Effects of exercise training on calf muscle oxygen extraction and blood flow in patients with peripheral artery disease.

We employed near-infrared optical techniques, diffuse correlation spectroscopy (DCS), and frequency-domain near-infrared spectroscopy (FD-NIRS) to test the hypothesis that supervised exercise training increases skeletal muscle microvascular blood flow and oxygen extraction in patients with peripheral artery disease (PAD) who experience claudication. PAD patients ( n = 64) were randomly assigned to exercise and control groups. Patients in the exercise group received 3 mo of supervised exercise training. Calf muscle blood flow and oxygen extraction were optically monitored before, during, and after performance of a graded treadmill protocol at baseline and at 3 mo in both groups. Additionally, measurements of the ankle-brachial index (ABI) and peak walking time (PWT) to maximal claudication were made during each patient visit. Supervised exercise training was found to increase the maximal calf muscle blood flow and oxygen extraction levels during treadmill exercise by 29% (13%, 50%) and 8% (1%, 12%), respectively [ P < 0.001; median (25th percentile, 75th percentile)]. These improvements across the exercise group population were significantly higher than corresponding changes in the control group ( P < 0.004). Exercise training also increased PWT by 49% (18%, 101%) ( P = 0.01). However, within statistical error, the ABI, resting calf muscle blood flow and oxygen extraction, and the recovery half-time for hemoglobin\myoglobin desaturation following cessation of maximal exercise were not altered by exercise training. The concurrent monitoring of both blood flow and oxygen extraction with the hybrid DCS/FD-NIRS instrument revealed enhanced muscle oxidative metabolism during physical activity from exercise training, which could be an underlying mechanism for the observed improvement in PWT. NEW & NOTEWORTHY We report on noninvasive optical measurements of skeletal muscle blood flow and oxygen extraction dynamics before/during/after treadmill exercise in peripheral artery disease patients who experience claudication. The measurements tracked the effects of a 3-mo supervised exercise training protocol and revealed that supervised exercise training improved patient ability to increase microvascular calf muscle blood flow and oxygen extraction during physical activity.

Fast blood flow monitoring in deep tissues with real-time software correlators.

We introduce, validate and demonstrate a new software correlator for high-speed measurement of blood flow in deep tissues based on diffuse correlation spectroscopy (DCS). The software correlator scheme employs standard PC-based data acquisition boards to measure temporal intensity autocorrelation functions continuously at 50 - 100 Hz, the fastest blood flow measurements reported with DCS to date. The data streams, obtained in vivo for typical source-detector separations of 2.5 cm, easily resolve pulsatile heart-beat fluctuations in blood flow which were previously considered to be noise. We employ the device to separate tissue blood flow from tissue absorption/scattering dynamics and thereby show that the origin of the pulsatile DCS signal is primarily flow, and we monitor cerebral autoregulation dynamics in healthy volunteers more accurately than with traditional instrumentation as a result of increased data acquisition rates. Finally, we characterize measurement signal-to-noise ratio and identify count rate and averaging parameters needed for optimal performance.

Fiber-optic Monitoring of Spinal Cord Hemodynamics in Experimental Aortic Occlusion.

BACKGROUND: Spinal cord ischemia occurs frequently during thoracic aneurysm repair. Current methods based on electrophysiology techniques to detect ischemia are indirect, non-specific, and temporally slow. In this article, the authors report the testing of a spinal cord blood flow and oxygenation monitor, based on diffuse correlation and optical spectroscopies, during aortic occlusion in a sheep model. METHODS: Testing was carried out in 16 Dorset sheep. Sensitivity in detecting spinal cord blood flow and oxygenation changes during aortic occlusion, pharmacologically induced hypotension and hypertension, and physiologically induced hypoxia/hypercarbia was assessed. Accuracy of the diffuse correlation spectroscopy measurements was determined via comparison with microsphere blood flow measurements. Precision was assessed through repeated measurements in response to pharmacologic interventions. RESULTS: The fiber-optic probe can be placed percutaneously and is capable of continuously measuring spinal cord blood flow and oxygenation preoperatively, intraoperatively, and postoperatively. The device is sensitive to spinal cord blood flow and oxygenation changes associated with aortic occlusion, immediately detecting a decrease in blood flow (-65 ± 32%; n = 32) and blood oxygenation (-17 ± 13%, n = 11) in 100% of trials. Comparison of spinal cord blood flow measurements by the device with microsphere measurements led to a correlation of R = 0.49, P < 0.01, and the within-sheep coefficient of variation was 9.69%. Finally, diffuse correlation spectroscopy is temporally more sensitive to ischemic interventions than motor-evoked potentials. CONCLUSION: The first-generation spinal fiber-optic monitoring device offers a novel and potentially important step forward in the monitoring of spinal cord ischemia.

Calibration of diffuse correlation spectroscopy blood flow index with venous-occlusion diffuse optical spectroscopy in skeletal muscle.

We investigate and assess the utility of a simple scheme for continuous absolute blood flow monitoring based on diffuse correlation spectroscopy (DCS). The scheme calibrates DCS using venous-occlusion diffuse optical spectroscopy (VO-DOS) measurements of arm muscle tissue at a single time-point. A calibration coefficient (γ) for the arm is determined, permitting conversion of DCS blood flow indices to absolute blood flow units, and a study of healthy adults (N=10) is carried out to ascertain the variability of γ. The average DCS calibration coefficient for the right (i.e., dominant) arm was γ=(1.24±0.15)×10(8) (mL·100 mL(−1)·min(−1))/(cm(2)/s). However, variability can be significant and is apparent in our site-to-site and day-to-day repeated measurements. The peak hyperemic blood flow overshoot relative to baseline resting flow was also studied following arm-cuff ischemia; excellent agreement between VO-DOS and DCS was found (R(2)=0.95, slope=0.94±0.07, mean difference=−0.10±0.45). Finally, we show that incorporation of subject-specific absolute optical properties significantly improves blood flow calibration accuracy.

Optical monitoring and detection of spinal cord ischemia.

Spinal cord ischemia can lead to paralysis or paraparesis, but if detected early it may be amenable to treatment. Current methods use evoked potentials for detection of spinal cord ischemia, a decades old technology whose warning signs are indirect and significantly delayed from the onset of ischemia. Here we introduce and demonstrate a prototype fiber optic device that directly measures spinal cord blood flow and oxygenation. This technical advance in neurological monitoring promises a new standard of care for detection of spinal cord ischemia and the opportunity for early intervention. We demonstrate the probe in an adult Dorset sheep model. Both open and percutaneous approaches were evaluated during pharmacologic, physiological, and mechanical interventions designed to induce variations in spinal cord blood flow and oxygenation. The induced variations were rapidly and reproducibly detected, demonstrating direct measurement of spinal cord ischemia in real-time. In the future, this form of hemodynamic spinal cord diagnosis could significantly improve monitoring and management in a broad range of patients, including those undergoing thoracic and abdominal aortic revascularization, spine stabilization procedures for scoliosis and trauma, spinal cord tumor resection, and those requiring management of spinal cord injury in intensive care settings.

Influence of probe pressure on the diffuse correlation spectroscopy blood flow signal: extra-cerebral contributions.

A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.

Tumor blood flow differs between mouse strains: consequences for vasoresponse to photodynamic therapy.

Fluctuations in tumor blood flow are common and attributed to factors such as vasomotion or local vascular structure, yet, because vessel structure and physiology are host-derived, animal strain of tumor propagation may further determine blood flow characteristics. In the present report, baseline and stress-altered tumor hemodynamics as a function of murine strain were studied using radiation-induced fibrosacomas (RIF) grown in C3H or nude mice. Fluctuations in tumor blood flow during one hour of baseline monitoring or during vascular stress induced by photodynamic therapy (PDT) were measured by diffuse correlation spectroscopy. Baseline monitoring revealed fluctuating tumor blood flow highly correlated with heart rate and with similar median periods (i.e., ∼9 and 14 min in C3H and nudes, respectively). However, tumor blood flow in C3H animals was more sensitive to physiologic or stress-induced perturbations. Specifically, PDT-induced vascular insults produced greater decreases in blood flow in the tumors of C3H versus nude mice; similarly, during baseline monitoring, fluctuations in blood flow were more regular and more prevalent within the tumors of C3H mice versus nude mice; finally, the vasoconstrictor L-NNA reduced tumor blood flow in C3H mice but did not affect tumor blood flow in nudes. Underlying differences in vascular structure, such as smaller tumor blood vessels in C3H versus nude animals, may contribute to strain-dependent variation in vascular function. These data thus identify clear effects of mouse strain on tumor hemodynamics with consequences to PDT and potentially other vascular-mediated therapies.

Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes.

Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2α-deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2α-dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2α-dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2α in ECs. These results indicate that HIF-1α and HIF-2α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.