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Patients with cardiac arrest show the way to a completely new gene

Through a large-scale collaboration between researchers from the Department of Clinical Medicine, the Department of Biomedicine and the Department of Molecular Biology and Genetics, researches have succeeded in identifying and characterising the consequence of a newly discovered mutation that is associated with cardiac arrhythmia.

Researchers from Aarhus University Hospital and Aarhus University have discovered a new mutation in a gene which causes serious hereditary heart disease and the risk of sudden unexpected heart failure. This gene has not previously been connected with heart disease, and the discovery provides a new view of how it is possible to develop a dangerous heart rhythm irregularity with the associated risk of sudden unexpected death.

Experimental analyses show that patients with this gene mutation have a defective transport of ions across the cell membranes resulting in increased pH and reduced chlorine ion concentration in the heart muscle cells. This causes the shortening of the duration of what is called an "action-potential”. This means that the time in which the heart pumps blood out during a heartbeat is shortened, and what is known as the QT interval in the heart diagram becomes shorter, which leads to the disorder known as short QT syndrome. It is a hereditary heart disease with a high risk of developing dangerous heart rhythm irregularities and death. 

Using clinical and genetic data, the researchers have identified two Danish families who have abnormal ECG and are at risk of sudden death from heart failure. Several family members have experienced ventricular fibrillation: Two have died from it, while two others have survived a cardiac arrest. These two family members will now be treated with a specialised pacemaker called an ICD that can give shocks when these dangerous heart rhythm disturbances arise. The shock makes the heart beat normally again. Many other relatives with the same risk are now being given preventive treatment with an ICD as a result of this research.

The scientific results have just been published in the internationally acclaimed scientific journal Nature Communications.

Zebra fish as laboratory animals

The results have been achieved through translational research, during which medical doctors and researchers have collaborated closely on the results during recent years. Zebra fish are a fish that most people only know from the aquarium, but here they have been used as a model organism. In the laboratory, fertilised eggs from the fish are used, as these have a beating heart after only 24 hours and an established blood circulation after only 48. The advantage of using the 'young' zebra fish is that they are transparent, i.e. the heart can be observed directly in the living fish through a microscope.

It has been documented that in the zebra fish, the mutation in question is actually pathogenic. In physiological experiments, the researchers have ascertained that the patient's mutation leads to loss of the ion transport across the membranes of the cells.

“We have been able to show that when we create the mutation in the zebra fish, the ion transport in the hearts of the zebra fish disappears and the zebra fish suffer the same problem as the patients, that is to say short QT syndrome," says Consultant, MD, DMSc and PhD Henrik Kjærulf Jensen from the Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University.

Major perspectives

The present results have major perspectives and open up for a completely new field that will be further investigated both clinically and experimentally.

“So far, we have ‘only’ identified two families with this mutation, but it can easily occur much more frequently and we are ready with initiatives to go out and screen more broadly in the population, both nationally and internationally," says Henrik Kjærulf Jensen.

The results can already help save lives, because the discovery of this gene gives rise to test a wide range of genes with similar functions for mutations in other patients. People who carry this mutation and are thereby at risk of developing dangerous heart rhythm irregularity and dying will be offered a ICD, which is preventive and potentially life-saving.

The research results - more information

Type of study: Translational research

Partners: Department of Cardiology and Department of Molecular Medicine, Aarhus University Hospital; Department of Clinical Medicine, Department of Biomedicine and Department of Molecular Biology and Genetics, Aarhus University; Rigshospitalet, University of Copenhagen, University of Oslo and University of Lithuania.

Link to the scientific article in Nature Communications:

Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

Read more: 

Read more details about the study (in Danish) in the Danish newspaper Politiken on 26 November 2017: "Zebrafisk røber hvorfor Sasja bærer på et sårbart hjerte" (in Danish).

Employees at AU can get access to read the full article by logging on to library.au.dk, and searching for the title "Zebrafisk røber hvorfor Sasja bærer på et sårbart hjerte" under newspaper articles in Infomedia database: https://apps-infomedia-dk.ez.statsbiblioteket.dk:12048/mediearkiv/.

You can also read the article: The zebra fish is an important laboratory animal.


Consultant, Clinical Associate Professor, MD, DMSc, PhD, Henrik Kjærulf Jensen, Department of Cardiology, Aarhus University Hospital, Department of Cardiology and
Aarhus University, Department of Clinical Medicine. 
Tel. (+45) 7845 2033
Mobil: (+45) 4058 3417
Email: hkjensen@clin.au.dk

Professor, DMSc, Christian Aalkjær
Aarhus University, Department of Biomedicine
Tel. (+45) 3045 4306
Email: ca@biomed.au.dk