Investigating Metabolic And Inflammatory Relationships In Two Distinct Models Of Right-Sided Cardiac Stress

This thesis summarizes data generated from two distinct models with unrelated underlying etiology that both implicate metabolic- and inflammatory-mediated adaptations in right-sided cardiac stress.

The first model, Duchenne muscular dystrophy (DMD), is a neuromuscular disease caused by mutations in the X-linked DMD gene that encodes the sub-sarcolemmal protein, dystrophin. While current standards of care –glucocorticoid administration and gene-editing therapies – provide promise for skeletal muscle impairments, the effects of these interventions on dystrophic cardiomyopathy are unclear. The purpose of this thesis was to characterize chamber-specific remodeling in young D2.B10-DMDmdx/2J (D2.mdx) mice, while concurrently exploring if an adiponectin peptidomimetic (ALY688) could alleviate underlying chamber-specific pathology.

Our results demonstrated that right ventricular (RV) fibrosis and cardiomyocyte hypertrophy in 4-week-old D2.mdx mice were related to lower mitochondrial respiration and increased complex I-stimulated mitochondrial H2O2. ALY688 prevented RV fibrosis and cardiomyocyte hypertrophy, concurrent with macrophage sub-population shifts towards an anti-inflammatory phenotype. Our findings identified that the dystrophic heart is heterogeneously affected, while ALY688 represents a viable intervention aimed at addressing secondary contributors to dystrophic cardiac remodeling.

The second model, on-pump coronary artery bypass grafting (CABG) surgery, is a common intervention for treatment of coronary artery disease. Key to this surgery is infusion of cardioplegia, which temporarily arrests the heart so surgeons can anastomose grafts around occluded coronary arteries while blood supply is maintained by cardiopulmonary bypass. The combination of ischemia and reperfusion remains a precipitator of post-operative complications. To date, repeated-measures mitochondrial stress responses associated with CABG have never been explored in a study design that compares right atrial appendage (RAA) samples from the same patient at multiple time-points.

Therefore, the purpose of this study was to investigate if post-CABG RAA exhibited alterations to mitochondrial stress responses (perturbed mitochondrial substrate-specific respiration and reactive oxygen species (ROS)-mediated protein adaptations) that correlated with patient discharge times.

Preliminary findings demonstrated that CABG is associated with increased fatty acid-supported respiration on the post-CABG RAA. It is unknown if this is a protective mechanism or a detrimental mitochondrial stress response. Correlative statistics suggest that the increase in fatty acid-supported respiration and ROS-mediated adaptations do not improve patient discharge times.