Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mayo Clinic researchers discover gene mutations that ’ignore’ stress, lead to heart failure

30.03.2004


Mayo Clinic researchers have discovered genetic mutations in heart patients that make them vulnerable to heart failure because they produce an abnormal protein that can’t decode stress messages from the body.



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).

Bob Nellis | PNNL
Further information:
http://www.mayo.edu/

More articles from Life Sciences:

nachricht Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society

nachricht 127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>