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The ongoing journey to understand heart function through integrative modeling.

See related article, pages 1216–1224 

Cardiac electrophysiology is a field with a rich history of integrative modeling that has been coupled closely with design and interpretation of experiments. The first models of the cardiac action potential (AP)1 were developed shortly after the Hodgkin–Huxley model of the squid AP and were formulated to explain the experimental observation that, unlike neuronal APs, cardiac APs exhibit a long duration plateau phase. Over the subsequent 20 years, refinement of these models to incorporate emerging experimental data on properties of voltage-gated membrane currents, transport and exchange processes regulating intracellular ion concentrations, and mechanisms of calcium (Ca2+)-induced Ca2+-release (CICR) led to the first integrative model of the cardiac AP, the DiFrancesco–Noble model.2 This landmark model of the Purkinje fiber AP provided the electrophysiological community a mathematical framework on which to build, thus stimulating development of a broad range of integrative cardiac myocyte models. These now include models of canine, guinea pig, human and rabbit ventricular myocytes,3–8 sinoatrial node cells (for review, see Wilders et al9) and atrial myocytes.10,11

Recent research efforts have been directed at extending the range of biophysical and biochemical mechanisms included in these models to enhance their explanatory and predictive capabilities. Important areas of research include: (1) use of single-channel and whole cell current data, in combination with knowledge of channel protein structure, to develop continuous time Markov chain models of voltage-gated channels …