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Hypertension is study focus of $10 million NIH grant to MCG

Medical College of Georgia at Augusta University



Dr. Treiber looks on while Sarita Vemulapalli performs an echocardiogram on study participant, Kimberly Hawkins.

Full size image available

A team of researchers is putting together key pieces of the puzzle of hypertension - stress, genetics, sodium retention and fitness - to define the role of each in a condition that impacts 20 percent of all adults and an even higher percentage of black adults.

The Medical College of Georgia researchers have received a $10 million Program Project grant from the National Institutes of Health to better identify young people at risk and provide them effective prevention programs.

For those who already are hypertensive, the work will enable development of more effective, targeted treatment to avoid the ravages of this risk factor for cardiovascular disease, stroke and other major organ damage.

"The theme of the grant is that environmental stress, particularly in combination with a genetic predisposition and unhealthy lifestyle behaviors are major contributors to the development of essential hypertension," said Dr. Frank Treiber, director of the Georgia Prevention Institute and principal investigator on the grant that begins July 1.

The diverse team of 17 researchers on the grant combines expertise in long-term studies of the impact of environmental stress on young people with a family history of hypertension with exercise physiologists studying how physical activity impacts the body with basic scientists studying the body's natural mechanisms for regulating blood pressure.

The grant makes it possible to further mesh these studies in humans with those in the laboratory, Dr. Treiber said. Their collective findings already show people with the highest blood pressure changes in response to behavioral stressors in the laboratory tend to be the same people who develop higher levels of resting blood pressure and increased muscle mass of the left ventricle, the heart chamber that pumps blood out to the body. They've also found that blacks tend to be among the biggest responders to the laboratory stressors. They've shown that in some people, blood pressure remains elevated for long periods after stress, even sometimes through the night, and have identified mechanisms, including increased sodium retention following stress, that help explain why. They've also found evidence about how abnormal responses to stress and sodium occur, how damage to the blood vessels results and how it might be prevented.

One project under the NIH grant will continue Dr. Treiber's longitudinal studies of children with a family history of hypertension. But now he'll be looking at whether environmental stressors such as low socioeconomic status and high personal stress packaged with genes that predispose children to have an exaggerated blood pressure response to stress ultimately results in the development of hypertension.

In the cohort of 500 young people he has followed since 1985, he will monitor changes in three body systems important to blood pressure regulation during laboratory stressors such as challenging video games and discussions of recent stressful events. He'll also study the genes that control those systems, including the sympathetic nervous system that responds to stress, the kidneys that control fluid and salt regulation and the endothelin system that controls blood vessel constriction. He'll continue to look for early indicators of elevated pressures, such as an increase in muscle mass of the left ventricle and decreases in the elasticity of arteries.

The second project will look at why some people's blood pressure doesn't come down following stress and the genes that are responsible. "What we are looking at is how stress impacts long-term blood pressure regulation as opposed to the acute response," said Dr. Gregory A. Harshfield, physiological psychologist at the GPI and a project leader on the $10 million grant.

He's already found that the kidneys of some young, healthy blacks tend to retain sodium even after the stress that elevated their blood pressure is gone. One way the body increases blood pressure is by regulating sodium retention and Dr. Harshfield has found that some healthy blacks have an impaired ability to excrete sodium in the urine. "Sodium excretion between those who retain and secrete salt is the same prior to the stressor. It's not until you introduce stress that you start differentiating."

He will seek to identify the genes responsible so he ultimately can identify the hormones responsible. "During stress, there is an increase in (the hormone) norepinephrine that increases (the vasoconstrictor) angiotensin 2 and that increases aldosterone," a hormone produced by the adrenal gland to get the kidneys to absorb more sodium, he said. "Which is the initiator? Where is the original abnormality? Once you find out what that abnormality is, you can find therapies to target that. That's my goal," Dr. Harshfield said.

Another goal is to explore whether this impaired system of sodium retention - which he found in 30 percent of healthy blacks he has studied and 15 percent of healthy whites - is the mechanism that makes some people have elevated pressures throughout the night. During sleep, blood pressure rates should drop significantly.

But in some people, especially blacks, rates remain high throughout the night, increasing the stress on the cardiovascular system. "If you look at blood pressure curves for black and whites, there is about a 10-year shift," he said. Blacks tend to develop the condition 10 years earlier and have higher pressures. "That shift may occur at nighttime when blood pressure should be dropping," Dr. Harshfield said.

A third project relates to the kidneys and salt sensitivity as well as the natural balance of blood vessel constrictors and dilators that goes awry in hypertension. The collaboration of Drs. Jennifer and David Pollock from the Vascular Biology Center with Georgia Prevention Institute researchers began in 1996 when Dr. David Pollock heard Dr. Treiber talk about how the black children he was following had greater blood pressure reactivity to stress than whites. Dr. Pollock told him afterward that elevated levels of the powerful vasoconstrictor, endothelin, could explain why.

The researchers don't know why blacks have higher levels of endothelin - it's likely related to environment, genetics or both - but they believe that elevation explains increased sodium retention. They think this happens when the combination of stress and salt disturbs the body's balance of the vasoconstrictor, endothelin, and the vasodilator, nitric oxide.

The truly novel part of the study is the idea that stress releases superoxides, a type of free radical, which is toxic to cells, Dr. Jennifer Pollock said. Superoxides and other free radicals are often found in the body, but the body has defense mechanisms to overcome them. The Pollocks theorize that in their animal model, Dahl salt-sensitive rats, as well as people who are sensitive to stress and salt, the buffering systems, which include enzymes that gobble up superoxides, aren't working well. They've shown that salt-sensitive animals make more superoxides when stressed. The grant will enable them to look at ways - which will have applications in humans as well - to get the system back in balance and prevent the blood vessel damage caused by too much endothelin.

A fourth project will look at exercise and its potential for improving the dilatation of blood vessels. "We think exercise will increase the amount of nitric oxide and decrease circulating endothelin," said Dr. Paule Barbeau, exercise physiologist at GPI. She and Dr. Bernard Gutin, an exercise physiologist and project leader on the NIH grant, are collaborators on the studies.

One of the exercise studies under way at GPI will be expanded under the grant. The study, which is looking at the impact of exercise on the cardiovascular fitness of black girls in the third, fourth and fifth grades, will be expanded to include black boys in the same age group. The children are enrolled in either a 10-month exercise program or a control group. During the school year, children in the exercise program exercise in the after-school hours; this summer they are exercising on weekday mornings. They have a period of skills instruction, such as learning to dribble a basketball, followed by 40 minutes of sustained aerobic activity, such as dance routines or volleyball, followed by 10 minutes of strength training and 10 minutes of stretching. Heart rates, body composition and weight measurements are recorded; under the new grant, the children also will have circulating endothelin levels measured, studies to look at the heart mass and function and give urine samples so kidney function can be studied.

The children also will get genotyping to pursue the hypothesis that although all the children may increase their nitric oxide levels with exercise, some have a genetic predisposition to a better response, Dr. Barbeau said. "I think this is one of the reasons that, if you take two people who are similar and put them both through the same exercise program, one may respond really well and the other doesn't." She wants to understand the gene-environment interaction because it may help identify ways to help the children whose genetics interfere with the beneficial effects of exercise.

"It's very exciting," Dr. Treiber said of the Program Project grant that is enabling the extensive collaboration. "This would not have been possible without the vision of the Dr. William Strong, the founder of the Georgia Prevention Institute; the support of the administration at the medical college in providing us the opportunity to recruit over the past several years this group of highly-accomplished investigators all working around the central theme of stress and the resources necessary to conduct our earlier studies which provided the foundation for the Program Project.

This grant will enable us to collectively accomplish much more than what each of us would have been able to do in our own labs."

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