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Vascular infiltration and associated alterations in microvascular blood flow are critical for complete bone graft healing. Therefore, real-time, longitudinal measurement of blood flow has the potential to successfully predict graft healing outcomes. Herein, we non-invasively measure longitudinal blood flow changes in bone autografts and allografts using diffuse correlation spectroscopy in a murine femoral segmental defect model. Blood flow was measured at several positions proximal and distal to the graft site before implantation and every week post-implantation for a total of 9 weeks (autograft n = 7 and allograft n = 10). Measurements of the ipsilateral leg with the graft were compared with those of the intact contralateral control leg. Both autografts and allografts exhibited an initial increase in blood flow followed by a gradual return to baseline levels. Blood flow elevation lasted up to 2 weeks in autografts, but this duration varied from 2 to 6 weeks in allografts depending on the spatial location of the measurement. Intact contralateral control leg blood flow remained at baseline levels throughout the 9 weeks in the autograft group; however, in the allograft group, blood flow followed a similar trend to the graft leg. Blood flow difference between the graft and contralateral legs (ΔrBF), a parameter defined to estimate graft-specific changes, was elevated at 1-2 weeks for the autograft group, and at 2-4 weeks for the allograft group at the proximal and the central locations. However, distal to the graft, the allograft group exhibited significantly greater ΔrBF than the autograft group at 3 weeks post-surgery (p < 0.05). These spatial and temporal differences in blood flow supports established trends of delayed healing in allografts versus autografts.

Over recent decades, a variety of advanced imaging techniques for assessing cardiovascular physiology and cardiac function in adults and children have been applied in the fetus. In many cases, technical development has been required to allow feasibility in the fetus, while an appreciation of the unique physiology of the fetal circulation is required for proper interpretation of the findings. This review will focus on recent advances in fetal echocardiography and cardiovascular magnetic resonance (CMR), providing examples of their application in research and clinical settings. We will also consider future directions for these technologies, including their ongoing technical development and potential clinical value.

Background Children with chronic kidney disease (CKD) have increased cardiovascular mortality. Identifying high-risk children who may benefit from further therapeutic intervention is difficult as cardiovascular abnormalities are subtle. Although transthoracic echocardiography may be used to detect sub-clinical abnormalities, it has well-known problems with reproducibility that limit its ability to accurately detect these changes. Cardiovascular magnetic resonance (CMR) is the reference standard method for assessing blood flow, cardiac structure and function. Furthermore, recent innovations enable the assessment of radial and longitudinal myocardial velocity, such that detection of sub-clinical changes is now possible. Thus, CMR may be ideal for cardiovascular assessment in pediatric CKD. This study aims to comprehensively assess cardiovascular function in pediatric CKD using CMR and determine its relationship with CKD severity. Methods A total of 120 children (40 mild, 40 moderate, 20 severe pre-dialysis CKD subjects and 20 healthy controls) underwent CMR with non-invasive blood pressure (BP) measurements. Cardiovascular parameters measured included systemic vascular resistance (SVR), total arterial compliance (TAC), left ventricular (LV) structure, ejection fraction (EF), cardiac timings, radial and longitudinal systolic and diastolic myocardial velocities. Between group comparisons and regression modelling were used to identify abnormalities in CKD and determine the effects of renal severity on myocardial function. Results The elevation in mean BP in CKD was accompanied by significantly increased afterload (SVR), without evidence of arterial stiffness (TAC) or increased fluid overload. Left ventricular volumes and global function were not abnormal in CKD. However, there was evidence of LV remodelling, prolongation of isovolumic relaxation time and reduced systolic and diastolic myocardial velocities. Conclusion Abnormal cardiovascular function is evident in pre-dialysis pediatric CKD. Novel CMR biomarkers may be useful for the detection of subtle abnormalities in this population. Further studies are needed to determine to prognostic value of these biomarkers.

The clinical quantitative assessment of exercise capacity is usually achieved through measurement of peak oxygen consumption (VO2) during cardio-pulmonary exercise testing (CPET). In most patients with cardiovascular disease reduced peak VO2 is primarily the result of a limited capacity to augment cardiac output (CO). An important secondary cause is reduced peripheral oxygen extraction. As conventional CPET does not measure CO or tissue oxygen extraction it cannot comprehensively determine the causes of exercise limitation. Invasive CPET combining conventional exercise testing with pulmonary and systemic arterial catheterisation can differentiate the causes of exercise impairment however it is practically challenging, suitable only for limited groups of patients and precluded in children. We developed an alternative non-invasive approach to exercise testing combining real-time magnetic resonance imaging (MRI) flow measurement with respiratory gas analysis, using a system modified for safe use in the MRI environment. Using the Fick equation it is possible to determine the arterio-venous oxygen concentration difference (a-vO2) in addition to CO and VO2 throughout exercise. The first part of this work describes the development of MR-augmented CPET (MR-CPET) and validation in 17 healthy adults. MR-CPET was well tolerated and demonstrated strong correlations with conventional CPET metrics. MR-CPET allowed differentiation of the contributions of a-vO2 and CO to peak VO2. The second part of this work describes the application of MR-CPET in 10 healthy children, 10 with repaired Tetralogy of Fallot (ToF) and 10 children with Pulmonary Arterial Hypertension (PAH). MR-CPET was found to be safe and feasible in all three groups and demonstrated different patterns of abnormal response to exercise in the two disease groups with a significantly lower peak a-vO2 in the PAH group and a greater rest to peak difference in CO but lower peak CO in the ToF group. The final part of this work describes the application of MR-CPET in 13 young adults with the Fontan circulation and 13 matched controls. Adults with the Fontan circulation demonstrated chronotropic incompetence with an inability to augment CO. Although a-vO2 was lower in patients than controls this was not significant.

IntroductionReduced exercise capacity is a common feature of many cardiovascular diseases. Quantitative assessment of exercise capacity is usually achieved by measuring peak oxygen consumption (VO2). However, measuring peak VO2 alone neglects the different components of reduced exercise capacity: namely reduced cardiac output (CO) and oxygen extraction (ΔcO2). A better approach would be to simultaneously measure VO2 and CO and then calculate ΔcO2. This could be achieved using MR augmented cardiopulmonary exercise testing (MR-CPET). The aims of this study were to demonstrate: 1) MR-CPET is feasible and well tolerated, 2) peak VO2 in the MR scanner correlates with conventional peak VO2 and 3) variation in peak VO2 is related to both peak CO and peak oxygen extraction (ΔcO2) as calculated by the Fick equation.Method17 healthy volunteers (21–55 years) underwent MR-CPET. Exercise was performed on an MR-compatible ergometer (Lode, Groningen, The Netherlands) and VO2 was assessed using a commercial respiratory gas analyser (Ultima, MedGraphics, St. Paul, USA) with a modified sampling tube that was MR compatible. Set-up for MR-CPET is shown in Figure 1. Aortic flow was continuously measured using a previously validated UNFOLD-SENSE spiral PCMR sequence. Images were reconstructed using a graphical processing unit card and analysed using an in-house plug-in for OsiriX software. Conventional CPET was also performed within 2 weeks of MR-CPET. For both tests, participants were asked to rate i) concern ii) comfort and iii) perceived helplessness.Abstract 134 Figure 1Set-up for MR-CPET: a) subject in exercise position on MR compatible ergometer b) subject with facemask attached to MR compatible umbilicus passing through the wave-guideResults15 out of 17 volunteers completed exercise; exclusions were due to claustrophobia (n = 1) and inability to master exercise technique (n = 1). Reported concern and discomfort was higher with MR-CPET, although still within acceptable limits. Peak VO2, peak VCO2 and VE showed strong correlation between conventional CPET and MR-CPET: VO2 peak (r = 0.94, p < 0.001); VCO2 (r = 0.87, p < 0.001); VE (r = 0.88, p < 0.001). Resting and peak values VO2, CO, HR, SV and ΔcO2 are shown in Table 1. Multiple linear regression analysis demonstrated that both peak CO and ΔcO2 were independent predictors of peak VO2 measured during MR-CPET (beta = 0.73 and 0.38 respectively, p < 0.001) and conventional CPET (beta = 0.78 and 0.28 respectively, p < 0.001).Abstract 134 Table 1Values at rest and Peak VO2 obtained at MR-CPETConclusionMR-CPET is feasible, well tolerated and demonstrates physiology not apparent with conventional CPET. In this study, we have shown that MR-CPET allows assessment of the differing contributions of CO and ΔcO2 to variation in peak VO2. We believe that will be useful in understanding the origin of reduced exercise capacity in cardiac disease.

IntroductionReduced exercise capacity is a common feature of many cardiovascular diseases. Quantitative assessment of exercise capacity is usually achieved by measuring peak oxygen consumption (VO2). However, measuring peak VO2 alone neglects the different components of reduced exercise capacity: namely reduced cardiac output (CO) and oxygen extraction ( Delta cO2). A better approach would be to simultaneously measure VO2 and CO and then calculate Delta cO2. This could be achieved using MR augmented cardiopulmonary exercise testing (MR-CPET). The aims of this study were to demonstrate: 1) MR-CPET is feasible and well tolerated, 2) peak VO2 in the MR scanner correlates with conventional peak VO2 and 3) variation in peak VO2 is related to both peak CO and peak oxygen extraction ( Delta cO2) as calculated by the Fick equation.Method17 healthy volunteers (21-55 years) underwent MR-CPET. Exercise was performed on an MR-compatible ergometer (Lode, Groningen, The Netherlands) and VO2 was assessed using a commercial respiratory gas analyser (Ultima, MedGraphics, St. Paul, USA) with a modified sampling tube that was MR compatible. Set-up for MR-CPET is shown in Figure 1. Aortic flow was continuously measured using a previously validated UNFOLD-SENSE spiral PCMR sequence. Images were reconstructed using a graphical processing unit card and analysed using an in-house plug-in for OsiriX software. Conventional CPET was also performed within 2 weeks of MR-CPET. For both tests, participants were asked to rate i) concern ii) comfort and iii) perceived helplessness.[Figure]Results15 out of 17 volunteers completed exercise; exclusions were due to claustrophobia (n = 1) and inability to master exercise technique (n = 1). Reported concern and discomfort was higher with MR-CPET, although still within acceptable limits. Peak VO2, peak VCO2 and VE showed strong correlation between conventional CPET and MR-CPET: VO2 peak (r = 0.94, p < 0.001); VCO2 (r = 0.87, p < 0.001); VE (r = 0.88, p < 0.001). Resting and peak values VO2, CO, HR, SV and Delta cO2 are shown in Table 1. Multiple linear regression analysis demonstrated that both peak CO and Delta cO2 were independent predictors of peak VO2 measured during MR-CPET (beta = 0.73 and 0.38 respectively, p < 0.001) and conventional CPET (beta = 0.78 and 0.28 respectively, p < 0.001).[Figure]ConclusionMR-CPET is feasible, well tolerated and demonstrates physiology not apparent with conventional CPET. In this study, we have shown that MR-CPET allows assessment of the differing contributions of CO and Delta cO2 to variation in peak VO2. We believe that will be useful in understanding the origin of reduced exercise capacity in cardiac disease.

Background In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). The aim of this single-blind, randomised, controlled phase II trial is to compare auto-adjusting CPAP (APAP) with standard care to standard care alone in individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life. Methods/Design Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of < 90% for < 30% of the night (i.e. not meeting current criteria for overnight oxygen therapy). Key exclusion criteria are: overnight respiratory support; respiratory or decompensated cardiac failure; chronic transfusion; or contraindications to APAP therapy or magnetic resonance imaging (MRI). Sixty individuals with HbSS (30 children and 30 adults) will be randomised to standard care + APAP or standard care alone for six months. Minimisation factors are: age group (8–11, 12–15, 16–22 and > 23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or < 90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment. Discussion Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events. Trial registration ISRCTN46012373 . Registered on 10 July 2015. Protocol Version: 6.0 Date: 24th December 2015 Sponsor: University Hospital Southampton. Sponsor’s protocol code: RHMCHIOT53