Research Points to Defect That May Yield Abnormal Heart Muscle Function

A leading cause of death, hypertension enlarges the heart, reduces heart muscle function and ultimately produces heart failure. A University of Wisconsin Medical School researcher and his collaborators can now explain a cellular defect that causes enlarged hearts to contract weakly.

Appearing in the May 2 issue of Science, the findings may help cardiologists treat hypertension, hypertrophy (enlarged heart) and heart failure more effectively.

In healthy heart muscle cells, contraction occurs when electrical signals tell a cell-surface protein to let in a small amount of calcium, which activates another protein inside the cell, causing it to release massive amounts of calcium from cellular stores. An elevation of cellular calcium is the event that leads to contraction of the heart.

The researchers studied heart muscle slices of rodents with hypertrophy stemming from hypertension. A special confocal microscope was used to monitor the two proteins, also known as ion channels, through which the calcium flows. Measuring the elevation of cellular calcium in specific cell regions, researchers found that in the hypertrophic rats, not enough calcium from the cell surface channel reached the internally situated channel for it to respond appropriately.

“Not enough calcium was transferred because the hypertrophy increased the physical distance between the two ion channels,” said UW Medical School assistant professor of physiology Hector Valdivia, noting that no defects were found in the channels themselves. “As a result, there was an insufficient level of calcium for the heart to contract normally.”

In a similar experiment using rats with heart failure, the reseachers found the same structural problem.

Valdivia, a member of the UW Cardiovascular Research Center, said hypertrophic heart cells in this situation normally compensate by providing the internal ion channel with an adrenaline-like chemical that yields the same flood of calcium. Muscle cells from the hypertrophic rats responded in this compensatory way, but cells from the animals in heart failure did not, he said.

The UW scientist said that by stopping hypertrophy-causing hypertension at an early enough stage, the heart can resume its normal size and the related distance problem between the ion channels can be reversed.

“However, if the hypertension and hypertrophy persist, the channels can become burned out or desensitized to the adrenaline-like stimulation and once this occurs, the situation is no longer reversible,” he said.

Cardiologists may use this new information to try harder to reduce hypertension before burn out results, said Valdivia, or drug companies may consider developing adrenaline-like therapies that improve heart contraction.

Collaborators on the project include scientists from the University of Maryland School of Medicine, the National Institute on Aging, St. George’s Hospital Medical School (London) and the Ohio State University.

CONTACT: Dian Land, 608-263-9893, dianland@macc.wisc.edu