D-AB03-02 - New Insights Into Human Unexplained Sudden Cardiac Death: Localized Right Ventricular Epicardial Conduction Abnormalities Associated With A Pathogenic SCN5A Variant (ID 1503)
E. Renard: Nothing relevant to disclose.
Background: Idiopathic ventricular fibrillation (IVF) is a significant cause of unexplained sudden cardiac death (SCD) in young individuals. Recent clinical studies have highlighted the presence of localized areas of fractionated electrograms in IVF survivors, but the underlying pathophysiological mechanisms remain unknown.
Objective: To investigate the electrophysiological and micro-structural alterations underlying unexplained SCD through detailed ex vivo explorations of human hearts.
Methods: A human heart was obtained through our organ donation program from a male patient (15yrs) who died following SCD. ECG and echocardiography at hospital admission prior to death showed no abnormalities. We performed ex vivo optical mapping and quantified right ventricular (RV) action potential properties at different pacing frequencies (0.5 to 4Hz) and after addition of the Ito activator NS5806 (10µM). Micro-structure was assessed by high-field magnetic resonance imaging (MRI 9.4T). Next generation sequencing of a 109 arrhythmia and cardiomyopathy genes panel was performed on NexSeq500 (Illumina) using the Sophia Genetics technology. Results were compared to a human heart from a donor with no cardiac disease.
Results: The RV conduction time, when pacing the RV free wall (FW) at 1Hz (60 bpm), was prolonged by 50% compared to the control heart. The transmural conduction velocity in the RV outflow tract (RVOT) and the RV FW were similar (20.64 vs 23.12 cm/s). On the epicardium, a localized region of delayed activation and biphasic optical upstrokes was observed near the RVOT. Increasing pacing frequency resulted in the enlargement of the epicardial area with abnormal conduction and the appearance of localized conduction blocks. NS5806 did not alter the upstroke morphologies nor further impair conduction. MRI showed no structural abnormalities or fatty infiltrations in the regions with altered conduction. Genotyping revealed a pathogenic variant in SCN5A previously associated with Brugada Syndrome.
Conclusion: These unique ex vivo human heart data demonstrate for the first time that sodium channel mutations, in the absence of an ECG phenotype or structural abnormalities, can be responsible for localized regions of impaired conduction underlying SCD.