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New Cause of Heart Disease Discovered

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February, 2003- Rarely does MBC research excite anyone outside scientific circles, but a paper in Nature has done just that. Dr. W. Jonathan Lederer , Director of the MBC and head of its Institute of Molecular Cardiology , has discovered a new mechanism for a form of sudden cardiac death (SCD), called "Long QT Syndrome, Type 4" (LQT4). Cardiovascular disease, of which cardiac arrhythmia and SCD are major symptoms, and stroke are the leading causes of death world-wide. Dr. Lederer led the investigation into the cellular cause of this inherited arrhythmic disturbance.

Using state-of-the-art instrumentation and a novel animal model, the research team examined why members of a family in France died suddenly and unexpectedly in the prime of life. Lederer and his team collaborated with other primary investigators from Duke University headed by Drs. Vann Bennett and Peter Mohler and with investigators at INSERM in Nantes, France, headed by Dr. Denis Escande. Key local investigators included Drs. S. Guatimosim, L-S. Song and K. Dilly from MBC and T. B. Rogers and W. duBell from the School of Medicine at University of Maryland, Baltimore.

The genetic defect in humans and in the mouse model was an inadequate amount of an important "adaptor" protein, ankyrin-B. This protein links one protein to another, permitting other proteins to be properly located within the structure of a cell. In the reduction or absence of ankyrin-B, proteins involved in cellular calcium regulation are placed improperly. This leads to an abnormal increase in the amount of calcium within the heart cell. This change in calcium causes the heart to beat improperly and, in the case of LQT4, chaotically. Interestingly, this does not happen all of the time and rarely in young individuals. The rare occurrence of the development of calcium-dependent electrical chaos in the heart accounts for the fairly normal behavior of the heart for most people who are afflicted with LQT4. The fatal event appears to be triggered by unexpected stress and possibly an increase in adrenaline - as would happen when individuals are startled. Even then, the death-causing electrical chaos is rare. Humans and animals are afflicted with LQT4 when only one of the two genes for ankyrin-B is defective or absent. When both are absent, the condition is lethal.

This research caused an immediate response in the scientific community, with two commentaries being published almost immediately. One was in same volume of Nature as the article; the other in Nature Medicine in March, 2003. The public became aware of this ground-breaking research when Dr. Terry Rogers, one of the collaborators, was interviewed by Donna Hamilton of WBAL-TV on the day the paper was published. The segment was aired on WBAL's 5:00 p.m. news program. Numerous other secondary sources have picked up on the research around the world.

By discovering the molecular and cellular causes of LQT4, Lederer and his colleagues open the door to possible therapies for this and related heart diseases. Furthermore, the work provides a clue to how important, specific proteins are organized within the cell and this too may lead to new diagnostics and therapies for heart disease.

Mohler, P.J., Schott, J.-J., Gramolini, A.O., Dilly, K.W., Guatimosim, S., duBell, W.H., Song, L.-S., Haurogn, K., Kyndt, F., Ali, M.E., Rogers,T.B., Lederer, W. J., Escande, D., Le Marec, H., Bennett, V. (2003) Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421(February 6):634-9.

Nattel, S. (2003) Lost anchors cost lives. Nature 421(February 6):587-590

Marks, A.R. (2003) Arrhythmias of the heart: beyond ion channels. Nature Medicine 9 (3):263-4

http://www.umbi.umd.edu/mbc/special-features/new-cause-of-heart-disease.php