In Parts I and II of this article,* we discussed monogenic arrhythmic disorders. These are determined or favored by an inborn alteration and for the most part are characterized by a single genetic alteration. This has allowed the use of “paradigms”; namely, diseases, such as the long-QT syndrome (LQTS), in which it has been possible to trace specific mutations on ion channel genes to their electrophysiological consequences in the patient. Unfortunately for the practicing cardiologist, these “simple” diseases constitute only a small part of the clinical conditions associated with cardiac arrhythmias. The majority of cases affect patients in whom the arrhythmogenic substrate is complex. Indeed, the expression of the molecular systems responsible for normal and abnormal electrical activity vary significantly, depending on a variety of factors, including age, regional factors (type of cells, myocardial perfusion), and such underlying chronic diseases as cardiac hypertrophy, myocardial infarction, and heart failure. The study of this complex system of interacting molecular functions requires an approach somewhat different from that required to consider monogenic disease. Accordingly, in this section we discuss broader themes that are essential to understand the integration of gene expression, ion channel function, and cell coupling in multicellular networks as a first step toward the comprehension of more frequent and more complex arrhythmogenic conditions. ### Diversity of Gene Expression in the Heart Understanding cell-to-cell variability in the cardiac action potential shape and the mechanisms underlying impulse propagation is the key to understanding normal and abnormal cardiac electrophysiology. Much of this variability can be attributed to variability in the characteristics of individual ion currents whose integrated behavior determines the shape and duration of action potentials in individual cardiac cells, as well as to variability in cell-to-cell communications. Ion currents are now recognized to flow through specific pore-forming membrane proteins called ion channels. The first gene encoding an ion channel protein was …