Copyright © 2005, European Society of Cardiology
Tornado in a dish: Revealing the mechanisms of ventricular arrhythmias in engineered cardiac tissues
Washington University, St. Louis, MO, USA
* Corresponding author. Washington University, St. Louis Department of Biomedical Engineering, Whitaker Hall, Campus Box 1097, 1 Brookings Drive, St. Louis, MO 63130-4899, USA. Tel.: +1 314 935 8612; fax: +1 314 935 8377. Email address: igor{at}wustl.edu
Received 20 October 2005; accepted 26 October 2005
See article by Bursac and Tung (pages 381–390) in this issue.
Ventricular tachycardia and fibrillation (VT/VF) are the leading, immediate causes of death in the developed world. Investigation of the mechanisms of VT/VF spans over a century and a half. However, despite a long and exciting history of discovery in the field, we are still asking the same questions posed by Carl J. Wiggers in 1940 [1]: "As to the fundamental mechanisms of fibrillation we have plenty of theories, but none is universally accepted... we may note in passing that they all center around two ideas, viz., (a) that the impulses arise from centers, or pacemakers, or (b) that the condition is caused by the re-entry of impulses and the formation of circles of excitation. Each of these views, again, has two groups of exponents, viz., (a) those who believe that a single focus, or excitation ring, occurs, and (b) those who favor the idea that multiple foci, or numerous circus rings, are developed." In addition to these fundamental questions, we can also ask: (a) Is VF neurogenic or myogenic in nature? (b) Is VF maintained by the "mother rotor" or "multiple wavelet" mechanism? (c) Is there a "critical mass" of VF?
The initial discovery of VT/VF produced by "faradisation" in Carl Ludwig's laboratory [2] during studies of autonomic control of the heart led to the domination of the neurogenic theory of VF. Yet, subsequent studies of Vulpian [3] and MacWilliam [4] laid to rest the neurogenic theory. They put forward a myogenic theory of VF that remained dominant for over a century. The triumph of this theory was imprinted in the term "fibrillation" coined by Vulpian. However, several recent studies [5,6] have cast some degree of doubt on this dogma. They show sympathetic hyperinnervation in canine and rabbit models of ventricular fibrillation.
In addition to the neurogenic–myogenic debates, focal and re-entrant theories of VF have been debated since the early days of arrhythmia research. The seminal work of Lewis [7] provided convincing support for the re-entrant theory of VT/VF. He introduced the "primary ring" hypothesis, which suggested that a single reentrant circuit is sufficient to maintain fibrillation. Based on recent experimental advances, this hypothesis has been further developed into the "mother rotor" theory by Jalife's group [8]. In contrast, Moe [9] suggested that multiple reentrant sources or wavelets are required for the maintenance of fibrillation. In its present day reincarnation, this hypothesis is also known as the "restitution" hypothesis. Thus, we presently have two predominant theories of initiation and maintenance of ventricular fibrillation: the "mother rotor" [7,10] and "restitution" [11,12] hypotheses.
Another important consideration is the size of tissue needed to sustain VF. MacWilliam was apparently the first to observe that heart size matters in the maintenance of VF [4]. Subsequently, a hypothesis known as the "critical mass of VF" remained commonly accepted for nearly a century. The theoretical basis of the critical mass theory was developed using the concept of wavelength [13], which is the product of the refractory period and the conduction velocity of an impulse. Recently, several groups have challenged the critical mass hypothesis by showing what seemed impossible to MacWilliam–fibrillation in the mouse heart [14]. However, the wavelength can change significantly in response to increased heart rate, pharmacological and genetic interventions, and autonomic effects. Thus, these studies do not necessarily contradict the critical mass hypothesis.
Investigation and experimental validation of these competing theories has been hampered by our inability to map electrical activity in the profoundly complex, three-dimensional, dynamically changing heart. A study of Bursac and Tung in this issue of Cardiovascular Research [15] presents evidence of an emerging new era in experimental electrophysiology: tissue-engineered models of arrhythmia. These models allow comprehensive mapping of electrical activity in the entire tissue, which sustains clinically relevant arrhythmias. Moreover, these models allow real-time control of gene expression and cell signaling in a spatially heterogeneous fashion [16,17]. Electrophysiological parameters that control dynamic electrical properties of an exceedingly complex system can now be sorted out using tissue engineering, fluorescent mapping, and traditional stimulation and electrode sensing techniques. In this elegant study, Bursac and Tung [15] have presented a convincing mechanistic explanation for a clinically important phenomenon that they reproduced in a Petri dish. Their study showed that, as in clinical therapy, antitachycardia pacing is highly successful; yet in some cases, it may result in acceleration of a reentrant arrhythmia instead of its termination. Cardiac myocyte monolayers implicated the depth and breadth of conduction velocity restitution in the failure of antitachycardia therapy.
Recently, great advances in genetic engineering have led to the creation of transgenic mouse models of arrhythmia. However, the utility of these models has been somewhat limited. With the exception of the connexin knockouts [18,19], few of these models have been shown to sustain clinically relevant arrhythmias in vivo. Transgenic models have the obvious limitation of incorporating the enormous complexity of an entire organism. Often, cardiac gene knockouts die as embryos or early in the postnatal period due to severe cardiac defects. Other times, these transgenic models do not necessarily have the expected arrhythmia phenotype due to the complexity and/or redundancy of the system.
Engineered tissue constructs may resolve some of these limitations while maintaining the exciting opportunity to manipulate gene and protein expression in a dish. Also, unlike transgenic models, study is not limited to just one species. Cells and tissue from nearly any species can be cultured, including co-cultures from different species [20] and different cell types: myocytes, fibroblasts, neurons, myoblasts, stem cells, etc. Ultimately, with the progress in stem and progenitor cell research we may be able to engineer human cell constructs, which may prove more relevant than any animal model and lead to new therapies. However, sorting out arrhythmia mechanisms in a dish is warranted before and not after clinical translation.
Future studies employing tissue engineering strategies will undoubtedly bring resolution to many outstanding problems in arrhythmia research that are associated with limitations of mapping or in vivo molecular biology methodologies. Bursac and Tung elegantly reproduced the success and failure of antitachycardia pacing in their cultures; however, it remains to be seen how many other clinically relevant phenomena will be faithfully reproduced in engineered tissue constructs. If their success can be matched, we may be seeing a lot more tornadoes in a dish.
 |
References |
|---|
 Top References |
|---|
- Wiggers C.J. The mechanism and nature of ventricular fibrillation. Am Heart J (1940) 20:399–412.[CrossRef][Web of Science]
- Hoffa M., Ludwig C. Einige neue Versuche uber Herzbewegung. Z. Ration. Med. (1850) 9:107–144.
- Vulpian A. Note sur les effets de la faradisation directe des ventricules du coeur le chien. Arch de Physiol (1874) i:975.
- MacWilliam J.A. Fibrillar contraction of the heart. J Physiol (Lond) (1887) 8:296.
[Free Full Text] - Liu Y.B., Wu C.C., Lu S., Su M.J., Lin C.W., Lin S.F., et al. Sympathetic nerve sprouting, electrical remodeling and increased vulnerability to ventricular fibrillation in hypercholesterolemic rabbits. Circ Res (2003) 92:1145–1152.
[Abstract/Free Full Text] - Chen P.S., Chen L.S., Cao J., Sharifi B., Karagueuzian H.S., Fishbein M.C. Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc Res (2001) 50:409–416.
[Abstract/Free Full Text] - Lewis T. The Mechanism and Graphic Registration of the Heart Beat. (1925) London: Shaw and sons.
- Gray R.A., Jalife J., Panfilov A.V., Baxter W.T., Cabo C., Davidenko J.M., et al. Mechanisms of cardiac fibrillation. Science (1995) 270:1222–1223. [discussion 1224–1225].
[Abstract/Free Full Text] - Moe G.K. A conceptual model of atrial fibrillation. J Electrocardiol (1968) 1:145–146.[Medline]
- Jalife J. Ventricular fibrillation: mechanisms of initiation and maintenance. Annu Rev Physiol (2000) 62:25–50.[CrossRef][Web of Science][Medline]
- Riccio M.L., Koller M.L., Gilmour R.F. Jr. Electrical restitution and spatiotemporal organization during ventricular fibrillation. Circ Res (1999) 84:955–963.
[Abstract/Free Full Text] - Garfinkel A., Kim Y.H., Voroshilovsky O., Qu Z., Kil J.R., Lee M.H., et al. Preventing ventricular fibrillation by flattening cardiac restitution. Proc Natl Acad Sci U S A (2000) 97:6061–6066.
[Abstract/Free Full Text] - Krinskii V.I., Fomin S.V., Kholopov A.V. Critical mass during fibrillation. Biofizika (1967) 12:908–914.[Medline]
- Vaidya D., Morley G.E., Samie F.H., Jalife J. Reentry and fibrillation in the mouse heart. A challenge to the critical mass hypothesis. Circ Res (1999) 85:174–181.
[Abstract/Free Full Text] - Bursac N., Tung L. Acceleration of functional reentry by rapid pacing in anisotropic cardiac monolayers: formation of multi-wave functional reentries. Cardiovasc Res (2006) 69:381–390.
[Abstract/Free Full Text] - Thomas S.P., Kucera J.P., Bircher-Lehmann L., Rudy Y., Saffitz J.E., Kleber A.G. Impulse propagation in synthetic strands of neonatal cardiac myocytes with genetically reduced levels of connexin43. Circ Res (2003) 92:1209–1216.
[Abstract/Free Full Text] - Gaudesius G., Miragoli M., Thomas S.P., Rohr S. Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circ Res (2003) 93:421–428.
[Abstract/Free Full Text] - Kirchhoff S., Nelles E., Hagendorff A., Kruger O., Traub O., Willecke K. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice. Curr Biol (1998) 8:299–302.[CrossRef][Web of Science][Medline]
- Gutstein D.E., Morley G.E., Tamaddon H., Vaidya D., Schneider M.D., Chen J., et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res (2001) 88:333–339.
[Abstract/Free Full Text] - Kehat I., Khimovich L., Caspi O., Gepstein A., Shofti R., Arbel G., et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol (2004) 22:1282–1289.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||