Actually, he always wanted to be both, says the Hamburg native: a pediatrician and a researcher. Because he wanted to help sick children and their parents in a very fundamental way, he ended up in human medicine after an excursion into biology, and from there into human genetics. In 2016, he and his team achieved a breakthrough in understanding the causes of congenital heart defects. This would not have been possible without the National Registry. We are curious to know how things are going on this basis and have actually reached him. On the road, of course.

Heart Explorer Magazine: Good afternoon, Professor Dr. Hitz, how nice that our phone call worked out. Where are you right now?

Marc-Phillip Hitz: I've just come from the laboratory in Kiel. We discussed our projects there this morning. And now I'm on my way to an event. But no problem. We can talk a bit before.

Heart Explorer Magazine: What are you working on right now?

Marc-Phillip Hitz: In addition to the clinical diagnostic sequencing of patients, we are investigating in Kiel which genes are involved in congenital heart defects and which gene alterations are more frequent in patients with severe congenital heart defects. We then test what these genes do in a suitable cell system, in zebrafish or in mice, to find out whether they are actually the cause of the occurrence of a congenital heart defect in humans.

All we know at this point is that there are certain genes that are associated with a certain type of congenital heart defect.

Heart Explorer Magazine: In this context, how significant is the research result you achieved in collaboration with the Wellcome Trust Sanger Institute? A few years ago you discovered three new genes involved in the development of complex heart defects.

Marc-Phillip Hitz: Right, that was the first part. Identifying the genes is the foundation. And now we are investigating in more detail in animal and cell models how and why these genes lead to congenital heart defects. This is not yet fully understood. We just know that certain genes are associated with congenital heart defects.

Heart Explorer Magazine: What is the role of the National Registry for Congenital Heart Defects in this kind of research results?

Marc-Phillip Hitz: Some of the most reliable evidence for disease-causing genes comes from genetic etiology research in large cohorts of patients. Without such a base of reliable and comparable data and samples from patients and their relatives, such studies would not be possible. The German cohort is one of the largest in the world and therefore of great importance. In addition, the National Registry is one of the few registries that covers the entire spectrum of congenital heart defects and heart disease in childhood and adolescence. However, our study is also the first time that the Competence Network for Congenital Heart Defects has conducted such a large genomic research project. We are still learning.

We could more quickly clinically validate our results and improve therapy accordingly.

Heart Explorer Magazine: In what way exactly? What should be improved?

Marc-Phillip Hitz: Currently, the data in the National Registry are collected for research purposes only. However, we also find changes that are clinically relevant for individual patients. For example, if we discover changes associated with cardiomyopathies, we should be able to reflect these findings. They have important consequences for patients and their families. They need to be monitored more closely. It may also be possible to intervene with medication.

Heart Explorer Magazine: That is why the National Registry asks the participating patients and their relatives for their consent to give feedback in such a case. Is that enough? Or do you think that clinical diagnostic evaluation should be carried out more systematically in parallel with genetic research?

Marc-Phillip Hitz: Well, our research must first be considered in isolation. But it is indeed necessary to establish a closer link between research and diagnostics. However, this should only happen if the changes in the genome are clinically relevant, i.e. if they have already been described as causative in other cohorts or in patients. Otherwise, studies in cell or animal models should clarify whether a causal relationship exists. In a second step, this investigation would then have to be repeated from a clinical diagnostic point of view in order to provide valid results for transfer to clinical practice.

Heart Explorer Magazine: And this translation process from research to practice could be accelerated?

Marc-Phillip Hitz: Yes, if, in parallel to sequencing in the clinical diagnostic setting, we follow the changes in the family in real time by a so-called segregation analysis. In addition, a faster link with clinical and imaging methods would also allow us to obtain information on disease progression that should be followed up more closely in the clinical-diagnostic setting. This would be ideal. It would allow the validity of our results to be translated into clinical practice more quickly and therapy to be improved accordingly.

Only then can we figure out what is the best way forward for those affected.

Heart Explorer Magazine: Your research on the three genes at least provides important new clues for diagnostics.

Marc-Phillip Hitz: That's right. We found altered genes in patients with complex congenital heart defects. The next step was to find out whether these changes were already present in the parents or whether it was really a new mutation, in order to use this segregation to clearly show that only those who carry such a change also have this specific clinical picture. And if this is confirmed, as in this case, then such discoveries are relatively quickly transferred to diagnostics, i.e. primarily to human genetic diagnostics. And after they have been checked again from a clinical diagnostic point of view, they can then be used in clinical routine. In other words, it is only then that they are made available to patients from a clinical diagnostic point of view.

Heart Explorer Magazine: How common are such severe congenital heart defects caused by new mutations?

Marc-Phillip Hitz: We are talking about certain syndromic heart defects. These conditions are very rare, but overall syndromal heart defects affect about 15 to 20 percent of children with congenital heart defects. In our large cohort of 2,000 patients initially studied, specific alterations in the newly identified genes alone affected between three and seven patients, depending on the gene. Thus, the newly identified genes are found in well under one percent of patients. However, mutations in known and previously unknown genes that are thought to cause heart defects are also carried by the other patients. So you can imagine how important such registries are, because of course we need many different patients with such a gene mutation to get meaningful results. This is the only way how we can find out what is the best therapeutic approach for future patients. And that is what we want to make much more possible. We need studies like this to support patients by finding a good diagnosis.

The competence network offers ideal conditions for ethical, independent research with verifiable results.

Heart Explorer Magazine: That's probably why government funding of research is very important, also from an ethical point of view?

Marc-Phillip Hitz: Definitely, yes. Countries like the USA are way ahead of us in this respect. And we're not just talking about private funding, which is more established in Anglo-Saxon countries, but also government programs. This also applies to England. Germany has a lot of catching up to do in genetic research. This is also evident in the literature. When it comes to large-scale genetic studies, Germany is not a pioneer. There are projects that are starting to do this, such as the German Center for Cardiovascular Research. In most cases, however, the focus is on translational research. But translational research depends on fundamental insights into genetic processes. And the Competence Network for Congenital Heart Defects offers ideal conditions for this research, because it enables ethical, independent research with verifiable results in a network of patients, physicians, and scientists.

Heart Explorer Magazine: Wouldn't it be necessary to invest more in this network structure, in the research service and in the data and sample base of the National Registry?

Marc-Phillip Hitz: That would have to be done much more intensively. From the point of view of human geneticists, the modern next-generation sequencing methods, which are providing us with many new and important insights, are very expensive. Without sufficient samples, we will not be able to obtain results that justify the cost. And it's not as if the data available in the registry can only be used for patients with congenital heart defects. On the contrary. I think it is quite conceivable that these data could also usefully complement the database for sequencing in other areas of research in order to achieve individualized medicine in the future, for example in the neurosciences, but also in cancer research. There is a potential for synergies here that we in Germany are still not exploiting enough, probably also because our federal structure makes it difficult.

This is where research into congenital heart defects can open a door.

Heart Explorer Magazine: You talk about potential synergies. How do you see that in the area of heart disease alone? What about research into mechanisms that promote regeneration of the heart? Would that also give us a different therapeutic approach, for example in acquired heart disease?

Marc-Phillip Hitz: That is indeed an important aspect. In particular, research into congenital heart defects can open a door here, because an important aspect of our research is the question of how a heart is formed, how it develops. This is also used in particular in research with IPS cells, i.e. induced pluripotent stem cells, to produce cardiac cells. In this research, the heart development programs are used to induce differentiation into the corresponding cardiac cell types. This then plays an important role in regeneration, because it allows different cardiac cells to be produced in the laboratory or initiated in the living organism to intervene in regeneration and also degeneration processes.

Heart Explorer Magazine: What is the current state of research in this field?

Marc-Phillip Hitz: There are results that indicate a great therapeutic potential, i.e., that in the future it might be possible to save or regenerate heart tissue. The results help to better understand the regeneration of heart cells. However, it is not yet possible to say when and how this will actually be therapeutically applicable. In order to do so, it makes sense to first understand the mechanisms of heart formation, including heart malformations, in much greater detail and then to "replay" them in vivo, both in animal models and in cell models. This is certainly one of the most exciting aspects of adult cardiology. If, one day, we are able to regenerate cardiomyocytes, for example, that would be a major breakthrough for the heart health of many people.

Physicians must also be able to devote themselves to research.

Heart Explorer Magazine: The Competence Network is approaching the topic from many different angles. In addition to your research, there are projects such as the NEOMY study, which is investigating the mechanisms of microRNA in the myocardium to track regeneration processes in the heart of newborns and infants. How intensive is the exchange of information within this research network?

Marc-Phillip Hitz: Of course we do exchange, and that is the goal. It is also our goal to network even more closely for joint research. However, this requires corresponding financial resources, and these first have to be acquired. This is not something that can be done on the side. You also have to be able to show  corresponding publications. And the less time an individual physician has for research, the more difficult it becomes. That is another critical factor. Doctors have to be able to devote themselves to research. Many of my pediatric colleagues are forced to outsource their research in their spare time. This is the unfortunate rule in Germany. So, there is still a lot to be done to realize our full potential and help patients with congenital heart defects to have a much better prognosis.

Heart Explorer Magazine: Professor Hitz, that's a key word. Thank you very much for talking to us.