scholarly journals Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome

2021 ◽  
Author(s):  
Julian O.M. Ormerod ◽  
Elizabeth Ormondroyd ◽  
Yanhui Li ◽  
John Taylor ◽  
Jinhong Wei ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Calcium Release ◽  
Human Subjects ◽  
Deficiency Syndrome ◽  
Response To Therapy ◽  
Exercise Stress ◽  
Functional Study ◽  
The Family ◽  
Provocation Testing

Background: A novel familial arrhythmia syndrome, RyR2 calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. Methods: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. Results: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2 , Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. Conclusions: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.

scholarly journals Investigation of the family of sudden cardiac death victims

2017 ◽  
Vol 45 ◽  
pp. 25-29 ◽  
Author(s):  
Alban-Elouen Baruteau ◽  
Elijah R. Behr
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
The Family

scholarly journals P859 Can we connect intraventricular exercise induced gradients to sudden cardiac death?

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
C Cotrim ◽  
F Costa ◽  
D Severino ◽  
L Baquero ◽  
J Guardado
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Heart Diseases ◽  
Young Male ◽  
Exercise Stress ◽  
Male Athlete ◽  
First Case ◽  
History Of ◽  
Intense Training ◽  
Exercise Induced

Abstract Background Some publications, on exercise induced intraventricular gradients, admit the possibility they can be related to some cases of unexplained sudden cardiac death (SCD). Clinical case We present the case of a young male athlete (16 years) that after winning a triathlon competition has sudden cardiac death. No cardiovascular risk factors. No family history of SCD A previous episode of dizziness, accompanied by nausea and vomiting related to intense training happens 6 months before. In September 2018 about 30 minutes after winning a triathlon competition has SCD episode having been resuscitated on site by the competition physician having been defibrillated and transported to intensive care unit. After discharge, cardiac MRI, Coronary AngioTC, complete genetic study for heart diseases, flecainid test, transthoracic echocardiogram, stress echocardiogram with hyperventilation and ergometrine. All have normal results (Figure) During 24 hours Holter ECG isolated premature ventricular complexes were detected and during exercise stress echocardiography a significant intraventricular gradient without systolic anterior movement of mitral valve was detected (Figure). The athlete was disqualified for sports practice, refuses CDI implantation and started bisoprolol 2,5 mg daily. To the best of our knowledge this is the first case of association between SCD and exercise induced intraventricular gradient. This possible association should be studied in the future. Abstract P859 Figure. Intraventricular gradient in SCD athlete

scholarly journals Human RyR2 (Ryanodine Receptor 2) Loss-of-Function Mutations

2021 ◽  
Vol 14 (9) ◽  
Author(s):  
Yanhui Li ◽  
Jinhong Wei ◽  
Wenting Guo ◽  
Bo Sun ◽  
John Paul Estillore ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Stress Testing ◽  
Functional Characterization ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Loss Of Function

Background: The overall objective of the present study is to extend our understanding of the clinical phenotype and underlying mechanism of a newly discovered cardiac arrhythmia syndrome through a multicenter study. Gain-of-function mutations in the cardiac Ca 2+ release channel (RyR2 [ryanodine receptor 2]) cause catecholaminergic polymorphic ventricular tachycardia, whereas loss-of-function RyR2 mutations are linked to a new cardiac arrhythmia disorder termed Ca 2+ -release deficiency syndrome (CRDS). Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmia disorder characterized by stress-induced bidirectional and polymorphic ventricular tachyarrhythmias and is routinely diagnosed by using exercise stress testing. Conversely, RyR2-CRDS is characterized by ventricular arrhythmias and sudden cardiac death but a negative exercise stress testing for catecholaminergic polymorphic ventricular tachycardia. There are currently no clinical diagnostic tests for CRDS and affected patients may manifest with sudden cardiac death as their first symptom. In the absence of effective clinical diagnostic tools, in vitro functional characterization of associated RyR2 mutations provides an alternative means to identify potential cases of CRDS. Methods: We searched for patients presenting with phenotypes compatible with CRDS that have RyR2 mutations and performed in vitro functional characterization. Results: We found that 3 novel (G570D, R4147K, and A4203V) and 2 previously reported (M4109R and A4204V) RyR2 mutations associated with CRDS phenotypes markedly reduced caffeine-induced Ca 2+ release and store overload-induced Ca 2+ release. We also characterized 2 additional loss-of-function RyR2 mutations previously reported (Q3925E and L4769S) that are located in the central and channel pore-forming domains critical for Ca 2+ activation and channel gating. Q3925E was identified through postmortem genetic testing in an individual who died suddenly, while L4769S is a variant of uncertain significance reported in ClinVar, suggesting that RyR2 CRDS may be under detected. Conclusions: These findings provide further support for the existence of an emerging RyR2 loss-of-function associated arrhythmia syndrome (CRDS) and shed new insights into the disease mechanism.

Novel frameshift mutation in Troponin C (TNNC1) associated with hypertrophic cardiomyopathy and sudden death

2011 ◽  
Vol 21 (3) ◽  
pp. 345-348 ◽  
Author(s):  
Wendy K. Chung ◽  
Carrie Kitner ◽  
Barry J. Maron
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Sudden Cardiac Death ◽  
Sudden Death ◽  
Cardiac Death ◽  
Frameshift Mutation ◽  
Troponin C ◽  
Rare Form ◽  
Common Cause ◽  
The Family ◽  
Genes Encoding

AbstractPurposeHypertrophic cardiomyopathy is the most common cause of sudden death in young people, including trained athletes, and is caused by mutations in genes encoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene (TNNC1) are a rare genetic cause of hypertrophic cardiomyopathy. We describe a novel type of mutation (c.363dupG) in Troponin C, a rare form of hypertrophic cardiomyopathy.MethodsA family in which a 19-year-old asymptomatic male died of sudden cardiac death due to hypertrophic cardiomyopathy was genetically studied by sequencing 17 genes associated with hypertrophic cardiomyopathy or its phenocopies.ResultsA c.363dupG mutation in Troponin C was identified, and tested across the family.ConclusionsWe report the first frameshift mutation (c.363dupG or p.Gln122AlafsX30) in Troponin C causing hypertrophic cardiomyopathy (and sudden cardiac death) in a 19-year-old male, and have demonstrated that the mutation segregates with hypertrophic cardiomyopathy within the family.

scholarly journals Left sided arrhythmogenic ventricular dysplasia in siblings

Heart ◽  
2001 ◽  
Vol 86 (2) ◽  
pp. 128-130
Author(s):  
C G De Pasquale ◽  
W F Heddle
Keyword(s):  
Sudden Cardiac Death ◽  
Left Ventricle ◽  
Cardiac Death ◽  
Fatty Infiltration ◽  
Ventricular Myocardium ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
The Family ◽  
The Right

A 32 year old man with no previous medical history suffered a sudden cardiac death. Post mortem examination revealed circumferential fibro-fatty infiltration of the left ventricular myocardium. Histological appearance was characteristic of arrhythmogenic right ventricular dysplasia but unusual for its localisation only to the left ventricle. As a result of this sudden cardiac death the family of the deceased was screened for cardiac disease. A brother of the index case was 36 years old and free of cardiac history and symptoms. Cardiac investigations revealed a functionally and electrically abnormal left ventricle with apparent sparing of the right ventricle. The brothers may have a left sided form of arrhythmogenic ventricular dysplasia and illustrate the importance of screening family members of young victims of sudden cardiac death.

scholarly journals How could analyzing the activity of two matrix metalloproteinases unveil the cause of sudden cardiac death

2016 ◽  
Vol 29 (4) ◽  
pp. 712-714 ◽  
Author(s):  
Ivan Sosa ◽  
Aron Grubesic
Keyword(s):  
Sudden Cardiac Death ◽  
Matrix Metalloproteinases ◽  
Cardiac Death ◽  
Cardiac Tissue ◽  
Transforming Growth Factor ◽  
Collagen Matrix ◽  
Unexpected Death ◽  
Humoral Factors ◽  
The Family ◽  
Myocardial Collagen

Sudden cardiac death is natural, unexpected death, related to cardiovascular disease. Its postmortem elucidation is significant, as the family of the deceased aspires to prevent other sudden deaths. Irrespective of the proper etiological entity, the myocardial collagen matrix remodels, associated with the progression of cardiovascular diseases. It has become evident that many mediators such as humoral factors, transforming growth factor (TGF)-β1 among them, are involved in the remodeling process. Cardiac remodeling is the balance of regenerative and eliminatory processes that include enzymes involved in the degradation of extracellular matrix (ECM) components. Enzymes capable of degrading native fibrillar collagen are interstitial collagenases, specifically matrix metalloproteinases (MMP)-1 and MMP-8. Here, we suggest a technique of visualizing turnover of collagen in cardiac tissue.

scholarly journals Cardiac ryanodine receptor calcium release deficiency syndrome

2021 ◽  
Vol 13 (579) ◽  
pp. eaba7287
Author(s):  
Bo Sun ◽  
Jinjing Yao ◽  
Mingke Ni ◽  
Jinhong Wei ◽  
Xiaowei Zhong ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Ventricular Arrhythmias ◽  
Calcium Release ◽  
Deficiency Syndrome ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Loss Of Function ◽  
Electrophysiological Studies ◽  
Genetic Evaluations ◽  
Cardiac Ryanodine Receptor

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.

Sign in / Sign up

Export Citation Format

Share Document