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New genetic cause of cardiac insufficiency discovered

The heart needs to pump approximately 250 million litres of blood through the body during a person’s lifetime. In order to do this effectively, the cardiac muscle fibres need to be extremely resilient. A team led by Dr. Wolfgang Rottbauer, assistant medical director of the Department of Internal Medicine III at the University Hospital of Heidelberg, has discovered a protein component that is responsible for the stability of the smallest muscle unit, the sarcomere. The team was able to show that the genetic alteration of this protein is one of the causes of chronic cardiac insufficiency. The results were published in an advance online publication in “Nature Medicine”.

Dr. Wolfgang Rottbauer, assistant medical director of the Department of Internal Medicine III at the University Hospital Heidelberg © University Hospital Heidelberg

Dilated cardiomyopathies are one of the most common causes of chronic cardiac insufficiency. Every year, 6 people in 100,000 are diagnosed with this disease, of which 20 per cent of cases have a genetic cause. Cardiomyopathies lead to the enlargement of the heart ventricles and atriums, which prevents them from being able to pump blood through the body effectively. The heart weakens and is no longer able to constantly withstand the mechanical forces during muscle contraction.

Muscle movement occurs in the smallest muscle unit, the sarcomere. Upon a specific stimulus, the actin and myosin filaments slide past each other in opposite directions, thus causing the contraction of the heart muscle. These flexible elements are anchored in the so-called Z-disk, a structural element of the muscle. With every heartbeat, extreme mechanical forces act on the Z-disks.

Torn Z-disks weaken the heart muscle 

"Our investigations on zebrafish have led to the discovery of a protein component that is essential for stabilising the Z-disks. If this protein (nexilin) is genetically altered, the mobile muscle elements are no longer effectively anchored to the disk. The muscles lose their strength and the heart starts to weaken," explained Dr. Tillmann Dahme, assistant physician and co-author of the study.

Dr. Tillmann Dahme, assistant physician © University Hospital Heidelberg

The researchers investigated the genetic material of patients with dilated cardiomyopathy and found nexilin mutations in 9 out of the 1000 study participants. The researchers also showed that nexilin mutations are the key cause of the cardiac Z-disk pathology in these patients. "For the first time, we were able to show that nexilin-associated dilated cardiomyopathies represent a new type of cardiac dilatation and we have also been able to define the mechanism underlying the disease, namely the perturbed stability of the Z-disks," explained Dahme.

The investigations also showed that the extent of Z-disk destruction depends directly on the mechanical strain acting on the heart. This finding has an effect on the clinical therapy of patients suffering from dilated cardiomyopathies. "Patients with nexilin mutations might be able to profit from early treatment with drugs that facilitate cardiac work. This might then reduce the mechanical strain on the Z-disks and counteract the progressive destruction of the heart muscle," explains Professor Dr. Rottbauer.

Original publication:

Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. David Hassel, Tillman Dahme, Jeanette Erdmann, Benjamin Meder, Andreas Huge, Monika Stoll, Steffen Just, Alexander Hess, Philipp Ehlermann, Dieter Weichenhan, Matthias Grimmler, Henrike Liptau, Roland Hetzer, Vera Regitz-Zagrosek, Christine Fischer, Peter Nürnberg, Heribert Schunkert, Hugo A Katus & Wolfgang Rottbauer, Nature Medicine, published online 1 Nov 2009, DOI 10.1038/nm.2037


Further information:
PD Dr. med. Wolfgang Rottbauer
Internal Medicine III - Cardiology
University Hospital Heidelberg
Im Neuenheimer Feld 410
69120 Heidelberg
Tel.:  +49 (0)6221 56 38851
Fax: +49 (0)6221 56 4866
E-mail: wolfgang.rottbauer(at)med.uni-heidelberg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/new-genetic-cause-of-cardiac-insufficiency-discovered