Table 1.

Nonclinical and clinical models used to evaluate cardiotoxicity potential of drugs and chemicals.

	Strengths	Limitations
In silico predictions [26, 27]	No experimentation needed after the model has been developed Rapid prediction of potential adverse effects	Most available models are focused on hERG blockade Limited domain of applicability for environmental chemicals
Ion channel assays [30]	Provide direct mechanistic data on ion channel function Large database(s) and broad familiarity with the methods	Challenges in identifying complex interactions Generally labor-intensive Inter-lab reproducibility is low
Microelectrode array (MEA) field potential measurements [148]	Assay of the electric current that is an integrator of the activity of multiple ion channels Cells can be paced to different beat rates	Low throughput (generally up to 24- or 48-well formats) Large number of cells are needed
Measurement of intracellular Ca2+ dynamics [51, 52]	High-throughput assay formats (up to 384-well plate format) Highly sensitive read outs High-content data outputs	Fluorescent dyes are cytotoxic to cells (i.e., terminal assay) Specialized imaging equipment is needed
Tissue slices [34]	A biomimetic culture system that preserves cellular architecture Available from humans and animals	Specialized expertise is needed Limited availability of high-quality human heart tissue
Tissue chips [36]	Ability to recapitulate complex tissue on a chip in 3D Enables assays of contractility	Rapidly evolving technology with few standardized platforms Special expertise/equipment needed
Zebrafish [149, 150]	Model that allows studies of heart development	Human relevance is uncertain
Rodents [38]	Common pre-clinical species used for testing of both drugs and chemicals Availability of genetic models	Major differences in physiology and electrophysiology with humans Phenotyping is limited to pathology
Dog [40]	Common large pre-clinical species Extensive regulatory database	Ethical considerations High cost and low throughput
Swine [151, 152]	Commonly used for testing of cardiovascular devices (stents, valves, etc.)	Not as traditionally used as dogs Low throughput
Non-human primates [43]	Most human-relevant species Extensive regulatory database	Ethical considerations High cost and low throughput
Thorough QT/QTc (TQT) study [45]	Direct human evidence for QT prolongation risk	High cost and narrow focus on QT as only one possible cardiotoxicity