Mayo researchers are the first to realize that these proteins do not recognize the stress alarm. As a result, they can't properly respond to cue adjustments within the heart that normally manage stress. These defects make the heart muscle susceptible to damage. The Mayo Clinic research team's report appears in the journal Nature Genetics, v. 36; no. 4, April 2004 (www.nature.com).
Research team leader Andre Terzic, M.D., Ph.D., a specialist in cardiac biology, describes the work as groundbreaking because it reveals critical molecular mechanisms which may in turn point to possible new treatments for heart failure. "Very little is known about stress tolerance of the heart in health and disease," says Dr. Terzic. "This discovery opens a new field of investigation in cardiovascular medicine as we uncover how and why the heart becomes vulnerable to stress."
In addition to collaborating with other researchers from Mayo Clinic, Dr. Terzic's team drew upon the expertise of the University of Minnesota Supercomputing Center to help model the shape of the protein under investigation.
Significance of the Findings
The significance of the Mayo Clinic findings is threefold. It: 1) for the first time, views heart failure as a communication or signaling problem in the stress-management system of heart cells, 2) tests the idea in human beings, and 3) offers convincing evidence that miscommunication of stress signals distresses the heart and plays a role in susceptibility to heart failure.
This work differs from most research into genetic causes of heart failure which has identified defects in proteins involved in the mechanics of cardiac pumping, not in the communication pathways of stress-management systems.
The Investigation
The current investigation involves Mayo Clinic patients who suffer from a severe heart disease known as "idiopathic dilated cardiomyopathy," which leaves the heart highly vulnerable to failure under stress. The cause is unknown, but the usual heart disease risk factors physicians look for -- high blood pressure, elevated cholesterol, smoking, obesity -- are not necessarily present. To the researchers, this suggested problems in this patient group that had been missed by the standard screening for heart disease: defects in the heart's stress management system.
Looking for Clues in Heart Patients' DNA
To get data from patients, Dr. Terzic's team collaborated with Timothy Olson, M.D., who directs the Mayo Clinic Cardiovascular Genetics Laboratory. Dr. Olson is a leader in identifying hereditary factors that cause heart disease. With the permission of selected patients who suffered heart failure of unknown origin, he carried out extensive genetic scans of DNA obtained from blood samples. Results showed that some patients shared a defect in a gene that makes a stress-reaction-type protein.
Says Dr. Olson: "By introducing a conceptually new mechanism for heart failure, our work points out how molecular genetics can provide a very powerful tool to diagnose a defect in a specific protein in a human disease." Several genes contribute to the heart's ability to adapt to stress. Mayo will be conducting further genomics and proteomics studies to help understand their role in heart failure and enable improved treatment.
After finding mutations, researchers reproduced the mutations in the laboratory using recombinant genetic techniques that allowed them to observe the molecular consequences of the mutations. They found that the mutations create an abnormality within vital structures of heart cells known as the ATP-sensitive potassium channel.
Potassium Channel at a Glance
In healthy people, the potassium channel synchronizes the proper balance of potassium and calcium flow in the heart. Calcium is needed for the heart's contractions. A proper level of potassium enables the cells to restore electrical balance following each heartbeat, and limits the entrance of calcium into the cells. Too much calcium damages cell structure and leads to heart failure.
The new finding shows ATP-sensitive potassium channels can work as defensive barriers, and if they are defective they cannot properly sense the body's state of stress. When this happens, they fail to decode the metabolic signals that synchronize the flow of potassium and calcium.
Implications of Research
In principle, researchers can apply these findings to other patients with heart failure and look for other stress-reactive proteins that miscommunicate vital electrical or mechanical responses. Dr. Terzic says the ultimate goal is to design better therapies for managing heart disease.
Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, Terzic A. (2004) ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic K(ATP) channel gating. Nature Genetics 36 (4) (April) (advance publication on line).
Journal
Nature Genetics