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Electrophysiological patterning of the heart
Boukens, B.J.D.
Publication date 2012
Link to publication
Citation for published version (APA):
Boukens, B. J. D. (2012). Electrophysiological patterning of the heart.
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Scope of the thesis
Sudden cardiac death accounts for 300.000 deaths annually in the United States.1 Although the
majority of sudden cardiac death is due to coronary heart disease, up to 5% is due to primary electrical or genetic ion channel abnormalities.2 To this category belong the
Wolff-Parkinson-White (WPW), Brugada and Long QT syndrome as well as congenital atrioventricular (AV) block or acquired diseases of the sinus node.3 The mechanism of arrhythmia differs between
these cardiac pathologies, but it may result, if untreated, in ventricular fibrillation or a-systole leading to sudden death.2 The majority of the patients with primary electrical disease or hereditary
ion channel abnormalities are treated effectively by implantation of a electronic pacemaker (for sinus node dysfunction AV block or the Brugada syndrome4, 5), by radiofrequency ablation (in
WPW patients6), or pharmacologically (in most Long QT syndrome patients7). In some of these
patients an automatic internal cardioverter defibrillator is implanted to treat VF with electroshock. In a small percentage (<10%) of the patients sudden cardiac death is the first manifestation of the disease.8, 9 Therefore, risk stratification of patients is important. Unfortunately, we lack
information on specific markers of an increased risk of death from arrhythmias in the general population and among those with nonspecific and intermediate risk profiles. The general hypothesis underlying this thesis is that understanding of the normal embryonic development of the electrical properties of the heart would provide insight into the mechanisms of abnormal development and function, and therefore can be used to define factors that are important for electrical dysfunction. Thus, the thesis seeks to bridge the gap between embryonic cardiac development and lethal function which, could lead to the identification of new specific markers for an increased risk of arrhythmias occurring in adulthood. We use Brugada syndrome, WPW syndrome, Sick sinus syndrome and AV node dysfunction as models for this approach. In chapter 1 we introduce the term ‘electrophysiological patterning’ and explain which transcription factors are involved in generating the electrophysiological properties of structures in the ventricular myocardium and the AV node. In chapter 2 we studied the role of T-box (Tbx) transcription factor 2 in patterning of the AV canal and its role in the formation of accessory pathways (related to WPW-syndrome). In chapter 3 we investigated the role of transcription factor Nkx2-5 and Tbx3 in the formation, function and maintenance of the AV conduction system. In chapter 4 we review the temporal and spatial expression of transcription factors in relation to electrophysiological heterogeneities that exist in the ventricular myocardium of the adult heart, with a main focus on the right ventricular outflow tract (RVOT, related to Brugada Syndrome). In chapter 5 we studied the differences in function and gene expression between RVOT and the right ventricle, and explored the hypothesis that the slow conduction property and gene expression program of the embryonic outflow tract are maintained in the adult RVOT. In chapter 6, an editorial, we comment on a study that introduced a new family of cAMP binding proteins called Popeye-containing-domain proteins, which is involved in age and stress
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dependent sinus node dysfunction. In chapter 7 we related local activation and repolarization times to the surface electrocardiogram (ECG) of the mouse. In chapter 8 the thesis is summarized.
Reference List
(1) Kong MH, Fonarow GC, Peterson ED, Curtis AB, Hernandez AF, Sanders GD, Thomas KL, Hayes DL, Al-Khatib SM. Systematic review of the incidence of sudden cardiac death in the United States. J Am Coll Cardiol 2011 February 15;57(7):794-801.
(2) Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med 2001 November 15;345(20):1473-82.
(3) Zipes DP, Wellens HJ. Sudden cardiac death. Circulation 1998 November 24;98(21):2334-51. (4) Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H,
Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: Report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Heart Rhythm 2005 April;2(4):429-40.
(5) Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009--a World Society of Arrhythmia’s project. Pacing Clin Electrophysiol 2011 August;34(8):1013-27.
(6) Cohen MI, Triedman JK, Cannon BC, Davis AM, Drago F, Janousek J, Klein GJ, Law IH, Morady FJ, Paul T, Perry JC, Sanatani S, Tanel RE. PACES/HRS expert consensus statement on the management of the asymptomatic young patient with a Wolff-Parkinson-White (WPW, ventricular preexcitation) electrocardiographic pattern: developed in partnership between the Pediatric and Congenital
Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the American Academy of Pediatrics (AAP), and the Canadian Heart Rhythm Society (CHRS). Heart Rhythm 2012 June;9(6):1006-24.
(7) Schwartz PJ, Crotti L, Insolia R. Long-QT Syndrome: From Genetics to Management. Circ Arrhythm Electrophysiol 2012 August 1;5(4):868-77.
(8) Berne P, Brugada J. Brugada syndrome 2012. Circ J 2012 June 25;76(7):1563-71.
(9) Bromberg BI, Lindsay BD, Cain ME, Cox JL. Impact of clinical history and electrophysiologic characterization of accessory pathways on management strategies to reduce sudden death among children with Wolff-Parkinson-White syndrome. J Am Coll Cardiol 1996 March 1;27(3):690-5.
