A dissection of the intercalated disk to stop sudden cardiac death (360G-Wellcome-208460_Z_17_Z)

Despite decades of research, every week in the UK, twelve individuals under 35 years of age die unexpectedly; a tragic event known as sudden cardiac death (SCD). I believe that a key to stopping SCD is elucidating what transpires at the intercalated disk (ID), the area of heart cell-cell mechanical and electrical coupling. We recently showed that a few proteins are redistributed from and to the ID in SCD, which has significantly improved diagnosis and management of surviving family members. The ID, however, was recently shown to contain > 760 proteins, a number so vast that begs the question; is our work hitherto just the ‘’tip of the iceberg’’? I will employ a novel technology to isoalte the IDs from formalin-fixed samples and through cutting-edge proteomics resolve for the first time the full spectrum of protein remodelling in SCD-IDs due to two distinct, yet overlapping disease entities; arrhythmogenic cardiomyopathy and Brugada syndrome. This high-throughput screening of the ID will uncover novel diagnostic signatures, whose specificity I will evaluate using the world’s largest bank of SCD myocardial samples. Finally, decrypting the IDs’ molecular remodelling will lay the foundations for much-needed mechanism-targeted therapies, necessary to reduce the burden of SCD in our society.