Mahurin Honors College Capstone Experience/Thesis Projects

Department

Kinesiology, Recreation, and Sport

Document Type

Thesis

Abstract

Heart failure (HF) is a complex syndrome with high mortality rates around the world. HF also has diverse etiology as many things contribute such as hypertension, obesity, coronary artery disease, inflammation, and cardiac arrhythmias. Studies have shown that unloading of a failing heart with a left ventricular assist device (LVAD) can lead to cardiac recovery in a subpopulation of individuals with advanced HF. RNA-sequencing and protein expression analysis of myocardial tissue from HF patients who underwent the LVAD implant and heart transplant indicated that subpopulation of HF patients who responded to LVAD unloading had significantly lower levels of mitochondrial pyruvate carrier 1 (MPC1) in the failing heart, but that is was recoverable following mechanical unloading of the LVAD. The purpose of the present study was to determine the role of MPC1 in the failing heart in an animal model. The hypothesis was that MPC1 deficiency may lead to HF and normalization of MPC1 during LVAD unloading could drive the recovery in adult humans. To test this hypothesis, cardiac-specific deletion of MPC1 in adult mice was generated using locus of x over bacteriophage cre recombinase technology (cre-lopx). Results of the homozygous MPC1 mutant showed the cardiac dysfunction around 11 weeks post tamoxifen induction with an ejection fraction of 15%, increased left ventricular end diastolic diameter (LVEDD) of 7mm, increased left-ventricular mass (LVM) of 150mg, end-systolic volume (ESV) of 110 µl, and a total weight of 24 g. The mice eventually succumbed to HF at around 16 weeks post tamoxifen induction. To further characterize the MPC1 mutant for future experimentation, metabolism, gene expression, mitochondria structure, respiratory function, and myocardium structures in these mice will be examined and compared to the wild type littermate to understand the mechanism and to identify the therapeutic targets for drug development.

Advisor(s) or Committee Chair

Rachel Tinius, Ph.D., EP-C

Disciplines

Cardiology | Exercise Science | Genetics | Genomics

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