Correlating SCD Risk with Cell Autonomous Arrhythmia Susceptibility

Project: SFRN


  • Alfred L George (PI)


Genomic determinants of risk for sudden cardiac death (SCD) include highly penetrant ultra-rare variants in genes such as those associated with monogenic arrhythmia susceptibility (e.g., long-QT syndrome [LQTS], Brugada syndrome) and familial cardiomyopathy, as well as more common variants that have been identified by genome wide association studies (GWAS). Although the pathophysiology of arrhythmia susceptibility is well-established for many genes, the mechanisms responsible for SCD risk in other populations are unknown. In Project 2, we seek to establish correlations between quantifiable genomic risk defined by the study outlined in Project 1 with arrhythmogenic properties of human cardiomyocytes derived from individuals of varying levels of risk. We will use the well-established paradigm of differentiating functioning cardiomyocytes from human patient-specific induced pluripotent stem cells (hiPSC), coupled with advanced strategies for cellular phenotyping. We hypothesize that hiPSC-derived cardiomyocytes (hiPSC-CMs) from individuals with the greatest clinical and genomic risk for SCD will exhibit greater degrees of proarrhythmic cellular behaviors than cells from individuals with lower risk burden. These investigations will connect genomic risk to specific cellular mechanisms that may predispose to SCD.
Award amount$817,940.00
Award date07/01/2019
Program typeStrategically Focused Research Network
Award ID19SFRN34820006
Effective start/end date07/01/201906/30/2023