© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Cardiac cellular heterogeneity and remodelling
Laboratory of Physiology, University of Oxford, Parks Road, OX1 3PT, Oxford, United Kingdom
* Tel.: +44 1865 272 114; fax: +44 1865 272 554. Email address: peter.kohl{at}physiol.ox.ac.uk
Received 16 August 2004; accepted 18 August 2004
See article by Zorn-Pauly et al. [17] (pages 250–259) in this issue.
Uniform cardiac pump function requires well-coordinated myocardial heterogeneity at the cellular level. This insight was eloquently presented some 15 years ago by Katz and Katz [9], who likened the serial and parallel summation of mechanical activity in various regions of cardiac muscle to the combined action of oarsmen on ancient Greek triremes. These battleships were powered by 170 men, placed in three tiers along both sides of the ship. In order to synchronise mechanical action and to achieve optimal propulsion, their rowing gear was ingeniously fine-tuned to match positional requirements from bow to stern (a kind of ‘base–apex gradient’) and between rows (‘trans-mural gradient’).
Indeed, recent research has confirmed the existence of complex regional differences in electro-mechanical cell properties in healthy ventricle [2], and highlighted pronounced alterations of this heterogeneity in pathological states [12]. Thus, in normal heart, the time-to-peak of contraction decreases from endocardium to epicardium which, in the presence of a corresponding delay in transmural activation timing, supports synchronised peak force development of the tissue as a whole [6]. Mechanical heterogeneity in ventricular cardiomyocyte properties is accompanied by differences in calcium handling, metabolic activity, electrophysiology, cell coupling and structure. In their combination, these physiological heterogeneities support uniform electro-mechanical activity of the heart. Any mal-adaptation—whether an increase or, indeed, a decrease—in this well-orchestrated heterogeneity is likely to render ventricular performance less efficient [11].
In the much more thin-walled atria, transmural gradients may be of less significance. Still, there are pronounced differences in regional tissue architecture (compare atrial free wall with Crista terminalis or auricular tissue), function (from sino-atrial node pacemaking to atrial working myocardium and atrio-ventricular conduction pathways) and coupling of both myocytes and connective tissue cells [3,15]. With the exception of specialised structures such as pacemaker tissue or conduction pathways, electrophysiological heterogeneity of atrial cardiomyocytes is predominantly studied in the context of pathological states, chiefly atrial fibrillation (AF).
AF is the most common arrhythmia in man and therefore of great clinical importance. Both the triggers and the sustaining mechanisms of atrial arrhythmias are the subject of intensive research. The crucial role of tissue remodelling in the domestication of atrial arrhythmias has been elegantly summarised by Allessie's group in the dictum ‘AF begets AF’ [16]. Pro-arrhythmic remodelling involves electrical, mechanical, and structural changes in atrial myocardium (Fig. 1, [1]). A thorough understanding of atrial remodelling pathways would be highly desirable, as it could guide the design of therapeutic interventions for the disruption of arrhythmia-sustaining feedback loops.
|
: conduction velocity; WL: wave length. From Ref. The identification of viable electrophysiological drug targets has been difficult [4], primarily because of the complexity and inter-dependence of mechanisms underlying atrial electrophysiology and remodelling, as recently reviewed by Dobrev and Ravens [7]. AF affects the expression and/or activity of a multitude of atrial ion channels, including connexin distribution. The extent and direction of AF-induced changes in ion handling proteins show some variation, although a reduction in channel expression appears to dominate (with L-type calcium channel down-regulation believed to play a pivotal role; Fig. 1). The link between ion channel expression and function is, however, not straightforward, and it appears that phosphorylation-dependent channel regulation can be altered in AF independently of expression levels [5].
The paper by Zorn-Pauly et al. [17] in this issue of Cardiovascular Research provides a further piece of the atrial electrophysiology puzzle: functional confirmation of the presence of hyperpolarisation-activated inward current, if, in the left atrium of human heart. This extends the previous characterisation of if in human right atrial preparations [8,13]. It also highlights the presence of regional differences in if expression, as left (and right) atrial appendage cells appear to exhibit more if than those from the left atrial wall.
While both atria can be the site of premature complexes and initiation of spontaneous AF in man [14], the left atrium is understood to often play a key role in the initiation and maintenance of atrial arrhythmias. The presence of if in this area could contribute to ectopic automaticity. Mathematical modelling by Zorn-Pauly et al. suggests that the experimentally observed if levels may well be sufficient to spontaneously trigger repetitive action potentials in left atrial myocytes, in particular if this were to coincide with a down-regulation in repolarising currents.
As is the case with virtually any new insight into complex and multi-factorial settings, the report by Zorn-Pauly et al. also exposes important open questions. Thus, it would be of interest to relate regional differences in if expression to the prevailing heart rhythm of tissue donors (sinus rhythm/paroxysmal AF/chronic AF)’a difficult task that could not be tackled in the present investigation for the relatively small patient numbers in each group. Furthermore, it would be desirable to relate if in isolated cells to a detailed characterisation of overall cell electrophysiology, including repolarising currents, action potential activation threshold, and the presence of automaticity. This is, of course, quite a challenge, given the heterogeneity of patient populations from which tissue samples may be obtained (age, sex, disease history, medication), and the technical difficulty of isolating viable myocytes from the very small blocks of biopsied atrial tissue (usually a few hundred milligrams only).
The findings by Zorn-Pauly et al. provide a new glimpse into the diversity of human atrial electrophysiology. Further research is required (i) to ascertain whether regional heterogeneity in electrophysiological parameters is of physiological relevance in the atria (for example in the guise of shorter action potential durations of left vs. right atrium, as seen in normal canine heart [10]); (ii) how electrophysiological remodelling of atrial heterogeneity may turn from a potentially compensatory response into an arrhythmogenic feedback loop; and (iii) how this process could be delayed and/or reversed in patients.
 |
Acknowledgements |
|---|
The author thanks Dr. Dobromir Dobrev, Department of Pharmacology at the TU Dresden, for helpful comments on the manuscript. PK is a Royal Society Research Fellow.
|
References |
|---|
 Top References |
|---|
- Allessie M.A., Ausma J., Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc. Res. (2002) 54:230–246.
[Abstract/Free Full Text] - Bryant S.M., Shipsey S.J., Hart G. Regional differences in electrical and mechanical properties of myocytes from guinea-pig hearts with mild left ventricular hypertrophy. Cardiovasc. Res. (1997) 35:315–323.
[Abstract/Free Full Text] - Camelliti P., Green C.R., LeGrice I., Kohl P. Fibroblast network in rabbit sino-atrial node: structural and functional identification of homo- and heterologous cell coupling. Circ. Res. (2004) 94:828–835.
[Abstract/Free Full Text] - Choudhury A., Lip G.Y. Antiarrhythmic drugs in atrial fibrillation: an overview of new agents, their mechanisms of action and potential clinical utility. Expert. Opin. Investig. Drugs (2004) 13:841–855.[CrossRef][Web of Science][Medline]
- Christ T., Boknik P., Wöhrl S., Wettwer E., Graf E.M., Bosch R.F., et al. L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation (2004) [in press].
- Cordeiro J.M., Greene L., Heilmann C., Antzelevitch D., Antzelevitch C. Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle. Am. J. Physiol. Cell Physiol. (2003) 286:H1471–H1479.
- Dobrev D., Ravens U. Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic Res. Cardiol. (2003) 98:137–148.[Web of Science][Medline]
- Hoppe U.C., Beuckelmann D.J. Characterization of the hyperpolarization-activated inward current in isolated human atrial myocytes. Cardiovasc. Res. (1998) 38:788–801.
[Abstract/Free Full Text] - Katz A.M., Katz P.B. Homogeneity out of heterogeneity. Circulation (1989) 79:712–717.
[Free Full Text] - Li D., Zhang L., Kneller J., Nattel S. Potential ionic mechanism for repolarization differences between canine right and left atrium. Circ. Res. (2001) 88:1168–1175.
[Abstract/Free Full Text] - Markhasin V.S., Solovyova O., Katsnelson L.B., Protsenko Y., Kohl P., Noble D. Mechano-electrical interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models. Prog. Biophys. Mol. Biol. (2003) 82:207–220.[CrossRef][Web of Science][Medline]
- McCrossan Z.A., Billeter R., White E. Transmural changes in size, contractile and electrical properties of SHR left ventricular myocytes during compensated hypertrophy. Cardiovasc. Res. (2004) 63:283–292.
[Abstract/Free Full Text] - Porciatti F., Pelzmann B., Cerbai E., Schaffer P., Pino R., Bernhart E., et al. The pacemaker current I(f) in single human atrial myocytes and the effect of beta-adrenoceptor and A1-adenosine receptor stimulation. Br. J. Pharmacol. (1997) 122:963–969.[CrossRef][Web of Science][Medline]
- Saksena S., Shankar A., Prakash A., Krol R.B. Catheter mapping of spontaneous and induced atrial fibrillation in man. J. Interv. Card. Electrophysiol. (2000) 4:21–28.[CrossRef][Web of Science][Medline]
- Verheijck E.E., van Kempen M.J.A., Veereschild M., Lurvink J., Jongsma H.J., Bouman L.N. Electrophysiological features of the mouse sinoatrial node in relation to connexin distribution. Cardiovasc. Res. (2001) 52:40–50.
[Abstract/Free Full Text] - Wijffels M.C., Kirchhof C.J., Dorland R., Allessie M.A. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation (1995) 92:1954–1968.
[Abstract/Free Full Text] - Zorn-Pauly K., Schaffer P., Pelzmann B., Lang P., Mächler H., Rigler B., et al. If in left human atrium: a potential contributor to atrial ectopy. Cardiovasc. Res. (2004) 64:250–259.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Snider, K. N. Standley, J. Wang, M. Azhar, T. Doetschman, and S. J. Conway Origin of Cardiac Fibroblasts and the Role of Periostin Circ. Res., November 6, 2009; 105(10): 934 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Banerjee, J. W. Fuseler, A. R. Intwala, and T. A. Baudino IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1694 - H1704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Banerjee, J. W. Fuseler, R. L. Price, T. K. Borg, and T. A. Baudino Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1883 - H1891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Borg and R. Markwald Periostin: More Than Just an Adhesion Molecule Circ. Res., August 3, 2007; 101(3): 230 - 231. [Full Text] [PDF]
|
|
|
|
|
|
T. A. Baudino, W. Carver, W. Giles, and T. K. Borg Cardiac fibroblasts: friend or foe? Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1015 - H1026. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||