Correlation of diabetic renal hypoperfusion with microvascular responses of the skeletal muscle: a rat model study using diffuse correlation spectroscopy.

Using diffuse correlation spectroscopy, we assessed the renal blood flow and thigh muscle microvascular responses in a rat model of type 2 diabetes. The blood flow index at the renal surface decreased significantly with arterial clamping, cardiac extirpation, and the progression of diabetic endothelial dysfunction. Renal blood flow measured in diabetic and nondiabetic rats also showed a significant correlation with the reactive hyperemic response of the thigh muscle. These results suggest shared microcirculatory dysfunction in the kidney and skeletal muscle and support endothelial responses in the skeletal muscle as a potential noninvasive biomarker of renal hypoperfusion.

Differential changes in blood flow and oxygen utilization in active muscles between voluntary exercise and electrical muscle stimulation in young adults.

The physiological effects on blood flow and oxygen utilization in active muscles during and after involuntary contraction triggered by electrical muscle stimulation (EMS) remain unclear, particularly compared with those elicited by voluntary (VOL) contractions. Therefore, we used diffuse correlation and near-infrared spectroscopy (DCS-NIRS) to compare changes in local muscle blood flow and oxygen consumption during and after these two types of muscle contractions in humans. Overall, 24 healthy young adults participated in the study, and data were successfully obtained from 17 of them. Intermittent (2-s contraction, 2-s relaxation) isometric ankle dorsiflexion with a target tension of 20% of maximal VOL contraction was performed by EMS or VOL for 2 min, followed by a 6-min recovery period. DCS-NIRS probes were placed on the tibialis anterior muscle, and relative changes in local tissue blood flow index (rBFI), oxygen extraction fraction (rOEF), and metabolic rate of oxygen (rMRO2) were continuously derived. EMS induced more significant increases in rOEF and rMRO2 than VOL exercise but a comparable increase in rBFI. After EMS, rBFI and rMRO2 decreased more slowly than after VOL and remained significantly higher until the end of the recovery period. We concluded that EMS augments oxygen consumption in contracting muscles by enhancing oxygen extraction while increasing oxygen delivery at a rate similar to the VOL exercise. Under the conditions examined in this study, EMS demonstrated a more pronounced and/or prolonged enhancement in local muscle perfusion and aerobic metabolism compared with VOL exercise in healthy participants.NEW & NOTEWORTHY This is the first study to visualize continuous changes in blood flow and oxygen utilization within contracted muscles during and after electrical muscle stimulation (EMS) using combined diffuse correlation and near-infrared spectroscopy. We found that initiating EMS increases blood flow at a rate comparable to that during voluntary (VOL) exercise but enhances oxygen extraction, resulting in higher oxygen consumption. Furthermore, EMS increased postexercise muscle perfusion and oxygen consumption compared with that after VOL exercise.

Deep-learning-based separation of shallow and deep layer blood flow rates in diffuse correlation spectroscopy.

Diffuse correlation spectroscopy faces challenges concerning the contamination of cutaneous and deep tissue blood flow. We propose a long short-term memory network to directly quantify the flow rates of shallow and deep-layer tissues. By exploiting the different contributions of shallow and deep-layer flow rates to auto-correlation functions, we accurately predict the shallow and deep-layer flow rates (RMSE = 0.047 and 0.034 ml/min/100 g of simulated tissue, R2 = 0.99 and 0.99, respectively) in a two-layer flow phantom experiment. This approach is useful in evaluating the blood flow responses of active muscles, where both cutaneous and deep-muscle blood flow increase with exercise.

Rapid vasodilation within contracted skeletal muscle in humans: new insight from concurrent use of diffuse correlation spectroscopy and Doppler ultrasound.

Previous studies showed that conduit artery blood flow rapidly increases after even a brief contraction of muscles within the dependent limb. Whether this rapid hyperemia occurs within contracted skeletal muscle in humans has yet to be confirmed, however. We therefore used diffuse correlation spectroscopy (DCS) to characterize the rapid hyperemia and vasodilatory responses within the muscle microvasculature induced by single muscle contractions in humans. Twenty-five healthy male volunteers performed single 1-s isometric handgrips at 20%, 40%, 60%, and 80% of maximum voluntary contraction. DCS probes were placed on the flexor digitorum superficialis muscle, and a skeletal muscle blood flow index (SMBFI) was derived continuously. At the same time, brachial artery blood flow (BABF) responses were measured using Doppler ultrasound. Single muscle contractions evoked rapid, monophasic increases in both SMBFI and BABF that occurred within 3 s after release of contraction. The initial and peak responses increased with increases in contraction intensity and were greater for BABF than for SMBFI at all intensities. BABF reached its peak within 5 to 8 s after the end of contraction. The SMBFI continued to increase after the BABF passed its peak and was decreasing toward the resting level and peaked about 10 to 15 s after completion of the contraction. We conclude that single muscle contractions induce rapid, intensity-dependent hyperemia within the contracted skeletal muscle microvasculature. Moreover, the characteristics of the rapid hyperemia and vasodilatory responses of skeletal muscle microvessels differ from those simultaneously evaluated in the upstream conduit artery.NEW & NOTEWORTHY Through the concurrent use of diffuse correlation spectroscopy and Doppler ultrasound, we provide the first evidence in humans that a single brief muscle contraction evokes rapid, intensity-dependent hyperemia within the contracted skeletal muscle microvasculature and the upstream conduit artery. We also show that the magnitude and time course of the contraction-induced rapid hyperemia and vasodilatory responses within skeletal muscle microvessels significantly differ from those in the conduit artery.

Evaluation of Local Skeletal Muscle Blood Flow in Manipulative Therapy by Diffuse Correlation Spectroscopy.

Manipulative therapy (MT) is applied to motor organs through a therapist's hands. Although MT has been utilized in various medical treatments based on its potential role for increasing the blood flow to the local muscle, a quantitative validation of local muscle blood flow in MT remains challenging due to the lack of appropriate bedside evaluation techniques. Therefore, we investigated changes in the local blood flow to the muscle undergoing MT by employing diffuse correlation spectroscopy, a portable and emerging optical measurement technology that non-invasively measures blood flow in deep tissues. This study investigated the changes in blood flow, heart rate, blood pressure, and autonomic nervous activity in the trapezius muscle through MT application in 30 volunteers without neck and shoulder injury. Five minutes of MT significantly increased the median local blood flow relative to that of the pre-MT period (p < 0.05). The post-MT local blood flow increase was significantly higher in the MT condition than in the control condition, where participants remained still without receiving MT for the same time (p < 0.05). However, MT did not affect the heart rate, blood pressure, or cardiac autonomic nervous activity. The post-MT increase in muscle blood flow was significantly higher in the participants with muscle stiffness in the neck and shoulder regions than in those without (p < 0.05). These results suggest that MT could increase the local blood flow to the target skeletal muscle, with minimal effects on systemic circulatory function.

The Possibility of Urinary Liver-Type Fatty Acid-Binding Protein as a Biomarker of Renal Hypoxia in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: Renal hypoxia is an aggravating factor for tubulointerstitial damage, which is strongly associated with renal prognosis in diabetic kidney disease (DKD). Therefore, urinary markers that can detect renal hypoxia are useful for monitoring DKD. OBJECTIVE: To determine the correlation between urinary liver-type fatty acid-binding protein (L-FABP) and renal hypoxia using a novel animal model of type 2 diabetes. METHODS: Male spontaneously diabetic Torii (SDT) fatty rats (n = 6) were used as an animal model of type 2 diabetes. Age- and sex-matched Sprague-Dawley (SD) rats (n = 8) were used as controls. Body weight, systolic blood pressure, and blood glucose levels were measured at 8, 12, 16, and 24 weeks of age. Urine samples and serum and kidney tissues were collected at 24 weeks of age. Microvascular blood flow index (BFI) was measured using diffuse correlation spectroscopy before sampling both the serum and kidneys for the evaluation of renal microcirculation at the corticomedullary junction. RESULTS: Obesity, hyperglycemia, and hypertension were observed in the SDT fatty rats. Focal glomerular sclerosis, moderate interstitial inflammation, and fibrosis were significantly more frequent in SDT fatty rats than in SD rats. While the frequency of peritubular endothelial cells and phosphoendothelial nitric oxide synthase levels were similar in both types of rats, the degree of renal hypoxia-inducible factor-1α (HIF-1α) expression was significantly higher (and with no change in renal vascular endothelial growth factor expression levels) in the SDT fatty rats. Urinary L-FABP levels were significantly higher and renal microvascular BFI was significantly lower in the SDT fatty rats than in the SD rats. Urinary L-FABP levels exhibited a significant positive correlation with renal HIF-1α expression and a significant negative correlation with renal microvascular BFI. CONCLUSIONS: Urinary L-FABP levels reflect the degree of renal hypoxia in DKD in a type 2 diabetic animal model. Urinary L-FABP may thus prove useful as a renal hypoxia marker for monitoring DKD in patients with type 2 diabetes in clinical practice.

Difference in the integrated effects of sympathetic vasoconstriction and local vasodilation in human skeletal muscle and skin microvasculature.

We investigated the integration of sympathetic vasoconstriction and local vasodilation in the skeletal muscle and skin microvasculature of humans. In 39 healthy volunteers, we simultaneously measured the blood flow index in the flexor carpi radialis muscle using diffuse correlation spectroscopy and the skin using laser-Doppler flowmetry. We examined the effects of acute sympathoexcitation induced by forehead cooling on relatively weak and robust vasodilatory responses during postocclusive reactive hyperemia (PORH) induced by 70-sec and 10-min arterial occlusion in the upper arm. To increase sympathetic tone during PORH, forehead cooling was begun 60 sec before the occlusion release and ended 60 sec after the release. In the 70-sec occlusion trials, acute sympathoexcitation reduced the peak and duration of vasodilation in both skeletal muscle and skin. The inhibition of vasodilation by sympathoexcitation was blunted in both tissues by the robust vasodilatory stimulation produced by the 10-min occlusion, and the degree of blunting was greater in skeletal muscle than in skin, especially the initial and peak responses. Sympathoexcitation reduced the peak vasodilation only in skin, while it accelerated the initial vasodilation only in skeletal muscle. However, the decline in vasodilation after the peak was significantly hastened in skeletal muscle, shortening the duration of the vasodilation. We conclude that, in humans, the integration of sympathetic vasoconstriction and local vasodilation has different effects in skeletal muscle and skin and is likely an important contributor to the selective control of perfusion in the microcirculations of different tissues.

Sympathoexcitation constrains vasodilation in the human skeletal muscle microvasculature during postocclusive reactive hyperemia.

We used diffuse correlation spectroscopy to investigate sympathetic vasoconstriction, local vasodilation, and integration of these two responses in the skeletal muscle microvasculature of 20 healthy volunteers. Diffuse correlation spectroscopy probes were placed on the flexor carpi radialis muscle or vastus lateralis muscle, and a blood flow index was derived continuously. We measured hemodynamic responses during sympathoexcitation induced by forehead cooling, after which the effects of the increased sympathetic tone on vasodilatory responses during postocclusive reactive hyperemia (PORH) were examined. PORH was induced by releasing arterial occlusion (3 min) in an arm or leg. To increase sympathetic tone during PORH, forehead cooling was begun 60 s before the occlusion release and ended 60 s after the release. During forehead cooling, mean arterial pressure rose significantly and was sustained at an elevated level. Significant vasoconstriction and decreases in blood flow index followed by gradual blunting of the vasoconstriction also occurred. The time course of these responses is in good agreement with previous observations in animals. The acute sympathoexcitation diminished the peak vasodilation during PORH only in the vastus lateralis muscle, but it hastened the decline in vasodilation after the peak in both the flexor carpi radialis muscle and vastus lateralis muscle. Consequently, the total vasodilatory response assessed as the area of the vascular conductance during the first minute of PORH was significantly diminished in both regions. We conclude that, in humans, the integrated effects of sympathetic vasoconstriction and local vasodilation have an important role in vascular regulation and control of perfusion in the skeletal muscle microcirculation. NEW & NOTEWORTHY We used diffuse correlation spectroscopy to demonstrate that acute sympathoexcitation constrains local vasodilation in the human skeletal muscle microvasculature during postocclusive reactive hyperemia. This finding indicates that integration of sympathetic vasoconstriction and local vasodilation is importantly involved in vascular regulation and the control of perfusion of the skeletal muscle microcirculation in humans.

Muscular blood flow responses as an early predictor of the severity of diabetic neuropathy at a later stage in streptozotocin-induced type I diabetic rats: a diffuse correlation spectroscopy study.

We propose a novel application of diffuse correlation spectroscopy to evaluate microvascular malfunctions of muscle tissue affected by hyperglycemia and determine their correlation with the severity of diabetic neuropathy at a later stage. Microvascular responses of the thigh muscle and the mechanical pain threshold of the hind paw of streptozotocin-induced type I diabetic rats were continuously monitored once per week for 70 days. Significantly decreased baseline blood flow and reactive hyperemia responses were observed as early as 1 week after hyperglycemia induction. The reactive hyperemia response at 2 weeks of hyperglycemia was highly correlated with the mechanical pain threshold at 8 weeks, at which time a decreased pain threshold was statistically confirmed in hyperglycemic rats relative to controls.