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A Histological Investigation into the Temporal Development of Respiratory Muscle Dysfunction in a Murine Model of Pressure-Overload Heart Failure

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Title: A Histological Investigation into the Temporal Development of Respiratory Muscle Dysfunction in a Murine Model of Pressure-Overload Heart Failure
Author: Arkell, Alicia Maria
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Simpson, Jeremy
Abstract: Heart failure is one of the leading causes of morbidity and mortality worldwide. One of the chief complaints of heart failure patients is exercise intolerance, characterized by fatigue and dyspnea. Currently, there are two theories meant to explain respiratory dysfunction in heart failure (HF). First, pulmonary edema increases the relative work of breathing, which predisposes the diaphragm to fatigue related injury (Ingram & Braunwald, 2005; Mulrow, Lucey & Farnett, 1993). Second, a HF induced catabolic state results in skeletal muscle atrophy, increasing ventilation via an over active ergo-reflex. Importantly, to date, only end stage HF has been examined, leaving incipient events in the pathogenesis of respiratory dysfunction unknown. Therefore, we sought to characterize the temporal development of respiratory muscle dysfunction during pressure-overload HF. We hypothesized that neither pulmonary edema, nor limb muscle myopathy were involved in the onset of respiratory dysfunction. Indeed, similar to clinical HF, animals displayed increased work of breathing in the absence of pulmonary edema. Diaphragmatic weakness occurred quickly following transverse aortic constriction (TAC) and was strongly correlated with muscle cell atrophy, preceding limb muscle myopathy. Further, chronic blockade of β-adrenergic signaling for four weeks prevented dysfunction and atrophy within the diaphragm. This work provides evidence towards the mechanism and preventable nature of HF-induced respiratory dysfunction.
URI: http://hdl.handle.net/10214/10484
Date: 2017-05-19


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