All ETDs from UAB

Advisory Committee Chair

Sumanth D Prabhu

Advisory Committee Members

Anupam Agarwal

James George

Frances Lund

Donald G Rokosh

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Acute myocardial infarction (MI) produces massive, sudden cardiomyocyte death, triggering an inflammatory and healing response that initially leads to scar formation and ultimately may induce progressive ischemic cardiomyopathy and heart failure (HF). Scar formation and left ventricular (LV) hypertrophy occur in response to MI to stabilize injury compensating for lost myocardial function. Over time, heart function can become decompensated due to neuroendocrine dysfunction and adverse LV remodeling, ultimately leading to HF. Adverse remodeling is characterized by continued dysregulated collagen deposition, cardiomyocyte hypertrophy, and increased inflammation. Studies have documented a resurgence in inflammatory cytokines and infiltrating leukocytes after resolution of the initial infarction, leading to a state of persistent chronic inflammation and HF. Despite the established role of neutrophils acutely after MI, the importance of neutrophils (as opposed to other innate immune cells) as mediators of sustained inflammatory response in HF is unknown. Analogous to their direct role as key effectors in other chronic inflammatory diseases, and role in recruitment and activation of other immune cells, we hypothesized neutrophils have a detrimental function during dysfunction and adverse remodeling in HF. Here, we demonstrated that in a chronic ischemic HF model (Eight weeks after permanent coronary ligation), neutrophils were increased in the circulation and failing heart. Increased bone marrow granulopoiesis served as a mechanism for neutrophil expansion. Detected increases in chemokines in the myocardium together with enhanced chemotactic potential of HF plasma could collectively describe neutrophil recruitment to the failing heart. Enhanced neutrophil activation resulted in neutrophil extracellular trap (NET) production, which can contribute to tissue injury and adverse remodeling in HF. The pathophysiological role of neutrophil expansion in HF was demonstrated by depleting neutrophils using a neutrophil-specific Ly6G surface receptor-targeted antibody and genetic Ly6G+ neutrophil-targeted diphtheria toxin receptor (DTR) expression. Depletion established that neutrophils contribute obligatorily to HF progression and LV dysfunction. Antibody depletion also indicated neutrophils contribute to fibrosis, thereby exacerbating adverse LV remodeling. These results support a key role for neutrophils in the pathogenesis of LV dysfunction and adverse remodeling in ischemic cardiomyopathy, suggesting mitigation of neutrophil activation as a potential therapeutic approach to attenuate progression of ischemic HF.



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