2021-02-04
Professor Henrik Kjærulf Jensen. Photo: Tonny Foghmar
The Danish professor Henrik Kjærulf Jensen is involved in an international collaboration which has discovered the cause of a previously unknown syndrome.
Cardiac arrest and sudden death in children and adolescents can in many cases not be explained. New knowledge on the molecular biological mechanisms explains the causes of rare cases of unexpected cardiac arrest. Henrik Kjærulf Jensen, professor at Department of Cardiology at Aarhus University Hospital and Department of Clinical Medicine, Aarhus University in Denmark together with a team of international collaborators headed by professor Wayne Chen, Canada have discovered a new genetic cause behind the development of cardiac arrest and sudden unexpected death.
It is well-known that CPVT (Catecholaminergic Polymorphic Ventricular Tachycardia), which is a hereditary cardiac disease, can cause dangerous arrhythmia at physical exertion and stress. CPVT is caused by genetic mutations, increasing the function of the heart’s ryanodine receptor (RyR2), controlling the level of calcium ions in the cells of the heart muscle as well as playing a role in the ability of the heart to contract.
The research team has found that also carriers of genetic mutations inhibiting the function of the heart’s RyR2 constitute a risk of sudden and serious cardiac disease. The diagnostic process requires advanced molecular biological examinations and so far, the role of mutations inhibiting the heart’s RyR2 has been unknown.
- We have made clinical and genetic studies of persons who have survived cardiac arrest and who have been carriers of mutations inhibiting RyR2. We have identified a number of families with such mutations. When we examined them, we found a strong association between the mutation and risk of developing cardiac arrest and sudden unexpected death, which was not related to physical exertion or stress, says professor Henrik Kjærulf Jensen.
Researchers have developed mice with the same genetic defects to study the effect of such genetic mutations inhibiting RyR2 in the heart.
Further, they also developed a standardised electrophysiological examination, which could induce serious arrhythmia in both mice and humans with a genetic mutation inhibiting RyR2. Moreover, treatment with kinidin and flecainid prevented development of serious arrhythmia at the electrophysiological examination in mice with the genetic defect.
- Mutations inhibiting RyR2 can thus explain a previously unknown syndrome characterised by sudden unexpected cardiac death/cardiac arrest with no relation to increased physical exertion. We have called the syndrome 'Cardiac Ryanodine receptor calcium release Deficiency Syndrome (CRDS)'. In addition to the study providing knowledge of the mechanisms behind CRDS, we have developed a possible invasive electrophysiological test for CRDS as well as found possible medical treatment options, says professor Henrik Kjærulf Jensen.
Behind the research result:
Type of study: Translational medical research.
Collaborators:
- Wayne Chen. Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada,
- Arthur Wilde. Amsterdam University Medical Centre, location AMC, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam, the Netherlands,
- Jason Roberts. Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada,
- Silvia Priori. Division of Cardiology and Molecular Cardiology, IRCCS Maugeri Foundation-University of Pavia, Pavia, Italy.
- Shubhayan Sanatani. Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, Canada.
Major international collaboration headed by professor Wayne Chen, Calgary, Canada.
External financing: Novo Nordisk Foundation grant no. 18OC0031258
Conflicts of interest: None
Read the scientific article:
Bo Sun, Jinjing Yao, Mingke Ni, Jinhong Wei, Xiaowei Zhong, Wenting Guo, Lin Zhang, Ruiwu Wang, Darrell Belke,Yong-Xiang Chen, Krystien V.V. Lieve, Anders K. Broendberg, Thomas M. Roston, Ivan Blankoff, Janneke A. Kammeraad, Johannes C. von Alvensleben, Julieta Lazarte, Alexander Vallmitjana, Loryn J. Bohne, Robert A. Rose, Raul Benitez, Leif Hove-Madsen, Carlo Napolitano, Robert A. Hegele, Michael Fill, Shubhayan Sanatani* Arthur A.M. Wilde,* Jason D. Roberts,* Silvia G. Priori,* Henrik K. Jensen,* and S. R. Wayne Chen* (*corresponding authors)
Cardiac ryanodine receptor calcium release deficiency syndrome.
Science Translational Medicine 03 Feb 2021:
Vol. 13, Issue 579, eaba7287
DOI: 10.1126/scitranslmed.aba7287
Further information:
Henrik Kjærulf Jensen, Professor, Senior Consultant Cardiologist
Department of Clinical Medicine, Aarhus University, Denmark
Department of Cardiology, Aarhus University Hospital, Denmark
Tel. +45 4013 5114
E-mail: hkjensen@clin.au.dk