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Purging arteries of the fatty deposits that clog them is much like clearing
the muck from a blocked drain: a simple task requiring a long pole, a brush
and sheer brute force. Doctors use this technique to clear blocked arteries
which restrict blood circulation and cause the painful chest pains of angina.
The pole is a thin wire with a tiny balloon at its tip. The balloon is
inflated to push the artery walls apart.

This technique, called angioplasty, is used in more than 500 000 patients
a year around the world. Yet within six months 40 per cent of patients go
back to have their pipes unblocked a second time. Finding a way to reduce
this need for repeat operations has taxed cardiologists for years, but
it is only now that researchers are beginning to understand why the blood
vessels become blocked so soon after surgery. This knowledge has led to
a flood of new drugs and physical techniques such as stents – mesh tubes
that are inserted inside the artery and act like wire netting – to keep
the arteries open. Many of these new approaches are wending their way through
clinical trials in the US and Europe at present.

One reason why techniques designed to prevent arteries blocking after
angioplasty have taken so long to reach the trial stage is because the constriction
process is complex. The blockage found in these patients is not a recurrence
of the original problem: it is a reaction to the stretching and pushing
involved in the angioplasty. The pressure of the balloon can damage the
wall of the artery, causing the muscles underneath the lining to swell up
and block the vessel – a process known as restenosis.

UNCONTROLLABLE DIVISION

When Andreas Gruentzig first carried out angioplasty at Zurich University
in 1977 he thought it worked by compressing the fatty deposits blocking
the artery. Now it is known that the vessel is opened more by stretching
the artery wall, which only partly bounces back after the balloon is removed.
Splits appear in the layer of cells lining the artery being treated. Blood
seeps into the muscle layer below and triggers a reaction that resembles
the progress of cancer. The muscle cells start to divide uncontrollably
and migrate through the lining to the inner surface of the artery. There
they mix with the platelets and white blood cells that gather at the site
of any injury. Together these cells form a thick layer which narrows the
channel and stops blood passing through.

Some researchers believe that the platelets release PDGF (platelet derived
growth factor) into the bloodstream, which starts the muscle cells dividing.
But Michael Reidy, professor of pathology at the University of Washington,
Seattle, has carried out tests on rats which suggest that another molecule,
fibroblast growth factor (FGF), stimulates cell division while PDGF causes
them to migrate. Reidy believes, therefore, that knocking out FGF may be
the key. He has shown that giving rats antibodies to FGF inhibits its action
and can prevent restenosis. The antibodies bind to the FGF, so preventing
it from interacting with the receptors on the muscle cells and stimulating
cell division. A similar view of the importance of FGF in restenosis is
held by Prizm Pharmaceuticals of San Diego – which has designed a drug that
combines FGF with a poison called saporin. In tests on rats, the poisoned
cocktail destroyed the FGF receptors on the walls of exposed muscle cells,
so preventing the cells from dividing and blocking the vessel.

But not all researchers are convinced by the results of tests carried
out on rats. Mark Taubman, an associate professor in the department of medicine
at the Mount Sinai School of Medicine, New York, says that even if a technique
looks promising in rats it often fails in humans, because the rat’s carotid
artery is different from the human cardiac artery. Over the past ten years
there have been a number of attempts to improve angina treatment. Some of
these have focused on different techniques for removing the initial blockage,
for example drills, lasers, sound wave generators and high powered water
jets. But all have proved less effective than angioplasty as they cause
more damage and so the occurrence of restenosis is higher. Other researchers
have concentrated on drug treatment of patients after angioplasty. Drugs
such as aspirin that reduces inflammation and warfarin which prevents blood
from clotting, are just two examples of the weapons used against restenosis.

BACK TO THE SUTURE

But the lack of any great improvement in the success of angioplasty
has forced cardiologists to look at more conservative approaches as well.
Tony Rickards, a consultant cardiologist at the Royal Brompton Hospital
– the National Heart and Lung Hospital – in London sees the process as a
race between the muscle cells growing out into the middle of the artery
and the lining cells recovering to repair the splits caused by the balloon.
In most patients the damage is repaired within six months of the first operation,
after which there is no evidence of further growth in the muscle layer.
If the channel that is left after this period is large enough to allow sufficient
blood through to prevent chest pain, the operation is considered a success.

Rickards has therefore concentrated on making the channel as wide as
possible in the hope that there will still be space for blood to flow after
six months of muscle cell growth. He argues that inflating the balloon as
far as possible increases the chances of success because it is more likely
that a channel for blood flow will remain even though there may be more
damage to the artery lining and so more growth in the muscle layer. There
are, however, some limitations to this technique. In particular, it is important
that the surgeon avoids rupturing the artery or sheering off part of its
inner layer by stretching it too far – a process that can leave flaps of
tissue which peel off and may block the vessel abruptly, causing a heart
attack.

An alternative approach that is now winning widespread support, is
the use of a stent to keep the blood vessel open during the critical first
six months after angioplasty. This involves inserting tiny metal tubes inside
the artery with the balloon. The hope is that when the balloon is removed,
these tubes will support the muscle cell layer, and prevent it from growing
into the centre of the vessel.

PATIENT STUDIES

Studies of patients who have had stents inserted during angioplasty
have been compared with similar studies on people without the stent. One
such trial, involving 520 patients at 28 hospitals in nine European countries,
has just been completed. It showed that patients given stents were 40 per
cent less likely to need a repeat operation than those treated by angioplasty
alone. In the six months after the operation there were also fewer major
complications – ranging from heart attacks to death – in the stent group.

Stents do have significant drawbacks, although these are deemed to be
of less risk than angina itself. They can only be fitted into straight sections
of larger arteries more than 3 millimetres in diameter. Another is financial
– using a stent doubles the cost of ‘disposables’, equipment used once only
during the operation, which itself can cost £900. The patient also
has to stay in hospital for longer – about eight days, compared with three
for ordinary angioplasty. And perhaps more importantly, clots can form on
the metal surface of the stent. These can break off, block the artery and
cause a heart attack.

Drugs such as heparin have been used to reduce the risk of clot formation,
but they can cause internal bleeding elsewhere. So doctors have to balance
the risks of restenosis using the balloon with the rare but more serious
problems when the stent is fitted as well. Nigel Buller, another consultant
cardiologist at the Royal Brompton Hospital, believes that in the future
stents will be used in about 30 per cent of the 10 000 operations which
take place each year in Britain – a trend that is likely to be followed
in the US. Spencer King, head of the cardiovascular unit at the Emory University
Hospital, Atlanta, believes that balloon angioplasty alone will be used
for most operations, and then if a patient looks as if they will suffer
from restenosis a second operation may be necessary to insert the stent.
Techniques such as ultrasound and angiography – X-rays of the coronary arteries
taken after injecting an opaque dye – can alert the cardiologist to the
onset of restenosis.

Stents are also likely to play an important role in bypass surgery,
where patients suffering from the blockage of several blood vessels have
veins taken from other parts of the body and grafted onto the surface of
the heart. This is still the only treatment for advanced disease affecting
several blood vessels at a time. But the technique has all the risks associated
with major surgery, such as infection, bleeding and death under anaesthesia,
and patients have to spend several months convalescing. And restenosis often
occurs in the grafted vein, usually at the junction with the artery where
the stitches are put in place.

FOCUSED MINDS

The potential benefits of inserting stents into heart patients on a
regular basis has focused the minds of researchers on finding ways of overcoming
the limitations of this technique, such as the danger of blood clot formation.
Patrick Serruys of the Thoraxcenter, Erasmus University, Rotterdam believes
that heparin could be bonded to the stent in a polymer coating to prevent
clot formation. The drug is then applied where it is needed and should not
cause bleeding in the rest of the body. There are, however, difficulties
in preventing the drug being washed off before it has finished the job.
And while the method has been successful in rats it is not clear whether
it will work in humans, he says.

The local drug delivery approach is also being tried to tackle restenosis
at its source. Two groups in the US are at the forefront of research using
antisense therapy to block muscle cell division. This involves producing
a specially engineered oligonucleotide molecule which matches a particular
sequence of DNA in the muscle cell nucleus. When it enters the cell the
molecule binds to the target DNA sequence or to the messenger RNA which
transfers the information on those genes within the cell. Either way it
stops the genes working.

Victor Dzau’s group at Stanford University has produced antisense sequences
for two genes that produce proteins involved in cell division. Similarly,
Robert Rosenberg of the Massachusetts Institute of Technology has suppressed
muscle cell division in rats following angioplasty using an antisense molecule
to the c-myb gene involved in regulating cell growth.

Both groups are now looking at ways of delivering the antisense molecule
to the injury site. Rosenberg’s team is trying a gel which can be applied
to the balloon and smeared on the artery lining. Meanwhile, the Stanford
group is working on a second catheter tube which is inserted after angioplasty
to release small doses of the oligonucleotide.

KEEPING THE PIPES CLEAN

Clinicians using angioplasty await the results of this work with interest.
But they also know that in the meantime many patients suffering from angina
will need more than a single brush with the medical equivalent of Dynarod.
As Rickards observes, ‘We are plumbers and there are a number of ways of
doing the job. If a 40-year-old man with coronary heart disease comes in
(to my surgery), I know it is likely that the plumbers will go into his
chest or leg three or four times before he reaches his three score and ten
years.’ Any technique that reduces this number of operations can only be
a bonus.

John Bonner is a freelance science writer based in London.