Abstract | Aims: Methods and results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation-negative relatives. A total of 38 (obligate) mutation-positive patients died suddenly or suffered life-threatening ventricular arrhythmia. Of these, 18 were aged >40 years, a high proportion of which had a clinical diagnosis of hypertension and/or cardiac hypertrophy. While pacemaker implantation was highly protective in preventing bradycardia-related SCD in young mutation-positive patients, seven of them aged >40 experienced life-threatening arrhythmic events despite pacemaker treatment. Of these, six had a diagnosis of hypertension/ hypertrophy, pointing to a modulatory role of this co-morbidity. Induction of hypertrophy in adult mice carrying the homologous mutation (Scn5a1798insD/+) caused SCD and excessive conduction disturbances, confirming a modulatory effect of hypertrophy in the setting of the mutation. The deleterious effects of the interaction between hypertrophy and the mutation were prevented by genetically impairing the pro-hypertrophic response and by pharmacological inhibition of the enhanced late sodium current associated with the mutation. Conclusion: This study provides the first evidence for a modulatory effect of co-existing cardiac hypertrophy on arrhythmia risk and treatment efficacy in inherited sodium channelopathy. Our findings emphasize the need for continued assessment and rigorous treatment of this co-morbidity in SCN5A mutation-positive individuals.
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Authors | Mathilde R Rivaud, John A Jansen, Pieter G Postema, Eline A Nannenberg, Yuka Mizusawa, Roel van der Nagel, Rianne Wolswinkel, Ingeborg van der Made, Gerard A Marchal, Sridharan Rajamani, Luiz Belardinelli, J Peter van Tintelen, Michael W T Tanck, Allard C van der Wal, Jacques M T de Bakker, Harold V van Rijen, Esther E Creemers, Arthur A M Wilde, Maarten P van den Berg, Toon A B van Veen, Connie R Bezzina, Carol Ann Remme |
Journal | European heart journal
(Eur Heart J)
Vol. 39
Issue 31
Pg. 2898-2907
(08 14 2018)
ISSN: 1522-9645 [Electronic] England |
PMID | 29718149
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- NAV1.4 Voltage-Gated Sodium Channel
- SCN4A protein, human
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Topics |
- Adult
- Age Factors
- Aged
- Animals
- Arrhythmias, Cardiac
(complications, genetics, physiopathology, therapy)
- Cardiac Pacing, Artificial
- Cardiomegaly
(complications)
- Channelopathies
(complications, genetics, physiopathology, therapy)
- Death, Sudden, Cardiac
(etiology, prevention & control)
- Disease Models, Animal
- Female
- Humans
- Hypertension
(complications)
- Male
- Mice
- Middle Aged
- Mutation
- NAV1.4 Voltage-Gated Sodium Channel
(genetics)
- Pedigree
- Risk Factors
- Treatment Outcome
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