Electrophysiological and molecular mechanisms of human atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting ~1% of the general population. It substantially increases the risk of stroke, heart failure and death. Currently available anti-arrhythmic drugs are only moderately effective and safe. The re-entrant and non-re-entrant 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).

The research team of Dr Antony (Tony) Workman 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 re-entry (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 atrial cellular ERP, by “pharmacological remodelling”, which may oppose re-entry (Workman AJ. Naunyn-Schmied Arch Pharmacol 2010;381:235-249). Our recent work in this field has identified potential 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; see figure below (Workman AJ et al. Heart Rhythm 2009;6:445-451). More recent experimental research in this field investigated how ventricular myocardial infarction (MI), a major cause of AF, affects atrial electrophysiological and intracellular calcium-cycling mechanisms which predispose to AF. We have discovered that chronic MI causes beat-to-beat alternation of atrial action potential shape, and spontaneous depolarisations, under beta-adrenergic-stimulation (Kettlewell S et al. Cardiovasc Res 2013;99:215-224). This work has implications for aiding the search for improved drug treatments for AF, because it identifies potential mechanisms of a predisposition to this arrhythmia by chronic MI.

Mathematical modelling is becoming an evermore 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. Other computer simulation work helped to identify 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). More recent modelling studies, in collaboration with Mike Colman (University of Leeds) and Henggui Zhang (University of Manchester) and their teams have led to an improved understanding of a variety of physiological, pharmacological, and pathological mechanisms related to AF and its diagnosis or potential treatment (Kharche SR et al. Europace 2014;16:1524-1533, Alday EAP et al. PLoS Comput Biol 2015;11:e1004026, Colman MA et al. Computing in Cardiology 2016;43:221-224). The latest study (Colman MA et al. Front Physiol 2018;9:1211) combines electrophysiological data from ~20 years-worth of experiments on human atrial cardiomyocytes from the Workman laboratory. This has resulted in the development of a new model, particularly useful for directly relating model to experiment, and offers a complementary tool to the available set of human atrial cell models with specific advantages resulting from the congruent input data source.

Recent experimental research focuses on the development and use of a powerful hybrid patch-clamp/computational modelling technique, the “dynamic-clamp”, to control and modify cardiac ion currents by linking a computer model with live cardiac cells in real time (Workman AJ et al. J Physiol 2012;590:4289-4305). 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. Our latest research using the dynamic-clamp focusses on the L-type Ca2+ current, ICaL. The results have potential implications for both the development and treatment of AF.

Heart Human Atrial Fibrillation 2

 

Publications list

  1. Colman MA*, Saxena P, Kettlewell S, Workman AJ. Description of the human atrial action potential derived from a single, congruent data source: novel computational models for integrated experimental-numerical study of atrial arrhythmia mechanisms. Front Physiol 2018; 9: 1211.
  2. Pandit SV*, Workman AJ. Atrial electrophysiological remodeling and fibrillation in heart failure. Clin Med Insights Cardiol 2016; 10 (Suppl 1): 41-46.
  3. Colman MA*, Sarathy PP, MacQuaide N, Workman AJ. A new model of the human atrial myocyte with variable T-tubule organization for the study of atrial fibrillation. Computing in Cardiology 2016; 43:221-224.
  4. Alday EAP, Colman MA, Langley P, Butters TD, Higham J, Workman AJ, Hancox JC, Zhang H*. A new algorithm to diagnose atrial ectopic origin from multi lead ECG systems - insights from 3D virtual human atria and torso. PLoS Comput Biol 2015; 11: e1004026.
  5. Kharche SR, Stary T, Colman MA, Biktasheva IV, Workman AJ*, Rankin AC, Holden AV, Zhang H*. Effects of human atrial ionic remodelling by β-blocker therapy on mechanisms of atrial fibrillation: a computer simulation. Europace 2014; 16: 1524-1533.
  6. Kettlewell S, Burton FL, Smith GL, Workman AJ*. Chronic myocardial infarction promotes atrial action potential alternans, afterdepolarizations, and fibrillation. Cardiovasc Res 2013; 99: 215-224.
  7. 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. 
  8. Grandi E, Workman AJ, Pandit SV*. Altered excitation-contraction coupling in human chronic atrial fibrillation. J Atr Fibrillation 2012; 2: 1-17. 
  9. 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. 
  10. 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. 
  11. Workman AJ*, Smith GL, Rankin AC. Mechanisms of termination and prevention of atrial fibrillation by drug therapy. Pharmacol Ther 2011; 131: 221-241. 
  12. 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. 
  13. 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.
  14. Workman AJ*. Cardiac adrenergic control and atrial fibrillation. Naunyn-Schmied Arch Pharmacol 2010; 381: 235-249.
  15. 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.
  16. Workman AJ*. Mechanisms of postcardiac surgery atrial fibrillation: more pieces in a difficult puzzle. Heart Rhythm 2009; 6: 1423-1424. 
  17. 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. 
  18. Workman AJ*, Kane KA, Rankin AC. Cellular bases for human atrial fibrillation. Heart Rhythm 2008; 5: S1-S6.
  19. 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. 
  20. 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.
  21. 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. 
  22. 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. 
  23. 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. 
  24. 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. 
  25. 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. 
  26. 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.