Advances in the treatment of heart disease

This article has been originally published on the website of the Hasso Plattner Institute.

In a large-scale analysis of Finnish and British health data, Henrike Heyne, Julian Wanner, and other researchers discovered that the T220I gene variant has a similar effect to a heart medication – in other words, it acts as if the variant carriers were taking the medication throughout their lives. By examining the gene variant, the effect of the drug can also be better understood – without the need for costly clinical trials.

The study has now been published in the American Heart Association's journal Circulation.  

Dr. Heyne explains: "T220I causes the replacement of an amino acid in a protein that acts as a sodium channel in the cell membrane, almost exclusively in the heart, where it plays a crucial role in our heart rhythm. T220I causes a mild blockade of this channel and thus acts like a lifelong sodium channel blocker, an established heart medication."  

People who carry this gene variant are ‘naturally’ more protected against cardiac arrhythmias such as atrial and ventricular fibrillation, in which the heart beats too fast. At the same time, however, they also experience similar "side effects" to those associated with taking the drug: they have more frequent cardiac arrhythmias, which cause the heart to beat too slowly, and also similar changes in the ECG (i.e., the electrical activity of the heart).  

This makes the T220I gene variant a so-called genetic proxy for the heart medication. This means that it is a kind of natural experiment, simulating lifelong use of the drug. Researchers can use the collected health data of people with this gene variant to investigate how the variant works under different conditions and in different life situations, and thus draw conclusions about the effect of the drug. This can be done solely on the basis of data that has already been collected, without the need for a new drug study.  

This is made possible by large biobanks such as UK Biobank and the FinnGen project. The FinnGen project stores the genetic and health data of 10% of the Finnish population. Digital data collection and the willingness of many Finnish citizens to make their data available for research purposes have resulted in a comprehensive database that enables extensive and long-term data studies. As part of the FinnGen project, Dr. Heyne's team had access to the health data of more than 500,000 people, of whom about 5,000 carried the gene variant.  

"We can gain new insights into the effects and potential applications of sodium channel blockers without having to conduct an ethically questionable clinical trial," says Dr. Heyne, explaining the advantages of analyzing such a genetic proxy. Overall, people with T220I, for example, are less likely to die from cardiac arrhythmias than people who do not have this gene variant. And variant carriers are also protected from various forms of heart failure.  

"However, our data also shows that carriers of T220I are more likely to die after a heart attack. This recapitulates a clinical study (1991) that found that sodium channel blockers also led to an increased mortality rate after heart attacks and therefore had to be discontinued prematurely. It would therefore be ethically impossible to conduct a similar study again. Instead, we can look at the “natural experiment” and track the effects of genetic sodium channel blockade after a heart attack over a long period of time," Dr. Heyne explains.  

The study confirms a hypothesis that Dr. Heyne had already formed in an earlier, much smaller study on T220I. At that time, Dr. Heyne discovered that carriers of the gene variant are only half as likely to have atrial fibrillation as the rest of the population. However, the data set was still too small to make reliable statements about other aspects of the variant.  

In their current paper, the team worked with a cohort from the FinnGen project that was three times larger and was able to not only confirm the function of the gene variant as a genetic proxy, but also derive further insights for the field of cardiology.  

In the future, these findings could also be used to optimize the heart medication itself. The data study by Dr. Heyne, Julian Wanner, and their team thus paves the way for important advances in the treatment of cardiac arrhythmias.  

The study was funded by the German Research Foundation. Other scientists from Finland, the US, and the Netherlands were also involved in the study.  

The entire paper can be read here: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.125.075057