Association between left atrial low-voltage area, serum apoptosis, and fibrosis biomarkers and incidence of silent cerebral events after catheter ablation of atrial fibrillation

  • Patrick Müller
  • Johannes Maier
  • Johannes-Wolfgang Dietrich
  • Sebastian Barth
  • Daniel P. Griese
  • Fabian Schiedat
  • Attila Szöllösi
  • Philipp Halbfass
  • Karin Nentwich
  • Markus Roos
  • Joachim Krug
  • Anja Schade
  • Rainer Schmitt
  • Andreas Mügge
  • Thomas Deneke



Silent cerebral events (SCE) have been identified on cerebral diffusion-weighted cerebral magnetic resonance imaging (DE-MRI) after catheter ablation (CA) of atrial fibrillation (AF). The purpose of this study was to investigate the impact of atrial remodeling on the incidence of SCE after AF CA.


Forty patients (67.8 ± 10 years, 47.5 % women) with symptomatic paroxysmal (n = 11, 27.5 %) or persistent AF undergoing AF CA were prospectively enrolled. LA fibrosis was estimated by intraprocedural bipolar voltage mapping in sinus rhythm. Apoptosis-stimulating fragment (Fas-Ligand) and amino terminal peptide from collagen III (PIIINP) concentrations were analyzed of LA and femoral vein blood. Cerebral DE-MRI was performed 1 to 2 days after CA of AF for detection of SCE. In nine patients (22.5 %), new SCE were detected on DE-MRI after AF CA.


Patients with SCE had higher CHA2DS2-VASc score, larger left atrial diameter (LADmax), and higher surface area of left atrial low-voltage (24 ± 11.2 vs 3.5 ± 4.2 %, p < 0.0001). Concentrations of peripheral PIIINP (103.7 ± 25.9 vs 81.8 ± 16.7 pg/ml, p < 0.01) and Fas-Ligand (124.1 ± 22.4 vs 87.6 ± 19.4 pg/ml, p < 0.01) were significantly higher in patients with SCE and correlated to low-voltage surface area (p < 0.01). Multivariable logistic regression analysis revealed peripheral Fas-Ligand, LADmax, CHA2DS2-Vasc score, and LA low-voltage area proportion to be independent predictors for the development of SCE.


LA remodeling, estimated by LADmax and LA low-voltage area, has significant relationship with the risk of SCE after AF ablation. Moreover, Fas-Ligand may act as an independent predictor for SCE in the context of AF CA.


Atrial fibrillation Atrial fibrosis Catheter ablation Silent cerebral events Thromboembolic risk 



Activated clotting time


Atrial fibrillation


Body mass index


Catheter ablation


Chronic kidney disease


Diffusion-weighted magnetic resonance imaging


Diffusion-weighted echo-planar imaging


Electroanatomic mapping


Apoptosis-stimulating fragment


Fluid-attenuated inversion recovery


Left atrial


Maximal left atrial diameter


Magnetic resonance imaging


Novel oral anticoagulation




Silent cerebral events


Transesophageal echocardiography


Amino terminal peptide from collagen III


Pulmonary vein isolation


Variance inflation factor


Conflict of interest

The authors declare that they have no competing interests.

Human rights statements and informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000(5). Informed consent was obtained from all patients for being included in this study.


  1. 1.
    Camm, A. J., Kirchhof, P., Lip, G. Y., Schotten, U., Savelieva, I., Ernst, S., Van Gelder, I. C., 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, S. H., Kolh, P., Le Heuzey, J. Y., Ponikowski, P., & Rutten, F. H. (2010). Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). European Heart Journal, 31, 2369–2429.CrossRefPubMedGoogle Scholar
  2. 2.
    Wolf, P. A., Abbott, R. D., & Kannel, W. B. (1991). Atrial fibrillation as an independent risk for stroke: the Framingham Study. Stroke, 22, 983–988.CrossRefPubMedGoogle Scholar
  3. 3.
    Calkins, H., Reynolds, M. R., Spector, P., Sondhi, M., Xu, Y., Martin, A., Williams, C. J., & Sledge, I. (2009). Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circulation. Arrhythmia and Electrophysiology, 2, 349–361.CrossRefPubMedGoogle Scholar
  4. 4.
    Cappato, R., Calkins, H., Chen, S. A., Davies, W., Iesaka, Y., Kalman, J., Kim, Y. H., Klein, G., Natale, A., Packer, D., Skanes, A., Ambrogi, F., & Biganzoli, E. (2010). Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation. Arrhythmia and Electrophysiology, 3, 32–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Hunter, R. J., & Schilling, R. J. (2010). Long-term outcome after catheter ablation for atrial fibrillation: safety, efficacy, and impact on prognosis. Heart, 96, 1259–1263.CrossRefPubMedGoogle Scholar
  6. 6.
    Page, S. P., Herring, N., Hunter, R. J., Withycombe, E., Lovell, M., Wali, G., Betts, T. R., Bashir, Y., Dhinoja, M., Earley, M. J., Sporton, S. C., Rajappan, K., & Schilling, R. J. (2014). Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted. Journal of Cardiovascular Electrophysiology, 6, 585–590.CrossRefGoogle Scholar
  7. 7.
    Gaita, F., Caponi, D., Pianelli, M., Scaglione, M., Toso, E., Cesarani, F., Boffano, C., Gandini, G., Valentini, M. C., De Ponti, R., Halimi, F., & Leclercq, J. F. (2010). Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Circulation, 122, 1667–1673.CrossRefPubMedGoogle Scholar
  8. 8.
    Deneke, T., Shin, D. I., Balta, O., Bünz, K., Fassbender, F., Mügge, A., Anders, H., Horlitz, M., Päsler, M., Karthikapallil, S., Arentz, T., Beyer, D., & Bansmann, M. (2011). Post-ablation asymptomatic cerebral lesions: long-term follow-up using magnetic resonance imaging. Heart Rhythm, 8, 1705–1711.CrossRefPubMedGoogle Scholar
  9. 9.
    Neumann, T., Kuniss, M., Conradi, G., Janin, S., Berkowitsch, A., Wojcik, M., Rixe, J., Erkapic, D., Zaltsberg, S., Rolf, A., Bachmann, G., Dill, T., Hamm, C. W., & Pitschner, H. F. (2011). MEDAFI-Trial (micro-embolization during ablation of atrial fibrillation): comparison of pulmonary vein isolation using cryoballoon technique vs. radiofrequency energy. Europace, 13, 37–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Schrickel, J. W., Lickfett, L., Lewalter, T., Mittman-Braun, E., Selbach, S., Strach, K., Nähle, C. P., Schwab, J. O., Linhart, M., Andrié, R., Nickenig, G., & Sommer, T. (2010). Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial ablation. Europace, 12, 52–57.CrossRefPubMedGoogle Scholar
  11. 11.
    Gaita, F., Leclercq, J. F., Schumacher, B., Scaglione, M., Toso, E., Halimi, F., Schade, A., Froehner, S., Ziegler, V., Sergi, D., Cesarani, F., & Blandino, A. (2011). Incidence of silent cerebral thromboembolic lesions after atrial fibrillation ablation May change according to technology used: comparison of irrigated radiofrequency, multipolar nonirrigated catheter and cryoballoon. Journal of Cardiovascular Electrophysiology, 9, 961–968.CrossRefGoogle Scholar
  12. 12.
    Deneke, T., Schade, A., Müller, P., Schmitt, R., Christopoulos, G., Krug, J., Szöllösi, G., Mügge, A., Kerber, S., & Nentwich, K. (2014). Acute safety and efficacy of a novel multipolar irrigated radiofrequency ablation catheter for pulmonary vein isolation. Journal of Cardiovascular Electrophysiology, 4, 339–345.CrossRefGoogle Scholar
  13. 13.
    Deneke, T., Nentwich, K., Schmitt, R., Christhopoulos, G., Krug, J., Di Biase, L., Natale, A., Szollosi, A., Mugge, A., Müller, P., Dietrich, J. W., Shin, D. I., Kerber, S., & Schade, A. (2014). Exchanging catheters over a single transseptal sheath during left atrial ablation is associated with a higher risk for silent cerebral events. Indian Pacing and Electrophysology Journal, 14, 240–249.Google Scholar
  14. 14.
    Di Biase, L., Gaita, F., Toso, E., Santangeli, P., Mohanty, P., Rutledge, N., Yan, X., Mohanty, S., Trivedi, C., Bai, R., Price, J., Horton, R., Gallinghouse, G. J., Beheiry, S., Zagrodzky, J., Canby, R., Leclercq, J. F., Halimi, F., Scaglione, M., Cesarani, F., Faletti, R., Sanchez, J., Burkhardt, J. D., & Natale, A. (2014). Does periprocedural anticoagulation management of atrial fibrillation affect the prevalence of silent thromboembolic lesions detected by diffusion cerebral magnetic resonance imaging in patients undergoing radiofrequency atrial fibrillation ablation with open irrigated catheters? Results from a prospective multicenter study. Heart Rhythm, 11, 791–798.CrossRefPubMedGoogle Scholar
  15. 15.
    Burstein, B., & Nattel, S. (2008). Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. Journal of the American College of Cardiology, 51, 802–809.CrossRefPubMedGoogle Scholar
  16. 16.
    Nattel, S., & Harada, M. (2014). Atrial remodeling and atrial fibrillation: recent advances and translational perspectives. Journal of the American College of Cardiology, 63, 2335–2345.CrossRefPubMedGoogle Scholar
  17. 17.
    Daccarett, M., Badger, T. J., Akoum, N., Burgon, N. S., Mahnkopf, C., Vergara, G., Kholmovski, E., McGann, C. J., Parker, D., Brachmann, J., Macleod, R. S., & Marrouche, N. F. (2011). Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. Journal of the American College of Cardiology, 57, 831–838.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Akoum, N., Fernandez, G., Wilson, B., Mcgann, C., Kholmovski, E., & Marrouche, N. (2013). Association of atrial fibrosis quantified using LGE-MRI with atrial appendage thrombus and spontaneous contrast on transesophageal echocardiography in patients with atrial fibrillation. Journal of Cardiovascular Electrophysiology, 24, 1104–1109.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Park, J. H., Joung, B., Son, N. H., Shim, J. M., Lee, M. H., Hwang, C., & Pak, H. N. (2011). The electroanatomical remodelling of the left atrium is related to CHADS2-Score/ CHA2DS2-Vasc score and events of stroke in patients with atrial fibrillation. Europace, 13, 1541–1549.CrossRefPubMedGoogle Scholar
  20. 20.
    Watson, T., Shantsila, E., & LIP, G. Y. H. (2009). Mechanisms of thrombogenesis in atrial fibrillation. Virchow’s triad revisited. Lancet, 373, 155–166.CrossRefPubMedGoogle Scholar
  21. 21.
    Wakili, R., Yeh, Y. H., Yan Qi, X., Greiser, M., Chartier, D., Nishida, K., Maguy, A., Villeneuve, L. R., Boknik, P., Voigt, N., Krysiak, J., Kääb, S., Ravens, U., Linke, W. A., Stienen, G. J., Shi, Y., Tardif, J. C., Schotten, U., Dobrev, D., & Nattel, S. (2010). Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs. Circulation. Arrhythmia and Electrophysiology, 3, 530–541.CrossRefPubMedGoogle Scholar
  22. 22.
    Schotten, U., Greiser, M., Benke, D., Buerkel, K., Ehrenteidt, B., Stellbrink, C., Vazquez-Jimenez, J. F., Schoendube, F., Hanrath, P., & Allessie, M. (2002). Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort. Cardiovascular Research, 53, 192–201.CrossRefPubMedGoogle Scholar
  23. 23.
    Sun, H., Gaspo, R., Leblanc, N., & Nattel, S. (1998). Cellular mechanisms of atrial contractile dysfunction caused by substained atrial tachycardia. Circulation, 98, 719–729.CrossRefPubMedGoogle Scholar
  24. 24.
    Kapa, S., Desjardins, B., Callans, D. J., Marchlinski, F. E., & Dixit, S. (2014). Contact electroanatomic mapping derived voltage criteria for characterizing left atrial scar in patients undergoing ablation for atrial fibrillation. Journal of Cardiovascular Electrophysiology, 25, 1044–1052.CrossRefPubMedGoogle Scholar
  25. 25.
    Hijazi, Z., Oldgren, J., Andersson, U., Connolly, S. J., Ezekowitz, M. D., Hohnloser, S. H., Reilly, P. A., Vinereanu, D., Siegbahn, A., Yusuf, S., & Wallentin, L. (2012). Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy. Circulation, 125, 1605–1616.CrossRefPubMedGoogle Scholar
  26. 26.
    Müller, P., Hars, C., Schiedat, F., Bösche, L. I., Gotzmann, M., Strauch, J., Dietrich, J. W., Vogt, M., Tannapfel, A., Deneke, T., Mügge, A., & Ewers, A. (2013). Correlation between total atrial conduction time estimated with tissue Doppler imaging (PA-TDI interval), structural atrial remodeling an new-onset of atrial fibrillation after cardiac surgery. Journal of Cardiovascular Electrophysiology, 24, 626–631.CrossRefPubMedGoogle Scholar
  27. 27.
    Deneke, T., Jais, P., Scaglione, M., Schmitt, R., DI Biase, L., Christopoulos, G., Schade, A., Mügge, A., Bansmann, M., Nentwich, K., Müller, P., Krug, J., Roos, M., Halbfass, P., Natale, A., Gaita, F., & Haines, D. (2015). Silent cerebral events/lesions related to atrial fibrillation ablation: a clinical review. Journal of Cardiovascular Electrophysiology, 4, 455–463.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Patrick Müller
    • 1
    • 3
  • Johannes Maier
    • 3
  • Johannes-Wolfgang Dietrich
    • 4
  • Sebastian Barth
    • 1
  • Daniel P. Griese
    • 1
  • Fabian Schiedat
    • 3
  • Attila Szöllösi
    • 1
  • Philipp Halbfass
    • 1
  • Karin Nentwich
    • 1
  • Markus Roos
    • 1
  • Joachim Krug
    • 1
  • Anja Schade
    • 1
  • Rainer Schmitt
    • 2
  • Andreas Mügge
    • 3
  • Thomas Deneke
    • 1
    • 3
  1. 1.Clinic for Interventional ElectrophysiologyHeart Center Bad NeustadtBad Neustadt an der SaaleGermany
  2. 2.Radiology and the DivisionsHeart Center Bad NeustadtBad Neustadt an der SaaleGermany
  3. 3.Cardiology & AngiologyHeart Center Bad NeustadtBad Neustadt an der SaaleGermany
  4. 4.Endocrinology and Diabetes of the University Hospital BergmannsheilRuhr-University BochumBochumGermany

Personalised recommendations