VIEWPOINTS Ventricular fibrillation and defibrillation—What are the major unresolved issues? Raymond E. Ideker, MD, PhD, Gregory P. Walcott, MD, Andrew E. Epstein, MD, Vance J. Plumb, MD, and Neal Kay, MD From the Division of Cardiovascular Diseases, Department of Medicine, Department of Physiology, and the Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama. This is the first in a new series of Viewpoint articles on fibrillation and defibrillation and lists a few of the major unresolved questions in basic science, clinical medicine, and public health dealing with these important subjects. Basic science What causes conduction block that initiates and maintains ventricular fibrillation (VF)? It was previously thought that conduction block was almost always caused by a nonuniform dispersion of refractoriness. However, recent studies indicate that block can also be caused by the restitution properties of the diastolic interval and of conduction velocity in addition to several other factors including excitability, wave front curvature, loading, regional differences in ion channels, and loss of synchrony between the action potential and calcium cycling. 1,2 The relative importance of each of these mechanisms in the initiation and maintenance of VF during sudden cardiac arrest is unknown. What are the incidence and causes of the different activation patterns that maintain fibrillation? Depending on the species studied, the drugs administered, and the duration of VF, two types of activation sequences have been identified in animal models of VF. 3 In one pat- tern, wandering wavelets of activation maintain fibrillation by forming short-lived sites of reentry that are constantly forming, drifting, and terminating throughout much of the myocardium. In the other pattern, a stationary, stable mother rotor is present in the fastest activating region that gives rise to activation fronts that fractionate to give the disorganized appearing pattern of fibrillation in the remainder of the myocardium. It is important to learn the predominant type of VF and the conditions under which it occurs, since therapies focused on halting or preventing the formation of a specific type of fibrillation may be effective. What role do anatomic structures play in the initiation and maintenance of fibrillation? In addition to the effects of fiber orientation, evidence points to the insertions of the papillary muscles, the courses of the major blood vessels on the epicardium, and the Purkinje fibers as regions where reentry is predominantly located during fibrillation. 4–6 The importance of these anatomic regions in the initiation of fibrillation and the reasons why reentry occurs preferentially in these regions are not known. Why is there a pause between a defibrillation shock and the earliest postshock recorded activation? For weak defibrillation shocks, activation is recorded almost immediately after the shock. However, for failed shocks that are near the defibrillation threshold in strength, earliest postshock activation is not recorded for tens of milliseconds with either epicardial or intramural electrical recordings or epicardial optical recordings. 7 It is not known whether this pause is real and earliest activation after the shock arises de novo such as from triggered activity or if activation is present within the heart wall during this pause but is missed by intramural electrical recordings because (1) it consists of propagat- ing graded responses that cause only slow, small deflec- tions in the extracellular space, (2) the activations are present only within the sparsely distributed Purkinje fi- bers during this interval that are missed by the widely spaced intramural electrical recordings, or (3) the activa- tions are present during this pause but are not detected in Supported in part by National Institutes of Health grant nos. HL-28429, HL-42760, HL-66256, and HL-67961. Address reprint requests and correspondence: Raymond E. Ideker, MD, PhD, B140 Volker Hall, 1670 University Blvd., University of Ala- bama at Birmingham, Birmingham, AL 35294-0019. E-mail address: rei@crml.uab.edu. (Received February 10, 2005.) 1547-5271/$ -see front matter © 2005 Heart Rhythm Society. All rights reserved. doi:10.1016/j.hrthm.2005.02.009