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Scientists Reveal Chemical Compound Linked To Increased Heart Risk

January 16, 2002

Scientists believe that they have found a chemical responsible for
increasing cardiovascular risk, it was revealed. And crucially they have
identified how it is made and destroyed in the body raising the possibilty
that new drugs to reduce the risk of heart disease are around the corner.

A team of scientists based at the new British Heart Foundation (BHF)
Laboratories at UCL first identified ADMA as a naturally occurring
substance that blocks the production of a gas made by the body - Nitric
Oxide. Nitric Oxide has been been know to scientists as an important
signalling molecule playing a major role in blood pressure regulation and
clotting implicating it strongly in the mechanisms behind heart attack and
strokes. The group at UCL suggested that a rise in ADMA levels in patients with kidney failure accounted for increased cardiovascular risk in this group.

Recent studies have confirmed these findings, and a paper from a group in Germany focused on observing 225 patients who had kidney failure and
therefore lost the ability to excrete ADMA naturally through their kidneys.Over an average period of 42 months the rate of cardiovascular events - heart attack, stroke and death - was 36%. Concentrations of ADMA within the patients varied among patients at the start of the study and, of interest to the team, was the fact that those patients with higher concentrations of ADMA had a greater death rate - some 26% higher.

The BHF scientists believe that the patient group experiencing higher
levels of ADMA are representative of a broader group that have additional risk factors for cardiovascular events that are independent of renal disease. This view has been backed up the recent research which found higher levels of ADMA in people with significant cardiovascular disease but with no accompanying renal failure.

Explaining how high concentrations of ADMA occur in patients without renal failure, the BHF scientific team believe that the enzyme DDAH - thought to responsible for its metabolism - may provide the answers.It is now thought that genetic environmental differences in the activity or control of DDAH between individuals may account for increased risk of many pathological conditions like cardiovascular and neurodegenerative disease. The chance of discovering new drugs which can control DDAH activity has been significantly increased by the discovery of the human forms of DDAH enzyme and detailed information on the structure of DDAH by the UCL team published recently in Nature Medicine.

Speaking on the eve of the opening of the new BHF Laboratories at UCL, Professor Patrick Vallance said;

`ADMA concentrations may now provide a new and powerful means for
predicting risk in patients with renal failure. Because it has been found
in high concentrations in people with cardiovascular disease, it may also
be a good predictor of risk of death from cardiovascular disease as well.`

Professor Vallance continued;

`If new drugs can be found to alter ADMA levels they might have a major
effect in reducing mortality rates for people otherwise destined to suffer
the consequences of heart disease. A lot of progress has been made in the first critical steps in the discovery of such drugs. Such compounds may also have much wider roles in situations in which blocking nitric oxide could be beneficial. We are at the early stages of drug discovery but we have certainly found a good target and have all the starting materials`.

University College London - UCL