Assessment of cerebrovascular responses to physiological stimuli in identical twins using multimodal imaging and computational fluid dynamics.

There is acknowledged variability in the Circle of Willis (CoW) in the general population, yet the structure and function relationship of the cerebrovasculature is poorly understood. We aimed to demonstrate the feasibility of combining high-resolution imaging techniques and computational fluid dynamics (CFD) to describe cerebrovascular structure and function in vivo. We tested our methodology by examining the null hypothesis that monozygotic twins (18-30 yr) would exhibit similar CoW structure and function. Six twin pairs underwent 3T magnetic resonance angiography of the head and neck and B-mode Doppler ultrasound for velocity and diameter recordings in the vertebral and internal carotid arteries under three conditions (rest, hypercapnia, and exercise). Artery diameter, length, tortuosity, and bifurcation angle were assessed in regions of interest of the CoW. We simulated hemodynamics to determine the cardiac-cycle time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT). We observed low and insignificant intraclass correlations (ICC) between twins in all regions for diameter (ICC range 0.000-0.657, P > 0.05), two of four regions for length (ICC range 0.355-0.368, P > 0.05), all regions for tortuosity (ICC range 0.270-0.505, P > 0.05), and all bifurcation angles (ICC range 0.000-0.547, P > 0.05). Similarly, no significant correlations were apparent for cerebral blood flow or CFD-derived measures of TAWSS, OSI, and RRT, at rest or in response to hypercapnia or exercise. Therefore, differences exist in CoW structure and associated shear stress in response to physiological stimulation. These data suggest that the structure, function, and health of cerebrovascular arteries are not primarily genetically dependent.NEW & NOTEWORTHY There is acknowledged variability in the Circle of Willis in the general population, yet the structure and function relationship of the cerebrovasculature is poorly understood. Using a combination of magnetic resonance imaging, high-resolution Doppler ultrasound, and computational fluid dynamic modeling, we show that monozygotic twins exhibit differences in cerebrovascular structure and function when exposed to physiological stimuli. These data suggest that the morphology, function, and health of cerebrovascular arteries are not primarily genetically determined.

Assessment of resistance vessel function in human skeletal muscle: guidelines for experimental design, Doppler ultrasound, and pharmacology.

The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions.

Assessment of the human cutaneous microvasculature using optical coherence tomography: Proving Harvey's proof.

William Harvey proved the circulation of blood 400 years ago using a combination of ligature application and astute observation that presaged the existence of capillaries. Here we report findings, based on our development of a novel application of optical coherence tomography (OCT), that directly confirm the impact of cuff inflation on microvessels as small as ~30µm. By emulating Harvey's proofs, using cuff inflation at low pressure in the presence and absence of skin heating, we have imaged and quantified significant effects on microvascular diameter and density in humans in vivo. The application of cuff pressure significantly increased microvascular diameter (40.5 ± 4.6 vs 47.1 ± 3.9 µm, P = .01) and density (8.33 ± 4.3 vs 15.1 ± 4.9%, P < .01). These impacts were reversed by cuff deflation. Our study also showed the profound impacts of skin heating on microvessel diameter (46.7 ± 5.8 vs 70.6 ± 7.8 µm, P < .01) and density (14.2 ± 6.5 vs 43.2 ± 9%, P < .01) in vivo, which were further exacerbated by cuff inflation. Our approach to the direct visualization of the human skin microvasculature is non-invasive, safe, and easily applied. Future experiments might be directed at questions of microvascular physiology and pathophysiology, such as how different mammals thermoregulate and what impacts cardiovascular disease and diabetes have on microvascular structure and function.

Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.

Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Novel Noninvasive Assessment of Microvascular Structure and Function in Humans.

INTRODUCTION: Optical coherence tomography (OCT) is a novel high-resolution imaging technique capable of visualizing in vivo structures at a resolution of ~10 µm. We have developed specialized OCT-based approaches that quantify diameter, speed, and flow rate in human cutaneous microvessels. In this study, we hypothesized that OCT-based microvascular assessments would possess comparable levels of reliability when compared with those derived using conventional laser Doppler flowmetry (LDF). METHODS: Speckle decorrelation images (OCT) and red blood cell flux (LDF) measures were collected from adjacent forearm skin locations on 2 d (48 h apart), at baseline, and after a 30-min rapid local heating protocol (30°C-44°C) in eight healthy young individuals. OCT postprocessing quantified cutaneous microvascular diameter, speed, flow rate, and density (vessel recruitment) within a region of interest, and data were compared between days. RESULTS: Forearm skin LDF (13 ± 4 to 182 ± 31 AU, P < 0.05) and OCT-derived diameter (41.8 ± 6.6 vs 64.5 ± 6.9 µm), speed (68.4 ± 9.5 vs 89.0 ± 7.3 µm·s), flow rate (145.0 ± 60.6 vs 485 ± 132 pL·s), and density (9.9% ± 4.9% vs 45.4% ± 5.9%) increased in response to local heating. The average OCT-derived microvascular flow response (pL·s) to heating (234% increase) was lower (P < 0.05) than the LDF-derived change (AU) (1360% increase). Pearson correlation was significant for between-day local heating responses in terms of OCT flow (r = 0.93, P < 0.01), but not LDF (P = 0.49). Bland-Altman analysis revealed that between-day baseline OCT-derived flow rates were less variable than LDF-derived flux. CONCLUSIONS: Our findings indicate that OCT, which directly visualizes human microvessels, not only allows microvascular quantification of diameter, speed, flow rate, and vessel recruitment but also provides outputs that are highly reproducible. OCT is a promising novel approach that enables a comprehensive assessment of cutaneous microvascular structure and function in humans.

Cost Utility Analysis of Topical Steroids Compared With Dietary Elimination for Treatment of Eosinophilic Esophagitis.

BACKGROUND & AIMS: Topical corticosteroids or dietary elimination are recommended as first-line therapies for eosinophilic esophagitis, but data to directly compare these therapies are scant. We performed a cost utility comparison of topical corticosteroids and the 6-food elimination diet (SFED) in treatment of eosinophilic esophagitis, from the payer perspective. METHODS: We used a modified Markov model based on current clinical guidelines, in which transition between states depended on histologic response simulated at the individual cohort-member level. Simulation parameters were defined by systematic review and meta-analysis to determine the base-case estimates and bounds of uncertainty for sensitivity analysis. Meta-regression models included adjustment for differences in study and cohort characteristics. RESULTS: In the base-case scenario, topical fluticasone was about as effective as SFED but more expensive at a 5-year time horizon ($9261.58 vs $5719.72 per person). SFED was more effective and less expensive than topical fluticasone and topical budesonide in the base-case scenario. Probabilistic sensitivity analysis revealed little uncertainty in relative treatment effectiveness. There was somewhat greater uncertainty in the relative cost of treatments; most simulations found SFED to be less expensive. CONCLUSIONS: In a cost utility analysis comparing topical corticosteroids and SFED for first-line treatment of eosinophilic esophagitis, the therapies were similar in effectiveness. SFED was on average less expensive, and more cost effective in most simulations, than topical budesonide and topical fluticasone, from a payer perspective and not accounting for patient-level costs or quality of life.

Optical coherence tomography in the assessment of acute changes in cutaneous vascular diameter induced by heat stress.

There are limited imaging technologies available that can accurately assess or provide surrogate markers of the in vivo cutaneous microvessel network in humans. In this study, we establish the use of optical coherence tomography (OCT) as a novel imaging technique to assess acute changes in cutaneous microvessel area density and diameter in humans. OCT speckle decorrelation images of the skin on the ventral side of the forearm up to a depth of 500 µm were obtained prior to and following 20-25 min of lower limb heating in eight healthy men [30.3 ± 7.6 (SD) yr]. Skin red blood cell flux was also collected using laser Doppler flowmetry probes immediately adjacent to the OCT skin sites, along with skin temperature. OCT speckle decorrelation images were obtained at both baseline and heating time points. Forearm skin flux increased significantly (0.20 ± 0.15 to 1.75 ± 0.38 cutaneous vascular conductance, P < 0.01), along with forearm skin temperature (32.0 ± 1.2 to 34.3 ± 1.0°C, P < 0.01). Quantitative differences in the automated calculation of vascular area densities (26 ± 9 to 49 ± 19%, P < 0.01) and individual microvessel diameters (68 ± 17 to 105 ± 25 µm, P < 0.01) were evident following the heating session. This is the first in vivo within-subject assessment of acute changes in the cutaneous microvasculature in response to heating in humans and highlights the use of OCT as an exciting new imaging approach for skin physiology and clinical research.

Assessment of flow-mediated dilation in humans: a methodological and physiological guideline.

Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans.

Diastolic function in healthy humans: non-invasive assessment and the impact of acute and chronic exercise.

Left ventricular (LV) diastolic function is important because the enhanced systolic function that underpins high levels of cardio-respiratory fitness has to be matched by changes in LV filling, and LV diastolic dysfunction plays a key early role in the development and progression of a myriad of cardiovascular diseases. This review serves to detail knowledge in relation to: (1) the definition of diastole and the mechanical processes that occur during the diastolic period, (2) the quantitative assessment of diastolic function, predominantly focusing on non-invasive echocardiographic imaging modes such as tissue Doppler imaging and deformation analysis, (3) the impact of acute aerobic exercise on diastolic function, from the augmentation of function necessary to meet the demand for an increased cardiac output at exercise onset, to current concerns related to the impact of prolonged or ultra-endurance activity on diastolic function during recovery, (4) the adaptation in diastolic function observed with chronic aerobic exercise training in athletes and sedentary individuals who undergo training programmes, and (5) directions for future research.

Validation of heart rate monitor-based predictions of oxygen uptake and energy expenditure.

To validate VO2 and energy expenditure predictions by the Suunto heart rate (HR) system against a first principle gas analysis system, well-trained male (n = 10, age 29.8 +/- 4.3 years, VO2 65.9 +/- 9.7 ml x kg x min) and female (n = 7, 25.6 +/- 3.6 years, 57.0 +/- 4.2 ml x kg x min) runners completed a 2-stage incremental running test to establish submaximal and maximal oxygen uptake values. Metabolic cart values were used as the criterion measure of VO2 and energy expenditure (kJ) and compared with the predicted values from the Suunto software. The 3 levels of software analysis for the Suunto system were basic personal information (BI), BI + measured maximal HR (BIhr), and BIhr + measured VO2 (BIhr + v). Comparisons were analyzed using linear regression to determine the standard error of the estimate (SEE). Eight subjects repeated the trial within 7 days to determine reliability (typical error [TE]). The SEEs for oxygen consumption via BI, BIhr, and BIhr + v were 2.6, 2.8, and 2.6 ml.kg.min, respectively, with corresponding percent coefficient of variation (%CV) of 6.0, 6.5, and 6.0. The bias compared with the criterion VO2 decreased from -6.3 for BI, -2.5 for BIhr, to -0.9% for BIhr + v. The SEE of energy expenditure improved from BI (6.74 kJ) to BIhr (6.56) and BIhr + v (6.14) with corresponding %CV of 13.6, 12.2, and 12.7. The TE values for VO2 were approximately 0.60 ml x kg x min and approximately 2 kJ for energy expenditure. The %CV for VO2 and energy expenditure was approximately 1 to 4%. Although reliable, basic HR-based estimations of VO2 and energy expenditure from the Suunto system underestimated VO2 and energy expenditure by approximately 6 and 13%, respectively. However, estimation can be improved when maximal HR and VO2 values are added to the software analysis.

The 6-minute walk test does not reliably detect changes in functional capacity of patients awaiting cardiac transplantation.

BACKGROUND: Peak oxygen consumption (Vo(2)peak) is a strong independent predictor of prognosis in patients with severe chronic heart failure (CHF) and is used to guide optimal timing of transplantation. However, its assessment is relatively expensive and time-consuming and requires sophisticated equipment and highly trained personnel. The purpose of this study was to determine whether changes in 6-minute walk test (6WT) distance, a simple, inexpensive potential alternative measure of functional capacity, can predict changes in Vo(2)peak in patients with severe CHF. METHODS: Sixteen subjects (ejection fraction 23+/-2%, Vo(2)peak 16.2+/-1.1 ml kg (-1)min(-1)) underwent repeated 6WT and Vo(2)peak assessments that included familiarization and 4 serial measures, 6 weeks apart (baseline and at Weeks 6, 12 and 18). Analysis compared baseline performance with each subsequent testing occasion. RESULTS: At baseline, mean (+/-SE) VO(2)peak was 16.3+/-1.1 ml kg(-1) min(-1) and 6WT distance was 458+/-21 m. 6WT and Vo(2)peak were strongly correlated at all timepoints (average r=0.82; all p<0.05). However, mixed model analysis, assessing the capacity of the changes seen in 6WT to predict changes in Vo(2)peak, showed no statistical significance (F=0.11; p=0.74). CONCLUSIONS: The 6WT is commonly used to assess functional capacity in patients with heart failure. This study demonstrates that, despite a strong cross-sectional correlation with Vo(2)peak, changes in the 6WT are not a reliable predictor of changes in Vo(2)peak within patients. Therefore, the 6WT has limited utility as a serial measure to assess changes in the clinical status of patients with severe heart failure.