A new US study found why a very small proportion of arterial plaques become deadly and lead to heart attack or stroke and why the vast majority others stay benign and apparently do no harm.


The study was the work of researchers at Columbia University Medical Center, and New York University Medical Center, both in New York, and is published in the 6 May issue of Cell Metabolism.

The researchers said that many people are wrong to believe that all arterial plaques inevitably result in heart attack or stroke and their study found out why so few of them are actually worth worrying about.

They also found an important protein that may be responsible for benign plaques turning into dangerous one.

While most atherosclerotic lesions are harmless, only about 2 per cent of them will eventually cause an acute and often fatal blood clot that leads to heart attack, sudden death or stroke, said the researchers.

What distinguishes a dangerous plaque from a benign one is the "billion dollar question" said Dr Ira Tabas, who is Richard J Stock Professor and Vice Chairman of Research, at the Department of Medicine at Columbia University and Professor of Medicine and Anatomy and Cell Biology.

Plaques or atherosclerotic lesions, are fatty, inflamed deposits that form on the inside walls of arteries. These deposits also collect white blood cells known as macrophages and the lesions build up at various spots along blood vessel walls, said Tabas, adding that it is not the size of the deposit but what lies beneath the surface that makes it a dangerous one.

He likened it to the magma or molten lava inside a volcano: rumblings in the core, which in the case of arterial plaques is made of dead cells, can erupt, and once a plaque ruptures it can form a blood clot in the lumen or the interior space of the artery through which the blood flows.

Their finding supports the idea that so-called endoplasmic reticulum (ER) stress together with the body's natural way of coping with that stress is one reason why the rupture takes place.

The ER of a cell does two things: it makes, folds and transports new proteins; and it controls the storage and release of the cell's store of calcium.

When something disturbs the cell's normal operation, it kicks into action a pathway called the unfolded protein response (UPR) which triggers cell suicide in those cells that are particularly stressed. The trigger for cell suicide is an ER stress effector conveniently called CHOP.

Tabas said it's OK for cells to die as long as they don't do so in large numbers. The ER pathway, when it works well, protects the whole organism, killing a a few cells here and there, But more and more scientists are beginning to realize that ER stress and the body's "overexuberant" reaction to it are common features of underlying neurodegenerative disease, aging, and diabetes, he said.

While earlier studies had suggested a link between ER stress and vulnerable plaques, this is the first to show a clear causal link between the two, said Tabas.

"It is this sudden clotting that restricts blood flow and can cause a heart attack, stroke, or sudden cardiac death," said Tabas, explaining that in our modern world most people have atherosclerosis by the time they reach the age of 20, and the challenge for the future will be stopping the harmless lesions in young people from becoming dangerous ones, or as he put it "soothing dangerous plaques so they don't rupture as we age".

Tabas said it was not obvious how to do that yet. There could be many reasons why plaques turn from benign to dangerous, but one of these is definitely linked to the presence of dead cells inside them, the necrotic core as the researchers termed it.

The dead cells release substances that weaken to cap that covers the lesion and hence allow it to erupt and trigger the formation of a clot, said Tabas.

For the study, Tabas and colleagues fed two groups of mice bred to have atherosclerosis a diet high in fat and cholesterol for 10 weeks. One group of mice had the CHOP gene deleted while the other did not. The mice without the CHOP gene produced smaller plaques than those with CHOP. But more importantly, the mice without the CHOP gene also showed 50 per cent lower rates of cell death and plaque necrosis.

Repeating the experiment with another strain of atherosclerotic mice showed essentially the same result, they noted.

Although previous studies have pointed to ER stress and UPR before, Tabas said their result still surprised them, especially the size of the effect.

"The fact that we were able to isolate one gene encoding one protein with such a profound effect on plaque necrosis was a big surprise," he said.

They were surprised because they were expecting this to be just one of many processes at work, including some that might compensate for the loss of the CHOP gene.

Tabas said that finding this effect in mice could translate to real clinical benefits for humans.

The finding opens the possibility that drugs targeting the CHOP gene could silence ER cell stress and be an effective way of treating heart disease, the number one killer in the US.

While cholesterol busting drugs can reduce the number of plaques that deposit inside arteries, they don't work for everyone, and besides, the deposits start quite early in life, with fatty streaks appearing in our arteries in our teens and plaques appearing in our 20s.

"A therapy that prevents the deaths of these cells may be able to reduce the number of vulnerable plaques and prevent heart attacks and strokes in the 70 percent of people who aren't protected from cholesterol-lowering drugs," said Tabas.

However, it might be years before an effective therapy based on this discovery is generally available, said the researchers, but it may be possible to bypass the problem of cell death by persuading other cells inside the plaque to capture and eliminate the dead cells before they can cause eruption.

In the meantime, there is another, well tested way. Although our knowledge of atherosclerosis may be changing, the best option may not, it may still be to have a healthy diet, take plenty of exercise, and keep an eye on cholesterol and blood pressure, said Tabas.