Science: Empty vessels

For the first time, scientists have grown new blood vessels `in situ' around the heart. Hilary Bower reports on a breakthrough that could wipe out clogged arteries, one of the biggest causes of serious illness and ill health

BLOCKAGES in the arteries that feed the human heart cause more ill health and death than almost any other body malfunction. But now we can look forward to a time when we will be able to run ring roads around these dangerously narrowed arteries with the help of gene therapy.

Scientists have managed for the first time, to grow blood vessels, in situ, in the human heart by using genetically engineered growth factors. The aim is to bypass the trouble spots that set the scene for heart attack and heart failure.

The idea of growing blood vessels in the heart has been discussed for many years. For a healthy, fully pumping organ, oxygen-loaded blood from the lungs needs to pour into the coronary arteries under pressure, and at speed, so that the momentum pushes it down into the hundreds of smaller branches that wrap the heart, and feed and nourish every bit of the continuously thumping muscle. Trouble occurs, however, when this rush of blood hits a blockage or narrow section.

Just as when morning rush hour traffic has to converge into a single lane on a motorway, there is a deathly silence on the other side of the hold-up, and even if blood can just seep through, the lost speed and pressure means it doesn't make it down into all the branch arteries, starving muscle areas of oxygen. This weakens the heart's beat and causes heart pain (angina) and other symptoms of heart disease like tiredness, dizziness, breathlessness and apprehensiveness.

Currently we can bypass blocked coronary arteries by grafting a vein from the leg to divert blood around the trouble spot, or clear out the artery with angioplasty - a technique which involves inflating a tiny balloon in the narrowed artery to compress the accumulated sludge back against its wall. More than 23,000 people have bypass surgery annually and about 15,000 have angioplasty; both are effective treatments.

Although these operations are successful, many people have accumulations of fatty plaque in the branch vessels which are too small to bypass or clear out, but cause major symptoms if blocked. Almost a third of bypass patients begin getting symptoms again within 10 years, and for one in 10, these start within a year of surgery.

The solution, suggest scientists from the Fulda Medical Centre in Germany, is to grow new, fresh and pristinely clear vessels to provide an alternative supply route. "We can bypass the bigger vessels surgically, but this does nothing for the additional lesions in the smaller vessels," explains Professor Thomas-Joseph Stegmann, head of the department of thoracic and cardiovascular surgery at Fulda. "But this new technique offers us a new way around a problem area."

The method involves a genetically engineered growth-factor protein called FGF-1 (basic fibroblast growth factor). In the first human trial, Professor Stegmann's team injected FGF-1 into the heart muscle of 20 patients in their 50s undergoing open-heart bypass surgery. All the patients also had inoperable blockages of the smaller branch vessels and the injection was targeted close to the site of the worst blockages.

The impact was rapid. Within four days, X-rays showed new capillary growth, radiating out from the point of the injection and heading off around the obstruction. By 12 weeks the blood flow to the starved areas of the heart had increased two to three times, and three years later, all 20 patients are on fewer drugs than the 20 control patients, with none reporting any negative side-effects. "This opens up new possibilities for treatment, it is a new therapeutic concept," says Professor Stegmann.

According to British Heart Foundation professor of vascular biology Andrew Newby, the new technique mimics what the body does naturally. At certain times - such as during pregnancy with the development of the placenta, in wound healing or diseases of poor circulation - the body itself triggers rapid growth of capillaries by generating growth factors which increase the cell production above that needed for normal daily repair. Although this also happens to a certain extent in the heart, it's not sufficient to outweigh the damage caused by blockages. "The body has the mechanisms to do this and they are all working," says Professor Newby. "It's a bit like giving the television a thump - you give the natural mechanism a huge and overwhelming stimulation."

But how is it that the veins grow nicely around the blockage rather than shooting off at random? Professor Jeffrey Isner, head of cardiovascular research at the St Elizabeth Medical Centre, Boston was the first to grow blood vessels in the body in research work on vascular disease in the legs.

He explains: "We think hypoxia [lack of oxygen] in the limb below the blockage acts as a kind of `homing' signal or magnet for the new cell growth. The new cells respond to the demand of the hypoxia by growing towards it and going around the blockage."

There are still plenty of technical problems with DIY blood vessels. One is how to get the growth factor to where it is needed, without invasive surgery, and not have it swept on where it's not wanted by the fast-flowing circulation of blood. Professor Isner's team used a balloon catheter, similar to that used in angioplasty, coated in the DNA that codes vaso- endothelial growth factor and inflated it near the blockage, this presses the growth factor into the vessel walls. Trying out this technique in the heart is his team's next task.

A further problem is that the growth factor activity appears to switch off after about 30 days. Although this does provides a natural mechanism to guard against out-of-control vessel growth, it also means that the new vessels remain small and not fully mature. Work in the leg, though, suggests that repeat doses of growth factor can produce maturer and bigger vessels - making the ability to give growth factor comfortably without invasive surgery even more important.

Whether the new vessels can be persuaded to grow to the size and strength needed to replace the powerful coronary arteries remains to be seen. But in time it is possible that operations for heart disease could, themselves, be bypassed. !

HOW TO BE SUPPORTIVE

While German scientists are busy trying to replace coronary artery bypass grafting (CABG), British scientists have developed a "support stocking" for blood vessels transplanted to the heart.

CABG involves taking the saphenous vein from the leg and using it to bypass the narrowed or blocked coronary arteries. The trouble is veins - which return the blood to the heart - are not as strong as arteries, which are built to withstand the high pressure of blood rushing out to our extremities. So when veins act as arteries, they thicken, often recreating the narrowing problem they are supposed to circumvent.

Now Professor Newby has found that encasing the vein in a mesh "support stocking" before its insertion alleviates the stress, stopping the vein from thickening.

The action of the stocking was a surprise discovery. Professor Newby was planning to use it as a way to deliver a digestive enzyme (TIMP) which may be an important component in the build-up of fatty sludge that blocks arteries and veins used in bypass surgery.

Work is continuing on TIMP, which may prove to be a key to preventing blockages in the first place. But in the meantime, support stockings are set to become the heart's desire.