Electrophysiological and molecular mechanisms of human atrial fibrillation

Atrial fibrillation (AF) is a disorder of the rhythm of the heart’s upper chambers. This disease affects ~1% of the general population, and decreases their life expectancy. My research aims to improve our understanding of the electrophysiological and molecular mechanisms of AF, in the hope that this will lead to more effective treatments.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting ~1% of the general population, and substantially increases the risk of stroke, heart failure and death. Currently available anti-arrhythmic drugs are only moderately effective and safe. The reentrant and non-reentrant electrophysiological mechanisms that initiate and sustain AF are multiple, complex and interacting. An improved understanding of these mechanisms at atrial cell and tissue level, and of how they are influenced by atrial remodelling from myocardial disease and chronic AF, will aid the search for new drug targets for preventing AF (Workman AJ et al. Pharmacol Ther 2011;131:221-241).

My research team demonstrated that ion currents and voltage signals generated by single atrial cells obtained from consenting patients with chronic AF are disturbed in a way that may exacerbate the disease, by “electrical remodelling”. For example, the atrial cell’s effective refractory period (ERP) is markedly shortened, which could promote reentry (Workman AJ et al. Cardiovasc Res 2001;52:226-235).  We also found that long-term treatment of patients with beta-blockers causes an adaptational prolongation of the human atrial cellular ERP, by “pharmacological remodelling”, which may oppose reentry (Workman AJ. Naunyn-Schmied Arch Pharmacol 2010;381:235-249). Our recent work in this field has identified underlying electrophysiological mechanisms (Marshall GE et al. Pflugers Arch 2012;463:537-548).  Heart failure, a major cause of AF, also remodels the atrium and we showed, for the first time in human atrial cells, that left ventricular systolic dysfunction in patients is associated with ERP-shortening, potentially predisposing to atrial reentry and AF (Workman AJ et al. Heart Rhythm 2009;6:445-451).

Mathematical modelling is an increasingly powerful tool for investigating electrophysiological and molecular mechanisms of AF. We contributed, as part of an international collaboration of modellers and experimental physiologists, to the development of the first mathematical model of human atrial cellular electrophysiology to incorporate experimental data and modern concepts relating to intracellular calcium homeostasis associated with AF (Grandi E et al. Circ Res 2011;109:1055-1066). This model is publicly available, and provides a useful tool to investigate atrioventricular differences with respect to arrhythmogenesis and potential therapeutic targets. Our other computer simulation work identified a novel electrophysiological mechanism that may suppress AF, by atrial-selective manipulation of the sodium ion current (Pandit SV et al. Cardiovasc Res 2011;89:843-851).  Our current research is focussed on the development of an innovative and novel technique, the “dynamic-clamp”, to control cardiac ion currents by linking a computer model with live cardiac cells (Workman AJ et al. J Physiol 2012;17:4289-4305). We have used this technique, for the first time in atrial cells isolated from patients, to electrically simulate selective changes in the transient outward potassium current (ITO) during action potential recording (see Figure below). We found that ITO decrease prolonged atrial cell action potential duration and, under beta-adrenergic-stimulation, provoked abnormal membrane potential oscillations (afterdepolarisations) that were preventable by ITO increase or a beta-blocker. The results have potential implications for both the development and treatment of AF.

Publications

1. Workman AJ*, Marshall GE, Rankin AC, Smith GL, Dempster J. Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes. J Physiol 2012; 17: 4289-4305. 
2. Grandi E, Workman AJ, Pandit SV*. Altered excitation-contraction coupling in human chronic atrial fibrillation. J Atr Fibrillation 2012; 2: 1-17. 
3. Marshall GE, Russell JA, Tellez JO, Jhund PS, Currie S, Dempster J, Boyett MR, Kane KA, Rankin AC, Workman AJ*. Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade. Pflugers Arch 2012; 463: 537-548. 
4. Grandi E, Pandit SV, Voigt N, Workman AJ, Dobrev D, Jalife J, Bers DM*. Human atrial action potential and Ca2+ model. Sinus rhythm and chronic atrial fibrillation. Circ Res 2011; 109: 1055-1066. 
5. Workman AJ*, Smith GL, Rankin AC. Mechanisms of termination and prevention of atrial fibrillation by drug therapy. Pharmacol Ther 2011; 131: 221-241. 
6. Pandit SV*, Zlochiver S, Filgueiras-Rama D, Mironov S, Yamazaki M, Ennis SR, Noujaim SF, Workman AJ, Berenfeld O, Kalifa J, Jalife J. Targeting atrioventricular differences in ion channel properties for terminating acute atrial fibrillation in pigs. Cardiovasc Res 2011; 89: 843-851. 
7. Workman AJ*, Rankin AC. Do hypoxemia or hypercapnia predispose to atrial fibrillation in breathing disorders, and, if so, how? Heart Rhythm 2010; 7: 1271-1272.
8. Workman AJ*. Cardiac adrenergic control and atrial fibrillation. Naunyn-Schmied Arch Pharmacol 2010; 381: 235-249.
9. Rankin AC*, Workman AJ. Duration of heart failure and the risk of atrial fibrillation: different mechanisms at different times? Cardiovasc Res 2009; 84: 180-181.
10. Workman AJ*. Mechanisms of postcardiac surgery atrial fibrillation: more pieces in a difficult puzzle. Heart Rhythm 2009; 6: 1423-1424. 
11. Workman AJ*, Pau D, Redpath CJ, Marshall GE, Russell JA, Norrie J, Kane KA, Rankin AC. Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF. Heart Rhythm 2009; 6: 445-451. 
12. Workman AJ*, Kane KA, Rankin AC. Cellular bases for human atrial fibrillation. Heart Rhythm 2008; 5: S1-S6.
13. Pau D*, Workman AJ, Kane KA, Rankin AC. Electrophysiological and arrhythmogenic effects of 5-hydroxytryptamine on human atrial cells are reduced in atrial fibrillation. J Mol Cell Cardiol 2007; 42: 54-62. 
14. Workman AJ*, Pau D, Redpath CJ, Marshall GE, Russell JA, Kane KA, Norrie J, Rankin AC. Post-operative atrial fibrillation is influenced by beta-blocker therapy but not by pre-operative atrial cellular electrophysiology. J Cardiovasc Electrophysiol 2006; 17: 1230-1238.
15. Redpath CJ, Rankin AC, Kane KA, Workman AJ*. Anti-adrenergic effects of endothelin on human atrial action potentials are potentially anti-arrhythmic. J Mol Cell Cardiol 2006; 40: 717-724. 
16. Pau D*, Workman AJ, Kane KA, Rankin AC. Electrophysiological effects of prucalopride, a novel enterokinetic agent, on isolated atrial myocytes from patients treated with beta-adrenoceptor antagonists. J Pharmacol Exp Ther 2005; 313: 146-153. 
17. Pau D*, Workman AJ, Kane KA, Rankin AC. Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic beta-adrenoceptor blockade. Br J Pharmacol 2003; 140: 1434-1441. 
18. Workman AJ*, Kane KA, Rankin AC. Characterisation of the Na, K pump current in atrial cells from patients with and without chronic atrial fibrillation. Cardiovasc Res 2003; 59: 593-602. 
19. Workman AJ*, Kane KA, Russell JA, Norrie J, Rankin AC. Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling. Cardiovasc Res 2003; 58: 518-525. 
20. Workman AJ*, Kane KA, Rankin AC. The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation. Cardiovasc Res 2001; 52: 226-235.