EHRA Key References on Basic electrophysiology

Electrophysiological basis of human action potential

Cellular basis and mechanism underlying normal and abnormal myocardial repolarization and arrhythmogenesis.
Antzelevitch C. Ann Med. 2004;36 Suppl 1:5-14.
This  review examines the ionic and cellular basis for electrical heterogeneities and their role in the Brugada and long-QT syndromes.

Molecular physiology of cardiac repolarization.
Nerbonne JM, Kass RS. Physiol Rev. 2005 Oct;85(4): 1205-53.
This  review is referred to the molecular physiology of cardiac repolarization and gives directions for future research.

Modelling the molecular basis of cardiac repolarization.
Rudy Y. Europace. 2007 Nov;9 Suppl 6:vi17-9.
This study shows that I(Ks) builds an 'available reserve' of channels that can open 'on-demand' to repolarize the AP and shorten its duration at fast rate ('rate-adaptation'). This property also makes I(Ks) effective in providing repolarization reserve when other repolarizing currents are compromised by disease or drugs.

Nodal electrophysiology and pacemaker mechanisms

The Role of the Funny Current in Pacemaker Activity
DiFrancesco D. Circ. Res., Feb 2010; 106: 434 - 446. Abstract:
This review describes the function of f-channels, their role in pacemaking and how the later can be modulated by drugs or gene and cell-based methods.

New Insights Into Pacemaker Activity: Promoting Understanding of Sick Sinus Syndrome.  
Dobrzynski H, Boyett MR, Anderson RH. Circulation 2007;115;1921-1932
In this review, the authors offer new insights into intrinsic causes of sick sinus syndrome that come from an understanding of the mechanisms underlying pacemaking.

A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker.
Lakatta EG, Maltsev VA, Vinogradova  TM. Circ Res. 2010 Mar 5;106(4):659-73.

This review examines evidence that forms the basis of a coupled-clock system concept in cardiac sinoatrial nodal pacemaker cells.

The funny current in the context of the coupled-clock pacemaker cell system.
Maltsev VA, Lakatta EG.
 Heart Rhythm. 2012, 9(2): 302-307.

"The funny current in the context of the coupled clock pacemaker cell system".
DiFrancesco D, Noble D.
Rebuttal: Heart Rhythm. 2012, 9(3): 457-458.

These two papers highlight the ongoing debate regarding the relative roles of the If current and periodic local Ca2+ releases in driving pacemaker activity.

Arrhythmogenic mechanisms

Mechanisms of disease: ion channel remodeling in the failing ventricle.
Nass RD, Aiba T, Tomaselli GF, Akar FG. Nat Clin Pract Cardiovasc Med. 2008 Apr;5(4):196-207.
In this Review, the authors consider key ventricular ionic changes that are associated with heart failure, with the intention of identifying molecular targets for antiarrhythmic therapy.

Calcium and arrhythmogenesis.
Ter Keurs HE, Boyden PA. Physiol Rev. 2007 Apr; 87(2):457-506
This is a systematic review of the mechanisms of Ca2+ transport (forward excitation-contraction coupling) in the ventricular cell as well as what is known for other cardiac cell types. Second, the authors review the molecular nature of the proteins that are involved in this process as well as the functional consequences of both normal and abnormal Ca2+ cycling (e.g., Ca2+ waves). Finally, they review what we understand to be the role of Ca2+ cycling in various forms of arrhythmias, that is, those associated with inherited mutations and those that are acquired and resulting from reentrant excitation and/or abnormal impulse generation (e.g., triggered activity).

Atrial remodeling and atrial fibrillation: mechanisms and implications.
Nattel S, Burstein B, Dobrev D. Circ Arrhythm Electrophysiol. 2008 Apr;1(1):62-73. This article reviews the types of atrial remodeling,their underlying pathophysiology, the molecular basis of their occurrence, and finally, their potential therapeutic significance.

From the ryanodine receptor to cardiac arrhythmias.
Eisner DA, Kashimura T, Venetucci LA, Trafford AW. Circ J. 2009 Sep;73(9):1561-7
In this review experimental evidence is presented to support the view that arrhythmias still require a threshold SR Ca(2+) content to be exceeded and that this threshold is decreased by increasing RyR open probability.

Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling.

Lou Q, Janks DL, Holzem KM, Lang D, Onal B, Ambrosi CM, Fedorov VV, Wang IW, Efimov IR.
Am J Physiol Heart Circ Physiol. 2012 Dec;303(12):H1426-34.

This optical mapping study performed in right ventricular free wall preparations from failing and non-failing human hearts further suggests that enhanced repolarization dispersion and abnormal conduction velocity restitution in failing human hearts are possibly key players in arrhythmogenesis.

Beat-to-beat variability of repolarization as a new biomarker for proarrhythmia in vivo.
Varkevisser R, Wijers SC, van der Heyden MA, Beekman JD, Meine M, Vos MA.
Heart Rhythm. 2012, 9(10): 1718-1726.

This paper gives a comprehensive review of the current knowledge on the utility of a novel potential proarrhythmia biomarker, beat-to-beat short term variability of cardiac repolarization for the cardiac safety evaluation of compounds under development, based on both animal experimental and clinical studies.

Cardiac ventricular repolarization reserve: a principle for understanding drug-related proarrhythmic risk.
Varró A, Baczkó I. Br J Pharmacol. 2011, 164(1): 14-36.

The concept of cardiac repolarization reserve is reviewed in this article, including its possible underlying mechanisms. The consequences of impaired repolarization reserve in pathophysiological settings and following administration of medications are also discussed.

Gender disparity in cardiac electrophysiology: implications for cardiac safety pharmacology.
Jonsson MK, Vos MA, Duker G, Demolombe S, van Veen TA. Pharmacol Ther. 2010, 127(1): 9-18.

This paper gives an update on gender related differences in cardiac repolarization in physiological and pathophysiological conditions and also describes the consequences for cardiac drug safety testing.

Molecular basis of human cardiac electrogenesis

Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart.
Gaborit N, Le Bouter S, Szuts V, Varro A, Escande D, Nattel S, Demolombe S. J  Physiol. 2007 Jul 15;582 (Pt 2):675-93.

This is the first report of the global portrait of regional ion-channel subunit-gene expression in the non-diseased human heart. The data point to significant regionally determined ion-channel expression differences, with potentially important implications for understanding regional electrophysiology, arrhythmia mechanisms, and responses to ion-channel blocking drugs. Concordance with previous functional studies suggests that regional regulation of cardiac ion-current expression may be primarily transcriptional.