A Clue to Congenital Heart Block
- Role of Hypoxia and cAMP in the Transdifferentiation of Human Fetal Cardiac Fibroblasts: Implications for Progression to Scarring in Autoimmune-Associated Congenital Heart Block
- Arthritis & Rheumatism, Volume 56, Number 12, December 2007, pp. 4120-4131
What is the topic?
Neonatal lupus is a condition that can occur when anti-SSA/Ro antibodies cross the placenta in pregnancy from the mother to her developing baby. Babies born to women who are positive for anti-SSA/Ro antibodies (even women who do not have lupus) are at greater risk for neonatal lupus, although this remains rare. A number of symptoms are seen in infants who are born with neonatal lupus, most commonly skin rashes or liver involvement, which go away over time as the infant’s own immune system develops, and the mother's antibodies are cleared from the baby’s system. Even more rarely, however, there is a potentially life-threatening heart condition that these babies can be born with, called congenital heart block (CHB). It is possible to diagnose this condition in the baby while it is still in the womb (usually in the second trimester of the pregnancy) by picking up an irregular heartbeat using a special kind of sonogram called a fetal echocardiogram. Early CHB may be reversible with treatment, but in the later stages a baby may require a pacemaker at the time of birth.
Just because a pregnant woman has anti-SSA/Ro antibodies does not automatically mean that her baby will develop CHB. In fact, the first offspring of only 2 percent of pregnant women who test positive for anti-SSA/Ro develop CHB; furthermore, in those women whose first babies did have CHB, there is only a 20 percent recurrence in future pregnancies. Also, when an anti-SSA/Ro mother has identical twins, more often one will develop CHB and the other will not. All of this evidence suggests that there are other additional factors besides anti-SSA/Ro that determine whether a baby will develop CHB.
What did the researchers hope to learn?
One important piece in the puzzle for the researchers in this study was the fact that CHB tissue has a lot of scarring; this was surprising because fetal tissue is supposed to heal without permanent scarring. They hoped that they could learn what was causing this scarring, and whether it could shed further light on the development of CHB. Previous work had led them to focus on the possibility that the heart cells were not receiving an adequate supply of oxygen, a condition called hypoxia.
Who was studied?
Studying changes at the cellular level that may be involved in CHB is especially challenging. Only a very small percentage of the cases of CHB result in the death of the fetus, and when death does occur, it is usually several weeks or more after the irregular heart beat that is characteristic of CHB is first detected. Tissue samples taken at that time may not accurately reflect the changes that brought on the abnormal rhythm.
The researchers in this study, however, had access to the hearts of two fetuses that died within days of showing the initial signs of CHB, one during the 20th week of the pregnancy and the other during the 22nd week. Tissue from these two hearts provided a picture of the state of the cells very close in time to the moment when the irregular heart beats were detected. They also had heart tissue from a fetus with no sign of CHB that had died at age 23 weeks.
In addition, the researchers obtained samples of cord blood from 67 babies whose mothers were positive for anti-SSA/Ro antibodies; 31 of these babies had CHB, while 36 did not. Cord blood is the baby’s blood that remains in the umbilical cord after the baby is delivered.
They also had heart tissue samples from seven other fetuses and both heart and lung tissue samples from three other fetuses. They treated cells from these tissues with chemicals that simulated the conditions that would occur if they did not receive a sufficient supply of oxygen in the womb. Following those treatments, the researchers used other techniques to get the treated cells to replicate over and over, to see if there were any changes after the exposure to low oxygen conditions.
How was the study conducted?
All of the work was done by examining cells and tissue samples with microscopes. Some of the cells were treated with chemicals to create changes similar to those that might occur under conditions of hypoxia in the womb. The cord blood was analyzed to measure the level of erythropoietin in the cells; because erythropoietin helps cells make use of oxygen, the researchers used increased levels of erythropoietin as a sign that the cells were not otherwise receiving enough oxygen, and therefore hypoxic.
What did the researchers find?
Examining the heart tissue from the 20- and 22-week-old fetuses with CHB, the researchers found cell types that cause scarring, and it appeared to have developed fairly recently, especially around the area of the heart that is responsible for regulating the heart rhythm. They also found chemicals in the tissue that are produced in reaction to hypoxia. The heart tissue from the 23-week-old fetus without CHB did not exhibit scarring, or signs of hypoxia.
The researchers used the heart and heart and lung tissues from the other fetuses to observe how the different tissues responded to hypoxic conditions. The fetal heart tissue showed changes in the activity of the cells, including making proteins associated with scarring. This was not found in the lung tissue, which continued to produce fetal cells that did not promote scarring.
Among the chemical changes that followed hypoxia in the heart tissue, the researchers found one compound was released that stimulated the production of cAMP, a chemical which helps to protect cells from producing scar tissue. However, it did not appear that even the higher levels of cAMP could fend off all of the scarring when CHB begins to develop.
The researchers noted significant differences in the levels of erythropoietin in the cord blood between infants born with CHD and those without, suggesting that the cells in the CHD infants were struggling, and needing more oxygen.
When they began this study, the researchers already had a theory of how CHB develops. They saw CHB resulting from a succession of immune response processes. One of those steps involved changes in heart tissue that would lead to the production of cells that cause scarring. The researchers see the findings of this study as supporting that theory, citing hypoxia as adding to the forces that cause scarring in fetal heart cells.
What were the limitations of the study?
The researchers for this study discuss some of the limitations of this study in their paper. Though this team of scientists was fortunate to obtain access to hearts of two rare fetuses that died soon after their CHB showed up, tissue samples from many more cases of CHB would need to be analyzed to see if their findings about hypoxia and scarring hold up.
What do the results mean for you?
Most women with lupus will deliver healthy babies. For the very small number of those with anti-SSA/Ro antibodies who are at risk for their baby developing neonatal lupus, CHB remains a concern, since, although it is rare, it can be life-threatening to the baby. This study offers an interesting perspective on what may be taking place to cause the baby’s abnormal heart rhythm, and contributes one more potentially important link in the progress towards defeating this complicated illness.
One biq question revolves around cause and effect: does the hypoxia cause the scarring of the heart tissue, or does the damaged tissue cause the heart to be unable to provide enough oxygen? And when does the damage occur? The change in the heart rhythm that indicates CHB may show up close to the 20th week of pregnancy, but that doesn’t mean the damage hadn’t begun weeks before. Also, the researchers don’t have the answer to why the increased cAMP doesn’t prevent the scarring, since that is one of its functions. Is it too little too late? Perhaps there is some damage to the heart that makes it unresponsive to cAMP. These and other questions will probably remain unresolved for some time, however, because of the difficulty in obtaining enough tissue samples from different cases when CHB is developing.