Type of stress, not duration, key to heart enlargement

DURHAM, N.C. -- When judging whether or not an enlarged heart is healthy or potentially at risk for heart disease, the nature of the physiological stress that produced the enlargement is more important than the duration of the stress, according to a new study led by Duke University Medical Center investigators.

This distinction has significant clinical implications, the researchers said. While enlargement of the heart can be a natural and beneficial response to exercise training, it can also be an early warning sign for such harmful conditions as heart failure.

These findings, based on a series of experiments in mice, could help settle a long-running controversy among cardiologists concerning heart enlargement, or cardiac hypertrophy, according to Duke cardiologist Howard Rockman, M.D., who led the team of Duke and University of North Carolina-Chapel Hill researchers.

The researchers published their findings on June, 1, 2006, in the Journal of Clinical Investigation. The study was supported by the National Institutes of Health.

"If you look at the hearts of athletes, they are larger than normal," Rockman said. "On the other hand, patients with high blood pressure also tend have larger-than-normal hearts. So why are some cardiac overloads, such as exercise, good for the heart, while others, such as high blood pressure, not?"

In athletes, the heart's pumping chambers enlarge to compensate for the body's increased demand for oxygen-rich blood. But in patients with heart failure, the heart walls themselves become thicker, heavier and less efficient in pumping blood.

"For more than a century there has been intense debate over why some stresses or overloads on the heart are beneficial and others lead to disease," Rockman continued. "The prevailing wisdom was that since exercise is an intermittent event and high blood pressure is a chronic condition, the duration of the cardiac stress was key. However, our studies appear to demonstrate that it is not the duration of stress that leads to a disease state, but rather its nature."

Their studies demonstrate that intermittent occurrences of cardiac stress in the form of high blood pressure, or hypertension, initiates a cascade of events that eventually leads to abnormalities in heart muscle cells as well as damage to blood vessels. The studies also showed that these potentially harmful responses can begin before the heart itself begins to enlarge, the researchers reported.

To test their hypothesis, the researchers developed a novel method for inducing hypertension in mice. The researchers tie a "slipknot" around each mouse's aorta with a suture, which they manipulate from outside the mouse through a small incision in the back. For their experiments, the researchers tied off, or occluded, the aortas in one group of mice for 90 minutes twice a day. A second group of mice exercised for 90 minutes twice a day, either by swimming or running in a wheel.

At various intervals, the researchers performed detailed genetic and histological analyses of the hearts and cardiovascular systems of all the mice. Comparisons between the exercising mice and hypertensive mice highlighted important differences quite early, Rockman said.

"After seven days, the hearts of the swimming mice were gorgeous," he said. "The hearts of the hypertensive mice were similarly enlarged and appeared from the outside to be functioning normally, but individual heart muscle cells already showed significant structural and cellular abnormalities."

Specifically, the researchers found a pronounced alteration in the function of beta-adrenergic receptors located on the surface of the heart muscle cells. These receptors, are protein switches that nestle in the cell membrane and are activated by the hormone adrenaline to enhance the heart's pumping action in response to exercise or stress.

"When blood pressure increases, it causes the myocytes to stretch," Rockman said. "We believe this stretching releases factors into the bloodstream that interfere with the integrity of the endothelial lining of blood vessels."

Rockman said that while endurance exercise, such as running and swimming, is beneficial in that the increased load on the heart is not harmful to myocytes, other activities that cause blood pressure spikes could lead to the pathological form of hypertrophy.

"We would predict that weightlifters, for example, would exhibit heart enlargement like that seen in the abnormal mice in our experiments because they have sudden bursts of extreme overload," he said. "We would also predict that patients suffering from sleep apnea, who often wake up suddenly in a panic state, would also have hearts like our abnormal mice. It appears that like many other things in life, moderation is the best policy.

"Our results indicate that hypertrophy of the heart is a time-dependant reaction to cardiac stress that by itself does not necessarily lead to negative effects on the heart," Rockman said. "Instead, it appears that the molecular signature of the overloaded heart, not the growth itself, is the trigger that leads to either cardiac adaptation or decline."

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Duke members of the team included Cinzia Perrino, Sathyamangla V. Naga Prassad, Lan Mao, Takahisa Noma and Zhen Yan. University of North Carolina, Chapel Hill collaborators included Hyung-Suk Kim and Oliver Smithies.


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