Cardiac ryanodine receptor calcium release deficiency syndrome
Por:
Sun, B, Yao, JJ, Ni, MK, Wei, JH, Zhong, XW, Guo, WT, Zhang, L, Wang, RW, Belke, D, Chen, YX, Lieve, KVV, Broendberg, AK, Roston, TM, Blankoff, I, Kammeraad, JA, von Alvensleben, JC, Lazarte, J, Vallmitjana, A, Bohne, LJ, Rose, RA, Benitez, R, Hove-Madsen, L, Napolitano, C, Hegele, RA, Fill, M, Sanatani, S, Wilde, AAM, Roberts, JD, Priori, SG, Jensen, HK, Chen, SRW
Publicada:
3 feb 2021
Resumen:
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 after-depolarizations. 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.
Filiaciones:
Sun, B:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Kunming Univ Sci & Technol, Med Sch, Kunming 650504, Yunnan, Peoples R China
Yao, JJ:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Ni, MK:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Wei, JH:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Zhong, XW:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Guo, WT:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Zhang, L:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Wang, RW:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Belke, D:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Chen, YX:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Lieve, KVV:
Univ Amsterdam, Heart Ctr, Dept Clin & Expt Cardiol, Locat AMC,Med Ctr, NL-1105 AZ Amsterdam, Netherlands
European Reference Network ERN GUARD Heart, Amsterdam, Netherlands
Broendberg, AK:
Aarhus Univ, Aarhus Univ Hosp, Dept Cardiol, Palle Juul Jensens Blv 99, DK-8200 Aarhus N, Denmark
Aarhus Univ, Dept Clin Med Hlth, Palle Juul Jensens Blv 99, DK-8200 Aarhus N, Denmark
Roston, TM:
Univ British Columbia, Dept Med, Div Cardiol, Vancouver, BC V5Z 1M9, Canada
Blankoff, I:
CHU Charleroi, Hop Civil Marie Curie, Chaussee Bruxelles 140, B-6042 Charleroi, Belgium
Kammeraad, JA:
Erasmus MC, Sophia Childrens Hosp, Dept Pediat Cardiol, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands
von Alvensleben, JC:
Univ Colorado, Childrens Hosp Colorado, Inst Heart, Div Cardiol, Aurora, CO 80045 USA
Lazarte, J:
Western Univ, Schulich Sch Med & Dent, Dept Med, London, ON N6A 5B7, Canada
Western Univ, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 5B7, Canada
Vallmitjana, A:
Univ Politecn Cataluna, Dept Automat Control, Barcelona 08034, Spain
Bohne, LJ:
Univ Calgary, Cumming Sch Med, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci & Physiol, Calgary, AB T2N 4Z6, Canada
Univ Calgary, Cumming Sch Med, Libin Cardiovasc Inst Alberta, Dept Pharmacol, Calgary, AB T2N 4Z6, Canada
Rose, RA:
Univ Calgary, Cumming Sch Med, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci & Physiol, Calgary, AB T2N 4Z6, Canada
Univ Calgary, Cumming Sch Med, Libin Cardiovasc Inst Alberta, Dept Pharmacol, Calgary, AB T2N 4Z6, Canada
Benitez, R:
Univ Politecn Cataluna, Dept Automat Control, Barcelona 08034, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, Biomed Res Inst Barcelona IIBB CSIC & IIB St Pau, Barcelona 08025, Spain
Napolitano, C:
European Reference Network ERN GUARD Heart, Amsterdam, Netherlands
Univ Pavia, Div Cardiol & Mol Cardiol, IRCCS Maugeri Fdn, I-27100 Pavia, Italy
Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy
Hegele, RA:
Western Univ, Schulich Sch Med & Dent, Dept Med, London, ON N6A 5B7, Canada
Western Univ, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 5B7, Canada
Fill, M:
Rush Univ, Dept Physiol & Biophys, Med Ctr, Chicago, IL 60612 USA
Sanatani, S:
Univ British Columbia, Child & Family Res Inst, Dept Pediat, Vancouver, BC V6H 3V4, Canada
Wilde, AAM:
Univ Amsterdam, Heart Ctr, Dept Clin & Expt Cardiol, Locat AMC,Med Ctr, NL-1105 AZ Amsterdam, Netherlands
European Reference Network ERN GUARD Heart, Amsterdam, Netherlands
Roberts, JD:
Western Univ, Dept Med, Div Cardiol, Sect Cardiac Electrophysiol, London, ON N6A 5A5, Canada
Priori, SG:
European Reference Network ERN GUARD Heart, Amsterdam, Netherlands
Univ Pavia, Div Cardiol & Mol Cardiol, IRCCS Maugeri Fdn, I-27100 Pavia, Italy
Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy
Ctr Invest Cardiovasc Carlos III, Mol Cardiol Lab, Madrid 28029, Spain
Jensen, HK:
Aarhus Univ, Aarhus Univ Hosp, Dept Cardiol, Palle Juul Jensens Blv 99, DK-8200 Aarhus N, Denmark
Aarhus Univ, Dept Clin Med Hlth, Palle Juul Jensens Blv 99, DK-8200 Aarhus N, Denmark
Chen, SRW:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4Z6, Canada
Rush Univ, Dept Physiol & Biophys, Med Ctr, Chicago, IL 60612 USA
Green Published
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