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A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy

Session Poster session 2

Speaker Associate Professor Carol Ann Remme

Event : EHRA 2018

  • Topic : arrhythmias and device therapy
  • Sub-topic : Pathophysiology and Mechanisms
  • Session type : Poster Session

Authors : C A Remme (Amsterdam,NL), MR Rivaud (Amsterdam,NL), JA Jansen (Utrecht,NL), PG Postema (Amsterdam,NL), EA Nannenberg (Amsterdam,NL), GA Marchal (Amsterdam,NL), SR Rajamani (Fremont,US), L Belardinelli (Fremont,US), JP Van Tintelen (Amsterdam,NL), MW Tanck (Amsterdam,NL), EE Creemers (Amsterdam,NL), AA Wilde (Amsterdam,NL), MP Van Den Berg (Groningen,NL), TAB Van Veen (Utrecht,NL), CR Bezzina (Amsterdam,NL)

C A Remme1 , MR Rivaud1 , JA Jansen2 , PG Postema1 , EA Nannenberg1 , GA Marchal1 , SR Rajamani3 , L Belardinelli3 , JP Van Tintelen1 , MW Tanck1 , EE Creemers1 , AA Wilde1 , MP Van Den Berg4 , TAB Van Veen2 , CR Bezzina1 , 1Academic Medical Center - Amsterdam - Netherlands , 2University Medical Center Utrecht - Utrecht - Netherlands , 3Gilead Sciences - Fremont - United States of America , 4University Medical Center Groningen - Groningen - Netherlands ,

Ventricular Arrhythmias and SCD - Pathophysiology and Mechanisms

European Heart Journal Supplements ( 2018 ) 20 ( Supplement 1 ), i140

Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. We here investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy.

Methods and Results: Follow-up data was collected from 164 carriers of the SCN5A-1795insD founder mutation and 247 related non-carriers. A total of 38 (obligate) mutation carriers 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 carriers, 7 mutation carriers aged >40 experienced life-threatening arrhythmic events despite pacemaker treatment. Of these, 6 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 SCD 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 carriers.

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