Infusion with reconstituted hdl may have some benefit for atherosclerosis




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Infusion with reconstituted HDL may have some benefit for atherosclerosis

Preliminary research suggests that use of reconstituted HDL may have some benefit in coronary atherosclerosis, according to a JAMA study published online March 26. The study is being released early to coincide with its presentation at the American College of Cardiology's annual conference.

There is a strong inverse association between high-density lipoprotein (HDL) cholesterol (the "good" cholesterol) and risk of coronary atherosclerotic disease, according to background information in the article. Preliminary data have suggested that HDL infusions can reverse atherosclerosis (the progressive thickening and hardening of the arterial walls as a result of fat deposits on their inner lining).

Jean-Claude Tardif, M.D., of the Montreal Heart Institute, University of Montreal, and colleagues with the Effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) study assessed the effects of infusion with a reconstituted HDL, CSL-111, on coronary atherosclerosis. CSL-111 consists of apolipoprotein A-I from human plasma combined with soybean phosphatidylcholine (a type of lipid molecule; the combination product) that chemically and biologically resembles HDL. Between July 2005 and October 2006, intravascular ultrasound (IVUS) and quantitative coronary angiography were performed on 183 patients to assess coronary atheroma (plaque deposit) at baseline and 2 to 3 weeks after the last study infusion. Sixty patients were randomly assigned to receive four weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. This highest dosage was discontinued early because of indications it caused a certain elevation in liver function tests, suggesting possible harmful liver effects.

"This study showed differences in coronary atheroma volume after 4 weekly infusions of CSL-111 or placebo (-3.4 percent vs. -1.6 percent, -5.3 mm³ vs. -2.3 mm³, respectively), but the differences between these groups were not statistically significant. However, CSL-111 may nevertheless potentially induce some favorable vascular effects as seen in the significant reductions of atheroma volume of 3.4 percent or 5.3 mm³ with active infusions in the analysis comparing follow-up to baseline values. Although the latter finding is not significantly different when compared with placebo and is only suggestive of a possible favorable treatment effect, both the plaque characterization indexes on IVUS and coronary score on quantitative coronary angiography revealed statistically significant differences between CSL-111 and placebo groups that support this analysis," the authors write.

Whether these findings will translate into clinical benefits to patients is not known. "Elevation of HDL remains a valid target in vascular disease and further clinical evaluation of HDL infusions with CSL-111 with longer follow-up appears warranted," the researchers conclude.



JAMA. 2007;297:(doi:10.1001/jama.297.15.jpc70004). Available pre-embargo to the media at www.jamamedia.org.)

Editor's Note: Funding for this study was provided by CSL Ltd, Parkville, Victoria, Australia. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.



Drug that mimics 'good' cholesterol has mixed effect on coronary atherosclerosis

New Orleans, La. (March 26, 2007) -- Patients with acute coronary syndromes (ACS), such as heart attack and recent-onset chest pain, remain at considerable risk of experiencing further serious cardiovascular problems despite improvements in care. HDL ("good" cholesterol) has properties that may protect these patients from further complications by reducing plaque in their coronary arteries.

The results of a study presented today at the American College of Cardiology’s 56th Annual Scientific Session showed that CSL-111, a drug that mimics HDL, did not significantly reduce plaque in coronary arteries in patients with a recent episode of ACS. However, patients taking the drug showed improvement in two indexes that assess changes in the blood vessels. ACC.07 is the premier cardiovascular medical meeting, bringing together cardiologists to further breakthroughs in cardiovascular medicine. The study will be simultaneously published in the Journal of the American Medical Association (JAMA) and will appear in the March 28 print issue.

The Effect of Reconstituted High-Density Lipoprotein on Atherosclerosis – Safety and Efficacy trial, also known as ERASE, was coordinated by the Montreal Heart Institute with 17 sites throughout Canada. In this randomized, blinded clinical trial, 183 patients suffering an ACS event within the previous two weeks received up to four weekly infusions of placebo (n=60), 40 mg/kg (n=111) or 80 mg/kg (n=12) of CSL-111. The higher dosage of CSL-111 was discontinued early because of liver function test abnormalities. Assessment of coronary arteries was performed using intravenous ultrasound (IVUS) at baseline and at two to three weeks after the study infusions. IVUS is a technique in which a tiny ultrasound probe is inserted into the coronary arteries, providing a precise and reproducible method for determining the change in plaque, or atheroma, during treatment. Quantitative coronary angiography also was used to assess changes in the blood vessels.

A total of 145 patients had evaluable, serial IVUS examinations. The difference in reduction in coronary atheroma volume after four weekly infusions of CSL-111 or placebo (-3.4% versus -1.6% respectively) was not significantly different. However, when compared to baseline, the results for patients infused with CSL-111 were statistically significant (p<0.0001).

The plaque characterization indexes on IVUS and coronary score on quantitative coronary angiography were significantly different between the CSL-111 and placebo groups (p=0.01 and 0.03 respectively), suggesting a beneficial effect of CSL-111 on atherosclerosis.

"Short-term infusions of CSL-111 resulted in no significant reduction in change in atheroma volume compared with placebo, but did result in statistically significant improvement in the plaque characterization index and atherosclerosis score on quantitative coronary angiography" said Jean-Claude Tardif, M.D., of the Montreal Heart Institute and lead author of the study. "Elevation of HDL remains a valid target in atherosclerosis and further evaluation of the effects of HDL infusions with CSL-111 on clinical outcomes is warranted."

Dr. Tardif will present the results of "Effect of Reconstituted High-Density Lipoprotein on Atherosclerosis: Safety and Efficacy (The ERASE Trial)" on Monday, March 26 at 9:15 a.m. in Hall A.



Long-term aspirin use associated with reduced risk of dying in women

Women who take low to moderate doses of aspirin have a reduced risk of death from any cause, and especially heart disease–related deaths, according to a report in the March 26 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Some studies have provided evidence that aspirin may reduce the risk of heart disease and some types of cancer, the two leading causes of death in U.S. women, according to background information in the article. However, it is unclear whether aspirin reduces the risk of death overall for women.

Andrew T. Chan, M.D., M.P.H., Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues examined the association between aspirin use and death in 79,439 women enrolled in the Nurses’ Health Study, a large group of female nurses who have been followed since 1976. Beginning in 1980 and again every two years through 2004, the women were asked if they used aspirin regularly and if so, how many tablets they typically took per week. At the beginning of the study, the women had no history of cardiovascular disease or cancer.

A total of 45,305 women did not use aspirin; 29,132 took low to moderate doses (one to 14 standard 325-milligram tablets of aspirin per week); and 5,002 took more than 14 tablets per week. By June 1, 2004, 9,477 of the women had died, 1,991 of heart disease and 4,469 of cancer. Women who reported using aspirin currently had a 25 percent lower risk of death from any cause than women who never used aspirin regularly. The association was stronger for death from cardiovascular disease (women who used aspirin had a 38 percent lower risk) than for death from cancer (women who used aspirin had a 12 percent lower risk).

"Use of aspirin for one to five years was associated with significant reductions in cardiovascular mortality," the authors write. "In contrast, a significant reduction in risk of cancer deaths was not observed until after 10 years of aspirin use. The benefit associated with aspirin was confined to low and moderate doses and was significantly greater in older participants and those with more cardiac risk factors."

There are several mechanisms by which aspirin could reduce the risk of death, the authors note. "Aspirin therapy may influence cardiovascular disease and cancer through its effect on common pathogenic pathways such as inflammation, insulin resistance, oxidative stress [damage to the cells caused by oxygen exposure] and cyclooxygenase (COX) enzyme activity," also linked to inflammation, they write.

Because the study looked at women who made the decision themselves whether or not to take aspirin, as opposed to a clinical trial where women are randomly assigned to aspirin or a placebo, the results do not suggest that all women should take aspirin. "Nevertheless, these data support a need for continued investigation of the use of aspirin for chronic disease prevention," the authors conclude.



(Arch Intern Med. 2007;167:562-572. Available pre-embargo to the media at www.jamamedia.org.)

Editor’s Note: This study was supported by grants from the National Institutes of Health. Dr. Chan is the recipient of a career development award from the National Cancer Institute, an American Gastroenterological Association/Foundation for Digestive Health and Nutrition Research Scholar Award, and a GlaxoSmithKline Institute for Digestive Health Research Award. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Sorting Through the Evidence About Aspirin’s Benefits for Women

These findings differ from the results of other studies regarding the benefits of aspirin use in healthy women, leaving confusion about aspirin’s role, writes John A. Baron, M.D., Dartmouth Medical School, Lebanon, N.H., in an accompanying editorial.

Dr. Baron points out that in the Women’s Health Study, researchers followed almost 40,000 women for 11 years and did not find any reduced risk of cardiovascular or other death associated with aspirin therapy, in contrast to the dramatic risk reduction seen in the Nurses’ Health Study. "Is aspirin really that good or is there some other explanation for the findings that differ so much from those of the WHS and other primary prevention trials?" he writes.

"The difference between the NHS and the aggregated data from the WHS and other trials is too large to be explained by potential weaknesses in the randomized studies," Dr. Baron writes. "At the same time, one has to consider that the observational NHS may not have been able to deal with the differences between aspirin users and non-users."

"Therefore, these new findings by Chan et al cannot overcome the accumulated evidence that aspirin is not particularly effective for the primary prevention of death from cardiovascular disease in women," he concludes.



(Arch Intern Med. 2007;167:535-536. Available pre-embargo to the media at www.jamamedia.org.)

Editor’s Note: Please see the article for additional information, including author contributions and affiliations, financial disclosures, funding and support, etc.

Researchers figure out what makes a simple biological clock tick

An interdisciplinary team of researchers at Vanderbilt University has analyzed the simplest known biological clock and figured out what makes it tick. The results of their analysis are published in the March 27 issue of the journal Public Library of Science Biology.

Biological clocks are microscopic pacemakers. They are found in everything from pond scum to human beings and appear to help organize a dizzying array of biochemical processes. A traveler experiences jet lag when his or her internal clock becomes out of synch with the environment. Seasonal Affective Disorder, some types of depression, sleep disorders and problems adjusting to changes in work cycles all can occur when an individual's biological clock acts up. Recent studies have even found links between these molecular timepieces and cancer.

In 2005, a group of Japanese researchers surprised the scientific community by showing that the three proteins which make up the biological clock in blue green algae will establish a 24-hour cycle on their own when placed in a test tube with adenosine triphosphate (ATP), the chemical that powers biological reactions.

"That was a big surprise," says Carl Johnson, the professor of biological sciences who headed the new study. "We all thought the system was much more complicated and required feedback from the cell’s genetic machinery in order to work."

The announcement prompted Johnson, who had been working along similar lines, to assemble an interdisciplinary team to figure out how these three proteins can establish and maintain a steady, 24-hour cycle. He and his long-time collaborator, Professor of Biochemistry Martin Egli, recruited a group of researchers who are experts in electron microscopy – Associate Professor Phoebe Stewart and Research Fellow Dewight Williams – and biophysics – Professor Hassane Mchaourab – all from the Department of Molecular Physiology. Biomathematician Mark Byrne, a research fellow in pharmacology, rounded out the group.

This illustration of KaiC shows the sites where ATP molecules (shown in green) attach and the location of the phosphorylation sites (shown in red).

Although the biological clock consists of only three basic parts – proteins that have been labeled KaiA, KaiB and KaiC – when they began analyzing what was taking place in the test tube they discovered a lot more was going on than they had imagined.

"The coolest part is that a simple biological machine can do such an astounding thing as keeping time," says Williams. "It is the most fascinating biological puzzle that I have come across in my career so far."

The basic question that the researchers set out to understand is how these molecules, which are undergoing reactions at a second-by-second and minute-by-minute frequency, can sustain a 24-hour cycle.

The largest cog in the bioclock is the protein KaiC. It is a large, barrel-shaped molecule assembled from six identical components. The diurnal cycle takes the form of the regular increase and decrease in the number of phosphate groups attached to the KaiC molecules. The attachment and detachment of phosphate groups – a process called phosphorylation and dephosphorylation – is a common method of protein regulation. When KaiC is phosphorylated it interacts in different ways with other proteins in the cell than it does when it is dephosphorylated. That allows the bioclock to turn various cellular processes on and off.

Based on previous research, Johnson and his colleagues had some insight into the role of the two smaller proteins. They knew that when KaiA binds to KaiC the phosphorylation rate increases, either by making it easier for phosphate groups to bind to the hexamer or making it more difficult for them to break away. KaiB, by contrast, doesn’t bind to KaiC until it is highly phosphorylated. But, when it does, KaiB counteracts the influence of KaiA.

At the outset, the researchers envisioned a relatively straightforward process: KaiA would bind with KaiC and phosphorylation would gradually increase for 12 hours. Then something would trigger KaiB to begin bonding with these complexes and the phosphorylation would gradually decrease for 12 hours. However, Johnson and Egli’s efforts to purify and crystallize the KaiAC and KaiABC complexes so they could determine their structure using X-ray crystallography repeatedly failed.

It wasn’t until they began putting the mixture under the transmission electron microscope that they realized the reason for this failure. "It turns out that the complexes do not form one static structure, which is why we could not crystallize them," says Stewart. "It doesn’t go from complex one to complex two three hours later and then three hours later to the next complex. Instead, you have mixtures of all different complexes at all time points, just in different ratios." The researchers divided the 24-hour cycle into seven equal phases: Starting at the lowest level of KaiC phosphorylation, in phases Up1 and Up2 the phosphorylation level increases until it reaches a peak level. Following this "P" phase, the hexamers begin dephosphorylating through phases Down1, Down2 and Down3, reaching its lowest level in the "T" phase (T for trough) and then it starts over.

The analysis also found that, in addition to KaiA, KaiB and KaiC, the test tube also contained large amounts of the three smaller molecules, called monomers, that are the basic building blocks for the bioclock proteins. KaiC is a hexamer that is made up of six monomers. KaiA is a dimer that is made up of two monomers. And KaiB is a tetramer that is made up of four monomers. At the same time that the three proteins are combining into complexes and breaking up again, KaiC is also breaking apart into monomers and then recombining.

While this provided a valuable new insight into the process, it did not explain what was actually going on. To help decipher the dynamics of this system, they turned to Byrne. "The task I was given by Carl was to figure out how this system of three proteins, when combined with ATP, can produce a 24-hour oscillation," says the biomathematician. "What we’ve come up with is our ‘best guess’ model for how the system works."

According to Byrne’s model, the key to the system’s stability is the role played by the exchange of monomers by KaiC hexamers. "The 24-hour cycle is the variation in the average phosphorylation level of the hexamers. To produce sustained rhythms in the system, you must have some way to synchronize the phosphorylation levels of individual hexamers," he says. The fact that the hexamers are exchanging monomers at a substantially faster rate than the process of phosphorylation and dephosphorylation keeps phosphorylation levels evenly distributed throughout the KaiC population. "If the population becomes asynchronous – that is, if some hexamers phosphorylate and dephosphorylate out of synch with the others – then the hexamers will start oscillating out of phase with each other and you will lose the rhythm."

The model successfully explains why a specific proportion of the three proteins is needed to establish the 24-hour rhythm, how temperature can reset the system and the general characteristics of the bioclock system. However, there is a great deal more to learn.

"This paper is our first step toward visualizing what is happening during the 24-hour cycle," says Stewart. "The next level of understanding will be how the proteins work together as a nanomachine to carry out their job."

Then, too, the researchers realize the way that bioclock systems work in living cells is substantially more complex than what takes place in a test tube. For one thing, there will be additional levels of regulation, such as control of the synthesis of the bioclock protein monomers, that influence their operation.



NOTE: A multimedia version of this story is available on Exploration, Vanderbilt’s online research magazine, at http://www.vanderbilt.edu/exploration/stories/bioclocktick.html

Severe dengue infections may go unrecognized in international travelers

Severe cases of a common travelers' infection may not be recognized if doctors rely on the World Health Organization's (WHO) guidelines for identifying it, according to a new study published in the April 15 issue of The Journal of Infectious Diseases, now available online.

Dengue is the most important emerging disease among international travelers, with a 30-fold increase in incidence over the past 50 years worldwide. Like malaria, dengue is transmitted to humans by mosquitoes.

Most cases are mild. Symptoms include fever, rash, headache, pain behind the eyes, and muscle and joint pain. According to the WHO, dengue hemorrhagic fever (DHF) is characterized by fever, low platelet count, clinical evidence of leaking capillaries, and spontaneous bleeding or fragile blood vessels. The most serious cases can lead to shock and death. There is no cure for dengue infection, but management of the disease's effects can prevent the worst outcomes.

The study, conducted by Ole Wichmann, MD, MCTM, DTM&H, at the Robert Koch Institute in Berlin, Germany, and colleagues throughout Europe, collected data through the European Network on Surveillance of Imported Diseases at 14 sites in 8 European countries.

Out of more than 200 patients treated for dengue infection at these sites over two years, less than 1 percent fit all four criteria necessary to meet the WHO definition of DHF. However, 11 percent had at least one manifestation of severe dengue disease, and a total of 23 percent required hospitalization due to dengue-related symptoms.

"Dengue exists more as a continuous spectrum," Dr. Wichmann said. "Severe disease can be present in patients who do not fulfill all four DHF criteria."

"The term 'dengue hemorrhagic fever' puts undue emphasis on bleeding," he added, noting that plasma leakage and shock can occur without it. "Clinicians who mainly focus on bleeding...may miss the most important conditions that require hospitalization and treatment."

Their findings also showed that travelers who acquire a second dengue infection are more at risk for severe cases of dengue, although some patients had severe symptoms when infected during their first trip to a dengue-endemic country.

It is becoming more and more crucial that health care providers understand the clinical spectrum of dengue and its diagnosis. "Given the increase in business travel and other travel, and the global spread of dengue fever, these findings have important implications for the future burden of severe imported dengue infections," Wichmann said. "It will also be of great interest to business and leisure travelers, and expatriates, who have experienced one dengue infection and are concerned about this risk of returning to a dengue endemic area."

As a next step to their study Wichmann highlighted the need for more inquiry into a clinical definition of dengue. "In order to perform more uniform surveillance and research, including vaccine trials, studies are urgently needed to establish new and more robust definitions for severe dengue."

Rabies treatment team urges veterinary schools to scientifically define the Milwaukee protocol

The appeal, by Rodney Willoughby, M.D., associate professor of pediatrics, appears in the April 2007 issue of Scientific American. In it he chronicles the scientific rationale behind the survival of a 15-year-old Wisconsin girl, Jeanna Giese, in 2004 and the six subsequent attempts made elsewhere to replicate the treatment, now dubbed the Milwaukee protocol.

"Our novel treatment has stirred controversy among medical specialists; some claim that Jeanna's cure was a fluke," says Dr. Willoughby. "Although the few attempts to replicate the treatment have not saved the lives of any other rabies patients, I fervently hope that we are on the right track. At the very least, researchers should initiate animal studies that parallel treatments in humans to determine which of the elements in our protocol can help defeat rabies."

Promising new research by Dr. Willoughby and faculty colleague Jeanette Vasquez-Vivar, Ph.D., along with Atlanta researchers, Dr. Keith Hyland at Horizon Molecular Medicine and Dr. Charles Rupprecht at the Centers for Disease Control and Prevention, offers new hope for a cure of this heretofore 100 percent fatal disease.

The researchers have discovered a deficiency of a vitamin-like molecule in rabies patients. The molecule, biopterin, can be supplemented and promises to make rabies even more treatable than it was when Jeanna survived.

According to Dr. Willoughby, of the six attempts by others to replicate the treatment, only two closely followed the protocol, and these two children survived twice as long as the average for rabies patients in the U.S. Although they ultimately died from complications of the disease or their care, both were clearing rabies virus from their bodies when they died.

"The sense is that we're very close to a second survivor," he says. "What is needed most is an animal model of rabies. Meanwhile, treatment of human rabies in medical intensive care units continues haphazardly, without scientific input."

Vaccines against the rabies virus can prevent development of the illness after a bite by an infected animal. But, until recently, doctors could hold out no hope for patients who failed to get immunized soon after being bitten. Once the symptoms of rabies appeared -normally within two months of the bite- death was inevitable, in a week or less.

Having pushed survival with human rabies from one week (untreated) to almost four weeks with the Milwaukee protocol, virtually nothing is known about how the body responds that far out. The problem, according to Dr. Willoughby, is that animal studies will also require intensive care of animals for a week or more. The researchers hope to find these answers by treating rabid animals in veterinary intensive care units.

Rabies is one of the oldest and most feared diseases. It attacks the brain, causing agitation, terror and convulsions. Victims suffer painful throat spasms when they try to drink or eat. Paralysis follows, yet people infected with rabies are intermittently alert until near death and can communicate their fear and suffering to family and caregivers.

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