Boukens group – Fighting lethal arrhythmias by revealing their mechanisms

The aim of my group is to understand cardiac physiology and pathology by employing an interdisciplinary approach. The experiments we do involve functional measurements of isolated cardiac myocytes, isolated heart and hearts in vivo.

Contact: B.J.D. Boukens (b.j.boukens@amc.uva.nl)

Research overview

The experiments we do center around three main research themes:

  1. Developmental and molecular basis for electrophysiological heterogeneities in the hearts
  2. Mechanisms underlying lethal cardiac arrhythmias
  3. The evolutionary adaptations in cardiac electrophysiology from ectothermic to endothermic vertebrates

Figure 1. Developmental basis for RVOT arrhythmias. The adult RVOT has formed from the embryonic outflow tract (left) which is composed primary myocardium exhibiting slow conduction and spontaneous activity. During development the embryonic outflow tract acquires a working myocardial phenotype, e.g. fast conduction, and transforms into the RVOT. A small ring of primary myocardium, however, still remains just below the pulmonary valve which may give rise to automaticity as seen in patients with idiopathic RVOT tachycardia. The myocardium of the free wall and septum of the adult RVOT has a working myocardial phenotype although expression of Cx43 and Scn5a is lower than in the right ventricle. This may set the stage for re-entrant based arrhythmias as seen in patients with the Brugada syndrome. LV, left ventricle; RV, right ventricle; OFT, outflow tract; RVOT, right ventricular outflow tract.

Figure 2. Fractionated electrograms with ST-segment elevation recorded from the human RVOT A. The traces show four different unipolar electrograms recorded at the RVOT and two corresponding bipolar electrograms (red). B. A photograph of the epicardial side of the wedge preparation showing the site recording at the proximal and distal RVOT and the corresponding unipolar recordings. Stimulation occurred at the right ventricle. The proximal electrode was located 2 cm from the site of stimulation and recorded activation at ~45 ms. The distal electrode was located twice as far but activated at ~250 ms suggesting delayed activation of RVOT. The monophasic morphology in the distal RVOT coincided with the electrogram at the proximal RVOT. C. shows unipolar electrograms record from the proximal and distal RVOT when stimulated on the distal RVOT. Note the sharp deflection and normal ST segment in the unipolar electrogram recorded from the distal RVOT. RVOT, right ventricular outflow tract; RV, right ventricle.

Figure 3. Conduction block by cuts in the dorsal alligator atrioventricular canal reveals a specialized atrioventricular conduction system. A-B. Cuts in a small region of the dorsal atrioventricular canal induces atrioventricular block (dorsal cut n=3 and ventral cut n=3). C-D. Extensive cuts to the ventral and lateral atrioventricular canal do not induce atrioventricular block. E. In vivo and ex vivo (in bath) QRS duration was not different (n=7). F. In bath optical mapping of ventricular activation revealed epicardial breakthrough of the impulse deep in the ventricle (n=6). G. The maximum rate of depolarization (red star) occurred earlier at position S than at position LV and RV of panel F (n=6). H-I. Optical recordings from the inside of the heart (H) show earliest activation in the septum (n=1) (I).  AVC, atrioventricular canal; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; s, ventricular sulcus; VS, ventricular septum.

People

Jae Sun Uhm – postdoc (jason@yuhs.ac)
Koen Scholman – PhD student (k.t.Scholman@amc.uva.nl)
Ingeborg Hooikaas – technician (i.b.hooikaas@amc.uva.nl)
Manuela Frimpong – master student (m.s.Frimpong@amc.uva.nl)

Publications
  1. Intramural clefts and structural discontinuities in Brugada syndrome: the missing gap? Boukens BJ, Remme CA. Cardiovasc Res. 2018 Jan 30.
  2. Fractionated electrograms with ST-segment elevation recorded from the human right ventricular outflow tract. Vigmond EJ, Efimov IR, Rentschler SL, Coronel R, Boukens BJ. HeartRhythm Case Rep. 2017 Sep 28;3(11):546-550. doi.org/10.1016/j.hrcr.2017.08.010. eCollection 2017 Nov.
  3. The end of the unique myocardial band: Part II. Clinical and functional considerations. MacIver DH, Partridge JB, Agger P, Stephenson RS, Boukens BJD, Omann C, Jarvis JC, Zhang H. Eur J Cardiothorac Surg. 2018 Jan 1;53(1):120-128. doi.org/10.1093/ejcts/ezx335.
  4. Single-site neural tube closure in human embryos revisited. de Bakker BS, Driessen S, Boukens BJD, van den Hoff MJB, Oostra RJ. Clin Anat. 2017 Oct;30(7):988-999. doi.org/10.1002/ca.22977. Epub 2017 Aug 29.
  5. Morpho-functional characterization of the systemic venous pole of the reptile heart. Jensen B, Vesterskov S, Boukens BJ, Nielsen JM, Moorman AFM, Christoffels VM, Wang T. Sci Rep. 2017 Jul 27;7(1):6644. doi.org/10.1038/s41598-017-06291-z.
  6. The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity. Veerman CC, Podliesna S, Tadros R, Lodder EM, Mengarelli I, de Jonge B, Beekman L, Barc J, Wilders R, Wilde AAM, Boukens BJ, Coronel R, Verkerk AO, Remme CA, Bezzina CR. Circ Res. 2017 Aug 18;121(5):537-548. doi.org/10.1161/CIRCRESAHA.117.310959. Epub 2017 Jun 21.
  7. Local transmural action potential gradients are absent in the isolated, intact dog heart but present in the corresponding coronary-perfused wedge. Boukens BJ, Meijborg VMF, Belterman CN, Opthof T, Janse MJ, Schuessler RB, Coronel R, Efimov IR. Physiol Rep. 2017 May;5(10). pii: e13251. doi.org/10.14814/phy2.13251.
  8. Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm. Nadadur RD, Broman MT, Boukens B, Mazurek SR, Yang X, van den Boogaard M, Bekeny J, Gadek M, Ward T, Zhang M, Qiao Y, Martin JF, Seidman CE, Seidman J, Christoffels V, Efimov IR, McNally EM, Weber CR, Moskowitz IP. Sci Transl Med. 2016 Aug 31;8(354):354ra115. doi.org/10.1126/scitranslmed.aaf4891.
  9. Transmural electrophysiological heterogeneity, the T-wave and ventricular arrhythmias. Boukens BJ, Walton R, Meijborg VM, Coronel R. Prog Biophys Mol Biol. 2016 Dec;122(3):202-214. doi.org/10.1016/j.pbiomolbio.2016.05.009. Epub 2016 May 21. Review.
  10. Embryonic development of the right ventricular outflow tract and arrhythmias. Boukens BJ, Coronel R, Christoffels VM. Heart Rhythm. 2016 Feb;13(2):616-22. doi.org/10.1016/j.hrthm.2015.11.014. Epub 2015 Nov 14. Review.
  11. Atrial Fibrillation: Biophysics, Molecular Mechanisms, and Novel Therapies. Glukhov AV, Rosenshtraukh LV, Bhargava A, Miragoli M, Boukens BJ. Biomed Res Int. 2015;2015:780671. doi.org/10.1155/2015/780671. Epub 2015 Jul 9.
  12.  Imaging of Ventricular Fibrillation and Defibrillation: The Virtual Electrode Hypothesis. Boukens BJ, Gutbrod SR, Efimov IR. Adv Exp Med Biol. 2015;859:343-65. doi.org/10.1007/978-3-319-17641-3_14. Review.
  13. Transmural APD gradient synchronizes repolarization in the human left ventricular wall. Boukens BJ, Sulkin MS, Gloschat CR, Ng FS, Vigmond EJ, Efimov IR. Cardiovasc Res. 2015 Oct 1;108(1):188-96. doi.org/10.1093/cvr/cvv202. Epub 2015 Jul 24.
  14. Feasibility of a semi-automated method for cardiac conduction velocity analysis of high-resolution activation maps. Doshi AN, Walton RD, Krul SP, de Groot JR, Bernus O, Efimov IR, Boukens BJ, Coronel R. Comput Biol Med. 2015 Oct 1;65:177-83. doi.org/10.1016/j.compbiomed.2015.05.008. Epub 2015 May 21.
  15. An activation-repolarization time metric to predict localized regions of high susceptibility to reentry. Child N, Bishop MJ, Hanson B, Coronel R, Opthof T, Boukens BJ, Walton RD, Efimov IR, Bostock J, Hill Y, Rinaldi CA, Razavi R, Gill J, Taggart P. Heart Rhythm. 2015 Jul;12(7):1644-53. doi.org/10.1016/j.hrthm.2015.04.013. Epub 2015 Apr 9.
  16. Overexpression of SCN5A in mouse heart mimics human syndrome of enhanced atrioventricular nodal conduction. Liu GX, Remme CA, Boukens BJ, Belardinelli L, Rajamani S. Heart Rhythm. 2015 May;12(5):1036-45. doi.org/10.1016/j.hrthm.2015.01.029. Epub 2015 Jan 23.
  17. Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties. Gillers BS, Chiplunkar A, Aly H, Valenta T, Basler K, Christoffels VM, Efimov IR, Boukens BJ, Rentschler S. Circ Res. 2015 Jan 30;116(3):398-406. doi.org/10.1161/CIRCRESAHA.116.304731. Epub 2014 Nov 6.
  18. Alk3 mediated Bmp signaling controls the contribution of epicardially derived cells to the tissues of the atrioventricular junction. Lockhart MM, Boukens BJ, Phelps AL, Brown CL, Toomer KA, Burns TA, Mukherjee RD, Norris RA, Trusk TC, van den Hoff MJ, Wessels A. Dev Biol. 2014 Dec 1;396(1):8-18. doi.org/10.1016/j.ydbio.2014.09.031. Epub 2014 Oct 6.
  19. Misinterpretation of the mouse ECG: ‘musing the waves of Mus musculus’. Boukens BJ, Rivaud MR, Rentschler S, Coronel R. J Physiol. 2014 Nov 1;592(21):4613-26. doi.org/10.1113/jphysiol.2014.279380. Epub 2014 Sep 25. Review.
  20. Mitochondrial depolarization and electrophysiological changes during ischemia in the rabbit and human heart. Sulkin MS, Boukens BJ, Tetlow M, Gutbrod SR, Ng FS, Efimov IR. Am J Physiol Heart Circ Physiol. 2014 Oct 15;307(8):H1178-86. doi.org/10.1152/ajpheart.00437.2014. Epub 2014 Aug 15.
  21. A century of optocardiography. Boukens BJ, Efimov IR. IEEE Rev Biomed Eng. 2014;7:115-25. doi.org/10.1109/RBME.2013.2286296. Epub 2013 Oct 23. Review.
  22. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, Simonet F, Verkerk AO, Schwartz PJ, Crotti L, Dagradi F, Guicheney P, Fressart V, Leenhardt A, Antzelevitch C, Bartkowiak S, Borggrefe M, Schimpf R, Schulze-Bahr E, Zumhagen S, Behr ER, Bastiaenen R, Tfelt-Hansen J, Olesen MS, Kääb S, Beckmann BM, Weeke P, Watanabe H, Endo N, Minamino T, Horie M, Ohno S, Hasegawa K, Makita N, Nogami A, Shimizu W, Aiba T, Froguel P, Balkau B, Lantieri O, Torchio M, Wiese C, Weber D, Wolswinkel R, Coronel R, Boukens BJ, Bézieau S, Charpentier E, Chatel S, Despres A, Gros F, Kyndt F, Lecointe S, Lindenbaum P, Portero V, Violleau J, Gessler M, Tan HL, Roden DM, Christoffels VM, Le Marec H, Wilde AA, Probst V, Schott JJ, Dina C, Redon R. Nat Genet. 2013 Sep;45(9):1044-9. doi.org/10.1038/ng.2712. Epub 2013 Jul 21. Erratum in: Nat Genet. 2013 Nov;45(11):1409. Borggrefe, Martin [added]; Schimpf, Rainer [added].
  23. Brief history of arrhythmia in the WPW syndrome – the contribution of George Ralph Mines. Boukens BJ, Janse MJ. J Physiol. 2013 Sep 1;591(17):4067-71. doi.org/10.1113/jphysiol.2013.259598. Epub 2013 Jul 15.
  24. Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract. Boukens BJ, Sylva M, de Gier-de Vries C, Remme CA, Bezzina CR, Christoffels VM, Coronel R. Circ Res. 2013 Jul 5;113(2):137-41. doi.org/10.1161/CIRCRESAHA.113.301565. Epub 2013 May 9.
  25. Identification and functional characterization of cardiac pacemaker cells in zebrafish. Tessadori F, van Weerd JH, Burkhard SB, Verkerk AO, de Pater E, Boukens BJ, Vink A, Christoffels VM, Bakkers J. PLoS One. 2012;7(10):e47644. doi.org/10.1371/journal.pone.0047644. Epub 2012 Oct 16.
  26. Early repolarization in mice causes overestimation of ventricular activation time by the QRS duration. Boukens BJ, Hoogendijk MG, Verkerk AO, Linnenbank A, van Dam P, Remme CA, Fiolet JW, Opthof T, Christoffels VM, Coronel R. Cardiovasc Res. 2013 Jan 1;97(1):182-91. doi.org/10.1093/cvr/cvs299. Epub 2012 Sep 20.
  27. Identifying the evolutionary building blocks of the cardiac conduction system. Jensen B, Boukens BJ, Postma AV, Gunst QD, van den Hoff MJ, Moorman AF, Wang T, Christoffels VM. PLoS One. 2012;7(9):e44231. doi.org/10.1371/journal.pone.0044231. Epub 2012 Sep 11.
  28. Ventricular fibrillation hampers the restoration of creatine-phosphate levels during simulated cardiopulmonary resuscitations. Hoogendijk MG, Schumacher CA, Belterman CN, Boukens BJ, Berdowski J, de Bakker JM, Koster RW, Coronel R. Europace. 2012 Oct;14(10):1518-23. Epub 2012 Apr 4.
  29. T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells. Bakker ML, Boink GJ, Boukens BJ, Verkerk AO, van den Boogaard M, den Haan AD, Hoogaars WM, Buermans HP, de Bakker JM, Seppen J, Tan HL, Moorman AF, ‘t Hoen PA, Christoffels VM. Cardiovasc Res. 2012 Jun 1;94(3):439-49. doi.org/10.1093/cvr/cvs120. Epub 2012 Mar 14.
  30. Electrophysiological patterning of the heart. Boukens BJ, Christoffels VM. Pediatr Cardiol. 2012 Aug;33(6):900-6. doi.org/10.1007/s00246-012-0237-4. Epub 2012 Feb 25. Review.
  31. Popeye proteins: muscle for the aging sinus node. Boukens BJ, Christoffels VM. J Clin Invest. 2012 Mar;122(3):810-3. doi.org/10.1172/JCI62588. Epub 2012 Feb 22.
  32. Arrhythmogenic pulmonary vein myocardium in heart failure. Boukens BJ, Baartscheer A, Higa S. Clin Exp Pharmacol Physiol. 2011 Oct;38(10):654-5. doi.org/10.1111/j.1440-1681.2011.05577.x.
  33. Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice. Aanhaanen WT, Boukens BJ, Sizarov A, Wakker V, de Gier-de Vries C, van Ginneken AC, Moorman AF, Coronel R, Christoffels VM. J Clin Invest. 2011 Feb;121(2):534-44. doi.org/10.1172/JCI44350. Epub 2011 Jan 25. PMID:
  34. Dietary fish oil reduces pacemaker current and heart rate in rabbit. Verkerk AO, den Ruijter HM, Bourier J, Boukens BJ, Brouwer IA, Wilders R, Coronel R. Heart Rhythm. 2009 Oct;6(10):1485-92. doi.org/10.1016/j.hrthm.2009.07.024. Epub 2009 Jul 16.
  35. The urokinase receptor (uPAR) facilitates clearance of Borrelia burgdorferi. Hovius JW, Bijlsma MF, van der Windt GJ, Wiersinga WJ, Boukens BJ, Coumou J, Oei A, de Beer R, de Vos AF, van ‘t Veer C, van Dam AP, Wang P, Fikrig E, Levi MM, Roelofs JJ, van der Poll T. PLoS Pathog. 2009 May;5(5):e1000447. doi.org/10.1371/journal.ppat.1000447. Epub 2009 May 22.
  36. Developmental basis for electrophysiological heterogeneity in the ventricular and outflow tract myocardium as a substrate for life-threatening ventricular arrhythmias. Boukens BJ, Christoffels VM, Coronel R, Moorman AF. Circ Res. 2009 Jan 2;104(1):19-31. doi.org/10.1161/CIRCRESAHA.108.188698. Review.
  37. Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system. Bakker ML, Boukens BJ, Mommersteeg MT, Brons JF, Wakker V, Moorman AF, Christoffels VM. Circ Res. 2008 Jun 6;102(11):1340-9. doi.org/10.1161/CIRCRESAHA.107.169565. Epub 2008 May 8.
  38. Dietary fish oil reduces the incidence of triggered arrhythmias in pig ventricular myocytes. Berecki G, Den Ruijter HM, Verkerk AO, Schumacher CA, Baartscheer A, Bakker D, Boukens BJ, van Ginneken AC, Fiolet JW, Opthof T, Coronel R. Heart Rhythm. 2007 Nov;4(11):1452-60. Epub 2007 Jul 17.