Cathodal Iontophoresis of Treprostinil Induces a Sustained Increase in Cutaneous Blood Flux in Healthy Volunteers : The Journal of Clinical Pharmacology

The study of microvascular function can be performed in humans using laser Doppler flowmetry of the skin. This technology lends itself to a wide range of applications for studying the endothelial function of skin blood vessels. We review the advantages and limitations of postocclusive hyperemia, local thermal hyperemia, acetylcholine iontophoresis, flowmotion and association with microdialysis as tools with which to investigate skin microvascular endothelial function in humans. Postocclusive hyperemia, thermal hyperemia and acetylcholine iontophoresis provide integrated indexes of microvascular function rather than specific endothelial markers. However, they are valuable tools and can be used as surrogate endpoints in clinical trials in which the assessment of microvascular function in humans is required.

We compared the inter-day reproducibility of post-occlusive reactive hyperemia (PORH) assessed by single-point laser Doppler flowmetry (LDF) and laser speckle contrast analysis (LSCI), and the reproducibility of local thermal hyperemia (LTH) assessed by LDF, laser Doppler imaging (LDI) and LSCI. We also tested whether skin blood flow assessment by LDF and by LSCI are correlated. Skin blood flow was evaluated during PORH and LTH using LDF, LDI (for LTH only) and LSCI on the forearms of healthy volunteers, at a 7day interval. Data are expressed as cutaneous vascular conductance (CVC), as a function of baseline and scaled to the thermal plateau. Reproducibility is expressed as within subject coefficients of variation (CV, in %) and intra-class correlation coefficients (ICC). Twenty-eight healthy participants were enrolled in this study. The reproducibility of the PORH peak CVC was better when assessed with LSCI compared to LDF (CV=8%; ICC=0.76 and CV=30%; ICC=0.54, respectively). Inter-day reproducibility of the LTH plateau was better when assessed with LSCI or LDI than LDF (CV=15%, ICC=0.66; CV=17%, ICC=0.51 and CV=42%, ICC=0.28 respectively). Finally, we observed significant correlation between simultaneous LDF and LSCI measurements of the PORH peak CVC (R=0.54; p=0.001). The recently developed LSCI technique showed very good inter-day reproducibility for assessing PORH and LTH. Moreover, we showed significant correlation between LSCI and single-point LDF for PORH. However, more data are needed to evaluate the linearity between the LSCI signal and skin blood flow. Copyright © 2010 Elsevier Inc. All rights reserved.

Effective evaluation of endothelial function is a powerful tool for determining patients at risk of development and progression of cardiovascular disease. As an alternative to invasive tests of endothelial function, several noninvasive methods have been developed, including the use of laser Doppler flowmetry/imaging to measure cutaneous perfusion accompanied by iontophoresis of acetylcholine and sodium nitroprusside. It is clear from previous studies that this technique provides an easy, validated, and reproducible method for investigators to assess and monitor endothelial function in patients with a variety of pathologic conditions, but it may also be used to examine disease progression over time and responsiveness to treatment, thereby facilitating clinical trials. However, a standardization of protocols would help reduce the apparent controversy seen in the literature. With its increasing use by other groups, it is anticipated that further published studies will help to provide a better understanding of the development and progression of cardiovascular disease.