Monday, April 20, 2009

Heart attack mystery: New clues found

April 18, 2009

Besides cholesterol levels, inflammation of blood vessels may have role in disease

By Mak Koon Hou

TODAY, we know that Galileo was wrongly condemned for saying that the Earth revolves around the Sun.

But he wasn't always right.

Nowadays, even primary school children can identify Saturn by the beautiful rings encircling the planet.

But in 1610, when Galileo first observed the rings of Saturn using his then state-of-the-art 20-power telescope, he described them as 'handles' or large moons on either side of the planet.

The reason for this disparity is unclear and may have been due to his poor eyesight. Scientists now want to exhume his body to analyse his DNA - to determine the cause of his visual impairment. Using computational modelling, they hope to recreate what Galileo actually saw.

Challenging old concepts with new findings happens continuously in the world of science and discovery. Our understanding of the world is constantly refined as novel observational and analytic techniques are developed.

This happened when researchers studied the link between the hardening of the arteries and cholesterol.

Cholesterol was assumed to cause the hardening - called atherosclerosis - which leads to a host of problems such as heart attacks and strokes.

This association was not surprising because atherosclerotic plaques, which lead to narrowing and hardening of the arteries, were found in post-mortem studies to be filled with fats, or lipids.

In humans, there is a genetic defect in which individuals do not have a low-density lipoprotein (LDL) receptor to process 'bad cholesterol', or it is dysfunctional. These people often suffer a heart attack at a young age.

For discovering the LDL-receptor, Dr Joseph Goldstein and Dr Michael Brown were awarded the Nobel Prize in Medicine in 1985.

Subsequent investigators were able to follow closely individuals with known cholesterol levels, and found that those with the highest levels were most likely to suffer from heart attacks.

After discovering how cholesterol is handled in the body, medicine was developed to lower cholesterol levels. Of these, statins have been the most potent in lowering LDL-cholesterol levels and reducing heart attacks and death from vascular diseases.

Gradually, the public came to know this group of life-saving drugs. In some countries, they are even available over the counter.

But despite overwhelming evidence linking cholesterol with heart attacks, there were still several gaps in our understanding.

Two groups of people stood out - those with moderately elevated cholesterol levels who did not get heart attacks, and people with normal cholesterol levels who did.

Considering the substantial proportion of individuals who end up suffering a heart attack, there is an urgent need to identify factors that can single out who will be a victim.

Investigations have led to a better understanding of atherosclerosis: Instead of depositing cholesterol passively into the vessel walls, it is now believed to be an active process, involving immune and inflammatory responses in blood vessels.

By looking at the various biomarkers - chemical indicators - of inflammation in the body, an old test has been transformed for use in modern technology.

The C-reactive protein was discovered in 1930 among patients who had pneumonia. Subsequently, researchers discovered that such protein levels were raised among those with heart attacks or other inflammatory conditions such as arthritis.

Studies have shown that this protein could be part of the missing link in the heart attack mystery.

On both ends of the spectrum: People with highest levels of cholesterol and C-reactive protein had the greatest risk for death and heart attacks; those with the lowest levels of both had the lowest.

The risk was intermediate among individuals with either high cholesterol or C-reactive protein levels.

Seven years ago, the United States Centres for Disease Control and Prevention, together with the American Heart Association, convened a Workshop on Markers of Inflammation and Cardiovascular Disease.

They recommended categorising patients into low, average and high risk based on the C-reactive protein levels.

When investigators re-analysed the clinical trials studying the efficacy of statins, they found that patients with both high cholesterol and C-reactive protein levels benefited from treatment.

On the other hand, the outcome was unchanged among those with high cholesterol but normal levels of C-reactive protein, even though their cholesterol levels were reduced by the drugs.

Armed with these early observations, the Jupiter (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial was conceived.

The investigators put up a bold hypothesis to further evaluate the relationship between inflammation and vascular disease: Treatment with statins would help patients with cholesterol levels in the normal range, but who had raised C-reactive protein levels - a group not previously considered at risk.

Almost 18,000 patients - men were aged above 50, women above 60 - were enrolled in this study.

These were healthy men and women without vascular diseases or diabetes, with normal cholesterol levels but high C-reactive protein levels.

Patients were randomly assigned to receive a statin drug or placebo.

Although the study was scheduled for five years, it was discontinued prematurely after close to two years.

This generally happens when the independent safety monitoring committee discovers overwhelming benefit or harm in one of the groups.

In this case, the drugs reduced LDL-cholesterol and high-sensitivity C-reactive protein levels by half in men, and 37 per cent in women, while the group taking the placebo experienced no change.

Correspondingly, the rate for death, heart attack, stroke or need for a bypass or angioplasty was significantly lowered, by 44 per cent in both the men and women on statins.

Importantly, death from any cause was also reduced by 20 per cent in the treatment group.

These findings certainly provide a sound basis for the strategy of identifying previously invisible but high-risk individuals without vascular disease or diabetes.

In the US alone, it is estimated that an additional 6.5 million men and women could benefit from such treatment. Lower the age limit to 20 years and older, and the number balloons to 36.6 million.

Although the findings are compelling, they have not yet become mainstream.

Doctors are generally cautious in adopting novel treatment approaches, and testing is also not done for C-reactive protein in many clinics. As the saying goes, one swallow does not make a summer.

Making accurate observations in the natural world has always been a challenge.

While Galileo was right in stating that the Earth revolves around the Sun, he was incorrect to say there were handles around Saturn.

But what Galileo saw, he recorded.

Four hundred years later, we are still doing the same thing.

The Jupiter study has changed our understanding of atherosclerosis.

Besides cholesterol levels, inflammation of the blood vessels plays a critical role, we have found.

Although we are still uncertain as to what triggers this response, the high sensitivity C-reactive protein test has given health-care providers an invaluable tool to determine who should receive treatment for a very common disorder.

The writer is a cardiologist in private practice, founding director of clinical trials at the National Heart Centre, and visiting associate professor in Nanyang Technological University's School of Mechanical and Aerospace Engineering.

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