Assessing Microvascular Function in Humans from a Chronic Disease Perspective

Abstract

Microvascular dysfunction (MVD) is considered a crucial pathway in the development and progression of cardiometabolic and renal disease and is associated with increased cardiovascular mortality. MVD often coexists with or even precedes macrovascular disease, possibly due to shared mechanisms of vascular damage, such as inflammatory processes and oxidative stress. One of the first events in MVD is endothelial dysfunction. With the use of different physiologic or pharmacologic stimuli, endothelium-dependent (micro)vascular reactivity can be studied. This reactivity depends on the balance between various mediators, including nitric oxide, endothelin, and prostanoids, among others. The measurement of microvascular (endothelial) function is important to understand the pathophysiologic mechanisms that contribute to MVD and the role of MVD in the development and progression of cardiometabolic/renal disease. Here, we review a selection of direct, noninvasive techniques for measuring human microcirculation, with a focus on methods, interpretation, and limitations from the perspective of chronic cardiometabolic and renal disease.

Keywords: Cardiometabolic disease; Microvascular dysfunction; Pathophysiology; Renal disease; endothelium.

Figure 1.

Capillary density in skin on the dorsum of the finger. Images are stills from videomicroscopy clips of exactly the same visual field (1 mm² of skin). Left: Baseline capillary density. Right: Capillary recruitment during postocclusive reactive hyperemia. The white arrows represent examples of nonperfused capillaries under baseline conditions that are recruited during postocclusive reactive hyperemia.

Figure 2.

Typical registration of skin microvascular perfusion, measured with laser-Doppler flowmetry, before and during local heating of the skin in a healthy volunteer. After 2 minutes of baseline flow registration, skin heating to 44°C is started for 23 minutes. Time (minute) is depicted on the x axis and skin perfusion (arbitrary perfusion units, PU) on the y axis. The heat-induced skin hyperemic response is expressed as the percentage increase in average perfusion units during the 23-minute heating phase over the average baseline perfusion units.

Figure 3.

Typical registration of diameter changes of a single retinal arteriole and venule before, during, and after a 30-second flicker light period (t=50 to t=80 seconds) in a healthy volunteer. Time (seconds) is depicted on the x axis and diameter (micrometers) on the y axis. The flicker light–induced vasodilator response is expressed as the average increase in diameter during flicker light as a percentage over baseline diameter.

Figure 4.

Hypothesis describing determinants contributing to MVD and subsequent organ dysfunction. We here define microvascular (dys)function being the result of vessel wall components’ (smooth muscle cells, matrix, endothelium) structure and function, and neurogenic and local metabolic influences. Early MVD leads to impaired insulin-mediated glucose uptake and raised peripheral resistance, which contributes to the development of insulin resistance/type 2 diabetes, and hypertension, respectively. The hyperglycemic milieu and hypertension in turn further aggravate MVD leading to a vicious cycle (dashed arrows). ↑, stimulated (levels of); ↓, reduced (levels of); AGEs, advanced glycation end products; FFA, free fatty acids.