Hypercholesterolemia and microvascular dysfunction: Altered mechanisms and interventional strategies
Date of Graduation
School of Medicine
Jefferson C. Frisbee.
Cardiovascular disease has a number of risk factors and confounding variables associated with the development and progression of the condition. Hypercholesterolemia is one of the few independent risk factors of peripheral vascular disease (PVD) and coronary artery disease (CAD) with causes stemming from a genetic predisposition and lifestyle management. The primary symptom of these diseases can be described as an endothelial cell dysfunction, which hypercholesterolemia can exacerbate, leading to a pro-inflammatory state of elevated oxidant stress and significant reduction in nitric oxide (NO) bioavailability, a key mediator of endothelium-dependent dilation. This environment can culminate into an impairment of the vascular reactivity due to mechanical and metabolic alterations.;The mechanical microvascular remodeling is evident within dyslipidemia producing a decrease in vascular perfusion; however there are significant differences between the remodeling within the condition of hypercholesterolemia leading to an early evolution of MCP-1 and increased wall stiffness and thickness and later progression of hyperlipidemia leading to an increase in TNF-alpha and microvascular rarefaction.;While the reduction in NO bioavailability, due to a reduced production or oxidative scavenge, leads to a maintained yet altered mechanism of peripheral skeletal muscle arteriolar endothelium dependent dilation with a shift to the reliance on increased production of metabolites of arachidonic acid metabolism, via the cyclooxygenase and lipoxygenase enzymatic pathways. These metabolites include 12- and 15-lipoxygenase and prostacyclin, with strong dilator effects, in addition to, thromboxane A2 a profound vasoconstrictor. The culmination of these products leads to a net reduced dilator effect evident in animals with genetic hypercholesterolemia.;Current interventions include a number of cholesterol lowering prescriptions and the inclusion of a regular exercise program, which have been shown to reduce cholesterol and improve the cardiovascular symptoms. Considerable attention has been given to the molecular mechanisms leading to the improvement of microvascular endothelial dysfunction and subsequent vascular reactivity; however the mechanistic consequences of these treatments are not well understood within the realms of inflammation, oxidative stress, and vascular reactivity. In both the hypercholesterolemic and normocholesterolemic groups the greatest benefit, with respect to inflammation and oxidant stress, was seen in the exercise only groups. Unexpectedly, the hypercholesterolemic groups saw no improvement in vascular reactivity to any of the interventions; while the normocholesterolemic group presented detrimental results to the vascular reactivity of the pharmaceutically treated animals. Therefore, the mechanistic and mechanical outcomes associated with the reported pleiotropic effects of the cholesterol lowering treatments warrants further study specific to hyper- and normocholesterolemic conditions.
Stapleton, Phoebe, "Hypercholesterolemia and microvascular dysfunction: Altered mechanisms and interventional strategies" (2010). Graduate Theses, Dissertations, and Problem Reports. 3260.