The last 30 years have seen remarkable advances in the treatment of congenital heart disease. Some mild defects can be treated with drugs, holes in the heart can be covered with tiny patches, closed valves can be opened, and the major blood vessels near the heart can be rerouted. The risk of death from such surgery has fallen from 30 per cent in the 1970s to 5 per cent in most cases today. Even so, with about one in 125 children being born with a congential heart defect, many defects remain very serious and potentially lethal.

“A congenital cardiovascular defect occurs when the heart or great vessels fail to develop normally before birth,” says Professor Shoumo Bhattacharya, a cardiologist and Wellcome Trust Senior Research Fellow, and a member of Oxford’s Cardiovascular Research Initiative. “It’s a major challenge to understand how genes control heart development, and the genetic basis of congenital heart defects.”

In his research at the Wellcome Trust Centre for Human Genetics in Oxford, Professor Bhattacharya has found a gene, Cited2, which plays a key role in mouse heart development: interestingly, it seems to work by controlling the heart’s asymmetry.

Left–right pump

We may draw symmetrical ‘love hearts’, but the reality is very different. “Many parts of the body are not symmetrical,” points out Professor Bhattacharya. “The left lung of humans has two lobes, whereas the right lung has three lobes, for example. And the left and right sides of the heart are quite different because they have different roles – the heart is a parallel pump.”

Blood returns from the body to the right side of the heart, is pumped to the lungs to be oxygenated, and then goes to the left side of the heart to be pumped around the body. These two parallel circulation systems are physically separated by septa, or walls in the heart.

In the early embryonic life of a mammal, however, the heart is a simple tube with a series circulation: blood comes out of the heart through the aortic arches, goes to the body, and placenta where it picks up oxygen, and then returns back to the heart. (At this stage, the heart is very similar to that of fish, where the blood goes from the ventricle to the aorta, picks up oxygen in the gills, supplies it to the body and then returns back to the heart.)

During embryonic development the heart ‘loops’ and contorts, forming the four chambers of the adult heart. This is necessary for two parallel circulations to develop, one to deliver blood to the lungs, and another to deliver blood to the body.

How is this complex process controlled? A clue came in 1995 when it was discovered that a very rare human disease called Rubinstein–Taybi syndrome, which is associated with heart defects, was caused by mutations in the CBP gene. The CBP protein is found in the nucleus and controls other genes. The hunt was therefore on to find which genes might be controlled by CBP, and which proteins interact with CBP – as any of these might also be involved in building the heart.

In 1995, Professor Bhattacharya identified a protein, Cited2, which binds to CBP and to CBP’s close relative p300. Cited2 was then found to bring together p300 and Ap2, another factor that controls genes involved in heart development. Did the gene have a role in heart formation?

“When the gene was removed – ‘knocked out’ – in mice, a large number of different heart defects resulted,” says Professor Bhattacharya. “These included defects in the septa between the ventricles or the atria, and defects in the aortic arches – the most common heart defects in humans. But it wasn’t clear why the same mutation in Cited2 resulted in so many different heart defects.”

Asymmetry

To get a closer picture, he turned to ‘pedigree’ mice that have been highly inbred. Without the Cited2 gene, these mice had very severe heart defects. The left side of the heart was developing as a right side, a condition called right isomerism that also occurs, rarely, in humans. Professor Bhattacharya concluded that Cited2 controls heart development by controlling left–right patterning.

“The diverse range of heart defects seen in the original, non-pedigree Cited2 mice now made sense,” he says. “The common congenital heart defects, such as defects in the septa, appear to be subtle manifestations of a left–right patterning problem. You only see the full impact in the inbred mice, so there are other factors in the mixed population of mice that are dampening down its effect. Of course, as humans, we’re not a pure bred population. A mutation in a patterning gene could give rise to a simple heart defect, not a full scale patterning defect. Many genes are involved in the left right patterning pathway – each one now becomes a candidate gene for common congenital heart disease.”

Knowing how the genes involved in heart development interact with other genes and with the environment in the womb will be crucial for our understanding of both mild and severe heart defects.

“We know, for example, that mothers with diabetes or who take anti-epileptic drugs have an increased risk of congenital heart defects in their children,” says Professor Bhattacharya. “On the other hand, pregnant women routinely take folate supplements to reduce the risk of neural tube defects such as spina bifida. So, in the future, what we need to do is find a way to alter the environment that modulates gene function – perhaps some nutritional supplement or drug – so we can reduce the risk of congenital heart defects as well.”

Finding new heart genes

To help find other genes involved in heart development, Professor Bhattacharya has teamed up with Stefan Neubauer and Jurgen Schneider, also in Oxford, experts in magnetic resonance imaging (MRI).

Normally, the heart is invisible as mouse embryos are not transparent, so the building of the walls between the atria and ventricles, and the building of the aortic arches cannot be followed. But using MRI, the internal structures of hearts only 2 mm across can be seen in great detail and problems found with high efficiency. Using 3D reconstructions shows how the problem relates to the whole organ.

“We are collaborating with groups, such as the MRC Harwell group, who are undertaking mutagenesis programmes with the chemical ENU. This produces mutations randomly, so we not only identify mutants with defects in heart development, but those in other organs such as the kidneys or adrenal glands – it is a resource for developmental biologists around the country.

“Once we have found a heart defect in an embryo, it is very straightforward to identify which gene has been mutated. And as the mutations are random, we make no assumptions as to what gene is involved. Finding that a mutation in an unexpected gene produces a defect opens up new avenues of investigation.”

See also

• Limiting damage from lack of oxygen
• Scientists in cardiovascular harmony
• The heart in Greek medicine and philosophy
• The virtual heart
• Cardiovascular disease in Eastern Europe
• Cardiovascular stress and sleep apnoea

External links

• Shoumo Bhattacharya
• University of Oxford, Wellcome Trust Cardiovascular Research Initiative
• The Wellcome Trust Centre for Human Genetics
• The MRC Harwell group