<p> The objective of this dissertation was to systematically investigate the hemodynamic response to exercise in heart failure with reduced ejection fraction (HFrEF) and healthy individuals of a similar age, with an emphasis on how the sympathetic nervous system (SNS) may contribute to the dysregulation of the cardiovascular system in this cohort. The first study aimed to determine how varying levels of metaboreceptor activation alters the mean arterial pressure (MAP) response as well as the degree in which cardiac output (CO) and systemic vascular conductance (SVC) contribute to the metaboreflex-induced increase in MAP. We observed similar increases in MAP induced by metaboreceptor activation in both groups; however, this response was driven primarily by increases in CO in the control group and reductions in SVC in the HFrEF group. These data suggest a preserved role of the metaboreflex-induced increase in MAP in HFrEF, but suggest that this response is governed by the peripheral circulation in this cohort, a maladaptation that may exacerbate systolic dysfunction through an increase in afterload. The second study of this dissertation was focused on investigating the peripheral vasodilatory and hyperemic response to exercise in isolation of central hemodynamic limitations in both the upper and lower limbs. This study documented an impaired hyperemic response to both static-intermittent handgrip exercise as well as dynamic single-leg knee-extensor exercise in HFrEF patients - impairments primarily attributed to vasodilatory dysfunction, as the increase in MAP induced by these exercise modalities was preserved compared to healthy individuals. Together, these findings have identified a significant attenuation of the exercise-induced hyperemic response during both upper and lower limb exercise, implicating maladaptions in the peripheral hemodynamic response to exercise as a potential contributor limiting exercise capacity in this patient group. The third study sought to address the contribution of the alpha-adrenergic receptor pathway in the regulation of blood flow to exercising skeletal muscle in HFrEF patients. At rest, alpha-1-adrenergic receptor vasoconstriction induced by local intra-arterial infusion of phenylephrine (PE) was reduced in HFrEF compared to control subjects. During exercise, the vasoconstrictor responsiveness to PE was significantly attenuated in the control group and preserved in HFrEF patients compared to rest. Additionally, nonspecific alpha-adrenergic receptor antagonism induced by local intra-arterial infusion of phentolamine increased blood flow to a greater degree in HFrEF compared to the control subjects, both at rest and during exercise. Together, these findings demonstrate a marked contribution of alpha-adrenergic receptor restraint of leg blood flow in HFrEF patients during exercise. Collectively, these three studies have provided new insight into the role the SNS and peripheral hemodynamics play in the maladaptive cardiovascular response to exercise displayed in patients with HFrEF, further implicating the peripheral expression of SNS activity as a primary contributor to impaired exercise capacity in this patient group. </p>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:10001028 |
| Date | 21 January 2016 |
| Creators | Barrett-O'Keefe, Zachary |
| Publisher | The University of Utah |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
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