Effect of Plasma Ceramides on Peripheral Vascular Function

Purpose: The overarching goal of this project is to correlate the effects of plasma ceramide with human in vivo vascular function.

Formulation of Research Questions: Following decades of decline in mortality, death due to heart disease is increasing, and remains the #1 cause of death in the United States. Although acute ischemic events are typically due to obstructive plaque within the coronary conduit arteries, strong evidence suggests that dysfunction within the coronary microvasculature is a more powerful predictor of major adverse cardiac events (MACE) than severity of atherosclerosis1. The coronary microvasculature likely also contributes to other forms of cardiovascular disease including heart failure with preserved ejection fraction (HFpEF)2. While assessment of the coronary microvasculature is highly invasive and expensive, interrogation of the peripheral microvasculature offers a more feasible approach. Recent studies have concluded that peripheral microvascular dysfunction mirrors the functional status of the coronary microvasculature3. Further, impaired peripheral microvascular function is associated with increased risk of MACE in patients with stable coronary artery disease (CAD), suggesting that the microvasculature plays a critical role in the pathogenesis of heart disease4.

Elevated plasma ceramides are also associated with risk of MACE in otherwise healthy individuals5 as well as in heart failure both with and without reduced ejection fraction (HFrEF and HFpEF, respectively)6. Recently it was shown that ceramide levels are increased in patients with early CAD that also exhibit impaired coronary microvascular endothelial dysfunction7. Using an in vitro model, the investigators have previously shown that exposure to exogenous ceramide causes microvascular endothelial dysfunction in arterioles from healthy individuals8. However the effect of ceramide on human in vivo peripheral microvascular function represents a critical knowledge gap that needs to be addressed. Increased plasma ceramide may evoke peripheral in vivo microvascular dysfunction that mirrors that of the coronary microvasculature thus providing a less invasive means to assess future cardiovascular risk.

Hypothesis: Following a single high-fat meal, increases in plasma ceramides will correlate with a reduction in peripheral large and small vascular function in the intact human adult.

At Adult TRU: