Interindividual differences in the ischemic stimulus and other technical considerations when assessing reactive hyperemia.

Reactive hyperemia is an established, noninvasive technique to assess microvascular function and a powerful predictor of all-cause and cardiovascular morbidity and mortality. Emerging evidence from our laboratory suggests a close link between reactive hyperemia and the metabolic rate of the ischemic limb and the existence of large interindividual differences contributing to markedly different stimuli to vasodilate. Here we relate forearm tissue desaturation (i.e., the ischemic stimulus to vasodilate, measured by near-infrared spectroscopy) to brachial artery hyperemic velocity and flow (measured using duplex ultrasound) across a wide range of ischemic stimuli. Twelve young and 11 elderly individuals were prospectively studied. To recapitulate conventional vascular occlusion testing, reactive hyperemia was first assessed using a standard 5-min occlusion period. Then, to evaluate the dose dependence of tissue ischemia on reactive hyperemia, we randomly performed 4-, 6-, and 8-min cuff occlusions in both groups. In all cases, peak velocity, as well as the 5-s average velocity, immediately after the cuff occlusion was significantly higher in the young than the elderly group; however, tissue desaturation was also much more pronounced in the young group (P < 0.05), representing a greater ischemic stimulus. Remarkably, when reactive hyperemia was adjusted for the ischemic vasodilatory stimulus, group differences in reactive hyperemia were abrogated. Together, these data challenge conventional interpretations of reactive hyperemia and show that the ischemic stimulus to vasodilate varies across individuals and that the level of reactive hyperemia is often coupled to the magnitude of tissue desaturation.

Age-related microvascular dysfunction: novel insight from near-infrared spectroscopy.

NEW FINDINGS: What is the central question of this study? Can near-infrared spectroscopy (NIRS)-derived post-occlusion tissue oxygen saturation recovery kinetics be used to study age-related impairments in microvascular function? What is the main finding and its importance? Using a previously established 5 min cuff occlusion protocol, we found that NIRS-derived indices of microvascular function were markedly reduced in elderly compared with young participants. However, when we controlled for the absolute level of vasodilatory stimulus and matched the tissue desaturation level between groups, we found similar responses in young and elderly participants. Overall, these data highlight the important role NIRS can serve in clinical vascular biology, but also establish the need for assessing tissue ischaemia during cuff occlusion protocols. Near-infrared spectroscopy (NIRS) has emerged as a promising tool to evaluate vascular reactivity in vivo. Whether this approach can be used to assess age-related impairments in microvascular function has not been tested. Tissue oxygen saturation (StO2) post-occlusion recovery kinetics were measured in two distinct age groups (<35 and >65 years of age) using NIRS placed over the flexor digitorum profundus. Key end-points included the following: (i) the desaturation rate during cuff occlusion; (ii) the lowest StO2 value obtained during ischaemia (StO2min); (iii) StO2 reperfusion rate; (iv) the highest StO2 value reached after cuff release (StO2max); and (v) the reactive hyperaemia area under the curve (AUC). At first, using a conventional 5 min cuff occlusion protocol, the elderly participants achieved a much slower rate of oxygen recovery (1.5 ± 0.2 versus 2.5 ± 0.2% s-1 ), lower StO2max (85.2 ± 2.9 versus 92.3 ± 1.5%) and lower reactive hyperaemia AUC (2651.8 ± 307.0 versus 4940.0 ± 375.8% s-1 ). However, owing to a lower skeletal muscle resting metabolic rate, StO2min was also significantly attenuated in the elderly participants compared with the young control subjects (55.7 ± 3.5 versus 41.0 ± 3.4%), resulting in a much lower ischaemic stimulus. To account for this important difference between groups, we then matched the level of tissue ischaemia in a subset of young healthy participants by reducing the cuff occlusion protocol to 3 min. Remarkably, when we controlled for tissue ischaemia, we observed no differences in any of the hyperaemic end-points between the young and elderly participants. These data highlight the important role NIRS can serve in vascular biology, but also establish the need for assessing tissue ischaemia during cuff occlusion protocols.

Skeletal Muscle Neurovascular Coupling, Oxidative Capacity, and Microvascular Function with 'One Stop Shop' Near-infrared Spectroscopy.

Exercise represents a major hemodynamic stress that demands a highly coordinated neurovascular response in order to match oxygen delivery to metabolic demand. Reactive hyperemia (in response to a brief period of tissue ischemia) is an independent predictor of cardiovascular events and provides important insight into vascular health and vasodilatory capacity. Skeletal muscle oxidative capacity is equally important in health and disease, as it determines the energy supply for myocellular processes. Here, we describe a simple, non-invasive approach using near-infrared spectroscopy to assess each of these major clinical endpoints (reactive hyperemia, neurovascular coupling, and muscle oxidative capacity) during a single clinic or laboratory visit. Unlike Doppler ultrasound, magnetic resonance images/spectroscopy, or invasive catheter-based flow measurements or muscle biopsies, our approach is less operator-dependent, low-cost, and completely non-invasive. Representative data from our lab taken together with summary data from previously published literature illustrate the utility of each of these end-points. Once this technique is mastered, application to clinical populations will provide important mechanistic insight into exercise intolerance and cardiovascular dysfunction.

Near-infrared spectroscopy detects age-related differences in skeletal muscle oxidative function: promising implications for geroscience.

Age is the greatest risk factor for chronic disease and is associated with a marked decline in functional capacity and quality of life. A key factor contributing to loss of function in older adults is the decline in skeletal muscle function. While the exact mechanism(s) remains incompletely understood, age-related mitochondrial dysfunction is thought to play a major role. To explore this question further, we studied 15 independently living seniors (age: 72 ± 5 years; m/f: 4/11; BMI: 27.6 ± 5.9) and 17 young volunteers (age: 25 ± 4 years; m/f: 8/9; BMI: 24.0 ± 3.3). Skeletal muscle oxidative function was measured in forearm muscle from the recovery kinetics of muscle oxygen consumption using near-infrared spectroscopy (NIRS). Muscle oxygen consumption was calculated as the slope of change in hemoglobin saturation during a series of rapid, supra-systolic arterial cuff occlusions following a brief bout of exercise. Aging was associated with a significant prolongation of the time constant of oxidative recovery following exercise (51.8 ± 5.4 sec vs. 37.1 ± 2.1 sec, P = 0.04, old vs. young, respectively). This finding suggests an overall reduction in mitochondrial function with age in nonlocomotor skeletal muscle. That these data were obtained using NIRS holds great promise in gerontology for quantitative assessment of skeletal muscle oxidative function at the bed side or clinic.

Multi-pathway exposure modeling of chemicals in cosmetics with application to shampoo.

We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3×10(-4) up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (<1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The presented PiF based framework offers a novel and critical advancement for life cycle assessments and high-throughput exposure screening of chemicals in cosmetic products demonstrating the importance of consistent consideration of near- and far-field multi-pathway exposures.