Human cardiac systems electrophysiology and arrhythmogenesis: iteration of experiment and computation

Abstract

Human cardiac electrophysiology (EP) is a unique system for computational modelling at multiple scales. Due to the complexity of the cardiac excitation sequence, coordinated activity must occur from the single channel to the entire myocardial syncytium. Thus, sophisticated computational algorithms have been developed to investigate cardiac EP at the level of ion channels, cardiomyocytes, multicellular tissues, and the whole heart. Although understanding of each functional level will ultimately be important to thoroughly understand mechanisms of physiology and disease, cardiac arrhythmias are expressly the product of cardiac tissue-containing enough cardiomyocytes to sustain a reentrant loop of activation. In addition, several properties of cardiac cellular EP, that are critical for arrhythmogenesis, are significantly altered by cell-to-cell coupling. However, relevant human cardiac EP data, upon which to develop or validate models at all scales, has been lacking. Thus, over several years, we have developed a paradigm for multiscale human heart physiology investigation and have recovered and studied over 300 human hearts. We have generated a rich experimental dataset, from which we better understand mechanisms of arrhythmia in human and can improve models of human cardiac EP. In addition, in collaboration with computational physiologists, we are developing a database for the deposition of human heart experimental data, including thorough experimental documentation. We anticipate that accessibility to this human heart dataset will further human EP computational investigations, as well as encourage greater data transparency within the field of cardiac EP.

Keywords: Human cardiac electrophysiology.

Figure 1

Tree map representations of the (A) IMW and (B) TNNP human cellular models, showing relative proportions of experimental data from specific species. Due to lack of EP data from non-failing human hearts, both models were generated based on a large fraction of non-human work. Experimental data proportions for each of these models were obtained from Niederer et al.

Figure 2

Multiscale human heart physiology programme distributions. Pie charts representing the distribution of recovered human hearts by (A) disease and (B) gender. (C) Chart representing the average number of hearts collected per month for the years spanning from 2007 to 2013. Points represent collection numbers for each individual month. Since initiation of the programme, number of hearts recovered has been increasing annually.

Figure 3

Structural representation of our multiscale human physiology database. Human heart data are identified based on heart number, and three overarching categories encapsulate the available data for each heart: (i) clinical, (ii) functional, and (iii) expression and morphology. For ease of locating data from specific heart regions, functional and expression and morphology data are indexed by anatomical chamber and experimental preparations for each chamber. For each of the experimental preparations, as highlighted by the pulmonary arteries example, several categories of data will be available, and the data will be accessible in formats ranging from processed data and to raw data arrays, with methodological details.