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Circulation Research. 2001;89:1089-1091

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(Circulation Research. 2001;89:1089.)
© 2001 American Heart Association, Inc.

Editorials

Recent Fibrillation Studies

Attempts to Wrest Order From Disorder

Raymond E. Ideker, Jian Huang, Vladimir Fast, William M. Smith

From the Departments of Medicine (R.E.I., J.H., W.M.S.), Biomedical Engineering (R.E.I., V.F., W.M.S.), and Physiology and Biophysics (R.E.I.), University of Alabama at Birmingham, Ala.

Correspondence to Raymond E. Ideker, MD, PhD, University of Alabama at Birmingham, 1530 3rd Ave S, VH B140, Birmingham, AL 35294-0019. E-mail rei{at}crml.uab.edu


Key Words: fibrillation • reentry • ion channels

Not so long ago, the basic mechanism of the maintenance of fibrillation was thought to be understood, with only the details to be worked out. Whereas the relative roles of reentry and foci were intensely debated during the first half of the twentieth century,1 by the 1970s, the preponderance of evidence suggested that fibrillation was maintained solely by reentry.2,3 This reentry was thought to be evanescent and unstable, maintained by wandering wavelets of activation following constantly changing paths of activation and exhibiting frequent conduction block caused by a nonuniform dispersion of refractoriness.2,4 In the last few years, these cherished ideas have been challenged from several different directions. Clinical data suggest that in some patients with paroxysmal atrial fibrillation, foci arising primarily from the pulmonary veins contribute to both the initiation and maintenance of the arrhythmia.5–7 Although recent experimental and simulation investigations still point to reentry as the sole mechanism for the maintenance of ventricular fibrillation,8–11 they suggest that there may be other causes of reentry than the dispersion of refractoriness and other types of reentry than wandering wavelets.

Some of these investigations have dealt with the nonlinear, temporal aspects of the relationship between the activation rate and the refractory period, ie, the restitution curve.12,13 Other investigations have dealt with the nonlinear, spatial aspects of activation and recovery8,10,14–16 and, from the study of excitable media, have introduced the concepts of wavefront, wavetail, wavebreak, and rotor as replacements for and improvements upon the classic concepts of activation sequence, recovery pattern, conduction block, and reentry. Rotors can be short-lived, equivalent to wandering wavelets or nonsustained reentry or they can be long-lived, equivalent to sustained monomorphic reentry. In a series of articles,10,17–21 Jalife’s group has described the importance of sustained, long-lived rotors in the maintenance of fibrillation. Although an early article in this series demonstrated the importance of a drifting, single, sustained rotor for the maintenance of fibrillation,10 more recent articles, the latest of which appears in this issue of Circulation Research,22 have emphasized the role of a stationary, single, sustained rotor for fibrillation maintenance.18–20 This rotor is located in the fastest activating region of the myocardium during fibrillation, which is also the region with the shortest refractory period. Wavefronts emanate from this source to activate the slower, remaining myocardium where they block because of the longer refractory periods and give the appearance of wandering wavelets. Although earlier articles from this series documented these findings in isolated atria or isolated ventricular wedges, the article in this issue by Samie et al22 demonstrates these findings for the first time in the entire ventricular myocardium of the heart.

Using optical mapping of membrane potential and FFT analysis, Samie et al report that the activation rate during ventricular fibrillation on the anterior left ventricular epicardium of isolated perfused guinea pig hearts was nearly 2 times faster than in the remainder of the ventricular epicardium. Rotors persisting for 4 to 150 rotations were observed in the rapidly activating anterior left ventricle whereas no persistent rotors were detected in the right ventricle. At the boundary between the rapidly and slowly activated regions, short-lived wavebreaks occurred with a higher frequency than in the rest of the myocardium. These findings are consistent with the concept of a stable rotor in the left ventricle maintaining fibrillation and giving rise to fractionated, short-lived wavefronts in the remainder of the myocardium that generate the disorganized electrocardiographic pattern of fibrillation.

A major contribution of this study is to provide evidence pointing toward the ionic mechanism responsible for the spatial gradients in activation rates and the rotor stability in the fastest activating region. Patch-clamp experiments on cells isolated from different parts of the heart demonstrated that the amplitude of the outward component of the background rectifier current, IK1, was larger in the rapidly activating left ventricular myocytes than in the slower activating right ventricular myocytes. Furthermore, the role of this difference in IK1 was examined in a computer model of activation spread. Regions with larger IK1 had shorter action potentials, faster activation rates, and more stable rotors than regions with larger IK1.

In summary, the article is a tour de force involving optical mapping, patch-clamping, and computer simulations to provide important, new findings about fibrillation. It takes us yet another step away from the concept of fibrillating tissue as an homogeneous mass of an almost amorphous soup of wandering wavelets and toward the characterization of fibrillation as a process governed by well-defined electrophysiological and anatomic characteristics that lead to a certain level of organization and repeatability during the arrhythmia and to regional differences in the characteristics of fibrillation. The important new step taken by this article, as well as another recent article by Choi et al,23 is the attempt to explain the characteristics of fibrillation based on regional differences in ionic channels.

Additional studies are sure to follow to address the loose ends left by Samie et al, such as the effects of other ion channels, the effects of ischemia during fibrillation, which was not present in the study, and the importance of the differences in ion channel activity not just on the epicardium but transmurally.

An important question is whether the findings obtained in the guinea pig heart can be applied to the human heart. The guinea pig heart is approximately 300 times lighter than the human heart with sudden cardiac arrest (1.3 versus 400 g),24,25 and the fibrillation rate in humans (mean cycle length of 218 ms)26 is over 4 times slower than in the guinea pig hearts (38 to 67 ms).22 The guinea pig heart lacks Ito, which is present in the human heart,27 and the human heart lacks Iks,28 which is present in the guinea pig heart.29 These differences raise the possibility that the maintenance of ventricular fibrillation in humans differs in some respects from that described in the guinea pig by Samie et al. For example, as in dog hearts,30 there may be more than one region in the human heart during fibrillation that activates faster than the surrounding neighboring regions. Even if there is only a single rapidly activating region in the human heart and the activation rate during fibrillation decreases with increased distance away from this region, wavefronts arising in this most rapidly activating region may not be responsible for maintaining fibrillation all the way to the opposite side of the ventricles, which can be over 10 cm in human hearts but less than 2 cm in guinea pig hearts. In addition, although halting activation in the fast activating region in the tiny guinea pig heart may halt fibrillation, in the human heart, halting activation in the fastest activating region would probably not halt fibrillation because the remaining tissue mass is sufficient to easily support several slightly slower rotors.

Even if the results of the study by Samie et al are not completely applicable to the human heart, this does not diminish the importance of this work because of the new concepts it introduces. It should be noted that there is a discrepancy between the results of this study and Choi et al23 mentioned above. Although Choi et al also performed optical mapping of ventricular fibrillation in isolated guinea pig hearts, they did not report faster activation in the anterior left ventricular epicardium nor did they observe sustained rotors in this region. Instead, their results suggested the presence of wavebreaks occurring throughout the mapped region consistent with the maintenance of fibrillation by multiple wandering wavelets in the tissue. Similar to the results of the articles from Jalife’s group, Choi et al reported that the activation rate during fibrillation was related to the action potential duration. However, the fastest activations and the shortest action potentials were observed in the apical part of the ventricles. Also similar to Samie et al, Choi et al reported that these regional differences are related to differences in the distribution of an ion channel. However, this ion channel in Choi et al is Ikr, not IK1 as in Samie et al.

Although both studies use the same experimental model, they do differ in some details, such as the optical mapping device, the composition of the perfusing solution, the manner in which heart motion was constrained, the duration of ventricular fibrillation before optical mapping was performed, and the manner in which the peak frequency in the recordings was determined. Whatever the cause for the differences, both articles are important because they are in the vanguard of current studies to understand the ionic mechanisms by which fibrillation is maintained. Further work is needed to reconcile the results from the 2 laboratories and extend them to larger mammalian hearts. The resulting research should lead to a better understanding of the dynamics and physiology of both atrial and ventricular fibrillation, demonstrating the beneficial effects of the scientific dialectic.

Acknowledgments

The author’s work was supported in part by National Institutes of Health Research Grants HL-28429 and HL-66256.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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