Mice uncover the secrets of Congenital Heart Defect

Every time your heart beats it pumps blood through the pulmonary artery and into your lungs where it soaks up oxygen before bring returned via the pulmonary vein to the heart, where the next beat pumps it out through the aorta and on to provide oxygen to all the tissues of your body.  All this is of course welcome to those of us who enjoy being alive, but there was one time in your life when such pulmonary circulation was a potential threat.  During fetal development the lungs are bathed in amniotic fluid and the body is supplied with oxygen via the placenta, and at this stage the pressure of blood being circulated through them would damage the delicate fetal lungs. Fortunately evolution has provided mammals with a means of avoiding this damage, a blood vessel called the ductus arteriosus which connects the pulmonary artery to the aorta, allowing most of the circulating blood to bypass the lungs.  As a baby takes its first breaths after birth the ductus arteriosus begins to close to allow normal pulmonary circulation to take place, a process that is normally complete within a few days. Unfortunately the ductus arteriosus does not always close, causing a condition known as Patent Ductus Arteriosus (PDA). If left untreated PDA can cause breathing difficulties and eventually lead to congestive heart failure, and is a particularly common and serious condition for preterm infants.  While it sometimes resolves itself with minimal intervention in many cases surgery is required to correct the fault.  Now research on mice has enabled scientists to uncover a key process in the closure of the ductus arteriosus that may show the way to less invasive treatments (1).

RA=right atrium, RV=right ventricle, PA=pulmonary artery, AO=aorta, LA=left atrium and LV=left ventricle

The team lead by  Dr Steffen Massberg and Dr Katrin Echtler in Munich knew from previous research that the closing of the ductus arteriosus was associated with the release of cytokines that are usually associated with the inflammatory response seen when tissue is damaged.  Knowing that such inflammatory responses recruit platelets, irregularly-shaped bodies produced by bone marrow cells that are crucial to blood clotting, to the damaged tissue they investigated the role of platelets in the closing of the ductus arteriosus. They decided to study the process in mice because the availability of a variety of tissue staining and genetic modification techniques which would allow them to study the whole process in great detail. They observed that within an hour of birth cells lining the ductus arteriosus were detached to provide attachment sited for platelets, and the platelets themselves quickly accumulated and soon formed a plug that stopped blood flow. They next used monoclonal antibodies and GM modification to remove two proteins that are required for platelet adhesion and activation, and found that the ductus arteriosus failed to close in the newborn mice, leading to the same problems seen in human babies with PDA.  The role of platelets was not confined to the initial blocking of the ductus arteriosus, Dr Echtler and her colleagues found that the platelets also attracted the specialized precursor cells that are required to remodel the ductus arteriosus and replace the temporary plug with a more permanent closure.

So it appears that platelets play a key role in the closure of the ductus arterious in mice, but what about humans?  While they could not study the process in the same detail in human babes as in mice they were able to obtain good evidence supporting a vital role for platelets in humans too.  First they examined samples of ductus arteriosus taken from newborn infants who had undergone heart surgery, and observed the same modifications to the lining of the ductus arteriosus  and platelet accumulation that they had seen in the mice.  They then studied a group of 123 premature infants and found a strong association between low platelet counts and PDA , further evidence that platelets are required for closure of the ductus arteriosus in humans just as they are in mice.

In an interview for the BBC stated that  “It is conceivable that transfusion of platelets reduces the risk of ductus arteriosus patency (lack of closure) in preterm newborns with low platelet count.”. We hope that he is right and that this discovery leads to a revolution in the treatment of PDA.  As for the question of where the platelets for such treatment will come from, that part is all up to you.


Paul Browne

1)    Echtler K. Et al “Platelets contribute to postnatal occlusion of the ductus arteriosus” Nature Medicine Published online: 6 December 2009 | doi:10.1038/nm.2060