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Cardiac ryanodine receptor calcium release deficiency syndrome. 2021

Bo Sun, and Jinjing Yao, and Mingke Ni, and Jinhong Wei, and Xiaowei Zhong, and Wenting Guo, and Lin Zhang, and Ruiwu Wang, and Darrell Belke, and Yong-Xiang Chen, and Krystien V V Lieve, and Anders K Broendberg, and Thomas M Roston, and Ivan Blankoff, and Janneke A Kammeraad, and Johannes C von Alvensleben, and Julieta Lazarte, and Alexander Vallmitjana, and Loryn J Bohne, and Robert A Rose, and Raul Benitez, and Leif Hove-Madsen, and Carlo Napolitano, and Robert A Hegele, and Michael Fill, and Shubhayan Sanatani, and Arthur A M Wilde, and Jason D Roberts, and Silvia G Priori, and Henrik K Jensen, and S R Wayne Chen
Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 4Z6, Canada.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.

UI MeSH Term Description Entries
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001145 Arrhythmias, Cardiac Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction. Arrhythmia,Arrythmia,Cardiac Arrhythmia,Cardiac Arrhythmias,Cardiac Dysrhythmia,Arrhythmia, Cardiac,Dysrhythmia, Cardiac
D016757 Death, Sudden, Cardiac Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as CHEST PAIN and CARDIAC ARRHYTHMIAS, particularly VENTRICULAR TACHYCARDIA, can lead to the loss of consciousness and cardiac arrest followed by biological death. (from Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., 2005) Cardiac Sudden Death,Sudden Cardiac Death,Cardiac Arrest, Sudden,Sudden Cardiac Arrest,Arrest, Sudden Cardiac,Cardiac Arrests, Sudden,Cardiac Death, Sudden,Death, Cardiac Sudden,Death, Sudden Cardiac,Sudden Death, Cardiac
D017180 Tachycardia, Ventricular An abnormally rapid ventricular rhythm usually in excess of 150 beats per minute. It is generated within the ventricle below the BUNDLE OF HIS, either as autonomic impulse formation or reentrant impulse conduction. Depending on the etiology, onset of ventricular tachycardia can be paroxysmal (sudden) or nonparoxysmal, its wide QRS complexes can be uniform or polymorphic, and the ventricular beating may be independent of the atrial beating (AV dissociation). Idiopathic Ventricular Tachycardia,Nonsustained Ventricular Tachycardia,Paroxysmal Supraventricular Tachycardia,Ventricular Tachyarrhythmias,Ventricular Tachycardia,Idiopathic Ventricular Tachycardias,Nonsustained Ventricular Tachycardias,Paroxysmal Supraventricular Tachycardias,Supraventricular Tachycardia, Paroxysmal,Tachyarrhythmia, Ventricular,Tachycardia, Idiopathic Ventricular,Tachycardia, Nonsustained Ventricular,Tachycardia, Paroxysmal Supraventricular,Ventricular Tachyarrhythmia,Ventricular Tachycardia, Idiopathic,Ventricular Tachycardia, Nonsustained,Ventricular Tachycardias
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D019837 Ryanodine Receptor Calcium Release Channel A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES. Calcium-Ryanodine Receptor Complex,RyR1,Ryanodine Receptor 1,Ryanodine Receptor 2,Ryanodine Receptor 3,Ryanodine Receptors,Ca Release Channel-Ryanodine Receptor,Receptor, Ryanodine,RyR2,RyR3,Ryanodine Receptor,Ca Release Channel Ryanodine Receptor,Calcium Ryanodine Receptor Complex,Complex, Calcium-Ryanodine Receptor,Receptor 1, Ryanodine,Receptor 2, Ryanodine,Receptor 3, Ryanodine,Receptor Complex, Calcium-Ryanodine,Receptors, Ryanodine

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