Ventricular fibrillation is the most important immediate cause of sudden cardiac death, which is the main source of mortality in developed countries. Currently, the only practical method for treating ventricular fibrillation is electrical defibrillation. External defibrillators accessible to public and implantable devices are becoming more widespread, reducing the risk of sudden cardiac death. Nevertheless, current defibrillation techniques have significant drawbacks. Shocks can be detrimental by causing pain, tissue damage, and reinducing arrhythmias.1 In addition, shocks may fail, which requires multiple shock application,2 or fibrillation can be terminated but normal heartbeat and blood circulation not restored.3'4 Therefore, there is a need to increase defibrillation efficacy and reduce its side effects, which underlies the continuing search for better defibrillation techniques. This search would have higher chances for success if it were guided by the exact knowledge of the defibrillation mechanism. Significant advances in understanding defibrillation were made in recent years using sophisticated electrical and optical mapping techniques as well as advanced mathematical models of cardiac excitation that provided a wealth of new information about the effects of electrical fields on cardiac tissue. Despite these efforts the defibrillation mechanism still remains a mystery. One of the main unresolved questions is why an electrical shock causes any significant effect on the heart at all; the other question is how exactly the shock affects the heart and stops abnormal electrical activity. Fibrillation is generally considered a distributed process, which is maintained by multiple reentrant circuits or randomly wandering wavelets in various parts of the heart.5-7 To interrupt such fibrillation, all reentrant wavefronts have to be extinguished. According to the "excitatory" hypothesis of defibrillation, this is achieved by simultaneous activation of cardiac tissue in the excitable and relatively refractory states.8'9 The newly depolarized tissue presents

Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA, [email protected]

I. R. Efimov et al. (eds.), Cardiac Bioelectric Therapy: Mechanisms and Practical Implications.

© Springer Science+Business Media, LLC 2009

functional obstacles to excitation waves, blocking their propagation and, therefore, arresting fibrillation. An important requirement of defibrillation is that abnormal activity must be stopped in a critical mass of ventricular myocardium estimated at 80-90% of the total mass.9'10 This means that the shock must change membrane potential (Vm) of nearly all cardiac cells across the ventricular wall. How this global shock effect is achieved is not presently known. The classical cable model of cardiac muscle indicates that shock-induced Vm changes should be restricted only to the tissue near shock electrodes or muscle surface,11 leaving the intramural bulk of the myocardium unaffected by the shock. This model's prediction about the locality of shock effects is in stark contradiction with the distributed nature of fibrillation. This contradiction was recognized about 20 years ago.12-14 To resolve it, a so-called secondary source hypothesis was proposed, which linked shock effects with the microscopic tissue structure. More specifically, it was postulated that shocks cause widespread changes of Vm due to numerous microscopic discontinuities in the tissue structure, such as cell boundaries.12-14

The hypothesis of microscopic secondary sources still remains unproven. Direct experimental verification of this hypothesis in the heart faces several obstacles. First, it requires measurement of Vm in the intramural myocardium with microscopic resolution, but such methods are not currently available. Second, even if microscopic Vm measurements were possible, interpretation of such data would be difficult because of the structural complexity of cardiac muscle, which contains discontinuities at different spatial scales. To circumvent these limitations, we adopted an indirect approach consisting of two main elements. The first element of this approach is to determine the effects of shocks on Vm in two-dimensional monolayers of cultured myocytes. The use of cell cultures allows for optical mapping of Vm with microscopic resolution. In addition, the structure of cell cultures can be controlled and modified using the techniques of patterned cell growth, which makes possible investigation of the contributions of individual structural elements into the shock effects. The second element of this approach is to measure the effects of shocks on intramural Vm at macroscopic resolution in isolated wedge preparations of left ventricular muscle. These measurements are then compared with the spatially averaged data obtained in microscopic studies of shock effects in cell cultures. This chapter describes results of experiments of both types and analyzes their similarities and differences. This analysis supports the important role of tissue structure in defibrillation and provides evidence that intramural secondary sources are caused by tissue discontinuities with microscopic dimensions.

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