google Scholar 

  24. Montserrat S, Gabrielli L, Borras R, Poyatos S, Berruezo A, Bijnens B, Brugada J, Mont L, Sitges M (2014) Left atrial size and function by three-dimensional echocardiography to predict arrhythmia recurrence after first and repeated ablation of atrial fibrillation. Eur Heart J Cardiovasc Imaging 15:515–522

    Article  PubMed  Google Scholar 

  25. Zhou T, Wang Z, Fan J, Chen S, Tan Z, Yang H, Yin Y (2015) Angiotensin-converting enzyme-2 overexpression improves atrial remodeling and function in a canine model of atrial fibrillation. J Am Heart Assoc 4(3):e001530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Henry BL, Gabris B, Li Q, Martin B, Giannini M, Parikh A, Patel D, Haney J, Schwartzman DS, Shroff SG, Salama G (2016) Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels. Heart Rhythm 13:983–991

    Article  PubMed  Google Scholar 

  27. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M (2010) Relaxin: review of biology and potential role in treating heart failure. Curr Heart Fail Rep 7:75–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Metra M, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Ponikowski P, Unemori E, Voors AA, Adams KF Jr, Dorobantu MI, Grinfeld L, Jondeau G, Marmor A, Masip J, Pang PS, Werdan K, Prescott MF, Edwards C, Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, Severin T, Teerlink JR, Investigators RELAX-AHF (2013) Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol 61:196–206

    Article  CAS  PubMed  Google Scholar 

  29. Samuel CS, Cendrawan S, Gao XM, Ming Z, Zhao C, Kiriazis H, Xu Q, Tregear GW, Bathgate RA, Du XJ (2011) Relaxin remodels fibrotic healing following myocardial infarction. Lab Invest 91:675–690

    Article  CAS  PubMed  Google Scholar 

  30. Parikh A, Patel D, McTiernan CF (2013) Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res 113:313–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Marrouche NF, Wilber D, Hindricks G, Jais P, Akoum N, Marchlinski F, Kholmovski E, Burgon N, Hu N, Mont L, Deneke T, Duytschaever M, Neumann T, Mansour M, Mahnkopf C, Herweg B, Daoud E, Wissner E, Bansmann P, Brachmann J (2014) Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation the DECAAF study. JAMA 311:498–506

    Article  CAS  PubMed  Google Scholar 

  32. Kuck KH, Fürnkranz A, Chun KR, Metzner A, Ouyang F, Schlüter M, Elvan A, Lim HW, Kueffer FJ, Arentz T, Albenque JP, Tondo C, Kühne M, Sticherling C, Brugada J, Investigators FIREANDICE (2016) Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial. Eur Heart J 37:2858–2865

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kalil C, Bartholomay E, Borges A, Gazzoni G, Lima ED, Etchepare R, Moraes R, Sussenbach C, Andrade K, Kalil R (2014) Atrial fibrillation ablation by use of electroanatomical mapping: efficacy and recurrence factors. Arq Bras Cardiol 102:30–38

    PubMed  PubMed Central  Google Scholar 

  34. D’Ascenzo F, Corleto A, Biondi-Zoccai G, Anselmino M, Ferraris F, di Biase L, Natale A, Hunter RJ, Schilling RJ, Miyazaki S, Tada H, Aonuma K, Yenn-Jiang L, Tao H, Ma C, Packer D, Hammill S, Gaita F (2013) Which are the most reliable predictors of recurrence of atrial fibrillation after transcatheter ablation? A meta-analysis. Int J Cardiol 167:1984–1989

    Article  PubMed  Google Scholar 

  35. Park J, Joung B, Uhm JS, Young Shim C, Hwang C, Hyoung Lee M, Pak HN (2014) High left atrial pressures are associated with advanced electroanatomical remodeling of left atrium and independent predictors for clinical recurrence of atrial fibrillation after catheter ablation. Heart Rhythm 11:953–960

    Article  PubMed  Google Scholar 

  36. Naruse Y, Tada H, Sekiguchi Y, Machino T, Ozawa M, Yamasaki H, Igarashi M, Kuroki K, Itoh Y, Murakoshi N, Yamaguchi I, Aonuma K (2011) Concomitant chronic kidney disease increases the recurrence of atrial fibrillation after catheter ablation of atrial fibrillation: a mid-term follow-up. Heart Rhythm 8:335–341

    Article  PubMed  Google Scholar 

  37. Li M, Liu T, Luo D, Li G (2014) Systematic review and meta-analysis of chronic kidney disease as predictor of atrial fibrillation recurrence following catheter ablation. Cardiol J 21:89–95

    Article  PubMed  Google Scholar 

  38. Liu J, Fang PH, Dibs S, Hou Y, Li XF, Zhang S (2011) High-sensitivity C-reactive protein as a predictor of atrial fibrillation recurrence after primary circumferential pulmonary vein isolation. Pacing Clin Electrophysiol 34:398–406

    Article  PubMed  Google Scholar 

  39. Smit MD, Maass AH, De Jong AM, Muller Kobold AC, Van Veldhuisen DJ, Van Gelder IC (2012) Role of inflammation in early atrial fibrillation recurrence. Europace 14:810–817

    Article  PubMed  Google Scholar 

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Funding

This research was supported by the National Natural Science Foundation of China [81570364, 81873468] and in part by the Science and Technology Planning Project of Wenzhou Science & Technology Bureau of Zhejiang Province of China [Y20150032, Y20160318, Y20170021].The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, The First Affiliated Hospital of Wenzhou Medical University, The South of Shangcai Village, Ouhai District, Wenzhou, 325000, Zhejiang, China

    Xiang Qu, Lingzhi Chen, Changxi Chen, Zhan Gao, Weijian Huang & Hao Zhou

  2. The Key Lab of Cardiovascular Disease of Wenzhou, Wenzhou, China

    Xiang Qu, Lingzhi Chen, Changxi Chen, Zhan Gao, Weijian Huang & Hao Zhou

  3. Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Lingyue Sun

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  1. Xiang Qu
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  2. Lingzhi Chen
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Correspondence to Hao Zhou.

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Qu, X., Chen, L., Sun, L. et al. Serum relaxin level predicts recurrence of atrial fibrillation after radiofrequency catheter ablation. Heart Vessels 34, 1543–1551 (2019). https://doi.org/10.1007/s00380-019-01386-1

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