Atrial fibrillation is estimated to affect around 6 million people in Europe, making it the most common arrhythmia observed in the clinic. The irregular heartbeat and disturbed electrical activity experienced by atrial fibrillation patients is commonly treated by surgical interventions such as pacemakers or the ablation of diseased tissue, or with non-selective class IC (Nav) and III (Kv) ion channel anti-arrhythmic drugs. However, these approaches can have serious side-effects, so extensive research has been devoted to better understand the cellular mechanisms behind the disease to develop safer and more effective treatments.
Unfortunately, drug discovery efforts underpinned by traditional preclinical animal and non-cardiac cell models of atrial fibrillation have achieved limited success in realising this goal. One major contributing factor is that these systems often do not reliably replicate the physiology of human atrial cardiomyocytes. Alternative models employing human atrial cardiomyocyte primary cells offer more potential. However, the viability and yield of live cells from human hearts is low, and studies can only be performed using limited amounts of material. What’s more, native human tissue typically comes from diseased donors and is often very fibrous – and therefore challenging to work with.
Human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocytes can often be a better solution. They offer a powerful model system for atrial fibrillation drug discovery and disease modelling thanks to three key benefits:
• They provide insights that are more translationally relevant
• They deliver more consistent results
• They are easier to use from a practical standpoint
Here, we consider how each of these advantages is helping to accelerate the delivery of innovative anti-arrhythmic drugs to patients (you can also learn more by downloading our whitepaper on this topic).
In this article:
- iPSC-derived atrial cardiomyocytes offer more physiologically relevant insight
- iPSC-derived atrial cardiomyocytes deliver more consistent results
- iPSC-derived atrial cardiomyocytes are easier to handle
- A robust platform for disease modelling and drug discovery
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iPSC-derived atrial cardiomyocytes offer more physiologically relevant insight
In many areas of human disease modelling and drug discovery, the translation of findings and predictions from test systems to patients is in urgent need of improvement. iPSC-derived cells can help with this challenge, as they can be used to create models that more faithfully reflect native human cells and tissues when compared to in vitro and animal in vivo systems. This helps to minimise the potential for unexpected side-effects and reduce rates of attrition.
In this way, human iPSC-derived atrial cardiomyocytes are an ideal platform for modelling atrial fibrillation, as they exhibit all of the physiological characteristics of native human atrial cells. Our team has developed a line of iPSC-derived atrial cardiomyocytes that can be used as a robust platform to support drug discovery in this area. The cells were created from iPSCs using footprint-free episomal reprogramming methods via the addition of specific differentiation factors at critical time points to drive atrial fate.
iPSC-derived atrial cardiomyocytes like these possess key genotypic and phenotypic features that make them a translationally useful in vitro system for reliable atrial fibrillation disease modelling and ion channel target drug discovery. Biophysical and pharmacological characterisation studies of these cells have demonstrated that they display a full range of functional properties associated with healthy atrial cardiomyocytes, including physiologically relevant action potential parameters (Figure 1). For the full details on these characterisation studies, download our whitepaper here.
Figure 1: Atrial-specific ion channel pharmacology of iPSC-derived cardiomyocytes. Manual patch current clamp recordings of spontaneous action potentials (APs) reveal characteristic effects of selective modulators of (A) IKur (50 μM 4-AP) and (B) IKACh channels (1 μM carbachol) known to be selectively expressed in human atria. Data generated in collaboration with Metrion Biosciences.
iPSC-derived atrial cardiomyocytes deliver more consistent results
For atrial cardiomyocytes to be useful as translationally predictive and reliable models for disease research, consistency and reproducibility are essential. One of the biggest challenges associated with the use of native human cardiomyocytes is that the data generated can vary considerably. This variability results from intra- and inter-patient differences, as well as the effects of harsh isolation techniques on delicate cells and tissues. Consequently, larger samples are required to reveal significant treatment effects.
Instead, more consistent data can be obtained from in vitro iPSC-derived atrial cardiomyocyte assays, reducing costs and data delivery timelines, while also improving data quality and predictive power. Axol’s iPSC-derived atrial cardiomyocytes are generated from a young, healthy donor, which is not always the case when native human atrial cells are extracted from atrial fibrillation patients (who tend to be older and present with fibrous atrial appendages). Many of these patients are suffering from chronic disease and have been exposed to multiple drug treatments, further increasing the variability of their baseline data prior to compound screening.
The biophysical and pharmacological profiles of these human iPSC-derived atrial cardiomyocytes were also found to be very consistent between pilot batches and commercial scale-up materials, further reducing variability. As batch-to-batch reproducibility is essential when using cell reagents and assays for drug discovery screening and disease modelling, this high level of consistency makes them a reliable source of cells for both.
iPSC-derived atrial cardiomyocytes are easier to handle
Using native human atrial cardiomyocytes for disease modelling and drug discovery efforts can be challenging due to the complexities associated with sourcing, extracting and culturing primary cell lines. In contrast, human iPSC-derived atrial cardiomyocytes offer far greater convenience and ease of use.
One of the biggest advantages offered by human iPSC-derived models is the ease of which cells can be sourced – either by the rapid delivery of fresh cells or through the storage of frozen cells. This ready supply of consistent and reliable human iPSC-derived atrial cardiomyocytes allows researchers to use larger quantities of material from the same differentiation batch, helping to boost the statistical significance of experimental findings.
The convenience of sourcing iPSC-derived cells can also help to facilitate better planning and execution of experiments, accelerating the delivery of screening data against tight timelines, for example. The robust phenotype of Axol’s human iPSC-derived atrial cardiomyocytes supports the complex experiments necessary to align iPSC data with native tissue data, as well as more traditional screening experiments performed using industry-standard, plate-based assay platforms.
A robust platform for disease modelling and drug discovery
iPSC-derived atrial cardiomyocytes are a highly consistent and translationally useful platform for disease modelling, capable of supporting a wide range of drug discovery applications. By overcoming many of the limitations associated with traditional native human cell lines and non-human animal models, iPSC-derived atrial cardiomyocytes are set to unlock a wealth of opportunities for atrial fibrillation researchers.
Download the whitepaper (developed in collaboration with Metrion Biosciences) to learn more about how our validated iPSC-derived atrial cardiomyocytes could help your research.download the whitepaper