HDL Modulation and Endothelial Function

Purpose: To determine the incremental value of extended-release (ER) niacin in combination with high dose statin therapy on brachial endothelial function in subjects with coronary atherosclerosis.

Hypotheses:

1. ER niacin will improve endothelial function measured as brachial flow-mediated dilation (FMD - primary end-point), hyperemic velocity and as pulse volume amplitude by PAT (20 end-point) in subjects with established atherosclerosis whose LDL cholesterol is optimally treated with statin therapy.
2. Hyperemic pulse volume amplitude in the finger assessed by pulse arterial tonometry (PAT) will correlate with brachial FMD as assessed by high resolution ultrasound of the brachial artery.

Background: In patients with established coronary atherosclerosis, secondary prevention strategies with lipid lowering agents have resulted in event reductions of 25-30%. Despite aggressive cholesterol lowering with statins event rates remain 2-3% per year for subjects at high risk. While many new therapeutic targets have been suggested, recently there has been much interest in modulation of HDL cholesterol. Low HDL is a powerful risk factor for coronary events. HDL functions in the reverse cholesterol transport system to remove excess cholesterol from tissues including the vessel wall. In addition, HDL has other vascular benefits including anti-oxidant and direct endothelial effects. The most effective available way to modulate HDL is with niacin. An ER formulation of niacin (Niaspan - Kos) will be available in Canada in 2005 and has been shown to be efficacious and safe.

The endothelium plays a key role in vascular homeostasis through the release of paracrine factors such as nitric oxide. Dysfunction of the endothelium occurs in response to risk factors and atherosclerosis. Endothelial function can be readily measured non-invasively in humans and pharmacotherapy that has been shown to reduce cardiovascular events improves endothelium-dependent vasodilation. In addition, recent studies have suggested that measures of endothelial function have prognostic implications for subjects at risk for vascular events. As such the measurement of endothelial function has become well established as a surrogate marker of disease activity and will be utilized in the current study. The effect of niacin on endothelial function has not been studied.