Cardiotoxicity is one of the leading causes of adverse health effects in patients, and therefore, drug failure. As drug development advances, there is a growing need for more reliable and accurate methods to assess cardiotoxicity early in the drug discovery process. Traditional in vitro models and animal testing methods often fall short in predicting human-specific cardiac responses. However, recent advancements in stem cell technology, particularly the use of human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, offer a groundbreaking solution for more accurate, non-invasive cardiotoxicity screening.

One of the most reliable approaches in this field is the use of base impedance measurement as an indicator of cell viability and function. This method allows for the real-time monitoring of cardiotoxicity over extended time periods, providing us with valuable insights into drug-induced heart damage and enabling safer, more effective therapeutic development.

Chronic cardiotoxicity assay: A novel approach to long-term screening for drug safety

Metrion has developed a chronic cardiotoxicity assay using hiPSC-derived cardiomyocytes that has been validated with a range of toxicant compounds. The assay takes advantage of base impedance measurements to assess both the structural and functional cardiotoxic effects of drug compounds over a prolonged period.

An important example of this assay’s application is the testing of doxorubicin, a chemotherapy drug widely used to treat various cancers, including breast cancer. While effective, doxorubicin is known to cause a range of severe cardiac side effects, including acute and chronic arrhythmias, cardiomyopathy, and congestive heart failure. These side effects often occur months or even years after treatment, making it challenging to assess the long-term cardiovascular risks associated with this drug using traditional models.

Our chronic cardiotoxicity assay recapitulates the known cardiotoxic effects of doxorubicin by producing a concentration-dependent decrease in base impedance following a 24-hour exposure period. This reduction in impedance reflects the functional and structural damage caused by the drug, which ultimately leads to compromised cardiomyocyte viability (Figure 1). By providing continuous, real-time monitoring of these changes, the assay offers a powerful tool for assessing the cumulative effects of doxorubicin over time and evaluating its potential cardiotoxic risks in a more human-relevant context.

The ability to mimic chronic cardiotoxicity in vitro offers a significant advantage over traditional acute assays, which may not fully capture the long-term effects of drugs on heart function. In addition, the assay is highly adaptable, allowing for the testing of a wide variety of compounds, including both known toxicants and new drug candidates. This flexibility makes it an invaluable tool for both early-stage drug screening and in-depth toxicological studies.

Base impedance: A highly sensitive indicator of drug-induced cardiotoxicity

Base impedance is a measure of the electrical resistance of living cells in response to an external signal. It is an important indicator of cell viability, cellular health, and overall function. Changes in base impedance can reflect alterations in cell morphology, membrane integrity, and the functionality of ion channels and transporters—key elements for maintaining healthy heart cells.

In the context of cardiotoxicity testing, base impedance offers a non-invasive and highly sensitive approach to detecting both structural and functional changes in cardiomyocytes over time. Traditional methods of assessing cardiotoxicity, such as histological analysis or conventional assays, can be invasive and may not capture the full spectrum of cardiotoxic effects, particularly in the early stages of drug exposure. Base impedance, on the other hand, allows for continuous, real-time monitoring of the cardiomyocyte response to test compounds, making it an ideal tool for chronic cardiotoxicity assays.

By measuring impedance changes in response to various test compounds, we can gain valuable insights into the drug's effects on cell viability, electrical activity, and overall heart function. The ability to detect these effects over a chronic time course allows for a deeper understanding of the long-term consequences of drug exposure on cardiac health.

We can assess compounds for such liabilities in hiPSC-CMs in a higher throughput 96-well plate-based format and continuously monitor impedance and for extended time periods in serum-free conditions.

The role of hiPSC-derived cardiomyocytes in cardiotoxicity testing to assess chronic drug-induced cardiac risk

hiPSCs are a powerful tool in modern biomedical research. These cells are derived from adult somatic cells and can be reprogrammed to a pluripotent state, enabling them to differentiate into virtually any cell type, including cardiomyocytes (heart muscle cells). hiPSC-derived cardiomyocytes provide a unique and highly relevant model for studying human-specific cardiac responses to drug exposure.

The use of hiPSC-derived cardiomyocytes in cardiotoxicity testing offers several advantages over traditional animal models. One of the most significant benefits is that these cells are genetically human, meaning they are far more representative of human cardiac physiology and pathology than animal-derived cells. This allows us to obtain more accurate predictions of how a drug may affect human heart tissue, reducing the risk of false positives or negatives that can arise from animal testing. This level of specificity and relevance is invaluable for drug developers seeking to identify potential cardiotoxicity risks early in the development process, ultimately leading to safer and more effective drugs.