Type A and can't handle it?

September 27, 2002

ROCHESTER, Minn. -- Mayo Clinic researchers today identified a genetic basis for the heart's ability to withstand fight-or-flight responses: a protein called Kir6.2 enables the heart to react to stress without distress.

Mice lacking this key protein had reduced cardiac tolerance for both exercise- and adrenaline-like stress. Nearly three-quarters (73 percent) of the Kir6.2-deficient mice died within 14 minutes after a stressor challenged their cardiac response -- yet all the mice that possessed Kir6.2 survived the stress tests.

As reported in the Oct. 1 edition of Proceedings of the National Academy of Sciences, the research provides provocative leads to understanding and treating stress-related disorders of the heart. These may range from sudden death of highly conditioned athletes to the cumulative effects of psychological stress at work, school or in family life.

"We have identified in the heart a protective mechanism against stress that is roughly analogous to an automatic sprinkler system that douses a fire in an emergency," says Andre Terzic, M.D., Ph.D, lead researcher. "The Kir6.2 protein senses stress and prevents damage to the heart by helping the cells maintain equilibrium even under peak workloads. Lack of Kir6.2 protein function causes sudden, irreversible damage to heart cells, which could lead to heart failure."

In the study, the Mayo Clinic team led by Dr. Terzic compared mice in which the gene that produces the Kir6.2 protein had been eliminated to a control group of mice that possessed the Kir6.2 protein. Their goal was to determine whether Kir6.2 enables heart cells to maintain high levels of activity without suffering damage, and to discover how it works.

Study Findings

In treadmill testing, the normal mice tolerated more than three times the workload that the Kir6.2-deficient mice could. Both groups of mice were also tested under stress induced by a compound similar in effect to adrenaline, the body's natural fight-or-flight hormone. In mice lacking Kir6.2, hearts did not contract as completely under stress -- and 73 percent developed severe heart rhythm disturbances called arrhythmias, then died suddenly.

By contrast, none of the normal mice experienced a fatal arrhythmia.

Study Significance

Kir6.2, a protein common to all animals, is at the core of the KATP channel complex that choreographs an intricate chemical dance between potassium and calcium flow in the heart. By conducting potassium, the KATP channel enables the cells to more quickly restore electrical balance following each heartbeat, thus limiting the entrance of calcium into the cells.

"The system needs to be fully orchestrated," says Dr. Terzic. "It must have perfect harmonization to bring sufficient calcium for contraction without overdoing it." When the orchestra is "off tempo," the chemical dancers are out of step. The result: cardiac distress under stress.

The Mayo Clinic study found that heart cells in the mice lacking Kir6.2 overloaded with calcium -- and this damaged cell structure. Administering calcium-channel blockers, a common heart medication, to those Kir6.2-deficient mice prevented the fatal arrhythmias in five out of six.

Thus, the Mayo Clinic study shows that Kir6.2 is crucial to survival under the sudden rush of cardiac output required by the flight-or-fight response of the sympathetic nervous system to threats -- be they from a saber tooth cat or a bear market. "Because of the selective advantage it confers, Kir6.2 has been maintained through evolution in the gene package of many organisms," explains Dr. Terzic.

The next steps for the Mayo Clinic researchers will be developing the diagnostic and therapeutic potential of these findings. A blood test could identify individuals who are deficient in KATP channel proteins, or whose supporting protein-signaling system isn't working, and drug or gene therapies could compensate for those deficiencies. "Understanding that this protein is so important, we can now work on ways to repair it when defective within the cells, or to boost its ability to respond," Dr. Terzic concludes.
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Additional Contact information for Lee Aase: 507-284-2511 (evenings)

Mayo Clinic

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