When ADAMTS19 is Lost
Gene Defect Leads to Heart Valve Disease
Breathe in, breathe out. And: Ptshshsh. Ptshshsh. Ptshshsh. This, or something similar, is how our heartbeat sounds. The cardiovascular system is a subtle magical device. It supplies our organs and tissue with the necessary oxygen. For this purpose, two circulations work together: the pulmonary circulation, also referred to as small circulation, and the large, systemic circulation. They circulate simultaneously and are based on each other. In this connection, the four heart chambers play an important role. They have to open and close completely for the blood to flow in the right direction.
Good to Know
The Large and the Small Circulation
In the large circulation, the oxygenated blood accumulates in the left atrium. From here it is carried through the mitral valve and to the left heart chamber. The chamber then pumps the blood through the aortic valve and into the main artery (aorta). The aorta proceeds to transport the blood to the single somatic cells via the arteries, arterioles and capillaries, that is, the blood vessels leading away from the heart. Thus, the somatic cells are supplied with fresh oxygen. At this stage of the cardiovascular system, the blood gives off the oxygen to the somatic cells in the different organs, while, at the same time, taking up the carbon dioxide produced in the organs. The “used” deoxygenated blood is then taken to the right atrium of the heart by the venules, smaller and larger veins. The diastole takes it to the right heart chamber from there.
This is where the pulmonary circulation starts. During systole, the right heart chamber pumps the deoxygenated blood to the pulmonary artery. This happens simultaneously to the left heart chamber pumping the oxygenated blood to the aorta. The pulmonary artery branches out into smaller arteries and arterioles and, eventually, into capillaries. These cover the pulmonary alveoli like a delicate net. Within the pulmonary alveoli, gas exchange happens: The blood gives off carbon dioxide and takes in fresh oxygen. The oxygenated blood flows through the pulmonary veins and into the left atrium. From here, the two blood circulations start anew.collapse
A Leak in the System
If a heart valve does not open and close properly, this puts an increasing strain on both the heart and the cardiovascular system. The heart has to work harder and the oxygenation ceases to function properly. In such cases, breathing becomes more difficult and one reaches one’s maximum exercise capacity quite quickly. Valve disease can occur in young age and advanced age. They can develop as a result of bacterial infections and other heart disease such as a heart attack. In some cases, heart valve disease is congenital.
In a Nutshell
The Four Heart Valves
The heart has four heart valves. By opening and closing, they guide the blood flow within the cardiovascular system. The two atrioventricular valves are located between the atria and the chambers. Between the left atrium and the left heart chamber, you find the mitral valve. The tricuspid valve is located between the right atrium and the right heart chamber. So-called Semilunar valves are located between the chambers and the corresponding outflow vessels. Each Semilunar valve features three pockets. The pulmonary valve (right side) opens and closes between the right heart chamber and the aorta, while the aortic valve does the same between the left heart chamber and the aorta.collapse
Loss of a Gene Has Been Detected
Could there be a predisposition for such defects? This suggested itself after two children with heart valve disease each that occurred in two biologically related families had been identified by means of a genetic sample analysis. The analyses were conducted by researchers led by Marc-Phillip Hitz, who is the head of the work group on cardiogenetics (Arbeitsgruppe Kardiogenetik) at the Department of Congenital Heart Disease and Paediatric Cardiology at the Christian-Albrechts-Universität zu Kiel (CAU).
By analyzing the genotype of the family members, Marc-Phillip Hitz and his team were able to detect a loss of the gene ADAMTS19 in the genotype of the affected children. The findings were able to be reconstructed in a mouse experiment afterwards. After the gene ADAMTS19 had been blocked, the mice also developed heart valve disease. During the transfer of genotype information to the somatic cells, an increased activity could be shown and pathological changes occurred in the somatic cell structure of the heart valves. Both the heart valves’ tissue structure, as well as their interaction with blood pressure, were impaired.
New Prospects for Therapy Design
Heart valve disease can be cured easily and often without any surgery by implanting a new valve by means of a catheter. However, this intervention is no complete repair. This is why the scientists set their hopes in further research based on their results. “The new findings can be used in new studies focusing on the objective to positively influence the regulatory circuit that is impaired by the genetic defect,” Marc-Phillip Hitz says. This might allow for stopping the damage to the heart valves that progresses with age in those affected.
Scientific Details of the Study
In a joint paper with Professor Gregor Andelfinger (Montreal), the research group led by Professor Marc-Phillip Hitz published the results of their studies in the renowned journal “Nature Genetics” on December 16. Marc-Phillip Hitz is the head of the work group on cardiogenetics (Arbeitsgruppe Kardiogenetik) at the Department of Congenital Heart Disease and Paediatric Cardiology at the Christian-Albrechts-Universität zu Kiel (CAU). He is also an endowed professor at the German Centre for Cardiovascular Research (DZHK). Professor Gregor Andelfinger works at the Centre hospitalier Universitaire Sainte-Justine Sainte, Montreal (Canada).
Read the press release of the DZHK here.
Learn more about the study design, material and methods, as well as the background of the study:
Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.
Wünnemann F, Ta-Shma A, Preuss C, Leclerc S, van Vliet PP, Oneglia A, Thibeault M, Nordquist E, Lincoln J, Scharfenberg F, Becker-Pauly C, Hofmann P, Hoff K, Audain E, Kramer HH, Makalowski W, Nir A, Gerety SS, Hurles M, Comes J, Fournier A, Osinska H, Robins J, Pucéat M, MIBAVA Leducq Consortium principal investigators , Elpeleg O, Hitz MP, Andelfinger G,
Nature genetics 52, 1, 40-47, (2020). Show this publication on PubMed.