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.

Continuing their groundbreaking research into the treatment of mood disorders in older adults, psychiatrists at the Weill Cornell Institute of Geriatric Psychiatry at the NewYork-Presbyterian Hospital/Westchester Division in White Plains will begin new studies on the effects of quetiapine (Seroquel: Astra Zeneca) and lamotrigine (Lamictal: GlaxoSmithKline). Although both drugs have been approved for aspects of the treatment of patients with bipolar disorder, to date there has been limited research into their effects on older adults with bipolar depression.

The studies are being led by Dr. Robert C. Young, professor of psychiatry at Weill Cornell Medical College, and his colleagues at the Institute of Geriatric Psychiatry. With more than 30 years of clinical and research experience, Dr. Young's focus has been to develop information that can improve the treatment of older adults suffering severe mood disorders.

Dr. Young, an attending psychiatrist at NewYork-Presbyterian/Westchester, said: "To date, most bipolar disorder treatment studies have been conducted in younger patients. In some older bipolar patients a good symptom response is difficult to achieve, and they often have recurring symptoms, disability, multiple medical disorders and increased mortality rates. We hope that findings from these studies will help physicians better manage the care of their geriatric bipolar patients."

Eligible participants must be 60 years of age or older with a diagnosis of bipolar disorder and currently suffering from symptoms of depression. They will be required to meet with a psychiatrist one day per week for a few hours and receive medication management from the treatment team.

Dr. Young and his colleagues are also continuing to lead another study, funded by the National Institute of Mental Health (NIMH) and now in its fourth year, comparing the efficacy of two commonly used mood stabilizers, lithium and valproate, for the treatment of bipolar disorder in older adults. To date, more than 140 individuals in six study sites across the United States including NewYork-Presbyterian/Westchester have participated.

Dr. Young added: "We've heard from some participants in the NIMH study that they have gotten satisfaction in knowing that the findings from this important research may be of benefit to other older individuals -- now and in the years ahead -- who are similarly afflicted with bipolar disorder."

Bipolar disorder involves periods of elevated mood -- mania or hypomania -- and periods of depression, or "mixed" episodes in which patients have both kinds of symptoms. Examples of manic symptoms are high levels of energy, going without sleep for extended periods, elated mood or irritability, and impulsive or reckless behavior. Patients may not recognize that they are having symptoms.

Very low levels of lithium in drinking water may help prevent suicide in the general population, according to a new study.

The study has prompted calls for further research into the possibility of adding lithium to drinking supplies - like water fluoridation to improve dental health.

Researchers at Oita University in Japan measured lithium levels in tap water in 18 municipalities in the Oita region. The lithium levels ranged between 0.7µg/l (micrograms per litre) and 59µg/l.

The researchers then calculated the suicide rate in each of the 18 municipalities. They found that the suicide rate was significantly lower in those areas with the highest levels of lithium in the water.

Writing in the May issue of the British Journal of Psychiatry, the researchers said: "Our study suggests that very low levels of lithium in drinking water can lower the risk of suicide. Very low levels may possess an antisuicidal effect."

Lithium is a naturally occurring metal found in variable amounts in food and water. In medicine, very high doses are used to treat bipolar disorder and mood disorders. But so far the potential benefit of using low levels of lithium to reduce the risk of suicide has not been studied closely.

Vancouver-based psychiatrist Professor Allan Young has described the study as "intriguing".

Commenting on the Japanese study in the same issue of the British Journal of Psychiatry, Professor Young said: "A logical first step would be for the Medical Research Council to convene an expert working party to examine the available evidence and suggest further research.

"Large-scale trials involving the addition of lithium to drinking water supplies may then be feasible, although this would undoubtedly be subject to considerable debate. Following up on these findings will not be straightforward or inexpensive, but the eventual benefits for community mental health may be considerable."

Twice weekly acupuncture treatments relieve debilitating symptoms of xerostomia - severe dry mouth - among patients treated with radiation for head and neck cancer, researchers from The University of Texas M. D. Anderson Cancer Center report in the current online issue of Head & Neck.

Xerostomia develops after the salivary glands have been exposed to repeated doses of therapeutic radiation. People who have cancers of the head and neck typically receive large cumulative doses, rendering the salivary glands incapable of producing adequate saliva, said Mark S. Chambers, M.S., D.M.D., a professor in the Department of Dental Oncology. Saliva substitutes, lozenges and chewing gum bring only temporary relief, and the commonly prescribed medication, pilocarpine, has short-lived benefits and bothersome side effects of its own.

"The quality of life in patients with radiation-induced xerostomia is profoundly impaired," said Chambers, the study's senior author. "Symptoms can include altered taste acuity, dental decay, infections of the tissues of the mouth, and difficulty with speaking, eating and swallowing. Conventional treatments have been less than optimal, providing short-term response at best."

M. Kay Garcia, LAc, Dr.P.H., a clinical nurse specialist and acupuncturist in M. D. Anderson's Integrative Medicine Program and the study's first author, noted that patients with xerostomia may also develop nutritional deficits that can become irreversible.

Garcia, Chambers and their team of researchers conducted a pilot study to determine whether acupuncture could reverse xerostomia. Acupuncture therapy is based on the ancient Chinese practice of inserting and manipulating very thin needles at precise points on the body to relieve pain or otherwise restore health. In traditional Chinese medicine, stimulating these points is believed to improve the flow of vital energy through the body. Contemporary theories about acupuncture's benefits include the suggestion that needle manipulation stimulates natural substances that dilate blood vessels and increase blood flow to different areas of the body.

The M. D. Anderson study included 19 patients with xerostomia who had completed radiation therapy at least four weeks earlier. The patients were given two acupuncture treatments each week for four weeks. The acupuncture points used in the treatment were located on the ears, chin, index finger, forearm and lateral surface of the leg. All patients were tested for saliva flow and asked to complete self-assessments and questionnaires related to their symptoms and quality of life before the first treatment, after completion of four weeks of acupuncture, and again four weeks later.

The twice weekly acupuncture treatments produced highly statistically significant improvements in symptoms. Measurement tools included: the Xerostomia Inventory, asking patients to rate the dryness of their mouth and other related symptoms; and the Patient Benefit Questionnaire, inquiring about issues such as mouth and tongue discomfort; difficulties in speaking, eating and sleeping; and use of oral comfort aids. A quality-of-life assessment conducted at weeks five and eight showed significant improvements over quality-of-life scores recorded at the outset of the study.

"In this pilot study, patients with severe xerostomia who underwent acupuncture showed improvements in physical well-being and in subjective symptoms," Dr. Chambers said. "Although the patient population was small, the positive results are encouraging and warrant a larger trial to assess patients over a longer period of time."

Garcia said that a phase III, placebo-controlled trial is planned and is currently under review. She also noted that in other studies, the M. D. Anderson researchers are examining whether acupuncture can prevent xerostomia in patients treated for head and neck cancer, not just treat it.

Dr. Hisao Asamura and his team of researchers at The National Cancer Center Hospital in Tokyo, Japan examined the records of 2,281 patients who underwent lung cancer resection surgery between 2000 and 2006. The study was published in the May issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer. Dr. Asamura and his team found that after classifying patients based on the technique used to diagnose their lung cancer, either through CT scans or x-rays, there was a marked difference in five-year survival rates. Those patients diagnosed using CT scans had a 91.2 percent 5-year survival rate while those diagnosed with x-rays demonstrated a 77.8 percent survival rate.

The researchers also divided the patients into groups based on the detection type, including screen detection, symptom detection and incidental detection. The patients that demonstrated the highest five-year survival rates were those diagnosed through screening (79.6 percent) and then those diagnosed because of symptoms (74.6 percent). The patients that were diagnosed incidentally demonstrated the lowest five-year survival rate (64.6 percent).

The study findings demonstrate the impact of lung cancer screening, particularly though CT-scans, can have on improving patient prognosis by detecting the disease at an early stage. The accuracy of CT scans allow physicians to detect cancerous growths while the tumor is at an early stage and physically smaller, making it more operable. With lung cancer prognosis and survival depending heavily on the stage of the disease upon diagnosis, it is important to keep findings such as these in mind.