Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Family Medicine

Committee Chair

Paul D Chantler

Committee Co-Chair

Taura L Barr

Committee Member

Gregory M Dick

Committee Member

Jefferson C Frisbee

Committee Member

Mark Olfert

Abstract

Metabolic syndrome (MetS) is a complex disease state defined by the manifestation of a cluster of cardiovascular (CV) risk factors including, abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Individuals afflicted with MetS have been demonstrated to assume the burden of a 3-fold increased risk of cardiovascular disease (CVD) mortality, myocardioal infarction, stroke, type II diabetes (T2DM) and all cause mortality. The national prevalence of hyperglycemia and abdominal obesity paralleled by a surge in sedentary lifestyle behavior underscore the importance of early identification and treatment of MetS. Deleterious adaptations to both vascular and myocardial structure and function have been demonstrated in MetS. Alterations in CV function associated with accelerated arterial aging have been implicated in the association between MetS and CVD. The underlying pathophysiology of MetS is not well understood and CV dysfunction has not been comprehensively examined in a MetS population free from confounding pathologies including T2DM and/or overt CVD. Furthermore, the effects of therapeutic lifestyle interventions for targeting subclinical CV dysfunction in MetS without T2DM and/or overt CVD require investigation. Therefore, the directive of the studies included in this dissertation was to perform a comprehensive assessment of CV function to validate the presence of CV dysfunction in MetS and to evaluate practical therapeutic strategies for improving cardiac and arterial dysfunction associated with MetS. Results from these studies identified subclinical left ventricular (LV) diastolic dysfunction at rest LV systolic dysfunction during exercise. Additionally, it was discovered that deleterious adaptations to large artery structure and function occur in individuals with MetS. Importantly, these alterations occurred in the absence of chronic disease including T2DM and clinical CVD. These results suggest for the first time that CV dysfunction does occur in individuals afflicted with MetS without T2DM and/or CVD. The investigation of exercise training as a therapeutic strategy for targeting arterial dysfunction revealed improvements in central arterial stiffness, central systolic blood pressure and aerobic capacity after 8 weeks of moderate/high intensity aerobic training. During peak exercise we have demonstrated improvements in arterial-ventricular coupling, LV contractility, peripheral vascular resistance, and aerobic capacity after 8 weeks of aerobic training in MetS. Exercise training was unable, however, to improve resting LV structure, LV diastolic function, or metabolic profile. Results from our investigation using a nutritional therapeutic approach to CV dysfunction in MetS demonstrate similar inconclusive findings. Single-dose supplementation with two doses of trans-resveratrol demonstrated no conclusive therapeutic potential for improving arterial stiffness or reducing central systolic blood pressure. These results would suggest that a greater understanding of the underlying pathology of MetS is required for identifying and optimizing therapeutic approaches to its treatment. Taken together the results of these collective documents demonstrate an understanding of the synergistic effects of co-occurring risk factors on CV function in the absence of chronic clinical disease. Further, these results highlight therapeutic and nutritional strategies for targeting CV dysfunction in MetS.

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