Reduction and integration in understanding the heart.

Abstract

The heart provides an excellent example of the limits of the reductive approach. Cardiac cells function through the interaction of a very large number of ion transporters, and the processes that link these to metabolic states and to contraction. Yet, the great majority of the advances made recently have been at the cellular and molecular levels. The pressing problem now is to begin to understand the highly complex interactions that create physiological function at a cellular level and, in turn, to understand the way in which large numbers of cells interact to produce the activity of the whole heart. Many kinds of arrhythmia, for example, can only be understood at the whole organ level. Successful interventions using drugs designed to treat cardiac disease depend on an integrative understanding, which at present we do not have. This is one of the reasons why clinical trials of drugs treating cardiac arrhythmias have been spectacularly disappointing. This paper illustrates some of these problems by analysing normal and abnormal heart rhythms, and by focusing on one particular transporter, the sodium-calcium exchanger, that is deeply involved both in normal calcium balance in the heart and in the generation of pathological states, including life-threatening arrhythmias. It will be shown that some surprising counterintuitive results appear when computations are done at an integrative level.