In a paper published in the journal Circulation Research, Dr Christopher Toepfer and his team use a new technique to understand how genetic errors that contribute to a heart condition change the cells of the heart.
Charged particles of calcium control how hard the heart pumps throughout the millions of heartbeats in a person’s life, with more calcium inside a heart muscle cell causing it to contract harder. Calcium signals may be important in understanding cardiomyopathies, a group of heart muscle disease where the heart contracts too often and too hard, and which often run in families.
But so far, scientists have not had a good way to rapidly track this calcium flow through the heart’s cells.
So Chris Toepfer, Yiangos Psaras and Francesca Margara developed a new technique to rapidly and automatically track calcium flow in artificially generated human heart cells. The cells they worked on contained genetic errors altering calcium flow, and the team generated these human heart cells using a genetic engineering technology called CRISPR/Cas-9. This allowed them to introduce the exact mutation that is present in patients into their ‘model’ system.
The team found that a subset of genetic variants increased how quickly and how hard heart cells beat, a sign of inherited disease. These genetic variants all control how cardiac cells respond to calcium. This is a different mechanisms from previously studied cardiomyopathies.
Testing new drugs
The team tested the effects of Mavacamten, a new drug currently in clinical trials for treating cardiomyopathies where their functional analysis indicated an effect on calcium. They found that while the drug does provide some benefit to the altered human heart cells in a petri dish, it could not fully correct the abnormal patterns of calcium flow in the cells.
This finding is important as it identifies that Mavacamten may be useful in treating this disease, but that new drugs that directly target calcium will further help cardiomyopathy patients.
- Dr Christopher Toepfer
The team now plan to use this tool to study many more genetic changes that lead to cardiomyopathies, including screening new drugs to define new treatments for patients.
Importantly, the research team have made their technique available for free to other scientists. Their collaborators, Professors Blanca Rodriguez and Alfonso Bueno-Orovio at the Department of Computer Science at Oxford University are now planning to use the data generated by this tool to test new compounds ‘in silico’, using computer modeling.
Funding: Funded by Wellcome and the BHF.
Read the full paper.