Normal Cardiac Excitation: Generation, Propagation and Coupling to Contraction
Principal Investigator: Ulrich Schotten

University: Universiteit Maastricht, The Netherlands

Main contributions:

  • provide goat model of atrial fibrillation for in-vivo and in-vitro studies on
    • electrophysiological remodelling and its control by novel antiarrhythmic agents.
    • contractile remodelling and its pharmacological modulation..

Lab web-page: http://www.fys.unimaas.nl/efstaff.html

Contact: schotten@fys.unimaas.nl

Lay Summary:

Restoration of contractility in atrial fibrillation:

Atrial stunning in AF patients is the major determinant of life-threatening thromboembolic events which require potentially harmful anticoagulation therapy. In this project, the mechanisms underlying atrial stunning are investigated. Mechanical properties of human atrial myofibrils from patients with different diseases, as well as from goat models of AF, are compared in order to clarify the time-course of development of stunning, and its recovery after cardioversion. The molecular determinant of contractile abnormalities are addressed by using biochemical approaches, trying to identify and to evaluate new drug targets, such as calpain, proteases, atrial potassium channels, for the restoration of atrial contraction. Biophysical properties (maximal force performance and Ca2+ sensitivity) of atrial myofibrils from fibrillating and dilated atria are studied with participant 1 (University of Florence). Biochemical analyses of contractile proteins (expression and phosphorylation levels) are used to identify the molecular mechanisms of the functional changes. Together with network partner 4 (University of Manchester) intracellular Ca2+ handling in atrial myocytes is studied in a model of rapid atrial pacing in rabbits. Using confocal microscopy the effect of tachycardia-induced atrial remodeling on the intracellular Ca2+ wave propagation and proarrhythmic Ca2+ release events are investigated. In cooperation with the network partners 5 (University Oxford) and 6 (Technical University Dresden), data on the effect of drugs on the atrial action potential and contraction as well as on the atrial conduction pattern during atrial fibrillation are integrated in mathematical models in order to attain an integrate view of drug effects in normal and diseased atrial tissue.

Relevant Publications:

  • Greiser M, Neuberger H, Harks E, El-Armouche A, Boknik P, Verheyen F, Verheule S, Schmitz W, Ravens R, Nattel S, Allessie M, Dobrev D & Schotten U. Distinct Contractile and Molecular Alterations in Two Goat Models of Atrial Dysfunction: A V-Block-induced Atrial Dilation and Atrial Fibrillation. J Mol Cell Cardiol 2009/46:385-394. 
  • Greiser M, Halaszovich C, Frechen D, Boknik P, Ravens U, Dobrev D, Luckhoff A & Schotten U. Pharmacological evidence for altered src kinase regulation of I (Ca,L) in patients with chronic atrial fibrillation. Naunyn Schmiedebergs Arch Pharmacol 2007/375:383-392. 
  • Blaauw Y, Schotten U, van Hunnik A, Neuberger H & Allessie M. Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat. Cardiovasc Res 2007/75:89-98. 
  • Schotten U, de Haan S, Verheule S, Harks E, Frechen D, Bodewig E, Greiser M, Ram R, Maessen J, Kelm M, Allessie M & van Wagoner D. Blockade of atrial-specific K-currents increases atrial but not ventricular contractility by enhancing reverse mode Na/Ca-exchange. Cardiovasc Res 2007/73:37-47. 
  • de Haan S, Greiser M, Harks E, Blaauw Y, van Hunnik A, Verheule S, Allessie M & Schotten U. VE0118, blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)), fully restores atrial contractility after cardioversion of atrial fibrillation in the goat. Circulation 2006/114(12) / Sep 19:1234-42.  (Link)
  • Schotten U, de Haan S, Verheule S, Harks EG, Frechen D, Bodewig E, Greiser M, Ram R, Maessen J, Kelm M, Allessie M, & van Wagoner DR. Blockade of atrial-specific K+-currents increases atrial but not ventricular contractility by enhancing reverse mode Na+/Ca2+-exchange. Cardiovascular Research 2007/73 (1) / Jan 1:37-47.  (Link)
  • Blaauw Y, Schotten U, van Hunnik A, Neuberger HR & Allessie MA. Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat. Cardiovascular Research 2007/Mar 30:(epub ahead of print).  (Link)
  • Kirchhof P & Schotten U. Hypertension begets hypertrophy begets atrial fibrillation? Insights from yet another sheep model. Eur Heart J 2006/27:2919-2920. 
  • De Haan S, Greiser M, Harks E, Blaauw Y, van Hunnik A, Verheule S, Allessie M & Schotten U. AVE0118, Blocker of the Transient Outward Current (Ito) and Ultrarapid Delayed Rectifier Current (IKur), Fully Restores Atrial Contractility After Cardioversion of Atrial Fibrillation in the Goat. Circulation 2006/114:1234-1242. 
  • Goette A & Schotten U. Inhibition of angiotensin II type 1 receptors reduces atrial stunning and spontaneous echo contrast after electrical cardioversion of atrial fibrillation. Eur Heart J 2006/27:2034-2035. 
  • Eijsbouts S, Ausma J, Blaauw Y, Schotten U, Duytschaever M & Allessie M. Serial cardioversion by class IC Drugs during 4 months of persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 2006/17:648-654. 
  • Schotten U, Dobrev D, Kirchhof P, Kääb S, Lewalter T, Goette A. Optimising the management of atrial fibrillation – insights from a national expert network. Deutsches Ärzteblatt 2006/103:A1743-1748. 
  • Allessie M & Schotten U. Paroxysmal atrial fibrillation: just a matter of nerves?. Heart Rhythm 2006/3:209-211. 
  • Neuberger H, Schotten U, Blaauw Y, Vollmann D, Eijsbouts S, van Hunnik A & Allessie M. Chronic atrial dilation, electrical remodeling, and atrial fibrillation in the goat. J Am Coll Cardiol 2006/47:644-653. 
  • Allessie M, Schotten U, Verheule S & Harks E. Gene therapy for repair of cardiac fibrosis: a long way to Tipperary. Circulation 2005/111:391-393. 
  • Vollman D, Blaauw Y, Neuberger H, Schotten U & Allessie M. Long-term changes in sequence of atrial activation and refractory periods: no evidence for "atrial memory". Heart Rhythm 2005/2:155-161. 
  • Neuberger H, Schotten U, Verheule S, Eijsbouts S, Blaauw Y, van Hunnik A & Allessie M. Development of a substrate of atrial fibrillation during chronic atrioventricular block in the goat. Circulation 2005/111:30-37. 
  • Blaauw Y, Beier N, van der Voort P, van Hunnik A, Schotten U & Allessie M. Inhibitors of the Na+/H+ exchanger cannot prevent atrial electrical remodeling in the goat. J Cardiovasc Electrophysiol 2004/15:440-446. 
  • Schotten U, De Haan S, Neuberger H, Eijsbouts S, Blaauw Y, Tieleman R & Allessie M. Loss of Atrial Contractility is the Primary Cause of Atrial Dilatation during the first Days of Atrial Fibrillation. Am J Physiol Heart Circ Physiol 2004/287:H2324-H2331. 
  • Eijsbouts S, Houben R, Blaauw Y, Schotten U & Allessie M. Synergistic action of atrial dilation and sodium channel blockade on conduction in rabbit atria. J Cardiovasc Electrophysiol 2004/15:1453-1461. 
  • Blaauw Y, Gogelein H, Tieleman R, van Hunnik A, Schotten U & Allessie M. "Early" class III drugs for the treatment of atrial fibrillation: efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat. Circulation 2004/110:1717-1724. 
  • Schotten U, Neuberger H & Allessie M. The role of atrial dilatation during the domestication of atrial fibrillation. Proc Mol Biol Biophys 2003/82:151-162. 
  • Schotten U, Duytschaever M, Ausma J, Eijsbouts S, Neuberger H & Allessie M. Electrical and contractile remodeling during the first days of atrial fibrillation go hand-in-hand. Circulation 2003/107:1433-1439. 
  • Allessie M, Ausma J & Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002/54:230-246. 
  • Schotten U, Greiser M, Benke D, Buerkel K, Ehrenteidt B, Stellbrink C, Vazquez-Jimenez J, Schoendube F, Hanrath P & Allessie M. Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort.. Cardiovasc Res 2002/53:192-201. 
  • Schotten U, Ausma J, Stellbrink C, Sabatschus I, Vogel M, Frenchen D, Schoendube F, Hanrath P & Allessie M. Cellular mechanisms of depressed atrial contractility in patients with chronical atrial fibrillation.. Circulation 2001/103:691-698.