We wait for the director of the clinic. It is early in the morning. The child-friendly corridors of the Clinic for Pediatric Cardiology at Saarland University Hospital are suddenly buzzing with activity. But Hashim Abdul-Khaliq is not one to be disturbed. He takes his time for crying babies, screaming toddlers, and many worried parents.

An elementary school-aged boy has just left the pediatric cardiologist's office, beaming with joy, equipped with a fancy ultrasound image and the tools to perform a cardiological examination on his stuffed animal. Now Hashim Abdul-Khaliq has an emergency. He makes a quick apology and hurries off. We won't see him again until the evening, in the human genetics research lab at Saarland University.

Heart Explorer Magazine: Dr. Abdul-Khaliq, it's been a long day. Did you just come from an emergency?

Hashim Abdul-Khaliq: Not exactly. I've just come from the cardiac catheterization lab. We had a patient with a very complex anatomical congenital heart defect, heterotaxy, single-ventricle heart, and deteriorating Fontan circulation. Fortunately, we were able to remove the stenosis in the pulmonary vessels by cardiac catheterization. This is nowadays an excellent, very gentle method to treat these children after complex surgery.

Heart Explorer Magazine: Before we talk to you about research and the Competence Network: We sat outside your office for a while this morning. One by one, children and their parents were called into your room. It was very busy. And they all came out happy. How are you, we asked one of your little patients. His immediate response: "Well, great!!!" How do you do that?

It's not all optimal. We need to do more research.

Hashim Abdul-Khaliq: We see many newborns, infants, and toddlers with simple to very severe congenital heart defects. And when we experience how, after successful treatment, they first go to kindergarten, then to school, and finally growing up and playing with us, it makes us very happy. It gives us a lot of energy for our daily work. It also drives us to stay on the ball, both clinically and in research. We do our research in addition to our clinical work, so mostly in our spare time. And without this motivation that we can do so much for these children today, and especially that we have to do so much, it just wouldn't be possible. Not everything is optimal yet. We have to continue to do research so that these patients can survive better and have a good quality of life.

Heart Explorer Magazine: It is said that ninety percent of children have a healthy heart after successful surgery and can lead a normal life. Is that true?

With the very complex heart defects, you can't talk about a cure.

Hashim Abdul-Khaliq: First of all, it is encouraging that most children today survive. This has even improved significantly over the last 15 years. And they can lead a fairly normal life. However, in the case of very complex heart defects, there is no such thing as a cure. Many moderate and severe heart defects can only be treated palliatively. This means that these patients often require a variety of follow-up treatments and lifelong monitoring, even into adulthood.

Heart Explorer Magazine: What does this mean in everday clinical practice?

Hashim Abdul-Khaliq: We spend about half of our time with these chronically ill children. Patients who have a single-ventricle heart and therefore a Fontan circulation cannot be cured anatomically. Many problems can occur over the course of the disease and in later life. The same applies to children with a biovalve in the pulmonary position, i.e. in relation to the pulmonary artery. They have to be monitored medically and at some point, that valve has to be replaced. Nowadays, this can often be done very well by cardiac catheterization.

Heart Explorer Magazine: What about milder heart defects?

Hashim Abdul-Khaliq: Most of these heart defects can be treated very well by surgery or catheterization. There's a study that's just been published from Denmark, a registry-based study - so you can see how important a registry at the national level is: this study showed that patients with mild congenital heart defects had significantly more heart problems fifty years after treatment than the rest of the population. The spectrum ranged all the way to sudden cardiac death. This means that even a patient with a ventricular septal defect or an atrial septal defect, for example, should have continuous medical monitoring.

If we didn't have the National Registry for Congenital Heart Defects, we'd have to invent it.

Heart Explorer Magazine: You just mentioned the importance of registry research for such findings.

Hashim Abdul-Khaliq: Each patient with their respective cardiac and vascular abnormalities is individual, each clinical picture is unique. We see so many patients who have the same heart defect and yet their course of the disease is different. In addition, we have a very broad spectrum of cardiac and vascular malformations. It is not as easy to form a cohort of patients for the research that is urgently needed as it is, for example, in adult medicine with arterial hypertension or coronary artery disease. This is why it is so important to enroll patients in the National Registry. With the National Registry, we can form such cohorts to investigate important questions about long-term outcomes and conduct appropriate studies. To make real progress in the quality of life of patients, we also need to be able to follow and analyze the health of patients for 30, 40, 50 years. So if we didn't have the National Registry for Congenital Heart Defects in Germany, we would have to invent it.

It is imperative that we continue on this path.

Heart Explorer Magazine: What is the role of such registries for international science?

Hashim Abdul-Khaliq: An immense role. Especially in our field of research, we depend on both national and international collaborations. Here in Germany, we were recently involved in a large international collaborative project. And what was the result? Excellent studies and publications, such as a Nature paper on basic research into syndromic and non-syndromic heart defects. And I think this is the way we need to continue.

Heart Explorer Magazine: What makes the National Registry so attractive?

Hashim Abdul-Khaliq: The researchers we work with appreciate that our samples are collected and maintained to high standards, that the clinical pictures are optimally characterized, and that the patients are accurately phenotyped. After all, as I said, the patients not only have tetralogy of Fallot or transposition of the great arteries, but also many extracardiac anomalies. It is extremely important to record not only the clinical picture but also the extracardiac anomalies and diseases and to process everything precisely, for example for genetic studies. And this is the case with the National Registry. The individual researchers are greatly relieved by the reliable basic work and can therefore concentrate fully on their research. All this makes our data and samples interesting for research groups in England and the USA.

The 'incidental findings' of the PAN study were highly interesting.

Heart Explorer Magazine: You mentioned the publication of the newly discovered genes in Nature Genetics. Looking back on the past years since the foundation of the Competence Network in 2003: What other outstanding study results do you see? Where, for example, has there been a direct transfer into practice?

Hashim Abdul-Khaliq: We have both clinical and genetic studies that are very important. The first clinical study was the PAN study on the prevalence of congenital heart defects in Germany. While the results on the distribution of congenital heart defects were not spectacular in themselves, they statistically confirmed what we already knew, based on a large national cohort. However, the "secondary findings" of this study were very interesting. One of them had to do with prenatal and postnatal screening. It became clear that many heart defects were not detected early enough for optimal treatment. Together with the German Society for Children with Heart Diseases and the German Society for Pediatric Cardiology and Congenital Heart Defects, we initiated the establishment of pulse oximetry as a screening method on the basis of the study results.

Heart Explorer Magazine: As a result, the pulse oximetry screening has found its way into postnatal screening?

Hashim Abdul-Khaliq: Yes, exactly. Since January 2017, it has finally become a mandatory part of the U1/U2. Point two: We were able to gain new insights into the association of congenital heart defects with preterm birth, twin births, and the age of the mothers at the time of pregnancy. As a result, we conducted a twin study in the Competence Network. The first results of this study show that congenital heart defects are significantly more common in children conceived by assisted reproductive techniques, such as in vitro fertilization or other fertilization methods. We will need to follow up and study this further in a large group of children nationwide. However, we can already see that the development of congenital heart defects may also be favored by certain environmental factors. We need to look more closely at these epigenetic correlations in the future.

Heart Explorer Magazine: Is there a link between in vitro fertilization and congenital heart defects?

Hashim Abdul-Khaliq: There are indications of that, yes.

Heart Explorer Magazine: What would be the consequence then, would it be better to avoid artificially induced pregnancy?

Hashim Abdul-Khaliq: Well, it's not that we have to say "hands off artificial insemination".  Rather, we believe that DNA damage is promoted by the procedure itself, and that it would be sufficient to improve the procedure.

Research in heart failure in children is still very new.

Heart Explorer Magazine: What are you currently researching in these rooms?

Hashim Abdul-Khaliq: We are in the Institute of Human Genetics. We work closely with Professor Meese and his colleagues.  Our research focus is the investigation of microRNA. In the past, microRNAs were not given much attention. But we now know that they play a role in turning genes on and off in both normal and pathological processes in the body. We are now analyzing microRNAs in the blood of children with different congenital heart defects. We have analyzed microRNA in the myocardium, the heart tissue of the children, before and after corrective surgery, with very interesting results that point to specific mechanisms of regeneration. This is a crucial aspect that we will now pursue in the Competence Network for Congenital Heart Defects.

Heart Explorer Magazine: Can you explain these mechanisms to us laymen?

Hashim Abdul-Khaliq: Yes, of course, I hadn't thought about that. In the heart muscle cell, as in all other cells in the body, many complex biological and biochemical processes take place. If these biological processes are disturbed, for example by a stressful situation, such as a lack of oxygen, or by corrective surgery where the heart is stopped due to hypothermia, then you can imagine that the processes in the cell will change.

Heart Explorer Magazine: And these changes can be observed?

Hashim Abdul-Khaliq: Yes, we are looking and analyzing which mechanisms or which microRNAs are important for the recovery, for the repair, for the regeneration of heart muscle cells after surgery using the heart-lung machine. In other words, we are trying to understand and characterize these processes. Research into heart failure in infants and newborns is still very new. There are hardly any research groups working on it, unlike research on heart disease acquired in adulthood. We want to find out what happens in the heart before and after surgery, before and after the use of the heart-lung machine. Not only histologically, but also in terms of molecular genetics. For example, microRNAs, which are involved in many signaling processes, are already important. We can now analyze these processes using a clinical model that we have developed. On this basis, we are now planning another larger study with the registry´s biobank at the Competence Network's.

I firmly believe that we can make a big difference in the future of cardiac medicine.

Heart Explorer Magazine: Is this the way to find out how the human body can repair its own heart? Recently, there has been a lot of talk about the zebrafish as a model that actually manage to do this.

Hashim Abdul-Khaliq: Yes, zebrafish and also fetal and neonatal mice have been studied very extensively in terms of myocardial regeneration. For a long time, it was thought that the mature heart muscle cell no longer divides. We now know that this is not entirely true. What is certain is that the cell's ability to divide and replicate is maintained for some time after birth. And we now also know from human fetuses and newborns that this regenerative ability of the heart muscle is still guaranteed by cell division

Heart Explorer Magazine: How do you deduce this?

Hashim Abdul-Khaliq: We have seen from the first analyzed samples of newborns after corrective surgery that newborns still have a significantly higher regenerative capacity than infants after the third month of life. After the stress of complex corrective surgery with cardiac arrest in deep hypothermia, the stem cells responsible for this were significantly increased in newborns, whereas they were comparatively decreased in the older children.

Heart Explorer Magazine: What are the implications for the future?

Hashim Abdul-Khaliq: I firmly believe that by studying myocardial regeneration in the neonatal period, we can do a lot for the future of cardiac medicine in childhood and adulthood. Our research also has an interesting interface with research projects in adult cardiology.

Heart Explorer Magazine: What could research into regenerative mechanisms mean for patients one day?

Hashim Abdul-Khaliq: That is still a long way off. First , we need to further explore and better understand the mechanisms of cardiac cell damage and regeneration in children and especially in neonates. But if we could take stem cells from every heart that is operated on in newborns and use them to regenerate the heart of that child or any other child or adult, that would be a wonderful future.

Heart Explorer Magazine: I guess it is going to be a very long time before that happens?

Hashim Abdul-Khaliq: This future is not too far away. There is already published work from Japan on this topic. They took samples from patients with hypoplastic left heart syndrome, regenerated stem cells, and then put these stem cells back into the children through the coronary artery using a cardiac catheter. The single-ventricle hearts of these children recovered significantly. So, we definitely need to continue to do research in this area. We have the infrastructure, we have the biobank, multicenter research within the Competence Network for Congenital Heart Defects is now established in Germany. If we can genetically characterize every heart defect, every child who has undergone heart surgery in the neonatal period, with regard to regeneration and perhaps regenerate stem cells from this heart, then this could be of considerable importance for the long-term quality of life of these children.

It's still all too easy for our patients' problems to get lost among the more common acquired heart conditions.

Heart Explorer Magazine: What do you see as the biggest hurdles for collaborative research on this path?

Hashim Abdul-Khaliq: There are a few. But I think we are basically on the right track. On the one hand, many institutions are working together in the competence network with its national registry and biobank. We are pleased that all pediatric heart centers are now participating in our research network. This is a great success. We are reaching a very large number of physicians, children, and parents, as well as adult patients with congenital heart defects. This is a really good foundation for the future. On the other hand, we are grateful for the start-up funding from the federal government, which provided significant financial support for the Competence Network until 2014, as well as for many private donations and support from the private sector and individual children's heart foundations. Since 2015, we have received substantial funding from the German Center for Cardiovascular Research. But this is not a matter of course. Just recently, we had to fight hard for continued funding of the research network for 2019. In view of our position in the international research landscape, we urgently need a solution to reliably secure the further development of our research infrastructure and collaborative research in the long-term.

Heart Explorer Magazine: Shouldn't that be a given? What makes it so difficult?

Hashim Abdul-Khaliq: There are very small patient populations with rare cardiovascular diseases in congenital heart disease. This makes researching very costly. Many companies are reluctant to fund such studies. The importance of researching small hearts for patients with acquired cardiac defects is often underestimated. The problems of our patients are still all too easily overlooked alongside the widespread acquired heart diseases. This is even reflected in legislation. Without government-funded research and targeted research incentives for pharmaceutical and medical device companies, we are failing these patients. This is neither scientifically nor ethically justifiable. With the Competence Network, we have built a very valuable house for the future. We must continue to design and maintain this house. Anything else would be irresponsible.

Heart Explorer Magazine: Professor Abdul-Khaliq, thank you very much for this interview.