Abstract
Purpose
The purpose of this report was to review the basic mechanisms underlying cardiac automaticity. Second, we describe our clinical observations related to the anatomical and functional characteristics of sinus automaticity.
Methods
We first reviewed the main discoveries regarding the mechanisms responsible for cardiac automaticity. We then analyzed our clinical experience regarding the location of sinus automaticity in two unique populations: those with inappropriate sinus tachycardia and those with a dominant pacemaker located outside the crista terminalis region.
Results
We studied 26 patients with inappropriate sinus tachycardia (age 34 ± 8 years; 21 females). Non-contact endocardial mapping (Ensite 3000, Endocardial Solutions) was performed in 19 patients and high-density contact mapping (Carto-3, Biosense Webster with PentaRay catheter) in 7 patients. The site of earliest atrial activation shifted after each RF application within and outside the crista terminalis region, indicating a wide distribution of atrial pacemaker sites. We also analyzed 11 patients with dominant pacemakers located outside the crista terminalis (age 27 ± 7 years; five females). In all patients, the rhythm was the dominant pacemaker both at rest and during exercise and located in the right atrial appendage in 6 patients, in the left atrial appendage in 4 patients, and in the mitral annulus in 1 patient. Following ablation, earliest atrial activation shifted to the region of the crista terminalis at a slower rate.
Conclusions
Membrane and sub-membrane mechanisms interact to generate cardiac automaticity. The present observations in patients with inappropriate sinus tachycardia and dominant pacemakers are consistent with a wide distribution of pacemaker sites within and outside the boundaries of the crista terminalis.
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References
Vassalle M. The relationship among cardiac pacemakers. Overdrive suppression Circ Res. 1977;41:269–77.
Vassalle M. Automaticity and automatic rhythms. Am J Cardiol. 1971;28:245–52.
Vassalle M. Analysis of cardiac pacemaker potential using a voltage clamp technique. Am J Phys. 1966;210:1335–41.
Peper K, Trautwein W. A note on the pacemaker current in Purkinje fibers. Pflugers Arch. 1969;309:356–61.
Noma A, Irisawa H. A time- and voltage-dependent potassium current in the rabbit sinoatrial node cell. Pflugers Arch. 1976;366:251–8.
Yanagihara K, Irisawa H. Inward current activated during hyperpolarization in the rabbit sinoatrial node cell. Pflugers Arch. 1980;385:11–9.
Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature. 1979;280:235–6.
Brown H, Di Francesco D. Voltage-clamp investigations of membrane currents underlying pacemaker activity in rabbit sino-atrial node. J. Physiol. 1980;308:331–51.
DiFrancesco D, Ojeda C. Properties of the current if in the sino-atrial node of the rabbit compare with those of current iK2 in Purkinje fibres. J Physiol. 1980;308:353–67.
Di Francesco D. A new interpretation of the pacemaker current in calf Purkinje fibres. J Physiol. 1981;314:359–76.
Di Francesco D. A study of the ionic nature of the pacemaker current in calf Purkinje fibres. JPhysiol. 1981;314:377–93.
Vasalle M, Hangang Y, Cohen IS. The pacemaker current in cardiac Purkinje myocytes. J Gen Physiol. 1995;106:559–78.
Shi W, Wymore R, Yu H, Wu J, Wymore RT, Pan Z, et al. Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res. 1999;85:e1–6.
Moonsmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem. 2001;268:1646–52.
DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature. 1991;351:145–7.
Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol. 1998;395:233–53.
Verheijck EE, van Ginneken AC, Wilders R, Bouman LN. Contribution of L-type Ca2 current to electrical activity in sinoatrial nodal myocytes of rabbits. Am J Phys. 1999;276:H1064–77.
Maltsev VA, Vinogradova TM, Lakatta EG. The emergence of a general theory of the initiation and strength of the heartbeat. J Pharmacol Sci. 2006;100:338–69.
Lakatta EG, Maltsev VA, Vinogradova TM. A coupled system of intracellular Ca2 clocks and surface membrane voltage clocks controls, the timekeeping mechanism of the heart’s pacemaker. Circ Res. 2010;106:659–73.
Maltsev VA, Lakatta EG. Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Heart Circ Physiol. 2009;296:H594–615.
Rubenstein DS, Lipsius SL. Mechanisms of automaticity in subsidiary pacemakers from cat right atrium. Circ Res 1089; 64: 648–657.
Bogdanov KY, Vinogradova TM, Lakatta EG. Sinoatrial nodal cell ryanodine receptor and Na+-Ca2+ exchanger: molecular partners in pacemaker regulation. Circ Res. 2001;88:1254–8.
Wilders R. Computer modelling of the sinoatrial node. Med Biol Eng Comput. 2007;45:189–207.
Vinogradova TM, Zhou YY, Maltsev V, Lyashkov A, Stern M, Lakatta EG. Rhythmic ryanodine receptor Ca releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ Res. 2004;94:802–9.
Maltsev VA, Lakatta EG. Synergism of coupled subsarcolemmal Ca++ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol Heart Circ Physiol. 2009;296:H594–615.
Cerbai E, Pino R, Porciatti F, Sani G, Toscano M, Maccherini M, et al. Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart. Circulation. 1997;95:568–71.
Hoppe UC, Beuckelmann DJ. Characterization of the hyperpolarization-activated inward current in isolated human atrial myocytes. Cardiovasc Res. 1998;38:788–801.
Brioschi C, Micheloni S, Tellez JO, Pisoni G, Longhi R, Moroni P, et al. Distribution of the pacemaker HCN4 channel mRNA and protein in the rabbit sinoatrial node. J Mol Cell Cardiol. 2009;47:221–2.
Shinohara T, Joung B, Kim D, Maruyama M, Luk HN, Chen PS, et al. Induction of atrial ectopic beats with calcium release inhibition: local hierarchy of automaticity in the right atrium. Heart Rhythm. 2010;7:110–6.
Fedorov VV, Glukhov AV, Chang R. Conduction barriers and pathways of the sinoatrial pacemaker complex: their role in normal rhythm and atrial arrhythmias. Am J Physiol Heart Circ Physiol. 2012;302:H1773–8.
Lou Q, Hansen BJ, Fedorenko O, Csepe TA, Kalyanasundaram A, Li N, et al. Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping. Circulation. 2014;130:315–24.
Yeh YH, Burstein B, Qi XY, Sakabe M, Chartier D, Comtois P, et al. Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome. Circulation. 2009;119:1576–85.
Lewis T, Meakins J, White PD. The excitatory process in the dog’s heart Part I The auricles. Phil Tran Roy Soc Lond 205: 375, 1914.
Boineau JP, Miller CB, Schuessler RB. Activation sequence and potential distribution maps demostrating multicentric atrial inpulse origin in dogs. Circ Res. 1984;54:332–47.
Boineau JP, Schuessler RB, Mooney CR. Multicentric origin of the atrial depolarization wave: the pacemaker complex. Relation to dynamics of atrial conduction, P wave changes and heart rate control. Circulation. 1978;58:1036–48.
Boineau JP, Canavan TE, Schuessler RB, Can ME, Corr PB, Cox JL. Demonstration of a widely distributed atrial pacemaker complex in the human heart. Circulation. 1988;77:1221–37.
Morillo CA, Klein GJ, Thakur RK, Li H, Zardini M, Yee R. Mechanism of ‘inappropriate’ sinus tachycardia. Role of sympathovagal balance. Circulation. 1994;90:873–7.
Scherlag BJ, Yamanashi WS, Rohit A, Lazzara R, Jackman WM. Experimental model of inappropriate sinus tachycardia: initiation and ablation. J Interventional Cardiac Electrophysiol. 2005;13:21–9.
Gonzalez MD, Rivera J, Shedd OL, Kyker KA, Erga KS. Ectopic dominant pacemakers originating from the atrial appendages. Heart Rhythm. 2005;2:S2.
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Dr. Naccarelli is a consultant to Janssen, Glaxo Smith Kline, and Omeicos. He has a research grant from Janssen. Dr. Gonzalez is a consultant to Janssen and Biosense Webster. He has an educational grant from Biosense Webster.
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The manuscript has not been published previous in part or full and has not been submitted to any other journal. All the information is original and no part of the text has been copied from another manuscript.
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Vetulli, H.M., Elizari, M.V., Naccarelli, G.V. et al. Cardiac automaticity: basic concepts and clinical observations. J Interv Card Electrophysiol 52, 263–270 (2018). https://doi.org/10.1007/s10840-018-0423-2
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DOI: https://doi.org/10.1007/s10840-018-0423-2