Left ventricular dysfunction and intra-ventricular dyssynchrony in idiopathic pulmonary arterial hypertension.

BACKGROUND: Left ventricular (LV) filling pressures are normal in idiopathic pulmonary arterial hypertension (IPAH). However, direct and indirect interactions between the RV and LV can affect LV performance. We explored LV strain and LV intra-ventricular dyssynchrony in IPAH using feature tracking CMR (CMR-FT). METHODS: Seventy IPAH patients and 40 healthy volunteers were included. Patients underwent CMR and right heart catheterisation. The 4-chamber cine was used to calculate LV longitudinal strain (EllLV). LV circumferential (EccLV) and radial strain (ErrLV) were derived from a short axis cine. LV longitudinal, circumferential and radial intra-ventricular dyssynchrony indices were calculated. RESULTS: There were no differences between the IPAH and healthy volunteer group in LV ejection fraction (66.1% vs 64.2% p = 0.6672). EccLV (-29.1 vs -32.1 p = 0.0323) and EllLV (-16.6 vs -23.7 p < 0.0001) were lower in IPAH. In patients with more severe disease, there was greater impairment of ErrLV compared to mild disease (50.9 vs 87.5 P < 0.0001). LV synchrony was impaired in all directions in IPAH. ErrLV was associated with RV ejection fraction (r = 0.66), RV end-systolic volume index (r = -0.59), pulmonary vascular resistance (PVR)(r = 0.51) and stroke volume index (SVI)(r = 0.44). In a multivariate model with age, SVI and PVR, ErrLV (HR 0.970 p = 002) and radial dyssynchrony (HR 3.759 p < 0.0001) independently predicted survival. CONCLUSION: In IPAH, LV is dyssynchronous with impaired function. Measures of LV strain and intraventricular synchrony were associated with known markers of disease severity. These LV variables which are likely to be related to ventricular interaction, may add incremental value to known prognostic variables in IPAH.

Imaging of nuclear magnetic resonance spin-lattice relaxation activation energy in cartilage.

Samples of human and bovine cartilage have been examined using magnetic resonance imaging to determine the proton nuclear magnetic resonance spin-lattice relaxation time, T1, as a function of depth within through the cartilage tissue. T1 was measured at five to seven temperatures between 8 and 38°C. From this, it is shown that the T1 relaxation time is well described by Arrhenius-type behaviour and the activation energy of the relaxation process is quantified. The activation energy within the cartilage is approximately 11 ± 2 kJ mol-1 with this notably being less than that for both pure water (16.6 ± 0.4 kJ mol-1) and the phosphate-buffered solution in which the cartilage was immersed (14.7 ± 1.0 kJ mol-1). It is shown that this activation energy increases as a function of depth in the cartilage. It is known that cartilage composition varies with depth, and hence, these results have been interpreted in terms of the structure within the cartilage tissue and the association of the water with the macromolecular constituents of the cartilage.

Role of vascular channels as a novel mechanism for subchondral bone damage at cruciate ligament entheses in osteoarthritis and inflammatory arthritis.

OBJECTIVES: The purpose of this work was to test whether normal peri-entheseal vascular anatomy at anterior and posterior cruciate ligaments (ACL and PCL) was associated with distribution of peri-entheseal bone erosion/bone marrow lesions (BMLs) in inflammatory arthritis (IA) and osteoarthritis (OA). METHODS: Normal microanatomy was defined histologically in mice and by 3 T MRI and histology in 21 cadaveric knees. MRI of 89 patients from the Osteoarthritis Initiative and 27 patients with IA was evaluated for BMLs at ACL and PCL entheses. Antigen-induced arthritis (AIA) in mice was evaluated to ascertain whether putative peri-entheseal vascular regions influenced osteitis and bone erosion. RESULTS: Vascular channels penetrating cortical bone were identified in knees of non-arthritic mice adjacent to the cruciate ligaments. On MRI of normal cadavers, vascular channels adjacent to the ACL (64% of cases) and PCL (71%) entheses were observed. Histology of 10 macroscopically normal cadaveric specimens confirmed the location of vascular channels and associated subclinical changes including subchondral bone damage (80% of cases) and micro-cyst formation (50%). In the AIA model, vascular channels clearly provided a site for inflammatory tissue entry and osteoclast activation. MRI showed BMLs in the same topographic locations in both patients with early OA (41% ACL, 59% PCL) and IA (44%, 33%). CONCLUSION: The findings show that normal ACL and PCL entheses have immediately adjacent vascular channels which are common sites of subtle bone marrow pathology in non-arthritic joints. These channels appear to be key determinants in bone damage in inflammatory and degenerative arthritis.

Potential role of the posterior cruciate ligament synovio-entheseal complex in joint effusion in early osteoarthritis: a magnetic resonance imaging and histological evaluation of cadaveric tissue and data from the Osteoarthritis Initiative.

OBJECTIVE: This study explored posterior cruciate ligament (PCL) synovio-entheseal complex (SEC) microanatomy to determine whether it may participate in the early osteoarthritis (OA) disease process. METHODS: SEC microanatomy and OA features were evaluated in 14 non-arthritic cadaveric knees (mean age = 69.9) using magnetic resonance imaging (MRI) and histology. MRI images of 49 subjects selected from the progression cohort of the Osteoarthritis Initiative (OAI) were evaluated by a musculoskeletal radiologist using an original semi-quantitative method for features associated with OA at the PCL tibial enthesis. Statistical analysis was performed using chi-square and Wilcoxon signed-rank tests to evaluate associations between SEC configuration and OA features. RESULTS: The PCL formed a SEC-like structure encompassing bone- and ligament-lining intra-articular cartilages to which the posterior root of the medial meniscus contributed. Degenerative features at the PCL-SEC included: neovascularisation (44%), enthesis chondrocyte clustering (44%), collagen matrix fissuring at the enthesis (56%) and in the PCL itself (67%), tidemark duplication (44%), bone remodelling (44%) and microscopic inflammatory changes (33%). In the OAI cohort, SEC-related pathology included bone marrow lesions (BMLs) (69%) and osteophytosis (94%) at locations that corresponded to SEC-related cartilages. Posterior joint recess effusion (49%) was linked to MRI abnormalities at PCL-SEC cartilages (χ2 = 7.27, P = 0.007). CONCLUSIONS: The PCL has a prominent SEC configuration that is associated with microscopic OA changes in aged clinically non-diseased joints. MRI determined knee OA commonly exhibited pathological features at this site which was associated with adjacent joint effusion. Thus, the PCL-SEC could play a hitherto unappreciated role in the early OA disease process.

Quantitative parametric MRI of articular cartilage: a review of progress and open challenges.

With increasing life expectancies and the desire to maintain active lifestyles well into old age, the impact of the debilitating disease osteoarthritis (OA) and its burden on healthcare services is mounting. Emerging regenerative therapies could deliver significant advances in the effective treatment of OA but rely upon the ability to identify the initial signs of tissue damage and will also benefit from quantitative assessment of tissue repair in vivo. Continued development in the field of quantitative MRI in recent years has seen the emergence of techniques able to probe the earliest biochemical changes linked with the onset of OA. Quantitative MRI measurements including T(1), T(2) and T(1ρ) relaxometry, diffusion weighted imaging and magnetisation transfer have been studied and linked to the macromolecular structure of cartilage. Delayed gadolinium-enhanced MRI of cartilage, sodium MRI and glycosaminoglycan chemical exchange saturation transfer techniques are sensitive to depletion of cartilage glycosaminoglycans and may allow detection of the earliest stages of OA. We review these current and emerging techniques for the diagnosis of early OA, evaluate the progress that has been made towards their implementation in the clinic and identify future challenges in the field.

Spin-lattice relaxation rates and water content of freeze-dried articular cartilage.

OBJECTIVE: Nuclear magnetic resonance (NMR) spin-lattice relaxation rates were measured in bovine and porcine articular cartilage as a function of water content. METHODS: Water content was varied by freeze-drying samples for short periods of time (up to 15 min). The samples were weighed at all stages of drying so that water content could be quantified. Spin-lattice relaxation rates were measured using magnetic resonance imaging (MRI). RESULTS: Linear correlations were observed between relaxation rate and two measures of inverse water content: (1) solid-to-water ratio (ρ), expressed as a ratio of the mass of the solid component of the cartilage (m(s)) and the mass of water at each freeze-drying time point (m(w)), and (2) a ratio of the total mass of the fully-hydrated cartilage and m(w) (1/w). These correlations did not appear significantly different for the bovine and porcine data. However, fitting the data to a piecewise-linear model revealed differences between these two species. We interpret the first two segments of the piecewise model as the depletion of different water phases but conjecture that the third segment is partially caused by changes in relaxation rates as a result of a reduction in macromolecular mobilities. CONCLUSIONS: Whilst we can produce linear correlations which broadly describe the dependence of the measured spin-lattice relaxation rate on (inverse) water content, the linear model seems to obscure a more complicated relationship which potentially provides us with more information about the structure of articular cartilage and its extracellular water.

Assessment of tissue edema in patients with acute myocardial infarction by computer-assisted quantification of triple inversion recovery prepared MRI of the myocardium.

The aim of this study was to design a computer algorithm to assess the extent of cardiac edema from triple inversion recovery MR images of the human left ventricular myocardium. Twenty-one patients presenting with acute myocardial infarction were scanned within 48 h of the onset of symptoms. Eight patients were scanned a second time, 4 weeks after the initial event. Myocardial edema was detected in 27 of 29 studies using visual contour-based manual segmentation. A reference standard, created from the segmentations of three raters by voxel-wise majority voting, was compared to the edema mass estimates obtained using a newly developed computer algorithm. At baseline (n=20), the reference standard yielded an edema mass of 16.4±15.0 g (mean±SD) and the computer algorithm edema mass was 16.4±12.6 g. At follow-up (n=7), the reference standard edema mass was 7.1±4.4 g compared to 16.3±7.7 g at baseline. Computer algorithm estimates showed the same pattern of change with 5.7±5.7 g at follow-up compared to 20.8±13.8 g at baseline. Although there was a significant degree of discrepancy between reference standard and computer algorithm estimates of edema mass in individual patients, their overall agreement was good, with intraclass correlation coefficient ICC(3, 1)=0.753.

Evaluation of the effect of myocardial segmentation errors on myocardial blood flow estimates from DCE-MRI.

Quantitative analysis of cardiac dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) perfusion datasets is dependent on the drawing (manually or automatically) of myocardial contours. The required accuracy of these contours for myocardial blood flow (MBF) estimation is not well understood. This study investigates the relationship between myocardial contour errors and MBF errors. Myocardial contours were manually drawn on DCE-MRI perfusion datasets of healthy volunteers imaged in systole. Systematic and random contour errors were simulated using spline curves and the resulting errors in MBF were calculated. The degree of contour error was also evaluated by two recognized segmentation metrics. We derived contour error tolerances in terms of the maximum deviation (MD) a contour could deviate radially from the 'true' contour expressed as a fraction of each volunteer's mean myocardial width (MW). Significant MBF errors were avoided by setting tolerances of MD ≤ 0.4 MW, when considering the whole myocardium, MD ≤ 0.3 MW, when considering six radial segments, and MD ≤ 0.2 MW for further subdivision into endo- and epicardial regions, with the exception of the anteroseptal region, which required greater accuracy. None of the considered segmentation metrics correlated with MBF error; thus, both segmentation metrics and MBF errors should be used to evaluate contouring algorithms.

A novel and non-destructive method to examine meniscus architecture using 9.4 Tesla MRI.

OBJECTIVE: To investigate the ability of high-field (9.4 T) magnetic resonance (MR) imaging to delineate porcine knee meniscal tissue structure and meniscal tears. MATERIALS AND METHODS: Porcine knees were obtained from a local abattoir, and eight medial menisci with no visible defects were dissected. Lesions simulating longitudinal tears were created on two of the menisci. MR images of the menisci were obtained at 9.4 T using a three-dimensional (3D)-FLASH sequence. A detailed 3D internal architecture of the intact and injured menisci was demonstrated on high-resolution MR images. RESULTS: High-resolution 3D MR imaging allowed visualisation of internal architecture of the meniscus and disruption to the internal structural network in damage models. The architecture of the porcine knee meniscus revealed by the MR scans appeared similar to the structures visualised by histology in previously reported studies. CONCLUSION: High-field MRI is a non-destructive technique to examine the internal structural components and damage/wear of meniscal tissue. It has tremendous potential in the field of functional cartilage/meniscus biomechanics and biotribology.

Magnetic resonance imaging in the assessment of metacarpophalangeal joint disease in early psoriatic and rheumatoid arthritis.

OBJECTIVES: The aim of this study was to determine whether magnetic resonance imaging (MRI)-related entheseal changes including osteitis and extracapsular oedema could be used to differentiate between metacarpophalangeal (MCP) joint involvement in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: Twenty patients (10 each with early RA and PsA) had dynamic contrast-enhanced MRI (DCE-MRI) of swollen MCP joints. Synovitis and tenosynovitis was calculated using quantitative analysis including the degree and kinetics of enhancement of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). Periarticular bone erosion and bone oedema were scored using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) proposals. Entheseal-related features including extracapsular soft tissue enhancement or regions of diffuse bone oedema were also evaluated. RESULTS: MRI was not able to differentiate at the group level between both cohorts on the basis of entheseal-related disease but a subgroup of PsA patients had diffuse extracapsular enhancement (30%) or diffuse bone oedema (20%). The RA patient group had a greater degree of MCP synovitis (p<0.0001) and tenosynovitis than PsA patients (p<0.0001). There were no significant differences in either the total number of erosions (p = 0.315) or the presence of periarticular bone oedema (p = 0.105) between the groups. CONCLUSION: Although conventional MRI shows evidence of an enthesitis-associated pathology in the MCP joints in PsA, this is not sufficiently common to be of diagnostic utility.

Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study.

OBJECTIVES: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFalpha) blocking therapy. METHODS: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. RESULTS: Sixteen patients (13 women) were studied; all had previously failed TNFalpha-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNgamma of -52% (95% CI -73 to -15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE-MRI showed a reduction of 15-40% in MRI parameters. CONCLUSION: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

Measurement of pharmacokinetic parameters in histologically graded invasive breast tumours using dynamic contrast-enhanced MRI.

Dynamic contrast-enhanced MRI (DCE-MRI) has demonstrated high sensitivity for detection of breast cancer. Analysis of correlation between quantitative DCE-MRI findings and prognostic factors (such as histological tumour grade) is important for defining the role of this technique in the diagnosis of breast cancer as well as the monitoring of neoadjuvant therapies. This paper presents a practical clinical application of a quantitative pharmacokinetic model to study histologically confirmed and graded invasive human breast tumours. The hypothesis is that, given a documented difference in capillary permeability between benign and malignant breast tumours, a relationship between permeability-related DCE-MRI parameters and tumour aggressiveness persists within invasive breast carcinomas. In addition, it was hypothesized that pharmacokinetic parameters may demonstrate stronger correlation with prognostic factors than the more conventional black-box techniques, so a comparison was undertaken. Significant correlations were found between pharmacokinetic and black-box parameters in 59 invasive breast carcinomas. However, statistically significant variation with tumour grade was demonstrated in only two permeability-related pharmacokinetic parameters: k(ep) (p<0.05) and K(trans) (p<0.05), using one-way analysis of variance. Parameters k(ep) and K(trans) were significantly higher in Grade 3 tumours than in low-grade tumours. None of the measured DCE-MRI parameters varied significantly between Grade 1 and Grade 2 tumours. Measurement of k(ep) and K(trans) might therefore be used to monitor the effectiveness of neoadjuvant treatment of high-grade invasive breast carcinomas, but is unlikely to demonstrate remission in low-grade tumours.

Further evidence that a cartilage-pannus junction synovitis predilection is not a specific feature of rheumatoid arthritis.

BACKGROUND: Qualitative differences in synovitis between the cartilage-pannus junction (CPJ) region and the adjoining suprapatellar pouch (SPP) have been reported in rheumatoid arthritis and the spondyloarthropathies. OBJECTIVE: To determine if the distribution of synovitis is the same in osteoarthritis (OA) using sensitive measures of inflammation derived from dynamic, contrast enhanced magnetic resonance imaging (DEMRI). METHODS: 20 subjects with established OA of the knee were recruited. Conventional MR images together with the DEMRI measurements were obtained. Areas of synovitis at the CPJ region and at a distant site in the SPP were calculated; differences in CPJ and SPP synovitis were determined using DEMRI parameters: the initial rate of contrast enhancement (IRE) and maximal enhancement (ME). RESULTS: The area of synovitis was significantly greater adjacent to the CPJ than in the SPP. IRE and ME measures were greater at the CPJ than the SPP. CONCLUSIONS: The magnitude of synovitis at the CPJ is not disease-specific and applies across the spectrum of degenerative disease as well as inflammatory diseases.

Cine MRI using steady state free precession in the radial long axis orientation is a fast accurate method for obtaining volumetric data of the left ventricle.

In this study we assessed the use of a steady state free precession (SSFP) cine sequence in a series of radially orientated long axis slices for the measurement of left ventricular volumes and mass. We validated the radial long axis approach in phantoms and ex vivo porcine hearts and applied it to normal volunteers and patients using the SSFP and turbo gradient-echo (TGE) sequences. High quality images were obtained for analysis, and the measured volumes with radial long axis SSFP sequence correlated well with short axis TGE and SSFP volumes (r > 0.98). The best interobserver agreement for left ventricular volumes was obtained using SSFP in the long axis radial orientation (variability < 2.3%). We conclude that this combination of sequence and scan orientation has intrinsic advantages for image analysis due to the improved contrast and the avoidance of errors associated with the basal slice in the short axis orientation.

Intra-articular primatised anti-CD4: efficacy in resistant rheumatoid knees. A study of combined arthroscopy, magnetic resonance imaging, and histology.

OBJECTIVES: CD4+ T cells sustain the chronic synovial inflammatory response in rheumatoid arthritis (RA). SB-210396/CE 9.1 is an anti-CD4 monoclonal antibody that has documented efficacy in RA when given intravenously. This study aimed to establish the safety and efficacy of the intra-articular administration of SB-210396/CE 9.1 compared with placebo, examining its mode of action using a combined imaging approach of arthroscopy, magnetic resonance imaging (MRI), and histology. METHODS: Thirteen RA patients with active, resistant knee synovitis, were randomised to intra-articular injection of placebo (n=3), 0.4 mg (n=3) or 40 mg (n=7) of anti-CD4 after sequential dynamic gadolinium enhanced MRI, followed by same day arthroscopy and synovial membrane biopsy. Imaging and arthroscopic synovial membrane sampling were repeated at six weeks. This study used a unique region of interest (ROI) analysis mapping the MRI area analysed to the specific biopsy site identified arthroscopically, thus providing data for all three modalities at the same synovial membrane site. RESULTS: 12 patients completed the study (one placebo treated patient refused further MRI). Arthroscopic improvement was observed in 0 of 2 placebo patients but in 10 of 10 patients receiving active drug (>20% in 6 of 10). Improvement in MRI was consistently observed in all patients of the 40 mg group but not in the other two groups. A reduction in SM CD4+ score was noted in the 40 mg group and in the 0.4 mg group. Strong correlations both before and after treatment, were identified between the three imaging modalities. Intra-articular delivery of SB-210396/CE 9.1 was well tolerated. CONCLUSIONS: SB-210396/CE 9.1 is safe when administered by intra-articular injection. A trend toward efficacy was found by coordinated MRI, arthroscopic, and histological imaging, not seen in the placebo group. The value of ROI analysis was demonstrated.

Stepping-table gadolinium-enhanced digital subtraction MR angiography of the aorta and lower extremity arteries: preliminary experience.

PURPOSE: To compare stepping-table digital subtraction gadolinium-enhanced magnetic resonance (MR) angiography of the distal aorta and lower extremity arteries with conventional catheter digital subtraction x-ray angiography in patients with arterio-occlusive disease. MATERIALS AND METHODS: Twenty patients underwent both conventional catheter angiography and fast three-dimensional gadolinium-enhanced MR angiography of the aorta and outflow vessels at 1.5 T; the images were acquired in three consecutive imaging locations during a single infusion of a gadolinium chelate. RESULTS: Compared with catheter angiography, according to the findings of two blinded independent reviewers, MR angiography had sensitivities of 81% and 89% and specificities of 91% and 95%, respectively, for demonstration of insignificant (< or = 50%) stenosis versus significant (51%-100%) stenosis. For demonstration of occlusion, the sensitivity and specificity were 94% and 97%, respectively, by consensus. There was good interobserver correlation between the two readers overall (kappa = 0.65 for reporting the degree of narrowing in all lesions; 0.86, for reporting of insignificant versus significant stenoses; and 0.928, for reporting of occluded versus patient segments). CONCLUSION: Stepping-table digital subtraction contrast material-enhanced MR angiography has high accuracy compared with catheter angiography in patients with arterio-occlusive disease of the aorta and outflow vessels. These preliminary study results suggest that this technique may ultimately provide a safe, noninvasive, and cost-effective alternative to catheter angiography.

Preliminary experience with medical applications of rapid prototyping by selective laser sintering.

Rapid prototyping techniques, originally developed for building components from computer aided designs in the motor industry, are now being applied in medicine to build models of human anatomy from high resolution multiplanar imaging data such a computed tomography (CT). The established technique of stereolithography and the more recent selective laser sintering (SLS), both build up an object layer by layer. Models have applications in surgical planning, for the design of customised implants and for training. Preliminary experience of using the SLS technique for medical applications is described, addressing questions regarding image processing, data transfer and manufacture. Pilot models, built from nylon, included two skills (a child with craniosynoslosis and an adult with hypertetorism) and a normal femur which was modelled for use in a bioengineering test of an artificial hip. The dimensions of the models were found to be in good agreement with the CT data from which they were built-for the child's skull the difference between the model and the CT data was less than 1.0 +/- 0.5 mm in each direction. Our experience showed that, with care, a combination of existing software packages may be used for data conversion. Ideally, image data of high spatial resolution should be used. The pilot models generated sufficient clinical interest for the technique to be pursued in the orthopaedic field.