Unraveling the genetics and mechanisms of cardiac arrhythmia

In this issue of the PNAS, Papadatos et al. (1) analyze the mechanism of arrhythmia in the heart after targeted disruption of the cardiac sodium channel, Scn5a. They combine a wide variety of techniques (including genetic deletion, cellular electrophysiology, morphology, and electrocardiography) in an integrated approach to unravel the sequence of events all of the way from the genetic to the whole organism level. They are therefore able to show that the effect of the deletion is to reduce the ionic current carried by sodium channels, so that the propagation among cardiac cells is slowed. This slowing generates arrhythmia because it allows more time for a wavefront to encounter cells that are reexcitable before the wavefront dies out. A sustained rapid reentrant circuit can then be established. This is called a tachycardia and can be fatal. The range of techniques used in this work is unusual. But such large-scale integrative work, involving several laboratories and therefore a substantial list of authors, is necessary if we are to connect genetics to cell, system, and whole-organ physiology. The reason is that there are many levels of organization among genes and their effects on organs and systems, including feedback on gene activation and expression from the higher levels. The mechanisms of a disease state may require detailed understanding at any one (and usually more than one) of these levels. Cardiac arrhythmia is a good example. First, because there are known mechanisms at several different levels—subcellular, cellular, and multicellular. The arrhythmia analyzed by Papadatos et al. (1) depends on slowed conduction between cardiac cells and necessarily requires study at the level of the whole organ to complement that at the gene and cellular levels. Second, because the genetic bases of a substantial number of cardiac arrhythmias are beginning to be understood (2). Thus, Clancy …