Grant: Project Grant

As many as 1/100 people have a genetic variant called TTNtv. TTNtv affects a large protein that helps the heart to beat. Some kinds of inherited structural heart disease are commonly found in people with TTNtv, and these affect males and females differently. We lack a detailed understanding of why people with TTNtv are more likely to develop these heart diseases. But, we do know they are more likely to first develop heart rhythm problems. Heart rhythm problems are also a common side effect of many drugs. To test for these drug effects, scientists use heart tissues that can be grown in the lab. New drugs are not approved for use if they cause rhythm problems in the heart tissues. Yet, drugs are not currently tested for differences between sexes, nor for TTNtv. We will test drugs using engineered heart tissues (EHTs) from TTNtv carriers of both sexes. Using EHTs, we can measure many different responses, including gene signatures, electrical signals, and contraction. We have already found differences between tissues with or without TTNtv, and between male and female tissues. To test the idea that drugs may trigger symptoms in TTNtv carriers, we will expose the different tissues to drugs known to cause heart rhythm problems, and determine whether the drugs affect the tissues differently, or at different doses. In TTNtv tissues, we may see differences when we test drugs that are not known to cause heart rhythm defects. This would indicate which drugs should be avoided by TTNtv carriers. The data we collect will inform computer simulations of the heart, which will help us predict other things to test or measure. We will also use the EHTs and tools we develop to discover new drugs that might help prevent the differences specific to tissues with TTNtv. This could lead to treatments for future patients at risk of heart rhythm disease or heart failure.