Assessments of Perfusion, Blood Flow, and Vascular Structure in Ambulatory Subjects: Guidance for Translational Research Scientists.

Research involving human subjects in ambulatory settings is a critical link in the chain comprising translational research, spanning preclinical research to human subject and patient cohort studies. There are presently a wide array of techniques and approaches available to investigators wishing to study blood flow, perfusion, and vascular structure and function in human subjects. In this multi-sectioned review, we discuss capillaroscopy, carotid intima-media thickness, flow-mediated dilation, laser Doppler flowmetry, near-infrared spectroscopy, peripheral arterial tonometry, pulse wave velocity, retinal fundus imaging, and vascular plethysmography. Each section contains a general overview and the physical basis of the technique followed by a discussion of the procedures involved and the necessary equipment, with attention paid to specific requirements or limitations. Subsequently, we detail which aspects of vascular function can be studied with a given technique, the analytical approach to the collected data, and the appropriate application and limitation(s) to the interpretation of the data collected. Finally, a modified scoping review provides a summary of how each assessment technique has been applied in previous studies. It is anticipated that this review will provide an efficient source of information and insight for preclinical investigators seeking to add translational aspects to their research programs.

Application of a novel index for understanding vascular health following pharmacological intervention in a pre-clinical model of metabolic disease.

While a thorough understanding of microvascular function in health and how it becomes compromised with progression of disease risk is critical for developing effective therapeutic interventions, our ability to accurately assess the beneficial impact of pharmacological interventions to improve outcomes is vital. Here we introduce a novel Vascular Health Index (VHI) that allows for simultaneous assessment of changes to vascular reactivity/endothelial function, vascular wall mechanics and microvessel density within cerebral and skeletal muscle vascular networks with progression of metabolic disease in obese Zucker rats (OZR); under control conditions and following pharmacological interventions of clinical relevance. Outcomes are compared to "healthy" conditions in lean Zucker rats. We detail the calculation of vascular health index, full assessments of validity, and describe progressive changes to vascular health index over the development of metabolic disease in obese Zucker rats. Further, we detail the improvement to cerebral and skeletal muscle vascular health index following chronic treatment of obese Zucker rats with anti-hypertensive (15%-52% for skeletal muscle vascular health index; 12%-48% for cerebral vascular health index; p < 0.05 for both), anti-dyslipidemic (13%-48% for skeletal muscle vascular health index; p < 0.05), anti-diabetic (12%-32% for cerebral vascular health index; p < 0.05) and anti-oxidant/inflammation (41%-64% for skeletal muscle vascular health index; 29%-42% for cerebral vascular health index; p < 0.05 for both) drugs. The results present the effectiveness of mechanistically diverse interventions to improve cerebral or skeletal muscle vascular health index in obese Zucker rats and provide insight into the superiority of some pharmacological agents despite similar effectiveness in terms of impact on intended targets. In addition, we demonstrate the utility of including a wider, more integrative approach to the study of microvasculopathy under settings of elevated disease risk and following pharmacological intervention. A major benefit of integrating vascular health index is an increased understanding of the development, timing and efficacy of interventions through greater insight into integrated microvascular function in combination with individual, higher resolution metrics.

A novel vascular health index: Using data analytics and population health to facilitate mechanistic modeling of microvascular status.

The study of vascular function across conditions has been an intensive area of investigation for many years. While these efforts have revealed many factors contributing to vascular health, challenges remain for integrating results across research groups, animal models, and experimental conditions to understand integrated vascular function. As such, the insights attained in clinical/population research from linking datasets, have not been fully realized in the basic sciences, thus frustrating advanced analytics and complex modeling. To achieve comparable advances, we must address the conceptual challenge of defining/measuring integrated vascular function and the technical challenge of combining data across conditions, models, and groups. Here, we describe an approach to establish and validate a composite metric of vascular function by comparing parameters of vascular function in metabolic disease (the obese Zucker rat) to the same parameters in age-matched, "healthy" conditions, resulting in a common outcome measure which we term the vascular health index (VHI). VHI allows for the integration of datasets, thus expanding sample size and permitting advanced modeling to gain insight into the development of peripheral and cerebral vascular dysfunction. Markers of vascular reactivity, vascular wall mechanics, and microvascular network density are integrated in the VHI. We provide a detailed presentation of the development of the VHI and provide multiple measures to assess face, content, criterion, and discriminant validity of the metric. Our results demonstrate how the VHI captures multiple indices of dysfunction in the skeletal muscle and cerebral vasculature with metabolic disease and provide context for an integrated understanding of vascular health under challenged conditions.