Sudden cardiac arrest is highly prevalent and results in overwhelming mortality. Unfortunately, there are no
pharmacologic therapies that have been shown to reliably increase survival after sudden cardiac arrest.
Survivors of sudden cardiac arrest typically have systemic organ damage requiring intensive care in the
hospital. The majority of these patients have reduced cardiac function and one quarter of these patients die
from cardiogenic shock. One of the mechanisms driving cardiac dysfunction after cardiac arrest and
resuscitation is the production of reactive oxygen species (ROS) in the heart, particularly in the mitochondria.
Mitochondrial ROS is known to cause damage to nearby mitochondrial DNA (mtDNA), which are crucial for
maintaining mitochondrial function. Preliminary work in our lab has shown that methods aimed at preserving
mtDNA integrity, including mitochondrial targeted antioxidant therapy and overexpression of mitochondrial
transcription factor A (TFAM), are protective to cardiac function in a mouse model of sudden cardiac arrest.
TFAM is a nuclear gene that regulates mtDNA expression, packaging, and copy number and is known to be
protective in a number of heart disease models.
My overarching hypothesis is that ischemia-reperfusion injury from cardiac arrest results in mtDNA damage
secondary to mitochondrial ROS production, leading to impaired electron transport chain protein regulation and
cardiac dysfunction. To explore this hypothesis, I will pursue two specific aims. In Aim 1, I will test the link
between cardiac arrest, ROS production, mtDNA damage, and cardiac function using mitochondrial
antioxidants in an in vivo mouse model of cardiac arrest as well as a cellular model of ischemia-reperfusion. In
Aim 2, I will test whether the levels of TFAM specifically in the cardiomyocytes modulate the development of
cardiomyopathy and survival in the cardiac arrest model.
Together, these aims will demonstrate that mtDNA damage following cardiac arrest is mediated by
mitochondrial ROS and contributes to post-arrest cardiomyopathy. Further, they will show that these changes
can be prevented by mitochondrial ROS scavenging and manipulation of TFAM, which may be targets for
novel therapeutic interventions in cardiac arrest patients.