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November 23, 2005


Black heart patients fare better in hospital

Racial disparities in cardiovascular outcomes are well-established, however new findings from Pitt researchers indicate that African Americans fare better in the short term following coronary interventions.

Oscar Marroquin, assistant professor of medicine at the Pitt School of Medicine, and colleagues studied the data of 3,692 white and 987 black patients enrolled in the multi-center National Heart Lung and Blood Institute Dynamic Registry who underwent coronary interventions between July 1997 and May 2004. Researchers compared the rates of myocardial infarction (heart attack), coronary bypass surgery, death and revascularization of patients at one-month, six-month and one-year intervals.

Despite having more adverse characteristics such as diabetes and high blood pressure, more acute myocardial infarction and less stent implantation, blacks were found to have a 70 percent lower risk of dying while in the hospital and better one- and six-month outcomes following their coronary interventions.

Those differences dissolved at the one-year mark, pointing to the need for aggressive adherence to risk-reduction recommendations.


Brain imaging studies offer Alzheimer’s clues

An imaging agent that binds to the telltale beta-amyloid deposits in the brain of Alzheimer’s patients is giving researchers information never before available about how and where the disease progresses in the brain.

Pitt researchers recently presented results involving Pittsburgh Compound-B (PIB) at the annual meeting of the Society for Neuroscience.

Before PIB, there had been no way to non-invasively monitor what occurs in the brains of Alzheimer’s patients, a significant barrier to studying disease progression and monitoring the efficacy of treatments.

PIB, which was developed at Pitt, gives researchers a picture of beta-amyloid or amyloid plaque deposits in the brain when coupled with positron emission tomography (PET).

The distinguishing factor between Alzheimer’s disease and other dementias is the presence of amyloid plaques that are thought to kill brain cells.

Previously, a definitive diagnosis of the disease could only be made through an autopsy after the patient’s death, typically at a very late stage of the illness.

Studies have demonstrated that PIB can detect the accumulation of amyloid plaques when patients are alive. This could lead to accurate diagnosis of Alzheimer’s disease at very early stages.

One Pitt study reported at the Society for Neuroscience meeting suggests that, based on the pattern of PIB retention in the brain, amyloid plaques deposit sequentially — first in the cingulate cortex/precuneus and frontal cortex areas, then in the parietal and temporal cortex and caudate. Finally, the disease ravages the occipital cortex and sensory-motor cortex. These findings may explain why memory and judgment are often the first brain functions affected in Alzheimer’s disease.

“We’ve had hints about the time course of brain changes in Alzheimer’s disease from autopsy studies but the current findings in living patients take these observations further,” said William E. Klunk, associate professor of psychiatry at the School of Medicine and co-inventor of PIB.

“If we can delineate the natural history of brain changes in Alzheimer’s disease, we then have a baseline against which to judge the success of therapies designed to prevent these changes,” he said.

The researchers hope that PIB soon will be used in clinical trials of Alzheimer’s therapies. To meet this goal, they have developed a simpler method for analyzing PIB study data, described in a separate study presented by Pitt radiology professors Chester A. Mathis and Julie C. Price.

The original approach required patients to have arterial blood samples drawn over the span of 90 minutes to define how much PIB actually got to the brain. Researchers then used a complex modeling analysis to determine where PIB had accumulated, signaling the location of amyloid plaque deposits.

In the current study, researchers found it may someday be possible to use PET scan data in place of the blood sampling, although arterial sampling may continue to be necessary for some uses of PIB.

Researchers believe that patients will be more comfortable participating in PIB research if arterial blood sampling can be eliminated. The simpler approach also will allow researchers at other centers to use PIB for large-scale investigation.

The National Institute of Mental Health, National Institute on Aging, the Alzheimer’s Association, U.S. Department of Energy and GE Healthcare supported the research.


Gene therapy advances may benefit heart patients

A Pitt research team reported at a meeting of the American Heart Association that it has found a gene vector that carries an inhibitor of metalloproteinase-2 (MMP-2), protected experimental mice from cardiac damage and death following a heart attack.

MMP-2 is a protein that has been shown to stimulate abnormal healing in heart tissue after a heart attack.

The benefits also correlated with a partial restoration of the normal ratios between MMP-2 and its specific inhibitor, tissue inhibitor of metalloproteinase-2 (TIMP-2).

Further studies are needed to determine the mechanism of this protective effect.

“Induction of metalloproteinases has been shown to contribute to adverse remodeling of cardiac tissue after myocardial infarction,” said Charles McTiernan, research assistant professor in the Department of Cardiology at the School of Medicine. “It has been hypothesized that supplementing post-MI tissue with TIMP-2 can normalize the balance of metalloproteinases and their specific inhibitors and protect against the damage of myocardial infarction.”

To determine if gene therapy could be used to improve outcomes following a heart attack, McTiernan and his co-workers gave one group of mice with experimental myocardial infarctions (MI) an injection of viral particles containing the TIMP-2 gene and compared their outcomes to untreated MI and control mice.

The investigators then assessed the left ventricular size and function of the surviving mice seven days after their myocardial infarction and also measured MMP-2 and -9 and TIMP-1 and -2 protein levels.

Among the mice that died, the major cause of death was rupturing of cardiac tissue. Among the mice that survived, left ventricular systolic function was not different between the treated and untreated MI mice. However, levels of MMP-2 and -9 were highest in the untreated MI group.

TIMP-1 levels were higher in all MI hearts compared to controls, but there was no significant difference between the treated and untreated MI groups. TIMP-2 levels, however, were highest in the treated MI group. Overall, 34 mice survived until the end of the study period, and survival was significantly better in the TIMP-2-treated group compared with the untreated MI group (56 percent vs. 34 percent).


More serotonin receptors, more fear

How we respond to stressful situations and difficult times could be due in part to dominance of one cell-surface marker over another in a region of the brain involved in regulating emotional responses and behaviors, results of a Pitt study presented at the annual meeting of the Society for Neuroscience suggest.

These two markers — both receptors that determine what effect the neurotransmitter serotonin has on a neuron — appear to be key intermediaries influencing emotional state and behavior during stress.

In a localized area of the prefrontal cortex, where thought and action are orchestrated, the number and ratio of serotonin receptors were found to be correlated directly to the activity of another part of the brain called the amygdala, critical for producing emotional states such as fear.

According to Ahmad Hariri, who led the research, these findings bring focus to what could be a fundamental factor contributing to the development of risk for psychiatric disorders and a key molecular mechanism to target as new therapies are developed.

A great deal of research has looked at the association between the amygdala and emotional behaviors and psychiatric diseases such as depression and anxiety, but relatively few studies have considered the added importance of the subgenual prefrontal cortex and its relationship to amygdala activity. The subgenual prefrontal cortex is one area where communication, or cross talk, takes place between the impulsive, reflexive amygdala and the more logical, staid prefrontal cortex.

“Our previous findings suggest that the subgenual prefrontal cortex provides an important forum for the cross talk that is necessary for regulating emotions and emotional behaviors. Now we’re learning that serotonin receptors in this region are serving as important mediators in that discussion, contributing to how we will eventually behave or respond in stressful situations. It’s as if they help set the tone of the discussion or determine if there will even be a discussion in the first place,” explained Hariri, assistant professor of psychiatry.

He also is the director of the Developmental Imaging Genomics Program at the School of Medicine and Western Psychiatric Institute and Clinic.

Research associate Patrick M. Fisher presented the group’s preliminary results involving 18 normal subjects.

The study is one of the few to collect data in research subjects using two different imaging methods, allowing for more complete interpretations to be drawn about the relationship between molecular changes in the brain and differences in behavior. The subjects underwent functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) tests.

Those subjects in whom PET showed a higher number of serotonin 5-HT1A receptors relative to 5-HT2A receptors in the subgenual prefrontal cortex had less brain activity in the amygdala during fMRI, as would be expected, since 5-HT1A is the inhibitory receptor. Yet, in these same subjects, the amygdala was much more stimulated than those who had a lower 5-HT1A-to-5-HT2A ratio or just more of the 5-HT2A receptors.

In essence, the researchers found that these specific serotonin receptors seem to help control the extent to which any rational “discussion” takes place in the subgenual prefrontal cortex. And absent the voice of reason, the amygdala can behave as it wishes.

“With this new information about cellular and molecular structures, we’re getting a more complete picture about the factors that lead to the activity of specific brain circuits that help determine emotional behavior,” said Hariri.

In earlier studies, Hariri and his colleagues established the brain basis of a relationship between genetic variation and behavior. Studying people who carry a form of a gene necessary for determining expression of the serotonin transporter, and who, because of this variation, are more vulnerable to develop depression in the face of stressful and difficult life circumstances, the researchers found less cross talk in the subgenual prefrontal cortex as well as greater amygdala activity.

Hariri plans to conduct additional studies to determine the impact this genetic variation has on individual differences in these serotonin receptors and the resulting activity of the subgenual prefrontal cortex and amygdala.

Collectively, the results of such studies should provide greater understanding of the specific biological pathways, from genes to molecules to brain circuits, that contribute to risk for disease.

Others who contributed to the research include Scott K. Ziolko, Julie C. Price and Carolyn C. Meltzer of radiology, and Eydie Moses-Kolko and Meryl Butters of psychiatry. Another author, Sarah L. Berga, is now at Emory University.

The research was supported by the National Institute of Mental Health of the National Institutes of Health.

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