Sep. 10, 2003 How fat contributes to high blood pressure is the focus of a new study at the Medical College of Georgia that is part of a National Institutes of Health initiative to understand the relationship between obesity and cardiovascular disease.
"You have obesity and you have hypertension. Where is the link?" says Dr. Gregory A. Harshfield, principal investigator on the $1.4 million grant from the NIH's National Heart, Lung and Blood Institute that will study 160 adolescents, half lean and half overweight or obese, in pursuit of that link. Dr. Paule Barbeau, exercise physiologist, is a co-investigator
Obesity is a risk factor for high blood pressure, which is a major risk factor for cardiovascular disease.
The Augusta researchers and others leaders in the field of hypertension say that obesity may increase pressure by increasing volume rather than constriction.
"We think it's increased volume because of sodium handling," Dr. Harshfield says. "When we put people under stress, the normal response is to increase your blood pressure through vasoconstriction." The kidneys also hold onto sodium to help increase blood volume throughout the body. As the stress ends, so should these normal physiological responses.
But Dr. Harshfield's studies at MCG's Georgia Prevention Institute have shown that some people keep holding onto sodium long after the stress has gone, delaying a process called natriuresis, the body's way of eliminating sodium. His studies have shown this mechanism is impaired in about 30 percent of adolescent blacks and 15 percent of adolescent whites; the prolonged, elevated pressures may contribute to the development of hypertension.
Fat, or adipose tissue, was once considered storage material only, says Dr. Barbeau. "Now we realize that it secretes all kinds of substances, such as angiotensinogen (which constricts blood vessels) and leptin. The more fat you have, the more of these substances you make."
And different fat depots secrete different substances. Subcutaneous fat, or fat under the skin, secretes leptin, an appetite suppressant also involved in functions such as reproduction and blood pressure regulation. Visceral fat, packed in and around the organs in the abdominal cavity, secretes angiotensinogen, which makes angiotensin II, a powerful vasoconstrictor that also directs the kidneys to absorb more sodium.
"When you gain weight, leptin is supposed to be secreted by the adipose tissue and that tells your brain, 'Don't eat that much,'" Dr. Barbeau says. "But for some reason, in obese people, that feedback loop doesn't work any more," she says, equating the scenario to a type 2 diabetic's resistance to insulin.
Another leptin-driven system seems to fail as well in the obese and contribute to hypertension. Leptin tells the brain to keep producing the neurotransmitter catecholamine which gears up the stress-triggered sympathetic nervous system. Catecholamine, in turn, is supposed to shut down leptin production, but, inexplicably, that doesn't happen either, says Dr. Harshfield.
The researchers say that stress increases angiotensin II levels and therefore blood pressure. Furthermore, in obese individuals, fat-produced leptin and angiotensinogen keep the blood pressure up by interfering with the natural process of sodium excretion that should occur when the stress is gone. The net result may be early development of hypertension and the damage it causes major organs such as the heart and kidneys.
"How stress interacts with fat in the production of damage to the kidneys is what we are looking at primarily," Dr. Harshfield says. "I think what we are going to see is that in the high-fat kids, the stress will produce greater sodium retention and longer levels of elevated blood pressure."
The MCG researchers began recruiting the 15- to 19-year-olds this fall, a mixture of black and white males and females. Each participant engages in a protocol developed by Dr. Harshfield that includes two hours of rest followed by an hour-long stressful video game, then two more hours of rest. Blood pressure and sodium excretion are measured throughout. Participants are put on a diet for three days prior to the test protocol to regulate their sodium levels. They also get a dual-energy X-ray absorptiometry, or DXA, study to measure body fat, and an MRI at MCG Medical Center to assess visceral fat in the abdominal cavity, as well as studies to look at the size of the heart's pumping chamber and kidney function.
"This is a logical place to go with the work we already are doing," Dr. Harshfield says, which is why he opted to pursue the proposal request from the National Heart, Lung and Blood Institute for novel approaches to help clarify the biologic basis of obesity-related cardiovascular problems such as hypertension and atherosclerosis.
Today more than 60 percent of Americans are either overweight or obese and Drs. Harshfield and Barbeau have seen some of the ill effects in the young people who come to the Georgia Prevention Institute with hopes of being a healthy participant in a study only to learn they already have high blood pressure or other problems.
"This is a highly meritorious application from an established productive (principal investigator) and outstanding investigative team," reviewers of the grant proposal wrote. "The goal of this study is to test a hypothesis that links adolescent obesity to cardiovascular disease through impaired stress-evoked pressure natriuresis. This is an interesting and novel hypothesis, and will be adequately approached by the proposed studies. Whether or not the hypothesis turns out to be correct, important new data will result from the proposed study."
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