There has been a lot of research around cardiac muscle cells, especially human iPSC (induced pluripotent stem cells)- derived cardiomyocytes in the last few years. The advent of cellular reprogramming technology has transformed biomedical research as iPSC-derived cardiomyocytes hold great promise for in vitro disease modelling and drug screening.
Read our blog below to find out more about the building blocks of cardiac muscle i.e. cardiomyocytes and toxicity associated with them.
What are cardiomyocytes?
Cardiomyocytes, also called myocardiocytes, are cells that make up the heart or cardiac muscle. They are responsible for generating the contractile force in the heart required for circulation. They display two exceptional features that facilitate contractions: automaticity, the ability of a single cardiac cell to contract, and autorhythmicity– the ability of cardiac cells to synchronise their contractions.
Sometimes, cardiomyocytes undergo abnormal enlargement due to enduring demand for increased contractile force resulting in cardiac hypertrophy. If left untreated, cardiac hypertrophy can lead to heart failure, and eventually death. Another major problem with adult cardiomyocytes is their limited ability to repair themselves or to replace dead cells via cell division. Although some stem cells that remain within the heart continue to divide and replace dead cells, newly formed or repaired cells are seldom as efficient as the original ones. There is ongoing research to unlock the mechanism that generates new cells, including better understanding of pluripotent stem cells.
Cardiomyocyte toxicity and iPSC-derived cardiomyocytes:
Did you know that up to 90% of compounds that pass pre-clinical screening fail at clinical trial level, with cardiotoxicity accounting for 45% alone?
Drugs are imperative to cure, halt or prevent a disease, especially when the disease is as threatening as cancer. However, some drugs given to kill cancer cells or control other diseases can also damage cardiomyocytes and cause cardiomyocyte toxicity.
Cardiotoxicity has a growing relevance because of the global improvement in cancer management with subsequent adverse effects of chemotherapeutic agents on the heart. It is also a big industrial challenge as potentially toxic compounds place a multi-billion-dollar burden on the pharmaceutical industry. Between 1990 and 2001, eight non-cardiovascular drugs were withdrawn from clinical use at an estimated cost of $12 billion due to drug-induced arrhythmia. These drugs block the hERG (human Ether-à-go-go–Related Gene) potassium channels that have a critical role in the normal electrical activity of the heart. There is an argument that over-reliance on animal models to predict cardiotoxic effect of new drugs in humans contributed to this problem. The ICH (International Conference on Harmonisation) S7B recommends the use of in vitro assays to assess whether a compound and its metabolites block the potassium channel encoded by hERG. Therefore, development of highly predictive in vitro assays suitable for low/medium/high-throughput screening (HTS) is critical to reduce the prohibitive costs and inefficiencies associated with compound failure in the clinic.
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Recent work on iPSC is making an enormous impact on the drug discovery world, as it allows the development of novel approaches for pharmacology and toxicity testing. Development of iPSC technology further provides the opportunity to generate iPSC-derived cardiomyocytes from human material, enabling scientists to create their own human cellular models. This is particularly useful as cardiomyocytes from the same genetic background can now be used in multiple experiments. iPSC-derived cardiomyocytes are ideal for use in cardiotoxicity testing, drug validation, drug screening as well as metabolism studies and electrophysiology applications.
As described in this poster, we phenotypically screened three different sources of human iPSC-derived cardiomyocytes grown in either a classic 2D culture or on 3D aligned nanofibre plates. 3D cardiomyocytes were seen to be more effective for observing the potentially subtle changes in beat peak profile caused by pharmacological compounds. If you are interested in how we performed the study and our results, follow the link to our poster.
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