Summary
This project aims to investigate the association between mitochondrial DNA (mtDNA) variation and the risk and resuscitation outcomes of sudden cardiac arrest (SCA), and to characterize the impact of specific mtDNA variations on mitochondrial function and cardiomyocyte electrical activity.
What they want
The project will test the hypothesis that mtDNA variation (including mtDNA copy number, inherited mtDNA haplotypes and rare mutations, and mtDNA heteroplasmy [somatic variants]) is associated with SCA risk and resuscitation outcomes. This involves two main aims: 1) Examining the association of SCA with mtDNA characteristics in 2,600 SCA cases from a large population-based case-control study, validating findings in two population-based cohort studies and two case-control studies of autopsy confirmed SCA subjects, and examining the association of mtDNA variation with cardiac resuscitation and brain recovery among 2,600 VF-SCA cases. 2) Characterizing the consequences of specific mtDNA variation on mitochondrial function and cardiomyocyte (CM) electrical activity by assessing the impact of mtDNA variants associated with known rare diseases with CM involvement across a range of heteroplasmies using human induced pluripotent stem cell CMs (hiPSC-CMs) and leveraging existing mtDNA base editing technologies.
Deliverables
- Data on the association of mtDNA characteristics with SCA risk and resuscitation outcomes
- Characterization of the consequences of specific mtDNA variation on mitochondrial function and cardiomyocyte electrical activity
- Insights leading to innovative approaches to prevent SCA and improve VF-SCA resuscitation outcomes
Technical requirements
- Computational tool to accurately assess somatic mutations in mitochondria (heteroplasmy)
- Human induced pluripotent stem cell CMs (hiPSC-CMs)
- Existing mtDNA base editing technologies
